Deep vein thrombosis associated with osteoarticular infection in two siblings with anti-thrombin III deficiency

The development of deep vein thrombosis in an osteoarticular infection in children is rare. We report the case of two siblings with an osteoarticular infection in the hip and in the knee, respectively, who developed deep vein thrombosis and, in one sibling, pulmonary thromboembolism. The only hematological alteration found was reduction of anti-thrombin III in both patients. This reduction was acquired and secondary to sepsis due to Staphylococcus aureus. Anti-thrombin III levels recovered after 2 weeks of treatment. The association of deep vein thrombosis and osteoarticular infection with sepsis should lead to suspicion of hematological deficiencies, including acquired anti-thrombin III deficiency.     

Quality of laparoscopic radical hysterectomy in developing countries: a comparison of surgical and oncologic outcomes between a comprehensive cancer center in the United States and a cancer center in Colombia

Objective

To help determine whether global collaborations for prospective gynecologic surgery trials should include hospitals in developing countries, we compared surgical and oncologic outcomes of patients undergoing laparoscopic radical hysterectomy at a large comprehensive cancer center in the United States and a cancer center in Colombia.

Methods

Records of the first 50 consecutive patients who underwent laparoscopic radical hysterectomy at The University of Texas MD Anderson Cancer Center in Houston (between April 2004 and July 2007) and the first 50 consecutive patients who underwent the same procedure at the Instituto de Cancerología-Clínica las Américas in Medellín (between December 2008 and October 2010) were retrospectively reviewed. Surgical and oncologic outcomes were compared between the 2 groups.

Results

There was no significant difference in median patient age (US 41.9 years [range 23-73] vs. Colombia 44.5 years [range 24-75], P = 0.09). Patients in Colombia had a lower median body mass index than patients in the US (24.4 kg/m² vs. 28.7 kg/m², P = 0.002). Compared to patients treated in Colombia, patients who underwent surgery in the US had a greater median estimated blood loss (200 mL vs. 79 mL, P < 0.001), longer median operative time (328.5 min vs. 235 min, P < 0.001), and longer postoperative hospital stay (2 days vs. 1 day, P < 0.001).

Conclusions

Surgical and oncologic outcomes of laparoscopic radical hysterectomy were not worse at a cancer center in a developing country than at a large comprehensive cancer center in the United States. These results support consideration of developing countries for inclusion in collaborations for prospective surgical studies.     

Pharmacokinetic analysis of topotecan after intra-vitreal injection. Implications for retinoblastoma treatment

Topotecan is a promising drug with activity against retinoblastoma, however, attaining therapeutic concentrations in the vitreous humor is still a challenge for the treatment of vitreous seeds in retinoblastoma. Our aim was to characterize topotecan pharmacokinetics in vitreous and aqueous humor, and to assess the systemic exposure after intra-vitreal injection in rabbits as an alternative route for maximizing local drug exposure. Anesthetized rabbits were administered intra-vitreal injections of 5 μg of topotecan. Vitreous, aqueous, and blood samples were collected at pre-defined time points. A validated high-performance liquid chromatography assay was used to quantitate topotecan (lactone and carboxylate) concentrations. Topotecan pharmacokinetic parameters were determined in vitreous, aqueous and plasma using a compartmental analysis.Topotecan lactone concentrations in the vitreous of the injected eye were about 8 ng/mL 48 h after drug administration. The median maximum vitreous, aqueous and plasma total topotecan concentrations (C_max) were 5.3, 0.68 and 0.21 μg/mL, respectively. The C_max vitreous/aqueous of treated eyes and the C_max vitreous/plasma were approximately 8 and 254, respectively. Total topotecan exposure (AUC) in the vitreous of the injected eye was 50 times greater than the total systemic exposure. These findings suggest that intra-vitreal administration of only 5 μg of topotecan reaches significant local levels over an extended period of time while minimizing systemic exposure in the rabbit. Intra-vitreal topotecan administration offers a promising alternative route for enhanced drug exposure in the vitreous humor with potential application for treatment of vitreal seeds in retinoblastoma while avoiding systemic toxicities.     

