Patterns of cardiac dysfunction after carbon monoxide poisoning.

Objective: To describe the structural sequelae of carbon monoxide (CO) poisoning on the heart assessed using stress cardiac MRI (CMR). CO poisoning is common. While acute cardiac injury is frequent among survivors, the mid- and long-term effects of CO on the myocardium are unclear. Methods: CMR studies performed between the years 2005 and 2014 for a primary diagnosis of CO poisoning at a tertiary care center were reviewed by an experienced cardiologist. Variables of interest were compared between patients with normal and abnormal studies to identify factors associated with cardiac dysfunction. Results: Eighty-eight patients underwent stress CMR, age 34 years (range 11-70); 49% were male, 74 had acute poisoning and 14 had chronic poisoning (CO exposure for longer than 24 hours). Time from CO poisoning to imaging was 24 months (1 day-120 months). Patients were stratified into four categories, which included those with acute poisoning imaged: ≤12 months; 12-60 months; >60 months from the event; and those with chronic poisoning. Overall, 26 studies (30%) were abnormal. The most common findings were: left ventricular systolic dysfunction in 14 patients, right ventricular systolic dysfunction in nine, and LV dilatation in six. Abnormalities were mild in most cases and were equally prevalent in all four patient categories. Dyspnea at the time of follow-up was more frequent among those with abnormal studies. Conclusion: Mild alterations in ventricular structure and function are frequent in survivors of CO poisoning. Myocardial scarring is rare, suggesting that acute hypoxic injury may not fully explain these abnormalities.

Nerve allograft transplantation for functional restoration of the upper extremity: case series.

BACKGROUND: Major trauma to the spinal cord or upper extremity often results in severe sensory and motor disturbances from injuries to the brachial plexus and its insertion into the spinal cord. Functional restoration with nerve grafting neurotization and tendon transfers is the mainstay of treatment. Results may be incomplete due to a limited supply of autologous material for nerve grafts. The factors deemed most integral for success are early surgical intervention, reconstruction of all levels of injury, and maximization of the number of axonal conduits per nerve repair. OBJECTIVE: To report the second series of nerve allograft transplantation using cadaveric nerve graft and our experience with living-related nerve transplants. PARTICIPANTS: Eight patients, seven men and one woman, average age 23 years (range 18-34), with multi-level brachial plexus injuries were selected for transplantation using either cadaveric allografts or living-related donors. METHODS: Grafts were harvested and preserved in the University of Wisconsin Cold Storage Solution at 5 degrees C for up to 7 days. The immunosuppressive protocol was initiated at the time of surgery and was discontinued at approximately 1 year, or when signs of regeneration were evident. Parameters for assessment included mechanism of injury, interval between injury and treatment, level(s) of deficit, post-operative return of function, pain relief, need for revision surgery, complications, and improvement in quality of life. RESULTS: Surgery was performed using living-related donor grafts in six patients, and cadaveric grafts in two patients. Immunosuppression was tolerated for the duration of treatment in all but one patient in whom early termination occurred due to non-compliance. There were no cases of graft rejection as of most recent followup. Seven patients showed signs of regeneration, demonstrated by return of sensory and motor function and/or a migrating Tinel's sign. One patient was non-compliant with the post-operative regimen and experienced minimal return of function despite a reduction in pain. CONCLUSIONS: Despite the small number of subjects, it appears that nerve allograft transplantation may be performed safely, permitting non-prioritized repair of long-segment peripheral nerve defects and maximizing the number of axonal conduits per nerve repair. For patients with long, multi-level brachial plexus injuries or combined upper and lower extremity nerve deficits, the use of nerve allograft allows a more complete repair that may translate into greater functional restoration than autografting alone.

Changes in skin tanning attitudes. Fashion articles and advertisements in the early 20th century.

Historical reviews suggest that tanning first became fashionable in the 1920s or 1930s. To quantitatively and qualitatively examine changes in tanning attitudes portrayed in the popular women's press during the early 20th century, we reviewed summer issues of Vogue and Harper's Bazaar for the years 1920, 1927, 1928, and 1929. We examined these issues for articles and advertisements promoting skin tanning or skin bleaching and protection. We found that articles and advertisements promoting the fashionable aspects of tanned skin were more numerous in 1928 and 1929 than in 1927 and 1920, whereas those promoting pale skin (by bleaching or protection) were less numerous. These findings demonstrate a clear shift in attitudes toward tanned skin during this period.

