Small-angle light scattering and birefringence properties of chick cornea

PURPOSE: Techniques employing polarized light propagation and scattering are useful in examining the cornea's lamellar structure. Recent advances in theoretical methods have significantly increased the ability to relate features of lamellar arrangements to measurements of transmitted polarized light. The chick cornea, because of its hypothesized structure of a gradual helical rotation of lamellar pairs, presents an interesting model for further development of this methodology. METHODS: Small-angle light scattering (SALS) and polarized transmission measurements were made on 7-week-old chick corneas under conditions that closely approximate the physiological state. Birefringence properties were determined from the transmission measurements and compared to the results of model calculations of polarized light propagating through lamellae organized according to the hypothesized structure for chick cornea. RESULTS: The I+ small-angle light scattering pattern had 4 cloverleaf lobes aligned with the crossed polarizer and analyzer axes. The lobes disappeared when the transcorneal pressure was increased from zero to 18 mmHg. Retardation measured at 18 mmHg was very small (approximately 0.01 microm). CONCLUSION: The disappearance of the I+ small-angle light scattering pattern when IOP is increased suggests that the lamellae undulate in their relaxed state and the undulations straighten when IOP is increased. Measured birefringence properties are consistent with the hypothesized lamellar structure.     

Smooth muscle relaxant activity of pterosin Z and related compounds

The natural products pterosin Z, acetylpterosin Z, originally from the fern Pteridium aquilinum, and their isopterosin analogues have been synthesized and their smooth muscle relaxation activity has been measured. All of the test compounds show activity with pterosin Z being the most active (EC50 = 1.3 +/- 0.1 x 10(-6) M), exhibiting 100 times the activity reported for the related fern metabolites onitin (EC50 = 1 x 10(-4) M), onotisin (EC50 = 2 x 10(-3) M) and otninoside (EC50 = 7 x 10(-4) M). The smooth muscle relaxant activity of pterosin Z is approximately equipotent with that of the related fungal pterosin (EC50 of 2.9 +/- 1.6 x 10(-6) M). These results suggest that smooth muscle relaxant activity is reduced when a phenol group is present in the pterosin nucleus and when one of the dimethyl groups is derivatized.     

Merosin-deficient congenital muscular dystrophy and cortical dysplasia.

Congenital muscular dystrophy (CMD) encompasses a heterogenous group of muscle disorders with autosomal recessive inheritance, characterized by muscular weakness and hypotonia at birth or within the first few months of life and developmental delay. Merosin-deficient CMD is a clinically distinct form which may be associated with significant abnormalities of the brain detectable by neuroimaging. We report two siblings of consanguineous parents with merosin-deficient CMD in an Irish family who in addition to the characteristic white matter abnormalities on neuroimaging, had occipital dysplasia. Clinical, electrophysiological muscle biopsy findings and neuroimaging were very similar in both cases. Although merosin-deficient CMD with white matter abnormalities on neuroimaging is well documented in the literature, the association with occipital dysplasia has only rarely been reported. The appearance of an identical cortical defect in these siblings suggests an underlying genetic mechanism.     

Accounting for intubation status in predicting mortality for victims of motor vehicle crashes

BACKGROUND: Two of the important predictors of mortality for trauma patients are the Glasgow Coma Scale and the respiratory rate. However, for intubated patients, the verbal response component of the Glasgow Coma Scale and the respiratory rate cannot be accurately obtained. This study extends previous work that attempts to predict mortality accurately for intubated patients without using verbal response and respiratory rate. METHODS: The New York State Trauma Registry was used to identify 1994 and 1995 victims of motor vehicle crashes (MVCs). For the subset of patients who were not intubated, we developed two statistical models to predict mortality: one did not contain verbal response or respiratory rate, and the other contained a predicted verbal response. These were compared with a model that did include verbal response and respiratory rate. We also compared the predictive abilities of the first two models for all MVC patients (intubated and nonintubated) and determined the extent to which intubated patients were at increased risk of dying in the hospital after having adjusted for other predictors of mortality. RESULTS: For nonintubated patients, the statistical model without verbal response and the model with predicted verbal response had slightly better discrimination and worse calibration than the model that included verbal response and respiratory rate. Predicted verbal response did not improve the strength of the model without verbal response. For all MVC patients (intubated and nonintubated), predicted verbal response was not a significant predictor of mortality when used in combination with the other predictors. Intubation status was a significant predictor, with intubated patients having a higher probability of dying in the hospital than patients with otherwise identical risk factors. CONCLUSION: Inpatient mortality for intubated MVC patients can be accurately predicted without respiratory rate or verbal response. There appears to be no need for predicted verbal response to be part of the prediction formula, but intubation status is an important independent predictor of mortality and should be used in statistical models that predict mortality for MVC patients.     

