Efficacy and toxicity of caspofungin in combination with liposomal amphotericin B as primary or salvage treatment of invasive aspergillosis in patients with hematologic malignancies

BACKGROUND: Caspofungin (CAS) as salvage therapy for refractory invasive aspergillosis (IA) had a response rate of 45% among a heterogeneous group of patients. The use of CAS with other agents is appealing given its unique mechanism of action. Therefore, the authors retrospectively evaluated the efficacy and toxicity of CAS plus liposomal amphotericin B (LipoAMB) in patients with documented (definite or probable) or possible IA. METHODS: Patients were evaluable for outcome if they received CAS/LipoAMB for at least 7 days. Patients who received CAS and LipoAMB sequentially were excluded. All patients were evaluable for toxicity. Outcome was assessed weekly and at the end of therapy. Stable disease and progression were considered treatment failures. RESULTS: Forty-eight patients with documented (n=23) or possible (n=25) IA were identified between March 2001 and December 2001. The majority of the patients (65%) received CAS/LipoAMB as salvage therapy for progressive IA despite 7 or more days of previous LipoAMB monotherapy. The overall response rate was 42%. No significant toxic effects were seen. Factors associated with failure at the end of therapy were documented IA (P=0.03), significant steroid use before the study (P=0.02), and duration of combination therapy for less than 14 days (P=0.01). The response rate in patients with progressive documented IA was low (18%). CONCLUSIONS: The CAS/LipoAMB combination is a promising preemptive therapy for IA and was generally well tolerated. This combination might have limited benefit as salvage therapy for documented IA.     

Determination of serum apolipoproteins A1 and B by immunoturbidimetry using the Cobas-Bio centrifugal analyzer. Influence of hyperlipemia

The authors describe an immunoturbidimetric technique for the determination of the serum apolipoproteins A1 and B using a Cobas-Bio centrifugal analyser. This methods is sensitive and reproducible (CV less than 5%) and show a good correlation with electroimmunodiffusion which was taken as method of reference. It may be applied to serum stored at 4 degrees C or frozen at -20 degrees C. No light is transmitted in the case of either turbid hyperlipemic sera or sera extensively icteric or hemolyzed. The physiological values found in a large population of men and women of various ages are in agreement with those reported in the literature. The method described thus provides a suitable means of investigation adapted to large series for screening for coronary disease states.     

Alpha-galactosylceramide-induced iNKT cells suppress experimental allergic asthma in sensitized mice: role of IFN-gamma

Allergic asthma is a multifaceted syndrome consisting of eosinophil-rich airway inflammation, bronchospasm, and airway hyper-responsiveness (AHR). Using a mouse model of allergic asthma, we previously reported that invariant NKT (iNKT) cells increase the severity of this disease. Herein, we demonstrate that a single i.v. injection of alpha-galactosylceramide (alpha-GalCer), 1 h before the first airway allergen challenge of OVA-sensitized mice, abrogates elicitation of AHR, airway eosinophilia, IL-4 and IL-5 production in bronchoalveolar lavage fluid, and specific anti-OVA IgE antibodies. Further, alpha-GalCer administered intranasally also strongly inhibited the major symptoms of asthma in sensitized and challenged mice. Alpha-GalCer treatment induces iNKT cell accumulation in the lungs, and shifts their cytokine profile from pro-asthmatic IL-4 to a protective IFN-gamma production. The role of IFN-gamma from iNKT cells in protection was shown by adoptive transfer of sorted iNKT cells from OVA-sensitized and alpha-GalCer-treated mice which protected immunized recipients from manifesting asthma by an IFN-gamma-dependent pathway. Our findings demonstrate for the first time that alpha-GalCer administered locally inhibits asthma symptoms, even in predisposed asthmatic mice, through an iNKT cell- and IFN-gamma-dependent pathway.     

Accuracy of virtual chromoendoscopy in differentiating gastric antral vascular ectasia from portal hypertensive gastropathy: A proof of concept study

BACKGROUNDAccurate detection of gastric antral vascular ectasia (GAVE) is critical for proper management of cirrhosis-related gastrointestinal bleeding. However, endoscopic diagnosis of GAVE can be challenging when GAVE overlaps with severe portal hypertensive gastropathy (PHG).AIMTo determine the added diagnostic value of virtual chromoendoscopy to high definition white light for real-time endoscopic diagnosis of GAVE and PHG.METHODSWe developed an I-scan virtual chromoendoscopy criteria for diagnosis of GAVE and PHG. We tested our criteria in a cross-sectional cohort of cirrhotic adults with GAVE and PHG when high-definition white light endoscopy (HDWLE) diagnosis was in doubt. We then compared the accuracy of I-scan vs HDWLE alone to histology.RESULTSTwenty-three patients were included in this study (65.2% Caucasians and 60.9% males). Chronic hepatitis C was the predominant cause of cirrhosis (43.5%) and seven adults (30.4%) had confirmed GAVE on histology. I-scan had higher sensitivity (100% vs 85.7%) and specificity (75% vs 62.5%) in diagnosing GAVE compared to HDWLE. This translates into a higher, albeit not statistically significant, accuracy of I-scan in detecting GAVE compared to HDWLE alone (82% vs 70%). I-scan was less likely to lead to an accurate diagnosis of GAVE in patients on dialysis (P < 0.05) and in patients with elevated creatinine (P < 0.05). I-scan had similar accuracy to HDWLE in detecting PHG.CONCLUSIONThis pilot work supports that virtual chromoendoscopy may obviate the need for biopsies when the presence of GAVE is in doubt. Larger studies are needed to assess the impact of virtual chromoendoscopy on success of endoscopic therapy for GAVE.     

