Frequency of constitutional MSH6 mutations in a consecutive series of families with clinical suspicion of HNPCC.

A large majority of constitutional mutations in hereditary non-polyposis colorectal cancer (HNPCC) are because of the MHL 1 or MSH 2 genes. In a lower fraction of cases, another gene of the mismatch repair (MMR) machinery, MSH6, may be responsible. Families with MSH6 mutations are difficult to recognize, as microsatellite instability (MSI) may not be detectable and immunohistochemistry (IHC) may give ambiguous results. In the present study, we proposed (i) to determine the frequency of MSH6 mutations in a selected population of colorectal cancer patients obtained from a tumor registry, (ii) to assess whether IHC is a suitable tool for selecting and identifying MSH6 mutation carriers. One hundred neoplasms of the large bowel from suspected HNPCC families were analyzed for MSI (BAT 25 and BAT 26 markers) and immunohistochemical expression of the MSH6 protein. We found on 12 tumors (from different families) showing instability or lack of MSH6 expression. Among these, four potentially pathogenic MSH6 mutations were detected (del A at 2984; del TT at 3119; del AGG cod 385; and del CGT cod 1242) by direct gene sequencing. These represented 12.9% of all families with constitutional mutations of the DNA MMR genes. Thus, some 5% of all HNPCC families are featured by constitutional mutation of the MSH6 gene. This appears, however, as a minimum estimate; routine use of IHC and the study of large numbers of individuals and families with little or no evidence of Lynch syndrome might reveal that mutation of this gene account for a large fraction of HNPCC.

The utility of traditional prehospital interventions in maintaining thermostasis.

OBJECTIVE: Hypothermia can have a negative effect on the metabolic and hemostatic functions of patients with traumatic injuries. Multiple methods of rewarming are currently used in the prehospital arena, but little objective evidence for their effectiveness in this setting exists. The purpose of this study was to assess the relative effectiveness of traditional prehospital measures in maintaining thermostasis in trauma patients. METHODS: Participating helicopter and ground ambulance ALS units were prospectively randomized to provide either routine care only (passive or no warming) or routine care (passive warming) in conjunction with active warming (either reflective blankets, hot pack rewarming, or warmed IV fluids). A total of 174 trauma code patients, aged >14 years, who met inclusion criteria were prospectively enrolled by prehospital providers. Patients who received a non-assigned intervention or who had incomplete temperature data were dropped from the analysis. A total of 134 patients were included in the final analysis. RESULTS: Patients who received hot pack rewarming showed a mean increase in body temperature during transport (+1.36 degrees F/0.74 degrees C), while all other groups (no intervention, passive rewarming, reflective blankets, warmed IV fluids, warmed IV fluid plus reflective blanket) showed a mean decrease in temperature during transport [-0.34 to -0.61 degrees F (-0.2 to -0.4 degrees C); p<0.01]. In addition, the hot pack group was consistent, with every patient who received hot pack warming showing an increase in body temperature during transport, while in all other groups there were patients who had both increases and decreases in temperature. The intervention groups did not differ significantly on exposure to precipitation, transport unit temperature, total prehospital time, initial vital signs, amount of fluid administered, Injury Severity Score, or Glasgow Coma Score. CONCLUSIONS: Most traditional methods of maintaining trauma patient temperature during prehospital transport appear to be inadequate. Aggressive use of hot packs, a simple, inexpensive intervention to maintain thermostasis, deserves further study as a potential basic intervention for trauma patients.

Tongue surface displacement during bilabial stops.

The goals of this study were to characterize tongue surface displacement during production of bilabial stops and to refine current estimates of vocal-tract wall impedance using direct measurements of displacement in the vocal tract during closure. In addition, evidence was obtained to test the competing claims of passive and active enlargement of the vocal tract during voicing. Tongue displacement was measured and tongue compliance was estimated in four subjects during production of /aba/ and /apa/. All subjects showed more tongue displacement during /aba/ than during /apa/, even though peak intraoral pressure is lower for /aba/. In consequence, compliance estimates were much higher for /aba/, ranging from 5.1 to 8.5 x 10(-5) cm3/dyn. Compliance values for /apa/ ranged from 0.8 to 2.3 x 10(-5) cm3/dyn for the tongue body, and 0.52 x 10(-5) for the single tongue tip point that was measured. From combined analyses of tongue displacement and intraoral pressure waveforms for one subject, it was concluded that smaller tongue displacements for /p/ than for /b/ may be due to active stiffening of the tongue during /p/, or to intentional relaxation of tongue muscles during /b/ (in conjunction with active tongue displacement during /b/).

Physiological modeling of speech production: methods for modeling soft-tissue articulators.

As the initial components of a comprehensive physiological model of speech production, methods have been developed for modeling soft tissue structures, such as the tongue and lips, as continua. This approach provides a foundation for applying finite element methods to simulate these structures in a biomechanical model of speech production. Movements and deformations of the structures can then be computed as the solutions of a nonlinear second-order constraint system of ordinary differential equations, which is obtained from a finite element approximation of an energy rate equation. The muscle fibers in the soft tissue structures are represented as fields that specify the directions in which active and passive tensile stress is produced. The elastic behavior of the passive components is modeled using an isotropic exponential constitutive strain energy function, and the viscous stress components, by using linear viscosity. Incompressibility is maintained elementwise in the simulation using a simultaneously solved system for the computation of Lagrange multipliers. As first step towards modeling a vocal tract, a preliminary model of a tongue with eight muscles has been completed. Simulation results demonstrate the validity of the method and they support the feasibility of a physiologically based model of speech production.