Activity Profile In Vitro of Micafungin against Spanish Clinical Isolates of Common and Emerging Species of Yeasts and Molds

A collection of 2,278 isolates belonging to 86 different fungal species was tested with micafungin and eight other drugs using the EUCAST procedures. Micafungin was active against species of Candida and Aspergillus (even azole-resistant species) as well as Penicillium spp., Scedosporium apiospermum, and Acremonium spp. It was inactive for species of Basidiomycota and Mucorales and for multiresistant species such as those of Fusarium.Micafungin is a new drug that belongs to the echinocandin class of antifungal agents. Its mechanism of action is by means of the inhibition of 1,3-β-d-glucan synthesis in the fungal cell wall (10).Micafungin has been recently approved in Europe and the United States for the treatment of candidemia, acute disseminated candidiasis, Candida peritonitis and abscesses, esophageal candidiasis, and recently for the prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation.The in vitro activity of micafungin against most common species of Candida is well known (4, 11-13). However, information is limited for uncommon species of yeasts as well as for molds.The aim of this study is to analyze the in vitro activity of micafungin and eight other antifungal agents against a collection of clinical isolates of yeasts and molds from human beings using the methods approved by AFST-EUCAST.The strains were recovered from 115 Spanish hospitals through a period of 3 years, from 2005 to 2007. A total of 2,278 clinical isolates were included in the analysis. Isolates were identified by morphological and biochemical methods and sequencing of DNA targets if necessary. They belonged to 86 different species of common and emerging fungal pathogens. The isolates were obtained from blood (559; 24.5%), biopsies and other deep sites (217; 9.5%), respiratory tract specimens (751; 33%), skin samples (180; 7.9%), and other locations (707; 25.1%).The following drugs were used: amphotericin B (range, 16.0 to 0.03 μg/ml; Sigma-Aldrich Quimica S.A., Madrid, Spain), flucytosine (64.0 to 0.12 μg/ml; Sigma-Aldrich), fluconazole (64.0 to 0.12 μg/ml; Pfizer S.A. Madrid, Spain), itraconazole (8.0 to 0.015 μg/ml; Janssen S.A., Madrid, Spain), voriconazole (8.0 to 0.015 μg/ml; Pfizer S.A.), posaconazole (8.0 to 0.015 μg/ml; Schering-Plough, Kenilworth, NJ), caspofungin (16.0 to 0.03 μg/ml; Merck & Co., Inc., Rahway, NJ), micafungin (16.0 to 0.03 μg/ml; Astellas Pharma Inc., Tokyo, Japan), and anidulafungin (16.0 to 0.03 μg/ml; Pfizer S.A.).Susceptibility testing was performed by using broth microdilution. For Candida species, MICs were determined using the reference procedure for testing fermentative yeasts described by AFST-EUCAST (7, 17). For Cryptococcus neoformans and other species of nonfermentative yeasts, such as Trichosporon and Rhodotorula spp., susceptibility testing strictly followed the recommendations by the EUCAST with a minor modification in order to improve the growth of microorganisms (3). For filamentous fungi, broth microdilution testing was performed following the AFST-EUCAST reference method (18). For testing echinocandins against molds, the MIC was defined as the lowest drug concentration resulting in aberrant hyphal growth by examination with an inverted microscope, that is, the minimum effective concentration (MEC) (2).Tables ​Tables11 and ​and22 display the susceptibility results obtained when the collection of clinical isolates was tested.

TABLE 1.

