Endocrine effects of dehydroepiandrosterone and its fluorinated analog,fluasterone, in rats

Cancer chemoprevention is the use of pharmacologic agents to inhibit the development of cancer. The adrenal steroid dehydroepiandrosterone (DHEA) has demonstrated chemopreventive efficacy in animal models of tumorigenesis. However, due to DHEA's undesirable hormonal actions, the fluorinated analog fluasterone (fl‐DHEA), which also has chemopreventive characteristics, was synthesized as a potential alternate agent. It is not known whether fl‐DHEA has hormonal actions. The endocrinologic effects of DHEA and fl‐DHEA in adult male and female Fischer 344 rats were examined following 28 days of daily oral treatment. Initial doses tested were 30 and 300 mg/kg/day for each drug (n=12/sex/group), which are equivalent to 104 and 1,042 µmoles/kg/day DHEA, and 103 and 1,034 µmoles/kg/day fl‐DHEA. However, due to weight loss at the high dose, doses were lowered to 150 mg/kg/day for each drug (521 and 517 µmoles/kg/day DHEA and fl‐DHEA, respectively). Administration of DHEA resulted in dose‐dependent increases in plasma DHEA and DHEA‐S 1 h after dosing in week 4. DHEA produced an estrogenic effect in female rats expressed as decreased plasma FSH and LH, inhibition of ovulation, prolonged estrus, and increased uterine estrogen receptors. DHEA also increased plasma levels of androstenedione in males and females. Administration of fl‐DHEA increased the estrus cycle length due to a prolonged diestrus II phase and decreased the weights of the uterus, prostate, seminal vesicles, and testes. In addition, fl‐DHEA decreased plasma FSH, LH, and tissue estradiol, and increased plasma dihydrotestosterone levels in both sexes. These results indicate that fl‐DHEA is hormonally active and additional studies are warranted to further describe its endocrinologic effects. Drug Dev. Res. 58:169–178, 2003. © 2003 Wiley‐Liss, Inc.     

Septic complications after splenectomy for sickle cell sequestration crisis

Patients with sickle cell disease (SCD) are predisposed to infections. There is a paucity of recent information on the incidence of post-splenectomy infectious complications in these patients. The purpose of this study was to determine whether splenectomy increases infectious complications in SCD. Twenty-nine patients with SCD had splenectomy for sequestration crises at our hospital between 1988 and 1992; 16 of them received all of their follow-up care at our institution. These 16 charts were reviewed for infectious-related admissions, hospital days, days of IV antibiotics, positive cultures, and episodes of sepsis. For each patient, these parameters in the pre- and postoperative period were compared and expressed as number per year. The mean age at time of splenectomy was 2.5 ± 0.4 years and the mean follow-up was 4.5 ± 0.4 years. There was no significant difference in the pre- and postoperative periods for admissions, hospital days, days of IV antibiotics, positive cultures, or episodes of sepsis per year. There were also no operative deaths. The incidence of pre-splenectomy sepsis was 0.04 ± 0.03 episodes per year compared to 0.09 ± 0.04 (P = ns) episodes/year after splenectomy. Sepsis occurred at an average of 20.8 (range 2–30) months postoperatively; Streptococcus pneumoniae was the most common causative organism. The total mortality after splenectomy in SCD patients was 3.4% (1/29) over a nearly 5-year period. Although infections are common in children with SCD, there was no increase in infections or episodes of sepsis in SCD patients who underwent splenectomy. Accepted: 6 March 1997     

Teratogenic effects of polychlorinated dibenzofurans in combination in C57BL/6N mice