Supramaximal doses of botulinum toxin for refractory blepharospasm.

PURPOSE: To investigate the response to supramaximal doses of botulinum toxin in patients with refractory blepharospasm. DESIGN: Prospective, nonrandomized, open-label interventional case series. PARTICIPANTS: Eight consecutive patients with blepharospasm requiring injections every 2 months despite receiving 100 U of botulinum toxin per session. INTERVENTION: Increasing the dose of botulinum toxin per session above the conventional maximum. MAIN OUTCOME MEASURES: Duration of treatment effect and patients' subjective response to treatment. RESULTS: Supramaximal dosages were well tolerated. Seven of 8 patients had a prolonged interval between injections relative to that associated with their previous dosing regimen. Four of the patients elected to continue with the new dosage. CONCLUSION: In select patients with essential blepharospasm who are refractory to standard treatment regimens, increasing the dosage of botulinum toxin above 100 U per session may decrease the interval between injections, improve the patient's quality of life, or both.

Prevalence of a normal C-reactive protein with an elevated erythrocyte sedimentation rate in biopsy-proven giant cell arteritis.

OBJECTIVE: The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are laboratory tests that have been said to have a strong correlation with a positive temporal artery biopsy in patients with suspected giant cell arteritis (GCA). Published reports suggest that the CRP is a more sensitive diagnostic indicator of GCA and can be elevated when the ESR is normal. It is also clear that the CRP and ESR can both be normal or both be elevated in patients with biopsy-proven GCA and that the CRP can be elevated when the ESR is normal. The purpose of this study was to ascertain if the CRP can be normal when the ESR is elevated in biopsy-proven GCA. DESIGN: Retrospective, longitudinal, comparative study. PARTICIPANTS: One hundred nineteen patients from 6 major tertiary-care university-affiliated medical centers. METHODS: The charts from 119 patients with temporal artery biopsies positive for GCA were reviewed for age, gender, pretreatment ESR, and pretreatment CRP. MAIN OUTCOME MEASURES: The ESR in millimeters per hour Westergren was graded as normal or abnormal based on 2 validated formulas. The CRP was graded as normal or abnormal based on established criteria set forth in the literature as well as at The Johns Hopkins Hematology laboratory. RESULTS: In this study, the ESR had a sensitivity of 76% to 86%, depending on which of 2 formulas were used, whereas an elevated CRP had a sensitivity of 97.5%. The sensitivity of the ESR and CRP together was 99%. Only 1 of the 119 patients (0.8%) presented with a normal ESR and normal CRP (double false negative); 2 patients (1.7%) had a normal CRP despite an elevated ESR according to both formulas. CONCLUSION: Although most patients with GCA have both an elevated ESR and CRP, there can be nonconcordance of the 2 blood tests. Although such nonconcordance is most often a normal ESR but an elevated CRP, the finding of an elevated ESR and a normal CRP also is consistent with GCA. The use of both tests provides a slightly greater sensitivity for the diagnosis of GCA than the use of either test alone.

Resection of an orbital lymphangioma with the aid of an intralesional liquid polymer.

A 28-year-old man with long-standing right proptosis presented with an extensive multilobulated partially cystic orbital mass thought to be a lymphangioma. Because of concern that excision or debulking of the lesion was likely to be complicated by excessive bleeding, the lesion was injected with a mixture of ethiodized oil (Ethiodol) and cyanoacrylate glue under direct observation. The mixture caused the injected lobules to assume a firm, rubbery texture, allowing them to be excised without bleeding.

Distinct properties and advantages of a novel peroxisome proliferator-activated protein [gamma] selective modulator.