Summary of susceptibility results of antifungal agents tested in vitro against yeast species^a

Cardiovascular risk and validation of cardiovascular risk prediction functions in a cohort of patients with type 2 diabetes followed for 10 years in Badajoz (SPAIN). AN observational study

AimsTo analyse whether diabetes behaves as an equivalent of coronary risk and assess the performance of the original and REGICOR Framingham functions in a cohort of patients with type 2 diabetes observed for 10 years in primary care practices in Badajoz, Spain.MethodsObservational, longitudinal study. A total of 643 patients (mean age 64.0 years, 55.7% women), without evidence of cardiovascular disease were studied. We assessed the incidence of cardiovascular events and the patients’ 10-year coronary risk predicted-values at the time of their recruitment.ResultThe actual incidence rate of coronary events was 14.5% (15.1% in women and 13.7% in men, p = 0.616). Patients who suffered coronary events were older (66.3 vs 63.6 years, p < 0.05), had higher total cholesterol (236.3 vs 219.5 mg/dl, p < 0.01), fasting plasma glucose levels (177.6 vs 159.8 mg/dl, p < 0.01), glycated haemoglobin (7.3 vs 6.7%, p < 0.05) and also higher prevalence of high blood pressure, dyslipidemia and chronic renal disease. The original Framingham equation overpredicted risk by 88%, whereas the REGICOR Framingham function underpredicted risk by 24%.ConclusionsDiabetes in our cohort does not behave as a coronary heart disease equivalent and both the original and REGICOR Framingham coronary risk functions have little utility in a diabetic population.     

Analysis of performance of a PCR-based assay to detect DNA of Aspergillus fumigatus in whole blood and serum: a comparative study with clinical samples

The performance of a real-time PCR-based assay was retrospectively analyzed (according to European Organization for Research and Treatment of Cancer/Mycosis Study Group criteria) in the samples of patients with invasive aspergillosis. A total of 711 serial samples (356 whole-blood and 355 serum samples) from 38 adult patients were analyzed. The Aspergillus fumigatus PCR assay results were positive for 89 of 356 (25%) whole-blood samples and 90 of 355 (25.35%) serum samples. Positive PCR results were seen in 29 of 31 (93.5%) patients for which serum was analyzed and in 31 of 33 (93.9%) cases with whole-blood specimens. Both blood and serum samples were available in 26 cases, and significant differences were not observed in this subgroup of cases. The average number of threshold cycles (C(T)) for positive blood samples was 37.6, and the average C(T) for serum was 37.4. The DNA concentration ranged between 2 and 50 fg per μl of sample, with average DNA concentrations of 10.2 and 11.7 fg in positive blood and serum samples, respectively (P > 0.01). The performance of this PCR-based quantitative assay was similar for both serum and blood samples. We recommend serum samples as the most convenient hematological sample to use for Aspergillus DNA quantification when serial determinations are done.     

PKC and PTPα participate in Src activation by 1α,25OH2 vitamin D3 in C2C12 skeletal muscle cells

Prolonged stimulation of FRTL-5 thyroid cells with cAMP-generating agents including thyroid-stimulating hormone (TSH) or cAMP analogues potentiates tyrosine phosphorylation of insulin receptor substrate (IRS)-2 triggered by insulin-like growth factor (IGF)-I, leading to enhancement of IGF-I-dependent proliferation. Because we identified HSP90 as an IRS-2-interacting protein, the roles of HSP90 in potentiation of IGF signals through IRS-2 were investigated. We found that prolonged dibutyryl cAMP treatment induced serine/threonine phosphorylation of IRS-2. Using a specific inhibitor of HSP90 chaperone activity, geldanamycin, or small interfering RNA against HSP90, we showed that HSP90 mediates cAMP-induced serine/threonine phosphorylation of IRS-2. Furthermore, inhibition of HSP90 by geldanamycin during dibutyryl cAMP pretreatment of cells for 24h suppressed cAMP-dependent potentiation of tyrosine phosphorylation of IRS-2 induced by IGF-I. Taking together, we conclude that HSP90 interacting with IRS-2 mediates cAMP-dependent serine/threonine phosphorylation of IRS-2 via its chaperone activity, leading to potentiation of tyrosine phosphorylation of IRS-2 induced by IGF-I.