A phase II,double-blind,randomized, placebo-controlled clinical trial of tgAAVCF using maxillary sinus delivery in patients with cystic fibrosis with antrostomies

tgAAVCF, an adeno-associated cystic fibrosis transmembrane conductance regulator (CFTR) viral vector/gene construct, was administered to 23 patients in a Phase II, double-blind, randomized, placebo-controlled clinical trial. For each patient, a dose of 100,000 replication units of tgAAVCF was administered to one maxillary sinus, while the contralateral maxillary sinus received a placebo treatment, thereby establishing an inpatient control. Neither the primary efficacy endpoint, defined as the rate of relapse of clinically defined, endoscopically diagnosed recurrent sinusitis, nor several secondary endpoints (sinus transepithelial potential difference [TEPD], histopathology, sinus fluid interleukin [IL]-8 measurements) achieved statistical significance when comparing treated to control sinuses within patients. One secondary endpoint, measurements of the anti-inflammatory cytokine IL-10 in sinus fluid, was significantly (p < 0.03) increased in the tgAAVCF-treated sinus relative to the placebo-treated sinus at day 90 after vector instillation. The tgAAVCF administration was well tolerated, without adverse respiratory events, and there was no evidence of enhanced inflammation in sinus histopathology or alterations in serum-neutralizing antibody titer to adeno-associated virus (AAV) capsid protein after vector administration. In summary, this Phase II trial confirms the safety of tgAAVCF but provides little support of its efficacy in the within-patient controlled sinus study. Various potentially confounding factors are discussed.     

cAMP target sequences enhCRE and CNRE sense low-salt intake to increase human renin gene expression in vivo

This study aimed to assess the role of cAMP target sequences enhancer cAMP response element (enhCRE) and cAMP and overlapping negative response element (CNRE) in the control of human renin gene (REN) in vivo. enhCRE and CNRE were silenced by mutations in a 12.2-kb human renin promoter fused to LacZ reporter gene. This construct was used to generate transgenic mice (RENMut-LacZ). The expression of the transgene was correctly targeted to the juxtaglomerular portions of renal afferent arterioles which express endogenous mouse renin. Therefore, enhCRE and CNRE do not seem to be relevant for the control of the cell-specific expression of the human renin gene. The β-adrenoreceptor agonist isoproterenol (10?mg/kg/day, for 2?days) stimulated the endogenous renin, but not the LacZ mRNA expression. Treatment of RENMut-LacZ mice with the angiotensin converting enzyme inhibitor (enalapril 10?mg/kg/day, for 7?days) or their crossing to angiotensin receptor type 1a knockout mice led to increased renin and LacZ mRNA levels. Renin expression was upregulated by low-salt diet (0.03% NaCl, for 10?days) and downregulated by high-salt diet (4% NaCl, for 10?days). In contrast, low-salt diet did not influence, while high-salt diet inhibited the expression of LacZ. In summary, enhCRE and CNRE appear to be necessary for the transactivation of the human renin gene through β-adrenoreceptors and by low-salt diet. Our data also suggest that different intracellular mechanisms mediate the effect of low- and high-salt intake on renin expression in vivo.     

Acute renal cortical necrosis due to acquired antiprotein S antibodies

Although varicella is a common disease of childhood, renal complications are quite rare. We report here the interesting case of a-22 month-old boy exhibiting renal cortical necrosis related to an acquired protein S deficiency following varicella. Ten days after the vesicle eruption appearance, he presented with ecchymosed heels, oligoanuric kidney failure, anemia [hemoglobin (Hb) 78 g/L], schizocytosis (2.5%), but normal platelet count. Kidney sonography and magnetic resonance imaging evoked renal cortical necrosis. All together, these features suggested acquired protein S deficiency secondary to varicella. Strikingly, it was confirmed by a dramatic decrease in protein S plasma activity and a huge increase in immunoglobulin (Ig)G antibodies against protein S in the plasma. Anticoagulation therapy in addition with plasmapheresis and steroid pulses allowed a dramatic decrease in the antibodies against protein S and recovery of normal protein S activity. Undelayed diagnosis and treatment did not avoid kidney insufficiency but prevented life-threatening complications. In the light of this case report, protein S deficiency due to antibody inhibition should be carefully monitored anytime in the context of varicella when kidney insufficiency or necrosis occurs.     

Endocrine and bone consequences of cyclic nutritional changes in the calcium, phosphate and vitamin D status in the rat: an in vivo depletion-repletion-redepletion study

Hypocalcemia secondary to vitamin D3 (D3) depletion (D-Ca-) perturbs extra- and intracellular calcium (Ca). To study the effect of cyclic nutritional changes in the D3 and calcium (Ca) repletion state, we investigated the lasting effects of calcium or D3 repletion on calcium and bone metabolism using a novel depletion-repletion-redepletion protocol. D-Ca- rats presenting osteomalacia without rickets and a significant impairment in whole body mineral content (BMC) accretion were repleted with either calcium alone [3% (Ca+3) or 0.5% (Ca+0.5)] or D3 and then switched back to the original D-Ca- diet. All repletion protocols, except Ca+0.5, normalized serum (S) Ca and parathyroid hormone (PTH) but Ca+3 exhibited growth retardation and hypophosphatemia. D3 normalized BMC in D-Ca- and healed osteomalacia while Ca+0.5 led to 50% normalization. In contrast, rickets with no BMC accretion was observed in Ca+3 most likely secondary to hypophosphatemia. Upon redepletion, S Ca rapidly decreased while S PTH and phosphate increased. D3 and Ca+0.5 survived the redepletion protocols but all Ca+3 died within 5 days upon sudden Ca withdrawal whereas progressive Ca redepletion significantly delayed the death rate. Data indicate that during the calcium redepletion period, correction of hypophosphatemia in Ca+3 allowed calcification of the enlarged growth plates thus resulting in an increased demand for calcium. It is postulated that this increased demand for calcium, in conjunction with low dietary calcium and the bone calcium reservoir incapacity to provide sufficient calcium to sustain S Ca, led to the observed acute hypocalcemia which was most likely the cause of death. This hypothesis is further supported by the observation that Ca+3 submitted to a progressive Ca deprivation exhibited a delay in death rate, a progressive involution of rickets and survival only upon return to the D-Ca- phenotype. Furthermore, in Ca+3, increasing dietary phosphate by 0.6% to achieve a Ca/P ratio similar to Ca+0.5 or D3 prevented the development of hypophosphatemia, slightly increased S Ca, significantly increased BMC, prevented the development of rickets and allowed 100% survival during rapid calcium withdrawal. Collectively, data clearly demonstrate the importance of the dietary Ca/P ratio to maintain S Ca/P at optimum concentrations for bone health.     

