Long-term deficits after somatosensory cortical lesions in rats.

Rats having either sham operations or one-stage bilateral lesions of the two somatosensory areas of the cortex were tested for acquisition of five tactile discriminations after postoperative recovery intervals of 14, 35, 180, 365 or 730 days. The group with lesions performed worse than its time-matched control group in every instance, and there was no evidence for recovery of function with the longer postoperative recovery periods. These results suggest that time per se is not a significant determinant of restitution after somatosensory cortical ablations.     

Trichosporon beigelii endocarditis as a complication of peritoneovenous shunt

Trichosporon is a common cause of superficial mycotic infection but has rarely been associated with endocarditis. The case of a patient who had a peritoneovenous shunt for chronic intractable ascites due to Laennec liver cirrhosis is described. The shunt was revised on several occasions, and the last procedure was complicated by a draining skin sinus wound. To the authors' knowledge, this is the first reported case of Trichosporon endocarditis complicating a peritoneovenous shunt.     

Ixodes ricinus density, and distribution and prevalence of Borrelia burgdorferi sensu lato infection along an altitudinal gradient

In this study, we measured the phenology of Ixodes ricinus ticks and their infection with Borrelia burgdorferi sensu lato (sl) simultaneously along an altitudinal gradient to assess the impact of climate on the phenology of ticks and on their infection with B. burgdorferi sl. From 1999 to 2001, free-living I. ricinus ticks were collected monthly by flagging vegetation at three different altitudes (620, 740, and 900 m above sea level) on the slope of a mountain in Chaumont (Neuchatel, Switzerland). I. ricinus ticks were examined for the presence of B. burgdorferi sl by using direct fluorescent antibody assay and isolation of spirochetes. Borrelia species were characterized by polymerase chain reaction followed by restriction fragment-length polymorphism. Tick density and tick phenology varied with altitude. Although the peak tick density decreased and the onset of ticks was delayed with altitude, the phenology was much more stable among years at the highest altitudes than at the lowest. The prevalence of B. burgdorferi infection in nymphs and adults decreased with altitude. The prevalence of infection differed significantly among years, and it was significantly higher in adults (30%) than in nymphs (21%). B. burgdorferi infection in adults was positively related with adult density, but this was not observed for nymphs. Five B. burgdorferi sl genospecies were successfully isolated: B. garinii, B. burgdorferi sensu stricto, B. afzelii, B. valaisiana, and B. lusitaniae. Mixed infections were obtained from five of 140 infected ticks. The greatest diversity in Borrelia species was observed at the lowest altitude where all five Borrelia species were present, whereas at the two highest altitudes, B. lusitaniae was not observed.     

Hypoxia aggravates lipopolysaccharide-induced lung injury

The animal model of inflammatory response induced by intratracheal application of lipopolysaccharide includes many typical features of acute lung injury or the acute respiratory distress syndrome. A number of experimental investigations have been performed to characterize the nature of this injury more effectively. In inflammatory conditions, hypoxia occurs frequently before and in parallel with pulmonary and non-pulmonary pathological events. This current study was designed to examine the in vivo effect of hypoxia as a potentially aggravating condition in endotoxin-induced lung injury. Lipopolysaccharide, 150 microg, was instilled intratracheally into rat lungs, and thereafter animals were exposed to either normoxia or hypoxia (10% oxygen). Lungs were collected 2, 4, 6 and 8 h later. Inflammatory response and tissue damage were evaluated by quantitative analysis of inflammatory cells and mediators, surfactant protein and vascular permeability. A significantly enhanced neutrophil recruitment was seen in lipopolysaccharide-animals exposed to hypoxia compared to lipopolysaccharide-animals under normoxia. This increased neutrophil accumulation was triggered by inflammatory mediators such as tumour necrosis factor-alpha and macrophage inflammatory protein-1beta, secreted by alveolar macrophages. Determination of vascular permeability and surfactant protein-B showed enhanced concentrations in lipopolysaccharide-lungs exposed to hypoxia, which was absent in animals previously alveolar macrophage-depleted. This study demonstrates that hypoxia aggravates lipopolysaccharide injury and therefore represents a second hit injury. The additional hypoxia-induced inflammatory reaction seems to be predominantly localized in the respiratory compartment, underlining the compartmentalized nature of the inflammatory response.     