A homozygous frameshift variant expands the clinical spectrum of SAMD9 gene defects

SAMD9, a ubiquitously expressed protein, is involved in several mechanisms, including endosome fusion, growth suppression and modulation of innate immune responses to stress and viral infections. While biallelic mutations in SAMD9 are linked to normophosphatemic familial tumoral calcinosis, heterozygous gain-of-function mutations in the same gene are responsible for MIRAGE, a multisystemic syndrome characterized by m yelodysplasia, i nfection, r estriction of growth, a drenal hypoplasia, g enital phenotypes, and e nteropathy. A two-and-a-half-year-old girl, from a consanguineous Lebanese family, was included in this study. She presents with pre- and post-natal growth retardation, recurrent fevers, persistent diarrhea, elevated CRP and intermittent hypoglycemia. Whole genome sequencing revealed a homozygous frameshift variant in SAMD9 (NM_017654.4: c.480_481del; p.Val162Ilefs*5) in the proband. Sanger sequencing confirms its segregation with the disease in the family, and immunoblotting showed that the detected variant abolishes SAMD9 expression in the patient. Our findings expand the clinical spectrum linked to SAMD9 and highlight the importance of investigating further cases with mutations in this gene, as this will pave the way towards the understanding of the pathways driving these diseases.     

Epidemiology, molecular mycology, and environmental sources of Fusarium infection in patients with cancer.

OBJECTIVE: To investigate the epidemiology and environmental sources of Fusarium infections in patients with cancer. DESIGN: Retrospective case-control study conducted following surveillance environmental cultures and DNA analysis of isolated organisms. SETTING: A tertiary-care, university cancer center. METHODS: In 1996 and 1997, environmental cultures were performed on air samples and water systems. A retrospective chart review was performed for 70 patients with cancer identified with fusariosis between 1987 and 1997. Patients with fusariosis were compared with 49 uninfected control patients who occupied hospital rooms with positive environmental cultures for Fusarium. With the use of random amplification of polymorphic DNA, organisms isolated from infected patients were compared with environmental organisms. RESULTS: Most of the patients with Fusarium (40, 57%) were infected on or within 3 days of admission, indicating community rather than nosocomial acquisition. Patients were comparable in terms of underlying immunocompromised status to 49 uninfected control patients. However, the duration from admission to infection in the patients with fusariosis tended to be shorter than the duration from admission to discharge in the exposed control patients (P = .06). Water cultured from the hospital tanks and from sinks and water fountains was negative for Fusarium. With the use of polymerase chain reaction, environmental isolates did not match clinical ones. Quantitative air sampling showed that the quantitative outdoor Fusarium levels were eightfold higher than the indoor levels. During the rainy summer season, outdoor air concentrations of Fusarium were at their highest, coinciding with the peak incidence of fusariosis at our center. CONCLUSION: The most likely source of fusariosis was the external environment rather than nosocomial sources, such as water.     

Hurler syndrome. Early diagnosis and successful enzyme replacement therapy: a new therapeutic approach. Case report]

Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder due to alpha-L-iduronidase deficiency. Its severe prognosis has been significantly improved by enzyme replacement therapy using recombinant human alpha-L-iduronidase (laronidase). We report the case of a boy who was diagnosed at 19 months of age with Hurler's disease, the most severe form of MPS I, and received thereafter a treatment by laronidase, resulting in clinical and biological improvement. The aim of this case report is to draw physicians' attention on the presenting signs of Hurler's disease, in order to enable an earlier diagnosis, increasing the treatment's benefits.     

Surgical adrenal diseases

There are four adrenal disorders in which surgery is the treatment of choice: pheochromocytoma, Cushing's syndrome due to ACTH-independent adrenal disease (adenoma, carcinoma or autonomous hyperplasia), primary aldosteronism due to an adrenal adenoma and some adrenal non-functional "incidentilomas". In all four categories, the optimal result of surgical intervention depends on the following factors: 1. Definitive diagnosis by accurate biochemical assessment of the functional status of the adrenal lesion. 2. Precise localization of the lesion using simple routine as well as advanced imaging techniques. 3. Adequate preoperative preparation and intraoperative monitoring. 4. Close immediate and long-term postoperative follow-up. In this review, the above factors are briefly summarized for each of the four disorders. A small proportion of adrenal lesions requiring surgery are bilateral and in such situations, special intra- and postoperative care should take into consideration the need for appropriate gluco-corticoid and mineralo-corticoid replacement. The advent of laparoscopic surgery has served to reduce the postoperative morbidity of adrenal surgery and is becoming increasingly the procedure of choice except for large lesions (> 8 cm in diameter).