The prenatal origin of childhood acute lymphoblastic leukemia

Until recently, the etiology of childhood acute lymphoblastic leukemia (ALL) has remained relatively elusive. Several studies have established a time frame for the development of ALL which could lead to the identification of specific exposures linked to leukemogenesis from the generation of the initial leukemic clone until clinical diagnosis. Utilizing newborn screening ('Guthrie') cards, leukemic clones have been detected retrospectively in dried blood spots using two different PCR-based approaches: (i) the amplification of patient/leukemia-specific breakpoint fusion sequences of rearranged oncogenes; and (ii) the amplification of clonal immunoglobulin heavy chain gene (IgH) or T cell receptor (TcR) gene rearrangements. These studies support the hypothesis that a large proportion of childhood ALL cases arise in utero. In several studies, a long latency period from the generation in utero of the initial ALL clone to clinical diagnosis, indicates that additional genetic events are required for the full development of the leukemia phenotype, potentially from postnatal exposures (e.g. infections). The identification of leukemia-associated translocations in umbilical cord blood samples of healthy newborns, suggest that in the future children may be identified prospectively who have an increased risk of developing leukemia.     

New syndrome of simplified gyral pattern,micromelia, dysmorphic features and early death

We report two sisters with a new syndrome of simplified gyral pattern, normal head circumference at birth but with subsequent development of microcephaly, intractable seizures, and early death. Dysmorphic features included coarse face, hypertrichosis, short nose, paranasal widening, long philtrum, short neck, upper limb micromelia, single transverse palmar lines, and clasp thumbs. The proband had repeated convulsions from shortly after birth and she required continuous artificial ventilation. Neurological examination showed absent sucking, rooting, Moro and grasping reflexes. MRI revealed a diffuse simplified gyral pattern with apparent agyria over the frontal lobes. Biochemical screening gave normal results. Her older sister had bilateral renal pelvic dilatation on prenatal ultrasound. She also developed severe convulsions on the first day of life, and she had to be artificially ventilated for 38 days. She had severe developmental retardation and neurological examination showed absence of spontaneous movements and Moro reflex, weak sucking reflex, and hypertonicity. CT scan of the brain showed a simplified gyral pattern. At 3 months, she developed hypocalcemia and hyperphosphatemia with normal levels of vitamin D and alkaline phosphatase, and parathyroid hormone level was low. Other biochemical tests gave normal results. She died at 5 months due to a massive aspiration event. Based on the unique clinical and radiological features found in our patients, we propose that this is a new syndrome.     

International variation in histologic grading is large,and persistent feedback does not improve reproducibility

Histologic grading systems are used to guide diagnosis, therapy, and audit on an international basis. The reproducibility of grading systems is usually tested within small groups of pathologists who have previously worked or trained together. This may underestimate the international variation of scoring systems. We therefore evaluated the reproducibility of an established system, the Banff classification of renal allograft pathology, throughout Europe. We also sought to improve reproducibility by providing individual feedback after each of 14 small groups of cases. Kappa values for all features studied were lower than any previously published, confirming that international variation is greater than interobserver variation as previously assessed. A prolonged attempt to improve reproducibility, using numeric or graphical feedback, failed to produce any detectable improvement. We then asked participants to grade selected photographs, to eliminate variation induced by pathologists viewing different areas of the slide. This produced improved kappa values only for some features. Improvement was influenced by the nature of the grade definitions. Definitions based on "area affected" by a process were not improved. The results indicate the danger of basing decisions on grading systems that may be applied very differently in different institutions.     

