Failure of recombinant human interleukin-3 therapy to induce erythropoiesis in patients with refractory Diamond-Blackfan anemia [see comments]

In two previous studies, we observed that recombinant human interleukin- 3 (IL-3) induced an increase in marrow burst-forming unit-erythroid- derived colonies in vitro in some patients with Diamond-Blackfan anemia (DBA). To determine whether a similar erythropoietic response could be induced in vivo, we treated 13 patients with DBA (aged 4 to 19 years) with two preparations of IL-3. All patients had absent absolute reticulocyte counts and markedly reduced to absent recognizable bone marrow erythroid elements; patients with circulating reticulocytes in the previous 12 months were excluded from study. All patients except 1 had failed steroid therapy and had been transfusion-dependent since infancy; 1 patient was maintained on high-dose prednisone at the time of enrollment. On the first arm of the study, IL-3 (Immunex Corp, Seattle, WA) was administered subcutaneously using a dose escalation regimen of 125 to 500 micrograms/m2/day in divided dosage at 12-hour intervals, coadministered with 1.5 mg/kg/d of oral ferrous sulphate. Of the 13 patients that entered the trial, 4 stopped prematurely because of adverse side effects. In the other 9 evaluable cases, reticulocytes increased transiently in 1 patient from 0 to 65 x 10(9)/L after 35 days of IL-3 therapy at 250 micrograms/m2, but transfusion dependency persisted. One transient peak in absolute reticulocyte count was noted in 6 other patients, but no erythroid response was observed after completion of a full course of IL-3. Oral prednisone at 0.5 mg/kg/d was then coadministered with IL-3 at 500 micrograms/m2 to 5 of the patients without effect, and treatment was stopped. In 2 patients, a second preparation of IL-3 (Sandoz Canada Inc, Dorval, Quebec, Canada) was initiated in a dose escalation regimen of 2.5 to 10 micrograms/kg and was coadministered with ferrous sulphate. No erythroid response was observed in either patient, and in one of the two, alternate-day subcutaneous recombinant erythropoietin at 300 U/kg was administered for 3 weeks in combination with daily IL-3 at 10 micrograms/kg, but no increased erythropoiesis was seen. Significant increases in white blood cell and eosinophil counts during administration of both preparations of IL-3 were observed in all patients. These data show that the response of DBA patients to IL-3 in vivo is heterogeneous and cannot be predicted from in vitro studies. The absence of a corrective effect of IL-3 in these patients with DBA indicates that a deficiency of the cytokine is not central in the pathogenesis of the disorder.     

Evaluation of R‐ (−) and S‐ (+) Clenbuterol enantiomers during a doping cycle or continuous ingestion of contaminated meat using chiral liquid chromatography by LC‐TQ‐MS

Clenbuterol is known to improve competition resistance and muscular growth in athletes. Although it is an illegal drug, its use by farmers is widely spread to induce growth of their cattle. Thus, when clenbuterol is found in the urine of an athlete, there is doubt whether it was consumed with doping purposes or if it is due to the consumption of meat from a clenbuterol‐fed animal. Previous studies suggest that enantiomeric relationship of clenbuterol may be different according to the intake source. However, the enantiomeric relationship throughout a doping cycle or a continuous intake of contaminated meat has not yet been explored. In this first approximation, our aim was the development and validation of a sensitive and rapid method for the determination of S‐ (+) and R‐ (─) clenbuterol enantiomers to be used in a controlled study in rats fed for one week with contaminated meat or simulating a doping cycle. Enantiomers were measured using liquid chromatography coupled to mass spectrometry with a triple quadrupole analyzer (LC‐TQ‐MS) and were separated on an AGP Chiralpak column. The method was fully validated following the VICH (Veterinary International Conference on Harmonization guidelines) and was linear in the range of 12.5–800 pg/mL with a correlation coefficient of ≥0.98 for each enantiomer, and with a limit of quantitation and detection (LOQ and LOD) of 12.5 pg/mL and 6.5 pg/mL, respectively, for both enantiomers. The application of this method pointed out the shift of the enantiomeric relationship in urine from rats during the first five days of the doping cycle compared to those fed with contaminated meat. This finding can be of substantial importance in further doping studies.     

Coexistence of anti-RNA polymerase III and anti-U1RNP antibodies in patients with systemic lupus erythematosus: two cases without features of scleroderma

Anti-RNA polymerase III (RNAP III) antibodies are highly specific for scleroderma (SSc) and associated with diffuse SSc and renal crisis. Coexistence of anti-RNAP III and other SSc autoantibodies is rarely documented. We report three cases with coexisting anti-RNAP III and anti-U1RNP. Autoantibodies in 3829 sera from rheumatology clinics were screened by immunoprecipitation. Anti-RNAP III-positive sera were also examined by immunofluorescence and anti-RNAP III ELISA. In total, 35 anti-RNAP III-positive sera were identified by immunoprecipitation, in which three had coexisting anti-U1RNP. All three were anti-RNAP III ELISA positive. Two had anti-RNAP I dominant (vs. RNAP III) reactivity and showed strong nucleolar staining. A case with anti-U1/U2RNP (U2RNP dominant) had systemic lupus erythematosus (SLE)-SSc overlap syndrome; however, the remaining two cases had SLE without signs of SSc. All three cases of anti-RNAP III?+?U1RNP fulfilled ACR SLE criteria but none in the group with anti-RNAP III alone (p?=?0.0002). In contrast, only one case in the former group had sclerodermatous skin changes and Raynaud's phenomenon, vs. 92% with scleroderma in the latter (p?相似文献   