Polychlorinated dibenzofurans (PCDFs) are highly toxic environmental contaminants which have been involved in several incidents of human poisoning. Two congeners, 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF) and 1,2,3,4,7,8-hexachlorodibenzofuran (HCDF), have been shown to persist in the tissues of victims of accidental ingestion from Japan and Taiwan. The teratogenicity of these compounds, both alone and in combination, was assessed in C57BL/6N mice. Pregnant mice were treated with 10 ml/kg corn oil containing no PCDFs, 4-PeCDF (0-30 micrograms/kg), HCDF (0-300 micrograms/kg), or a combination of the two on gestation Days 10-13, followed by necropsy on gestation Day 18. Maternal and fetal toxicity were assessed and selected soft tissues were examined for abnormalities. Both chemicals caused hydronephrosis and cleft palate in the absence of any overt toxicity. Hydronephrosis occurred at doses approximately fivefold lower than those causing cleft palate. The combination of 4-PeCDF and HCDF was additive for terata based on responses predicted by probit analysis. In addition, the combination of 2,3,4,5,3',4'-hexachlorobiphenyl (0-60 mg/kg), a structurally related compound also present in PCDF poisoning victims, and 4-PeCDF appears additive. Thus, these chemicals, which cause toxic effects similar to those of 2,3,7,8-tetrachlorodibenzo-p-dioxin, are additive in the induction of fetal anomalies in the mouse.     

Reimagining care for young adults living with type 1 diabetes

Young adults living with type 1 diabetes often struggle to achieve what clinicians consider to be optimal levels of metabolic control. Despite the impact that this can have on a young person''s future risk of complications, there are relatively few studies reporting new ways of organizing or delivering care to this cohort. In this article, we explore some of the reasons why young adult diabetes care is challenging, and describe approaches to “re‐imagining” how care might be improved. The work is informed by the ‘Making Care Fit’ collaborative and by a program of research, entitled D1 Now, involving co‐design of a complex person‐centered intervention with young adults.     

Figure drawing size as a reflection of self-concept or self-esteem

In two independent studies, objective measures of self-concept and selfesteem were assessed relative to the primary indicators of self-esteem or selfconcept in human figure drawings, size, area, etc. The results of both studies showed that when groups were differentiated significantly on either self-concept or self-esteem, the size of a figure drawn was not related to the level of self-concept or self-esteem.     

Evaluation of Reduced Susceptibility to Quaternary Ammonium Compounds and Bisbiguanides in Clinical Isolates and Laboratory-Generated Mutants of Staphylococcus aureus

The MICs and minimum bactericidal concentrations (MBCs) for the biocides benzalkonium chloride and chlorhexidine were determined against 1,602 clinical isolates of Staphylococcus aureus. Both compounds showed unimodal MIC and MBC distributions (2 and 4 or 8 mg/liter, respectively) with no apparent subpopulation with reduced susceptibility. To investigate further, all isolates were screened for qac genes, and 39 of these also had the promoter region of the NorA multidrug-resistant (MDR) efflux pump sequenced. The presence of qacA, qacB, qacC, and qacG genes increased the mode MIC, but not MBC, to benzalkonium chloride, while only qacA and qacB increased the chlorhexidine mode MIC. Isolates with a wild-type norA promoter or mutations in the norA promoter had similar biocide MIC distributions; notably, not all clinical isolates with norA mutations were resistant to fluoroquinolones. In vitro efflux mutants could be readily selected with ethidium bromide and acriflavine. Multiple passages were necessary to select mutants with biocides, but these mutants showed phenotypes comparable to those of mutants selected by dyes. All mutants showed changes in the promoter region of norA, but these were distinct from this region of the clinical isolates. Still, none of the in vitro mutants displayed fitness defects in a killing assay in Galleria mellonella larvae. In conclusion, our data provide an in-depth comparative overview on efflux in S. aureus mutants and clinical isolates, showing also that plasmid-encoded efflux pumps did not affect bactericidal activity of biocides. In addition, current in vitro tests appear not to be suitable for predicting levels of resistance that are clinically relevant.     

Intentional internal iliac artery occlusion to facilitate endovascular repair of aortoiliac aneurysms