Antidiabetic thiazolidinediones (TZDs) and non-TZD compounds have been shown to serve as agonists of the peroxisome proliferator-activated receptor gamma (PPARgamma). Here, we report the identification and characterization of a novel non-TZD selective PPARgamma modulator (nTZDpa). nTZDpa bound potently to PPARgamma with high selectivity vs. PPARalpha or PPARdelta. In cell-based assays for transcriptional activation, nTZDpa served as a selective, potent PPARgamma partial agonist and was able to antagonize the activity of PPARgamma full agonists. nTZDpa also displayed partial agonist effects when its ability to promote adipogenesis in 3T3-L1 cells was evaluated. Assessment of protein conformation using protease protection or solution nuclear magnetic resonance spectroscopy methods showed that nTZDpa produced altered PPARgamma conformational stability vs. full agonists, thereby establishing a physical basis for its observed partial agonism. DNA microarray analysis of RNA from 3T3-L1 adipocytes treated with nTZDpa or several structurally diverse PPARgamma full agonists demonstrated qualitative differences in the affected gene expression profile for nTZDpa. Chronic treatment of fat-fed, C57BL/6J mice with nTZDpa or a TZD full agonist ameliorated hyperglycemia and hyperinsulinemia. However, unlike the TZD, nTZDpa caused reductions in weight gain and adipose depot size. Feed efficiency was also substantially diminished. Unlike TZDs, nTZDpa did not cause cardiac hypertrophy in mice. When a panel of PPARgamma target genes was examined in white adipose tissue, nTZDpa produced a different in vivo expression pattern vs. the full agonist. These findings establish that novel selective PPARgamma modulators can produce altered receptor conformational stability leading to distinctive gene expression profiles, reduced adipogenic cellular effects, and potentially improved in vivo biological responses. Such compounds may lead to preferred therapies for diabetes, obesity, or metabolic syndrome.

Usefulness of peak exercise oxygen consumption and the heart failure survival score to predict survival in patients >65 years of age with heart failure.

Peak exercise oxygen consumption (Vo(2)) and the Heart Failure (HF) Survival Score (HFSS) were developed in middle-aged patient cohorts referred for heart transplantation with HF. The prognostic value of Vo(2) in patients >65 years has not been well studied. Accordingly, the prognostic value of peak Vo(2) was evaluated in these patients with HF. A retrospective analysis of 396 patients with HF >65 years with cardiopulmonary exercise testing was performed. Peak Vo(2) and components of the HFSS (presence of coronary artery disease, left ventricular ejection fraction, heart rate, mean arterial blood pressure, presence of intraventricular conduction defects, and serum sodium) were collected. Follow-up averaged 1,038 +/- 983 days. Outcome events were defined as death, implantation of a left ventricular assist device, or urgent transplantation. Patients were divided into risk strata for peak Vo(2) and HFSS based on previous cut-off points. Survival curves were derived using Kaplan-Meier analysis and compared using log-rank analysis. Survival differed markedly by Vo(2) stratum (p <0.0001), with significantly better survival rates for the low- (>14 ml/kg/min) versus medium- (10 to 14 ml/kg/min), low- versus high- (<10 ml/kg/min), and medium- versus high-risk strata (all p <0.05). Survival also differed markedly by HFSS stratum (p <0.0001), with significantly better survival rates for the low- (> or =8.10) versus medium- (7.20 to 8.09), low- versus high- (< or =7.19), and medium- versus high-risk strata (all p <0.0001). In conclusion, peak Vo(2) and the HFSS were both excellent parameters to predict survival in patients >65 years with HF.

Induction of CYP1A in the beagle dog by an inhibitor of kinase insert domain-containing receptor: differential effects in vitro and in vivo on mRNA and functional activity.

Compound I [3-[5-(4-methanesulfonyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-1H-quinolin-2-one] is a potent inhibitor of human kinase insert domain-containing receptor (KDR kinase), which is under investigation for the treatment of cancer. Bile duct-cannulated male beagle dogs were administered 6 mg/kg compound I q.d. for 14 days. There was an approximately 2.5-fold decrease in the mean plasma area under the curve of I on days 7 and 14 (approximately 11.3 microM . h), relative to day 1 (28.2 microM . h). In the dog, compound I was eliminated by metabolism, with a major pathway being aromatic hydroxylation and subsequent sulfation to form the metabolite M3. Metabolic profiling suggested that the pathway leading to the formation of the sulfated conjugate M3 was induced upon multiple dosing of I. Studies conducted in vitro suggested that CYP1A1/2 was responsible for the formation of the hydroxylated metabolite, which is sulfated to yield M3. Additional studies confirmed induction of CYP1A protein and activity in the livers of dogs treated with I. However, studies in a dog hepatocyte model of induction showed a surprising decrease both in CYP1A mRNA and enzymatic activity in the presence of I, emphasizing the need to consider the results from a variety of in vitro and in vivo studies in deriving an understanding of the metabolic fate of a drug candidate. It is concluded that the autoinduction observed after multiple treatments with compound I occurs since compound I is both an inducer and a substrate for dog CYP1A.