Intimate Partner Violence Among Women Veterans: Previous Interpersonal Violence as a Risk Factor

Experiences of abuse during childhood or military service may increase women veterans’ risk for intimate partner violence (IPV) victimization. This study examined the relative impact of 3 forms of interpersonal violence exposure (childhood physical abuse [CPA], childhood sexual abuse [CSA], and unwanted sexual experiences during military service) and demographic and military characteristics on past‐year IPV among women veterans. Participants were 160 female veteran patients at Veterans Afffairs hospitals in New England who completed a paper‐and‐pencil mail survey that included validated assessments of past‐year IPV and previous interpersonal violence exposures. Women who reported CSA were 3.06 times, 95% confidence interval (CI) [1.14, 8.23], more likely to report past‐year IPV relative to women who did not experience CSA. Similarly, women who reported unwanted sexual experiences during military service were 2.33 times, 95% CI [1.02, 5.35], more likely to report past‐year IPV compared to women who did not report such experiences. CPA was not associated with IPV risk. Having less education and having served in the Army (vs. other branches) were also associated with greater risk of experiencing IPV in the past year. Findings have implications for assisting at risk women veterans in reducing their risk for IPV through detection and intervention efforts.     

Can core biopsy reliably diagnose mucinous lesions of the breast?

Mucinous lesions in the breast are uncommon. They constitute a wide spectrum of lesions ranging from extravasated mucin associated with fibrocystic change to mucinous carcinoma. There are limited data on the reliability of core biopsy in the diagnosis of mucinous lesions of the breast. We reviewed the core biopsy and surgical biopsy diagnoses in 32 mucinous lesions of the breast. We conclude that core biopsy is highly reliable for accurate diagnosis of mucinous lesions of the breast.     

Portal hypertension. Evidence-based guide

Treatment of portal hypertension has evolved widely during the last decades. Advances in physiopathology have allowed better application of therapeutic options and also have permitted to know the natural history of varices and variceal bleeding, predicting which patients have a higher risk of bleeding. It also permits probability of designing patient treatment. According to liver function and subadjacent liver disease, it is possible to offer different alternatives within the three possible scenarios (primary prophylaxis, acute bleeding episode, and secondary prophylaxis). For primary prophylaxis, pharmacotherapy offers the best choice. Endoscopic banding is also growing in these scenarios and probably will be accepted in the near future. For the acute bleeding episode, endoscopic therapy (sclerosis and/or bands) and/or pharmacologic therapy (octreotide, terlipresin) represent best choice, considering TIPS as a rescue option. Surgery is not used routinely in this scenario in most centers. For secondary prophylaxis, pharmaco- and endoscopic therapy are first-line treatments, while TIPS and surgery as second-line treatments. TIPS is mainly used in patients on a waiting list for liver transplantation. Surgery offers good results for low-risk patients, with good liver function and with portal blood-flow preserving procedures (selective shunts, extensive devascularizations). Liver transplantation is recommended for patients with poor liver function because together with portal hypertension, it treats subadjacent liver disease.     

Comparison of balance performance between masters Olympic weightlifters and runners

Balance disorders are a common problem among older adults that greatly increase susceptibility for falls and fractures. Aerobically trained older (masters) athletes tend to exhibit superior balance abilities compared to that of healthy age-matched counterparts. Olympic weightlifting involves tremendous power production and motor skill coordination throughout the body which may prompt unique sensory information acquisition and integration adaptations. The purpose of this investigation was to compare a modified clinical test of sensory interaction and balance performance between middle-aged (~40-60 years) masters Olympic weightlifters (OWL, n = 48) and runners (RUN, n = 42). Average mediolateral center of pressure velocity (MLCPV) was computed during completion of 2 double leg trials (30-s) completed on firm (FI) and foam (FO) surfaces with eyes open (EO) and eyes closed (EC). While there were no significant differences between the groups for either the EO-FI (P = .143, d = 0.34) or EO-FO (P = .209, d = 0.26), the OWL demonstrated significantly better balance (lower MLCPV) than the RUN for both the EC-FI (P = .009, d = 0.59) and EC-FO (P = .001, d = 0.70). The most salient result of this investigation was the identification of better balance performance by the OWL, particularly when visual inputs were unavailable (ie, EC), compared to the RUN. These results suggest that Olympic weightlifting may provide a superior training stimulus for somatosensory and vestibular function compared to running in middle-aged adults, a benefit that may help to offset archetypal age-related balance deficits.