Residual disease detection using fluorescent polymerase chain reaction at 20 weeks of therapy predicts clinical outcome in childhood acute lymphoblastic leukemia

PURPOSE: Ninety-five percent of children with acute lymphoblastic leukemia (ALL) will achieve a remission, but approximately 25% will relapse. Identifying these patients is difficult, as patients with adverse prognostic features at presentation are rare and the majority are standard risk. Analysis of minimal residual disease (MRD) may be able to determine those at risk of relapse, but the best method by which this can be accomplished has yet to be defined. The object of this study was to determine the predictive value of residual disease detection in a group of standard-risk patients with precursor-B ALL at a fixed point in therapy (week 20) using a simple fluorescent consensus immunoglobulin H (IgH) heavy chain polymerase chain reaction (PCR). PATIENTS AND METHODS: Forty-two patients who presented with precursor-B ALL with standard-risk clinical features and treated according to either the Medical Research Council (MRC) UKALL X or XI protocols were assessed using a combination of both fluorescent consensus framework I and framework III Ig heavy-chain PCR. The results of the PCR were analyzed on an ABI 373 gene sequencer with genescan software (Applied Biosystems, Foster City, CA). Clonal rearrangements detected at presentation were looked for at week 20. RESULTS: Of 42 patients, 35 had a clonal population detectable at presentation; of these, seven had more than two clonal rearrangements; this latter group showed a similar disease-free survival (DFS) to the group as a whole. Thirty of 35 patients were analyzed before their second course of intensification therapy at week 20. At this point, nine of 30 had a detectable clonal rearrangement, eight (89%) of whom have since relapsed with a median DFS of 27.5 months. Of the rest of the group (n=21), in whom no clonal rearrangement was detectable, only six (21%) have relapsed. CONCLUSION: Fluorescent IgH PCR at week 20 provides a sensitive and specific means to predict ultimate relapse (57% and 89%, respectively) and is a simple yet promising technique for the identification of patients at risk of poor outcome.     

Large gradient across a partially ligated left atrial appendage

The left atrial appendage is frequently ligated during mitral valve surgery to decrease the future risk of embolic events. The postoperative detection of a partially occluded left atrial appendage has previously been reported with the use of transesophageal echocardiography. We describe an unusual case in which Doppler echocardiography demonstrated a remarkably high-velocity jet emanating from a partially ligated left atrial appendage.     

Pseudomonas aeruginosa as a cause of infectious diarrhoea

Pseudomonas aeruginosa is not generally considered a cause of infectious diarrhoea. However, it was the predominant organism isolated from the faeces of 23 unrelated, hospital outpatients investigated in the course of a year for persistent (> 1 week duration) diarrhoea. To investigate the possible aetiological role of P. aeruginosa, these patient histories were reviewed and a selection of their faecal isolates were investigated in vitro (n > or = 10) and in vivo (n = 2) for virulence. The patients had a mean age of 60 years, were receiving antibiotics and/or had an underlying illness. Extensive microbiological investigations identified no other potential or recognized enteropathogen in the faeces of 20 of these patients. More than 40% of the isolates tested were able to adhere to HEp-2 cells and exhibited twitching motility (type IV pili), properties indicative of their ability to colonize the human intestine. Cytotoxic activity was demonstrated in bacterium-free cell supernatants of over 80% of isolates; supernatants of four isolates tested in infant mice were weakly enterotoxigenic. Two isolates intragastrically inoculated into clindamycin pre-treated rats established persistent infections and induced signs and symptoms of enteritis. Overall these findings suggest that P. aeruginosa can cause diarrhoea particularly in immunodeficient individuals.     

Epidemiology and natural history of pelvic floor dysfunction

Pelvic floor dysfunction, including urinary incontinence, anal incontinence, and pelvic organ prolapse, is extremely common, affecting at least one-third of adult women. A minority of patients sustaining these conditions volunteer their symptoms. Risk factor identification and the development of tactics for prevention are significant priorities for future research. Understanding both the specific predisposing factors that place an individual woman at risk and the precise events of the labor and delivery process that initiate injury and dysfunction is important for primary prevention. Defining the relative importance of various promoting and decompensating factors is essential for secondary prevention.     