Treatment of rosacea with intense pulsed light

Rosacea is a chronic disease that affects millions of men and women. Topical and oral antibiotics are effective, yet often leave individuals with treatment plateau associated erythema and persistent flushing. We investigated the use of intense pulsed light for treatment of the redness, flushing, and breakouts associated with rosacea. Thirty-two consecutive patients of Fitzpatrick skin types I-III underwent 1 to 7 treatments with intense pulsed light. Patients were assessed clinically and photographically. In addition, patients completed a detailed questionnaire regarding their response to treatment. Following treatment, eighty-three percent of patients had reduced redness, 75% noted reduced flushing and improved skin texture, and 64% noted fewer acneiform breakouts. Complications were minimal and transitory. It appears that intense pulsed light is an effective treatment for the signs and symptoms of rosacea and represents a new category of therapeutic options for the rosacea patient.     

The impact of co-morbid disease on cancer control and survival following radical cystectomy

PURPOSE: We clarified the impact of concurrent medical disease on tumor control and survival following radical cystectomy. MATERIALS AND METHODS: A total of 106 consecutive patients with clinically localized (cT2 or less) disease underwent radical cystectomy at the University of Michigan between 1997 and 1998. The Charlson Index, a validated risk adjustment index, was used to assess preoperative co-morbidity. The 3 primary end points were pathological stage, disease specific survival and overall survival. Logistic regression models were used to determine the relationship between Charlson Index and pathological stage, while Cox regression models were used for the 2 survival end points. RESULTS: Of our study population 24% had a Charlson Index score of 2 or greater. Myocardial infarction, nonurothelial solid malignancies and cerebrovascular disease were the most common co-morbid conditions at 14%, 12% and 10%, respectively. On bivariate analysis the Charlson Index was significantly associated with decreased disease specific (p = 0.049) and overall (p = 0.016) survival. In a multivariate model the index was independently associated with decreased cancer specific survival (p = 0.049) and increased risk of extravesical disease (p = 0.033). CONCLUSIONS: We demonstrated an association between co-morbid illness and adverse pathological and survival outcome following radical cystectomy. This finding underscores the value of assessing overall health before recommending and proceeding with surgery. Moreover, our results emphasize the need to adjust for co-morbidity when comparing outcomes following radical cystectomy.     

Methods for a multisite randomized trial to investigate the effect of constraint-induced movement therapy in improving upper extremity function among adults recovering from a cerebrovascular stroke

This article describes the study design, methodological considerations, and demographic characteristics of a phase III RCT to determine if 1) constraint-induced therapy (CI therapy) can be applied with therapeutic success 3 to 9 months after stroke across different sites, 2) gains that might occur persist over 2 years, 3) initial level of motor ability determines responsiveness to CI therapy, and 4) the treatment effect differs between those treated before 9 months and after 1 year. Six sites will screen and recruit poststroke survivors stratified on initial level of motor ability and after randomization allocate participants to immediate or delayed intervention. Primary outcomes include a laboratory-based measure of function (Wolf Motor Function Test [WMFT]) and a real-world participant-centered functional use measure (Motor Activity Log [MAI]). Secondary outcomes concern function, behavior, and compliance. This is the first multisite, single-blind RCT of a formal training intervention for upper extremity rehabilitation in subacute stroke in the United States.     

Bradykinin receptor subtype 1 expression and function in prostate cancer

Kinins exert multiple pathophysiological functions, including vascular permeability and mitogenesis, by activating their cognate receptors, bradykinin subtype 1 receptor (B1R) and bradykinin subtype 2 receptor (B2R), which belong to the superfamily of G protein-coupled receptors. Tissue-specific expression pattern or contribution of the individual kinin receptors to pathological prostate cell growth is not known. We report here the differential expression of B1R and B2R in human benign and malignant prostate specimens. Whereas B2R is ubiquitously expressed, the B1R is detected only in prostatic intraepithelial neoplasia and malignant lesions and not in benign prostate tissues. Using androgen-insensitive prostate cancer PC3 cells, we show that specific stimulation of endogenous B1R promotes cell growth, migration, and invasion. These findings identify B1R as an early marker for pathological growth of the prostate and suggest its potential utility as a drug target effective for the treatment of prostate cancer.     