PURPOSE: The safety of intentional occlusion of patent internal iliac arteries (IIAs) to facilitate the endovascular repair of aortoiliac artery aneurysms (abdominal aortic aneurysms [AAAs] and iliac aneurysms [IAs]) was evaluated. METHODS: We analyzed the techniques and clinical sequelae of selective occlusion of one or both IIAs in 103 patients and correlated these findings with the results of preoperative angiograms to identify vascular anatomy that may predict postoperative pelvic ischemia. To quantify the clinical presentation of pelvic ischemia, we developed these criteria: class 0, no symptoms; class I, nonlimiting claudication with exercise; class II, new onset impotence, with or without moderate to severe buttock pain, leading to physical limitation with exercise; class III, buttock rest pain, colonic ischemia, or both. IIA occlusion was achieved in 100% of the patients by means of either catheter-directed embolization or orificial coverage with a stent-graft. No patient in this study had angiographic evidence of significant visceral occlusive disease before the procedure. Sixty-four patients had isolated AAAs, 23 patients had AAAs and IAs, and 16 patients had isolated IAs. Ninety-two patients had one IIA selectively occluded, and 11 patients had both IIAs selectively occluded. RESULTS: After IIA occlusion, 12 patients were categorized in class I, 9 patients were categorized in class II, and 1 patient was categorized in class III, for a total of 22 patients (21%) with pelvic ischemia. Sixteen (17%) of 92 patients had unilateral IIA occlusions, and six (17%) of 11 patients had bilateral IIA occlusions. Five patients in class I improved and had no symptoms within 1 year, and one patient in class II was downgraded to class I because of improved symptoms. Two unique preoperative angiographic findings were identified in the remaining 16 patients (16%) with chronic pelvic claudication: (1) stenosis of the remaining IIA origin (> 70%) with nonopacification of more than three of the six IIA branches (63%); and (2) small caliber, diseased or absent medial and lateral femoral circumflex arteries ipsilateral to the side of the IIA occlusion (25%). One patient with class III ischemia died of cardiovascular collapse associated with colon infarction caused by either acute ischemia or particulate embolization. CONCLUSION: The incidence of pelvic ischemia after IIA occlusion is 20% immediately after endovascular aortoiliac aneurysm repair. A total of 25% of patients had no symptoms within 1 year. Two preoperative radiologic findings may help identify patients who are at risk for pelvic ischemia: stenosis of the patent IIA and disease deep femoral ascending branches ipsilateral to the occluded IIA. The risk of colon ischemia appears to be small after selective IIA occlusion to facilitate endovascular AAA repair.     

Incidence and clinical significance of distal embolization during percutaneous interventions involving the superficial femoral artery

OBJECTIVE: Distal embolization of plaque or thrombus may cause organ ischemia following percutaneous peripheral interventions. The purpose of this study was to evaluate the incidence and clinical significance of particulate embolization during percutaneous superficial femoral artery (SFA) intervention by monitoring with continuous Doppler ultrasound. The rate and timing of embolization at various phases of intervention such as guidewire crossing, balloon angioplasty, stent deployment, and directional atherectomy were analyzed and compared. METHODS: Sixty patients underwent SFA intervention. Of these 60 patients, 10 patients underwent percutaneous transluminal angioplasty (PTA) alone, 40 patients underwent PTA with stenting, and 10 patients underwent plaque excision with the SilverHawk atherectomy device (8) or Spectranetics excimer laser (2) with or without additional PTA or stent placement. A 4-MHz Doppler probe was used for continuous monitoring in the ipsilateral popliteal artery. Distal embolization was registered as embolic signals (ES). ES were quantitatively assessed during critical portions of the procedure including guidewire crossing, balloon angioplasty, stent deployment and/or atherectomy. ES during different phases of intervention were compared using analysis of variance (ANOVA). RESULTS: ES was noted in every patient during wire crossing, angioplasty, stent deployment and atherectomy. The average number of ES noted during guidewire crossing was 8, PTA was 12, stent deployment was 28, SiverHawk atherectomy was 49, and Spectranetics excimer laser was 51. The frequency of ES was statistically higher during stent deployment vs wire crossing or balloon angioplasty but equivalent to that generated by plaque excision. ES was observed more frequent during balloon angioplasty than during wire crossing. In one patient who was treated with the excimer laser, a single runoff vessel was occluded with embolic debris but patency was restored angiographically after thrombolysis. The patient went on to require below knee amputation. During follow-up, all patients with claudication reported improved symptoms and those with ulcers or gangrene demonstrated healing. The average increase in ankle-brachial index following intervention was 0.31. CONCLUSION: While ES were recorded at each step of SFA intervention, the frequency was greatest during stent deployment. Despite the frequency of these events, only one patient developed angiographically and clinically significant embolization. Thus, our findings do not support the routine use of protection devices during percutaneous SFA intervention.