SIV/HIV Nef recombinant virus (SHIVnef) produces simian AIDS in rhesus macaques

The simian immunodeficiency virus (SIV) nef gene is an important determinant of viral load and acquired immunodeficiency syndrome (AIDS) in macaques. A role(s) for the HIV-1 nef gene in infection and pathogenesis was investigated by constructing recombinant viruses in which the nef gene of the pathogenic molecular clone SIVmac239 nef was replaced with either HIV-1sf2nef or HIV-1sf33nef. These chimeras, designated SHIV-2nef and SHIV-33nef, expressed HIV-1 Nef protein and replicated efficiently in cultures of rhesus macaque lymphoid cells. In two SHIV-2nef-infected juvenile rhesus macaques and in one of two SHIV-33nef-infected juvenile macaques, virus loads remained at low levels in both peripheral blood and lymph nodes in acute and chronic phases of infection (for >83 weeks). In striking contrast, the second SHIV-33nef-infected macaque showed high virus loads during the chronic stage of infection (after 24 weeks). CD4+ T-cell numbers declined dramatically in this latter animal, which developed simian AIDS (SAIDS) at 47-53 weeks after inoculation; virus was recovered at necropsy at 53 weeks and designated SHIV-33Anef. Sequence analysis of the HIV-1sf33 nef gene in SHIV-33Anef revealed four consistent amino acid changes acquired during passage in vivo. Interestingly, one of these consensus mutations generated a tyr-x-x-leu (Y-X-X-L) motif in the HIV-1sf33 Nef protein. This motif is characteristic of certain endocytic targeting sequences and also resembles a src-homology region-2 (SH-2) motif found in many cellular signaling proteins. Four additional macaques infected with SHIV-33Anef contained high virus loads, and three of these animals progressed to fatal SAIDS. Several of the consensus amino acid changes in Nef, including Y-X-X-L motif, were retained in these recipient animals exhibiting high virus load and disease. In summary, these findings indicate that the SHIV-33Anef chimera is pathogenic in rhesus macaques and that this approach, i.e., construction of chimeric viruses, will be important for analyzing the function(s) of HIV-1 nef genes in immunodeficiency in vivo, testing antiviral therapies aimed at inhibiting AIDS, and investigating adaptation of this HIV-1 accessory gene to the macaque host.     

Efficacy and safety of mometasone furoate nasal spray in nasal polyposis

BACKGROUND: Studies have suggested that topical corticosteroids are effective in the treatment of nasal polyps; however, this has yet to be confirmed in a large, robust clinical trial. OBJECTIVE: To evaluate the efficacy and safety of mometasone furoate nasal spray (MFNS) for nasal polyposis. METHODS: A total of 354 subjects with bilateral nasal polyps and clinically significant congestion/obstruction participated in this multinational, randomized, double-blind, placebo-controlled study. Subjects received MFNS 200 microg once or twice daily or placebo for 4 months. Coprimary endpoints were (1) change from baseline to last assessment in physician-evaluated bilateral polyp grade score and (2) change from baseline averaged over month 1 in subject-assessed nasal congestion/obstruction. ANOVA was used for all efficacy endpoints, except for change in bilateral polyp grade score, for which baseline polyp grade was added as a covariate. RESULTS: Compared with placebo, MFNS 200 microg administered once or twice daily produced significantly greater reductions in bilateral polyp grade score (P < .001, P = .010, respectively) and congestion/obstruction (P = .001, P < .001), as well as improvement in loss of smell (P < .001, P = .036), anterior rhinorrhea (P < .001 for both), and postnasal drip (P < .001, P = .001) over month 1. MFNS 200 microg twice daily was superior to MFNS 200 microg once daily in reducing congestion/obstruction (P = .039), and there were more improvers in the MFNS 200 microg twice daily group (P = .035). MFNS was well tolerated in both groups. CONCLUSION: MFNS 200 mug, once or twice daily, was safe and significantly superior to placebo in reducing polyp grade (size and extent) and improving congestion/obstruction and return of sense of smell. MFNS is an effective medical treatment for nasal polyposis and may reduce or delay the need for surgery.     