Congenital microangiopathic hemolytic anemia and thrombocytopenia with unusually large von Willebrand factor multimers and von Willebrand factor-cleaving protease

Infantile or congenital cases of thrombotic microangiopathy have been reported that were familial and characterized by ongoing microangiopathic hemolysis and thrombocytopenia in the absence of regular fresh-frozen plasma transfusions. The authors describe a child with congenital microangiopathic hemolytic anemia and thrombocytopenia (CMHAT) who has received regular fresh-frozen plasma transfusions since infancy and has never had thrombotic complications. von Willebrand factor (vWF)-cleaving protease activity was studied in the patient's pretransfusion and posttransfusion plasma samples as well as in her parents' plasma. The effects of the patient's and a control subject's plasma on human microvascular endothelial cells were also investigated. Unusually large vWF multimers were present in the patient's plasma both before transfusion (thrombocytopenic) and after transfusion. Unlike cases of chronic relapsing thrombotic thrombocytopenic purpura, vWF-cleaving protease activity was present and treatment of cultured human endothelial cells with the patient's plasma did not induce apoptosis. These findings suggest that the patient with CMHAT may represent a different group in the broad spectrum of thrombotic microangiopathies.     

Acceptability of oesophagogastroduodenoscopy without intravenous sedation: patients' versus endoscopist's perception with special reference to older patients

Objective::This study was undertaken to compare (1) patients'' perception of discomfort with the endoscopist''s perception of patients'' discomfort for the unsedated OGD, (2) tolerability between older (⩾75 years) and younger (<75 years) patients. Design and subjects::A total of 130 consecutive patients attending a day case endoscopy unit were recruited for the study. The patients and endoscopist recorded their assessment using a visual analogue scale (VAS). The results were analysed using non-parametric tests. Thirty patients were excluded from the study based on exclusion criteria. Sixty three (57%) patients were aged ⩾75 years and 37 (43%) were <75 years. Results::A significant difference was noted between patients'' perception of the discomfort and the endoscopist''s assessment of the patient''s discomfort as suggested by the overall higher VAS scores for patients (median 4.9, SD 2.6) than those of the endoscopist (median 2.2, SD 1.2), giving a significant difference in median VAS score of 3.4 (p<0.001). Older and younger patients had similar scores, with median (SD) VAS scores of 4.8 (2.5) for ⩾75 years and 4.9 (2.8) for <75 years. The endoscopist''s median scores for these two groups were 2.2 (1.2) and 2.1 (1.3), respectively. Conclusions::Patients'' discomfort during OGD performed without sedation was greatly underestimated by the endoscopist. There was no significant difference in acceptability between old and the young patients.     

Pediatric constraint-induced movement therapy for a young child with cerebral palsy: two episodes of care

BACKGROUND AND PURPOSE: This case report describes the use of "Pediatric Constraint-Induced Therapy (Pediatric CI Therapy)" given on 2 separate occasions for a young child with quadriparetic cerebral palsy. CASE DESCRIPTION: The child was 15 months of age at the beginning of the first episode of care. She had previously received weekly physical therapy and occupational therapy for 11 months, but she had no functional use of her right upper extremity (UE), independently or in an assistive manner. She scored from 5 to 7 months below her chronological age on developmental assessments in gross motor, fine motor, and self-help skills. INTERVENTION: Pediatric CI Therapy involved placement of a full-arm, bivalved cast on the child's less affected UE while providing 3 weeks of intensive intervention (6 hours a day) for the child's more affected UE (intervention 1). Therapy included activities that were goal oriented but broken down into progressively more challenging step-by-step tasks. Pediatric CI Therapy was administered again 5 months later to promote UE skills and independence (intervention 2). OUTCOMES: The child developed new behaviors throughout both interventions. During intervention 1, the child developed independent reach, grasp, release, weight bearing (positioned prone on elbows) of both UEs, gestures, self-feeding, sitting, and increased interactive play using both UEs. During intervention 2, she had increased independence and improved quality of UE movement, as supported by blinded clinical evaluations and parent ratings.