Selecting doctors for postgraduate training in paediatrics using a competency based assessment centre.

The design and implementation of an assessment centre in the South Yorkshire and South Humberside deanery for selecting doctors into postgraduate training in paediatric medicine is described. Eleven competency domains were identified in the job analysis. An assessment centre comprising of four exercises was implemented to assess candidates. There were modest relationships between candidates' performance on the various assessment centre exercises. Outcomes based on interview performance were related to, but not the same as, outcomes based on the combined results of the three other assessment centre exercises. Candidates perceived the assessment centre to be a fair selection method. It is concluded that an assessment centre approach to SHO recruitment is feasible and provides a greater breadth and depth of information about candidates than does a structured interview.     

Proteasome inhibition with bortezomib (PS-341): a phase I study with pharmacodynamic end points using a day 1 and day 4 schedule in a 14-day cycle.

PURPOSE: We performed a phase I study of a day (D) 1 and D4 bortezomib administration once every 2 weeks to determine the recommended phase II dose and toxicity profile, and the extent of 20S proteasome inhibition obtained. PATIENTS AND METHODS: Patients with solid tumors or lymphomas were treated with bortezomib at 0.25 to 1.9 mg/m2 on D1 and D4, every 2 weeks. 20S proteasome levels in blood were assayed at baseline and at 1, 4, and 24 hours postdose in cycle 1. RESULTS: On this D1 and D4 every 2 weeks' schedule, dose-limiting toxicity (DLT) was evident at the 1.75 and 1.9 mg/m2 dose levels, most commonly in patients receiving individual total doses > or = 3.0 mg. The main DLT was peripheral neuropathy evident at the higher doses and in patients previously exposed to neurotoxic agents. Other DLTs included diarrhea and fatigue; grade 3 thrombocytopenia was also noted. Reversible inhibition of 20S proteasome activity was dose dependent and best fit a total dose (mg) per fraction rather than mg/m2; 70% of baseline activity was inhibited by a dose of 3.0 to 3.5 mg given on D1 and on D4 every other week. Antitumor effects short of confirmed partial responses were observed in patients with melanoma, non-small-cell lung cancer, and renal cell carcinoma. CONCLUSION: Bortezomib (PS-341) is a novel antineoplastic agent that is well tolerated at doses not exceeding 3.0 mg (equivalent to 1.75 mg/m2), repeated on D1 and D4 every other week. This dose correlates with 70% inhibition of 20S proteasome activity. DLTs include neuropathy, fatigue, and diarrhea.     

Pre and postnatal diagnosis of fetus‐in‐fetu

Differentiation of abdominal masses detected on prenatal ultrasound is difficult and requires careful characterization of the mass and precise localization. Differentiation is required in order to distinguish benign from potentially malignant conditions. We describe a case of fetus‐in‐fetu with pre and postnatal imaging.     

Clinical correlation and molecular evaluation confirm that the MLH1 p.Arg182Gly (c.544A>G) mutation is pathogenic and causes Lynch syndrome

Approximately 25 % of mismatch repair (MMR) variants are exonic nucleotide substitutions. Some result in the substitution of one amino acid for another in the protein sequence, so-called missense variants, while others are silent. The interpretation of the effect of missense and silent variants as deleterious or neutral is challenging. Pre-symptomatic testing for clinical use is not recommended for relatives of individuals with variants classified as ‘of uncertain significance’. These relatives, including non-carriers, are considered at high-risk as long as the contribution of the variant to disease causation cannot be determined. This results in continuing anxiety, and the application of potentially unnecessary screening and prophylactic interventions. We encountered a large Irish Lynch syndrome kindred that carries the c.544A>G (p.Arg182Gly) alteration in the MLH1 gene and we undertook to study the variant. The clinical significance of the variant remains unresolved in the literature. Data are presented on cancer incidence within five kindreds with the same germline missense variant in the MLH1 MMR gene. Extensive testing of relevant family members in one kindred, a review of the literature, review of online MMR mutation databases and use of in silico phenotype prediction tools were undertaken to study the significance of this variant. Clinical, histological, immunohistochemical and molecular evidence from these families and other independent clinical and scientific evidence indicates that the MLH1 p.Arg182Gly (c.544A>G) change causes Lynch syndrome and supports reclassification of the variant as pathogenic.