Association of the Src homology 2 domain-containing inositol 5' phosphatase (SHIP) to releasability in human basophils

During the study of the biology of the Human recombinant Histamine Releasing Factor (HrHRF), we uncovered a hyperreleasable phenotype of basophils from HrHRF-responder donors. Basophils from these donors released histamne to HrHRF, IL-3 and D(2)O. While there has been a significant amount of work elucidating signal transduction events in human basophils, the reason for this hyperreleasable phenotype remained illusive. A clue to the releasability of these highly allergic, asthmatic HrHRF-responder donor basophils was demonstrated in studies using SHIP knockout mice. Bone marrow-derived mast cells from the SHIP knockout mice demonstrated hyperreleasability to stimuli through the IgE receptor and alteration of subsequent signal transduction events. We have demonstrated a highly significant negative correlation between the amount of SHIP protein per cell equivalent and maximum histamine release to HrHRF. These results provide a clue to the hyperreleasable phenotype and implicate SHIP as an additional regulator of secretion in human basophils.     

Recurrent myocardial infarction with patent coronary arteries.

Two separate episodes of severe chest pain occurred several years apart in a 25-year-old male patient with typical clinical findings of acute myocardial infarction with each episode. Cardiac catheterization following the second infarction confirmed the presence of myocardial dysfunction with apical akinesis and dyskinesis. Both coronary arteries were radiologically patent; however, there was evidence of probable recanalization of the right coronary artery. Several months later, the patient developed flank pain, hematuria, progressive renal failure, and cardiac decompensation, and died with intractable arrhythmias. At autopsy, a large apical mitral thrombosis was found and was the presumptive source of multiple systemic emboli.     

Shoulder muscle activity in Parkinson’s disease during multijoint arm movements across a range of speeds

Bradykinesia is one of the primary symptoms of Parkinson disease and leads to significant functional limitations for patients. Single joint movement studies, that have investigated the mechanism of bradykinesia, suggest that several features of muscle activity are disrupted, including modulation of burst amplitude and duration, and the number of bursts. It has been proposed that it is the blending of these different burst deficits that collectively defines bradykinesia. This study adds two new approaches to the study of bradykinesia. First, we examined the features of shoulder muscle activities during multijoint arm movement in bradykinetic and control subjects, such that previously reported single joint hypotheses could be tested for generalized arm movement. Second, we directly manipulated speed while keeping distance constant for a large range of speeds. In this manner, we could compare individual trials of muscle activity between controls and subjects with Parkinsons disease (PD) for movements matched for both speed and movement duration. Our results showed that while a multiple burst pattern of shoulder muscles was a common strategy for all subjects (young, elderly controls and PD), subjects with PD showed several burst abnormalities, including deficits in initial agonist burst amplitude and duration at both fast and slow speeds. Subjects with PD also (1) failed to produce a one-burst pattern at fast speeds and, instead, produced a predominance of multiple burst patterns and (2) showed a relationship between the number of burst deficits and the severity of disease. These results extend the findings of single joint studies to multi-joint and similarly indicate that a combination of burst modulation abnormalities correlate with bradykinesia and disease severity.     

Rapid prescreen of cervical liquid-based cytology preparations: results of a study in an academic medical center