ORIGINAL ARTICLE Visual Outcome of Juvenile Rheumatoid Arthritis-Associated Uveitis in Adults

Purpose: Juvenile rheumatoid arthritis (JRA) is the systemic disease most frequently associated in childhood uveitis. The disease may cause several ocular complications, visual impairment, and blindness. Recent studies revealed a more favorable ocular prognosis. Our purpose was to analyze the long-term visual outcome of JRA-associated uveitis. Methods: Ocular complications and visual outcome in adult patients with JRA-associated uveitis were evaluated. Among 18 patients included in the study, uveitis was bilateral in 12 (66.7%) and unilateral in six (33.3%), for a total of 30 eyes with ocular involvement. Results: The mean durations of JRA and its associated uveitis were 24.9 and 20.5 years, respectively. All eyes (100%) had at least one ocular complication. The most frequently observed ocular complications were cataract (83.3%), band keratopathy (60%), posterior synechia (46.7%), glaucoma (33.3%), hypotony (16.7%), and macular pathology (13.3%). Final visual acuity was impaired in 40% of the eyes, poor in 20%, and totally lost in 10%. Therefore, 70% of the eyes were either visually handicapped or totally blind. Most eyes underwent at least one surgical procedure. Inflammation was active at last examination in 63.3% of eyes. All patients were still treated topically and with systemic NSAID. Sixty-one percent of the patients were using an immunosuppressive agent. Conclusion: JRA-associated uveitis still has a severe course and blinding potential. Patients suffer from uveitis and its complications even during the adulthood period. However, because our series represents a more severe subset of the disease, the outcome may be poorer than that of some other outcome studies.     

The optimal timing of autologous bone marrow transplantation in Hodgkin's disease patients after a chemotherapy relapse.

PURPOSE: The optimal sequence of salvage chemotherapy (SC) and autologous bone marrow transplantation (ABMT) for Hodgkin's disease (HD) patients who relapse after primary chemotherapy is unknown. We created a decision analysis model to determine the optimal treatment strategy and the most cost-effective approach. METHODS: The decision tree simulated a 25-year-old HD patient who relapsed less than 12 months after mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) chemotherapy. Four strategies used ABMT in some sequence with SC; the final strategy considered SC alone. Clinical data were derived from 17 published reports chosen by explicit criteria. Costs of care were estimated from the published literature and institutional experience. RESULTS: The optimal strategy was ABMT in second relapse, which was superior to the SC-only option by 1.9 years at an incremental cost of $26,200 per each year of life saved. When the probabilities of complete remission and disease-free survival were reduced for SC, similar to the clinical expectation of SC after a seven- or eight-drug regimen like MOPP/doxorubicin, bleomycin, and vinblastine with or without dacarbazine (MOPP/ABV[D]), ABMT in first relapse was the preferred strategy and provided 6 additional months. However, when the data from favorable (or unfavorable) SC and ABMT reports were compared head-to-head in this model, SC followed by ABMT in second relapse was always optimal. CONCLUSIONS: All relapsed HD patients should plan to use ABMT in some sequence with SC, if necessary. In most situations the optimal strategy is ABMT in second relapse. This analysis will assist clinicians in planning treatment for relapsed HD patients. It could be refined if historical series were updated to report the incidence and outcomes of SC relapse from seven- or eight-drug regimens.     

Alport syndrome and diffuse leiomyomatosis: deletions in the 5' end of the COL4A5 collagen gene.

Alport syndrome (AS) is an hereditary glomerulonephritis that is mainly inherited as a dominant X-linked trait. Structural abnormalities in the type IV collagen alpha 5 chain gene (COL4A5), which maps to Xq22, have recently been detected in several patients with AS. The association of AS with diffuse esophageal leiomyomatosis (DL) has been reported in 24 patients, most of them also suffering from congenital cataract. The mode of transmission and the location of the gene(s) involved in this association have not been elucidated. Southern blotting using cDNA probes spanning the whole COL4A5 and a 5' end COL4A5 genomic probe showed that three out of three patients with the DL-AS association had a deletion in the 5' part of the COL4A5 gene extending beyond its 5' end. This indicates that the same gene, COL4A5, is involved in classical AS and in DL-AS and that the transmission of DL-AS is X-linked dominant. These results also suggest that leiomyomatosis might be due to the alteration of a second gene involved in smooth muscle cell proliferation, which is located upstream of the COL4A5 gene, and that there might be a contiguous gene deletion syndrome, involving at least the genes coding for congenital cataract, DL and AS.