Nonmyeloablative stem cell transplantation is an effective therapy for refractory or relapsed hodgkin lymphoma: results of a spanish prospective cooperative protocol.

We report the results of reduced-intensity conditioning allogeneic stem cell transplantation (allo-RIC) in patients with advanced Hodgkin lymphoma (HL). Forty patients with relapsed or refractory HL were homogeneously treated with an RIC protocol (fludarabine 150 mg/m(2) intravenously plus melphalan 140 mg/m(2) intravenously) and cyclosporin A and methotrexate as graft-versus-host disease (GVHD) prophylaxis. Twenty-one patients (53%) had received >2 lines of chemotherapy, 23 patients (58%) had received radiotherapy, and 29 patients (73%) had experienced treatment failure with a previous autologous stem cell transplantation. Twenty patients (50%) were allografted in resistant relapse, and 38 patients received hematopoietic cells from an HLA-identical sibling. Five patients (12%) died from early transplant-related mortality (before day +100 after allo-RIC). One-year transplant-related mortality was 25%. Acute GVHD developed in 18 patients (45%). Chronic GVHD developed in 17 (45%) of the 31 evaluable patients. The response rate 3 months after the allo-RIC was 67% (21 [52%] complete remissions and 6 [15%] partial remissions). Eleven patients received donor lymphocyte infusions (DLIs) for disease relapse. The response rate after DLI was 54% (3 complete remissions and 3 partial remissions). Overall survival (OS) and progression-free survival (PFS) were 48% +/- 10% and 32% +/- 10% at 2 years, respectively. Refractoriness to chemotherapy was the only adverse prognostic factor for both OS (63% +/- 12% versus 35% +/- 13%; P = .05) and PFS (55% +/- 16% versus 10% +/- 9%; P = .006). For patients with failure of a prior autologous hematopoietic stem cell transplantation, results were especially good for those who experienced late relapses (>/=12 months: 2-year OS and PFS were 75% +/- 16% and 70% +/- 18%, respectively). These data suggest that allo-RIC is feasible in heavily pretreated HL patients and has an acceptable early transplant-related mortality. Results are better in patients allografted in sensitive disease. Both responses observed after the development of GVHD and DLI may suggest a graft-versus-HL effect. Allo-RIC has to be considered an effective therapeutic approach for patients who have had treatment failure with a previous autologous hematopoietic stem cell transplantation.     

Sexually dimorphic expression of protease nexin-1 and vanin-1 in the developing mouse gonad prior to overt differentiation suggests a role in mammalian sexual development

The mammalian sex-determining pathway is controlled by the presence or absence of SRY expression in the embryonic gonad. Expression of SRY in males is believed to initiate a pathway of gene expression resulting in testis development. In the absence of SRY, ovary development ensues. Several genes have now been placed in this pathway but our understanding of it is far from complete and several functional classes of protein appear to be absent. Sex-determining genes frequently exhibit sexually dimorphic patterns of expression in the developing gonad both before and after overt differentiation of the testis or ovary. In order to identify additional sex-determining or gonadal differentiation genes we have examined gene expression in the developing gonads of the mouse using cDNA microarrays constructed from a normalized urogenital ridge library. We screened for genes exhibiting sexually dimorphic patterns of expression in the gonad at 12.5 and 13.5 days post-coitum, after overt gonad differentiation, by comparing complex cDNA probes derived from male and female gonadal tissue at these stages on micro-arrays. Using in situ hybridization analysis we show here that two genes identified by this screen, protease nexin-1 (Pn-1) and vanin-1 (Vnn1), exhibit male-specific expression prior to overt gonadal differentiation and are detected in the somatic portion of the developing gonad, suggesting a possible direct link to the testis-determining pathway for both genes.