Role of Upper Endoscopy in Evaluation of Upper Gastrointestinal Symptoms in Patients Undergoing Bone Marrow Transplantation

We reviewed our upper endoscopy (esophagogastroduodenoscopy, EGD) experience in a group of 65 consecutive patients receiving carmustine (BCNU) 600 mg/m², cisplatin 200 mg/m², VP-16 2400 mg/m², and autologous bone marrow transplantation (BMT) for relapsed or refractory non-Hodgkin's lymphoma or Hodgkin's disease. Forty-one patients (33 with chest irradiation) underwent 48 EGDs for the following symptoms: upper gastrointestinal bleeding (melena and/or hematemesis) (12/48); persistent nausea and vomiting (7/48); odynophagia (25/48); and dysphagia (14/48). All patients who had dysphagia or odynophagia had endoscopic evidence of severe esophagitis, with confluent erosions or ulcerations. Gastrointestinal bleeding, which presented as melena or hematemesis, was caused by severe esophagitis in 11 of 12 patients. Yeasts were detected in 11/42 histological, or cytological specimens and were isolated in 4/26 cultures. No bleeding or infectious complications occurred in any patient as a result of the EGD procedure. We conclude that severe esophagitis documented by EGD is common in lymphoma patients receiving autologous BMT. Use of EGD, however, did not affect the decision to initiate empirical therapy with amphotericin B for persistent fever.     

Multicentric osteolysis: report of the second successful renal transplant

A patient with end stage renal disease due to sporadic idiopathic multicentric osteolysis (type 3 multicentric osteolysis) is described. His pre-transplant course was similar to those of previously described patients, while his post-transplant course has been uncomplicated. The pathology and pathogenesis of the nephropathy of sporadic idiopathic multicentric osteolysis is not well characterized. The short term outcome of renal transplantation is excellent in our patient and in the other similar case known to have been transplanted.     

Development of questionnaires to measure patient preferences for intranasal corticosteroids in patients with allergic rhinitis.

OBJECTIVE: To develop a questionnaire to evaluate preferences for attributes of intranasal corticosteroids (INSs) in clinical trials with allergic rhinitis (AR) patients. STUDY DESIGN AND SETTING: Established questionnaire development practices were used, including performance of a literature review and use of patient and physician focus groups, cognitive debriefing interviews, and pilot testing before validation. RESULTS: Findings from patient and physician focus groups suggest that sensory attributes are relevant to AR patients when choosing INSs. Physician focus groups identified the need for 2 distinct preference instruments, a clinical trial patient preference questionnaire (CTPPQ) and a clinical practice preference questionnaire (CPPPQ). A pilot study suggests that the CTPPQ is capable of discriminating between 2 INSs in the clinical trial setting. CONCLUSIONS: Initial findings suggest that items in the CTPPQ and CPPPQ are easy to understand and relevant to patients. Further validation studies with larger sample sizes are needed to assess the psychometric properties of both questionnaires. EBM rating: B-20.     

Regional distribution of glutamate and aspartate in adult and old human brain

In previous studies on rat brain we found that the observed heterogeneity of the regional distribution of amino acids was much greater when small well-defined anatomical structures were assayed. We therefore reinvestigated the distribution of glutamate and aspartate in 50 discrete areas from adult and old human brain. The concentration of glutamate in the area of highest level was 4.5 and 4.7 times as high as in the area of lowest level in adult and old brain respectively; for aspartate these values were 3.0 and 6.6. Several changes in old brain were noted. The human pattern differed from that in rat.     

A review of recorded information given to patients starting to take clozapine and the development of guidelines on disclosure, a key component of informed consent

Clozapine is a very effective drug with both significant benefits and significant risks in treatment-resistant schizophrenia. Informed consent is generally accepted as both desirable and necessary in order to ensure that the patient's human rights and dignity are respected. Disclosure is a key element of informed consent. It is unclear if the adequate documentation of disclosure is standard practice before initiation of clozapine. The aim of this study was to assess the adequacy of the documentation of disclosure in consent to clozapine treatment in an adult mental health service and to develop guidelines on disclosure. The method was a retrospective analysis of charts of patients given clozapine who received the drug through the pharmacy of a single North Dublin psychiatric hospital. Results show that current practice has evident gaps. The professional, ethical and legal issues are discussed.     