The GM2-1 ganglioside islet autoantigen in insulin-dependent diabetes mellitus is expressed in secretory granules and is not beta-cell specific

The pancreatic islet monosialo-ganglioside (GM2-1), an autoantigen in insulin-dependent diabetes mellitus (IDDM) recently shown to be the target of autoantibodies associated with diabetes development in relatives of IDDM patients, is islet specific within the pancreas, and its expression is metabolically regulatable. In the present study we sought to establish 1) whether GM2-1 is beta-cell specific, and 2) its intracellular localization. To this end, we analyzed the pattern of ganglioside expression in highly purified beta- and non-beta-cells isolated from rat islets. In addition, ganglioside levels were determined in subcellular fractions of a rat beta-cell line (INS). No qualitative or quantitative difference was found in the pattern of ganglioside expression between beta and non-beta rat islet cells, with GM3, GM2-1, and GD3 gangliosides expressed in both cell populations. Within INS cells, GM2-1 ganglioside was expressed in the fraction containing secretory granules and, to a lesser extent, in plasma membranes; GM3 was expressed in secretory granules, whereas GD3 was found only in plasma membranes. These data indicate that the GM2-1 autoantigen is not beta-cell specific within the islets, in accordance with the observation that this molecule is a target of islet cell autoantibodies that bind to the whole pancreatic islet. Interestingly, this autoantigen is present in secretory granules similarly to other autoantigens in IDDM (insulin, carboxypeptidase H, 38-kDa protein, etc.), suggesting that the autoimmunity to the components of this organelle may be central to the pathogenesis of the disease.     

Dual task performance after diazepam intake: can resource depletion explain the benzodiazepine-induced amnesia?

It was tested whether a depletion in resources can account for the benzodiazepine-induced memory impairment. In two experiments, it was examined whether dividing attention had a disproportionately detrimental effect on learning semantically related and unrelated word pairs after diazepam intake. Word pairs had to be learned in both a single task condition and while performing a visual discrimination task concurrently (dual task condition). Moreover, the complexity of the visual discrimination task was manipulated systematically. Diazepam (15 mg, orally) or placebo was administered in a double-blind, between-subjects design. Subjects after diazepam intake were clearly impaired in learning unrelated word pairs, but not in learning related word pairs. Dividing attention in the dual task condition was associated with a reduction in learning unrelated word pairs, but this was not disproportionately reduced after diazepam intake. Moreover, the magnitude of resource depletion did not correlate with the severity of the diazepam-induced memory impairment. In general, the pattern of results does not support the hypothesis that a depletion of resources can explain the benzodiazepine-induced memory impairment.     

5-Hydroxytryptamine receptor subtype messenger RNAs in human dorsal root ganglia: a polymerase chain reaction study

Wound healing is critical to the survival of the species after injury. Using hamsters as an experimental model, we have shown that eosinophils infiltrate prominently into skin wounds and that they express transforming growth factor-alpha and -beta 1 mRNAs and proteins. We hypothesized that eosinophils are important in wound healing. As no animal model is genetically deficient in eosinophils, a suitable way to test the hypothesis is to selectively reduce and/or deplete the influx of eosinophils into the wound sites. In this study, we report that anti-interleukin-5 monoclonal antibody (TRFK-5) treatment can deplete eosinophils in cutaneous healing wounds. We found that wound closure by re-epithelialization in the experimental group was 4 days faster than in the control group (P < 0.01). The density of eosinophils in day-9 wounds was significantly lower in the experimental group (P < 0.01). Wound-associated eosinophils in each of the TRFK-5-treated hamsters were depleted to the level comparable to unwounded hamster skin. These results demonstrate that anti-interleukin-5 monoclonal antibody treatment can effectively decrease eosinophil infiltration into hamster cutaneous healing wounds and indicate a role for eosinophils in negatively affecting wound re-epithelialization.