A rapid prescreening or rapid rescreening method for quality assurance in cervical cytology has been used in Europe and in Canada but has not been accepted in the United States. The rapid prescreen method was tested in a cytology laboratory that serves an academic medical center with a high‐risk population for cervical cancer. For a period of 3 months, a tray of 20 sequentially numbered Surepath? liquid‐based preparations, randomly selected from the cervical cytology daily workload, were each prescreened in a random fashion for 1 minute. Experienced cytotechnologists performed the rapid prescreen. Results were recorded as negative, further review needed, or epithelial cell abnormality, category specified. The 20 cervical cytology preparations were then replaced in their same position in the daily workload for routine screening performed by another cytotechnologist. Final interpretation was by a cytopathologist as requested or required by Clinical Laboratory Improvement Amendments of 1988. The rapid prescreen data was tabulated and compared with data for a similar time period using the laboratory's normal quality assurance program. Seven hundred and twelve cases underwent rapid prescreen. Six hundred and forty‐two were interpreted as negative. Twenty‐six cases were interpreted as low‐grade squamous intraepithelial lesion (LGSIL) or higher. Forty‐four cases were classified as needing further review. For the 642 negative cases by rapid prescreening, routine screening reported 537 as negative and 105 as either abnormal or needed cytopathologist review. The error rate for the rapid prescreen is 50 of 712 (7.0%); for LGSIL and above 19 of 712 (2.6%). Of the 105 abnormal cases or those submitted for cytopathologist review, 31 were interpreted as atypical squamous cells of undermined significance (ASCUS), 41 cases as reactive/repair, 17 as LGSIL, 4 as unsatisfactory, 1 as atypical squamous cells, cannot rule out high‐grade squamous intraepithelial lesion (ASC‐H), 8 as the presence of endometrial cells in a women aged >40, 1 as malignant melanoma, and 2 as within normal limits with the presence of Actinomyces. The laboratory's routine quality assurance program selects cases, 10% of initially interpreted negative cases plus any gynecologic cytology on patients with a prior abnormal cervical cytology, or history of cervical epithelial cell abnormality. This quality assurance program averages 29% of cases, 4,045 of a total of 13,767, in 2008. Thirty‐seven (0.9%) cases were detected in this rescreen (ASCUS, 16 cases; LGSIL, 13 cases; 1 high‐grade squamous intraepithelial lesion; 4 ASC‐H; and 3 atypical glandular cells of undetermined significance). Eliminating ASCUS cases, eight significant cases were detected, with an error rate of 0.2%. In this cytology laboratory, the rapid prescreen did not prove as reliable as routine quality assurance program for cervical cytology cases. Diagn. Cytopathol. 2012. © 2010 Wiley Periodicals, Inc.     

The natural history of a genetic subtype of arrhythmogenic right ventricular cardiomyopathy caused by a p.S358L mutation in TMEM43

To determine the phenotype and natural history of a founder genetic subtype of autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC) caused by a p.S358L mutation in TMEM43. The age of onset of cardiac symptoms, clinical events and test abnormalities were studied in 412 subjects (258 affected and 154 unaffected), all of which occurred in affected males significantly earlier and more often than unaffected males. Affected males were hospitalized four times more often than affected females (p ≤ 0.0001) and died younger (p ≤ 0.001). The temporal sequence from symptoms onset to death was prolonged in affected females by 1–2 decades. The most prevalent electrocardiogram (ECG) manifestation was poor R wave progression (PRWP), with affected males twice as likely to develop PRWP as affected females (p ≤ 0.05). Left ventricular enlargement (LVE) occurred in 43% of affected subjects, with 11% fulfilling criteria for dilated cardiomyopathy. Ventricular ectopy on Holter monitor was common and occurred early: the most diagnostically useful clinical test. No symptom or test could rule out diagnosis. This ARVC subtype is a sex‐influenced lethal arrhythmogenic cardiomyopathy, with a unique ECG finding, LV dilatation, heart failure and early death, where molecular pre‐symptomatic diagnosis has the greatest clinical utility.     

EuroQol EQ-5D and condition-specific measures of health outcome in women with urinary incontinence: reliability, validity and responsiveness

Objectives To evaluate the measurement properties of the EuroQoL EQ-5D and two condition-specific patient-reported outcome measures—the Symptom Severity Index (SSI) and the Urinary Incontinence-Specific Quality of Life instrument (I-QoL)—in women with urinary incontinence. Methods A questionnaire comprising all instruments was completed by women taking part in a clinical trial of physiotherapy for urinary incontinence. Follow-up questionnaires were at 6 weeks and 5 months. Data quality, internal consistency reliability, validity and responsiveness were assessed. Results One hundred and seventy-four patients taking part in the clinical trial completed the questionnaire. Instruments had low levels of missing data. The EQ-5D had a large ceiling effect and poor responsiveness. The SSI had poor validity and responsiveness. The I-QoL had levels of reliability that supported application in group assessment, and in some cases, individual assessment, and good evidence of validity. The I-QoL was the most responsive instrument at both 6 weeks and 5 months. Conclusion The I-QoL was the best performing instrument and is recommended as a continence-specific measure of quality of life in a clinical trial setting. The SSI and EQ-5D are not recommended. Alternative generic instruments, which support economic evaluation, require further evaluation in trials of female urinary incontinence. On behalf of the West Midlands Incontinence Research Collaboration.