FGF10 missense mutations in aplasia of lacrimal and salivary glands (ALSG)

Aplasia of lacrimal and salivary glands (ALSG) is an autosomal dominant congenital anomaly characterized by aplasia, atresia or hypoplasia of the lacrimal and salivary systems. Affected individuals present with irritable eyes and dryness of the mouth with variable expressivity. Mutations in FGF10 were recently described in ALSG and in lacrimo-auriculo-dento-digital (LADD) syndrome which are overlapping clinical entities. We present here two families with ALSG associated with missense mutations (R80S and G138E, respectively) affecting highly conserved residues in FGF10. The clinical features of these patients further broaden the knowledge of FGF10-related phenotypes.     

Lineage tracing demonstrates the venous origin of the mammalian lymphatic vasculature

The origin of the mammalian lymphatic vasculature has been debated for more than 100 years. Whether lymphatic endothelial cells have a single or dual, venous or mesenchymal origin remains controversial. To resolve this debate, we performed Cre/loxP-based lineage-tracing studies using mouse strains expressing Cre recombinase under the control of the Tie2, Runx1, or Prox1 promoter elements. These studies, together with the analysis of Runx1-mutant embryos lacking definitive hematopoiesis, conclusively determined that from venous-derived lymph sacs, lymphatic endothelial cells sprouted, proliferated, and migrated to give rise to the entire lymphatic vasculature, and that hematopoietic cells did not contribute to the developing lymph sacs. We conclude that the mammalian lymphatic system has a solely venous origin.     

Mutagenicity of zidovudine, lamivudine, and abacavir following in vitro exposure of human lymphoblastoid cells or in utero exposure of CD-1 mice to single agents or drug combinations

Experiments were performed to investigate the impact of zidovudine (AZT), lamivudine (3TC), and abacavir (ABC) on cell survival and mutagenicity in two reporter genes, hypoxanthine-guanine phosphoribosyltransferase (HPRT) and thymidine kinase (TK), using cell cloning assays for assessing the effects of individual drugs/drug combinations in (1) TK6 human lymphoblastoid cells exposed in vitro and (2) splenic lymphocytes from male CD-1 mice exposed transplacentally on days 12-18 of gestation. In TK6 cells, dose-related increases in HPRT and TK mutant frequencies were found following 3 days of exposure to AZT or 3TC alone (33, 100, or 300 microM), or to equimolar amounts of AZT-3TC. Compared with single drug exposures, AZT-3TC coexposures generally yielded enhanced elevations in HPRT and TK mutant frequencies. Mutagenicity experiments with ABC alone, or in combination with AZT-3TC, were complicated by the extreme cytotoxicity of ABC. Exposure of cells either to relatively high levels of AZT-3TC short-term (100 microM, 3 days), or to peak plasma-equivalent levels of AZT-3TC for an extended period (10 microM, 30 days), resulted in similar drug-induced mutagenic responses. Among sets of mice necropsied on days 13, 15, or 21 postpartum, Hprt mutant frequencies in T-cells were significantly elevated in the AZT-only (200 mg/kg bw/day) and AZT-3TC (200 mg AZT + 100 mg 3TC/kg bw/day) groups at 13 days of age. These results suggest that the mutagenicity by these nucleoside analogs is driven by cumulative dose, and raises the question of whether AZT-3TC has greater mutagenic effects than AZT alone in perinatally exposed children.     

Identification of a lectin causing the degeneration of neuronal processes using engineered embryonic stem cells

Unlike the mechanisms involved in the death of neuronal cell bodies, those causing the elimination of processes are not well understood owing to the lack of suitable experimental systems. As the neurotrophin receptor p75(NTR) is known to restrict the growth of neuronal processes, we engineered mouse embryonic stem (ES) cells to express an Ngfr (p75(NTR)) cDNA under the control of the Mapt locus (the gene encoding tau), which begins to be active when ES cell-derived progenitors start elongating processes. This caused a progressive, synchronous degeneration of all processes, and a prospective proteomic analysis showed increased levels of the sugar-binding protein galectin-1 in the p75(NTR)-engineered cells. Function-blocking galectin-1 antibodies prevented the degeneration of processes, and recombinant galectin-1 caused the processes of wild-type neurons to degenerate first, followed by the cell bodies. In vivo, the application of a glutamate receptor agonist, a maneuver known to upregulate p75(NTR), led to an increase in the amount of galectin-1 and to the degeneration of neurons and their processes in a galectin-1-dependent fashion. Section of the sciatic nerve also rapidly upregulated levels of p75(NTR) and galectin-1 in terminal Schwann cells, and the elimination of nerve endings was delayed at the neuromuscular junction of mice lacking Lgals1 (the gene encoding galectin-1). These results indicate that galectin-1 actively participates in the elimination of neuronal processes after lesion, and that engineered ES cells are a useful tool for studying relevant aspects of neuronal degeneration that have been hitherto difficult to analyze.