Antiendotoxin therapies for septic shock

Gram-negative shock is thought to result primarily from the effects of endotoxin, a component of the bacterial outer membrane. Accordingly, therapies aimed at inhibiting, neutralizing, or clearing endotoxin have been extensively explored. Despite over 30 years of research, no antiendotoxin approach to the treatment of human septic shock is of proven benefit. In recent randomized clinical trials of monoclonal antibodies against endotoxin, therapeutic efficacy was not convincingly demonstrated. This result, however, does not eliminate the possibility that other antiendotoxin therapies may be effective. The antibodies used in these clinical trials do not appear to neutralize endotoxin in vitro and are not reproducibly protective in animal models of sepsis. Newer agents with well-defined mechanisms of antiendotoxin activity may help clarify the role of endotoxin in septic shock and prove useful therapy for some patients.     

The role of tyrosine-114 in the enzymatic activity of the Shiga-like toxin I A-chain

Shiga-like toxin I (SLT-I), the potent cytotoxin produced by certain pathogenic strains of Escherichia coli, is a member of a burgeoning family of ribosome-in-activating proteins (RIPs), which share common structural and mechanistic features. The prototype of the group is the plant toxin ricin. Recently we proposed a structural model for the Slt-IA active site, based in part on the known geometry of the enzymatic subunit of the ricin toxin. The model places three aromatic residues within the putative Slt-IA active site cleft: tyrosine 77, tyrosine 114, and tryptophan 203. Here we present biochemical and biophysical data regarding, the phenotypes of conservative point mutants of Slt-IA in which tyrosine 114 is altered. We used oligonucleotide-directed mutagenesis to replace tyrosine 114 with either phenylalanine (Y114F) or serine (Y114S). Periplasmic extracts of E. coli containing wild-type or mutant Slt-IA were tested for their ability to inhibit protein synthesis in vitro. Relative to wild-type, the activity of mutant Y114F was attenuated about 30-fold, while the mutant Y114S was attenuated about 500 to 1000-fold. In order to address the possibility that differential activation of the mutants rather than local effects at the active site might account for their diminished activity, we engineered the same mutations into a truncated slt-IA cassette that directs expression of a product corresponding to the activated A1 form of Slt-IA (wild-type-delta). The same general relationships held: relative to wild type-delta, Y114F-delta was attenuated about 7-fold, and Y114S-delta about 300-fold.(ABSTRACT TRUNCATED AT 250 WORDS)     

Experimental evaluation of velocity and power estimation forultrasound blood flow imaging, by means of a two-dimensionalautocorrelation approach

This paper evaluates experimentally the performance of a novel axial velocity estimator, the 2D autocorrelator, and its Doppler power estimation counterpart, the 2D zero-lag autocorrelator, in the context of ultrasound color flow mapping. The evaluation also encompasses the well-established 1D autocorrelation technique for velocity estimation and its corresponding power estimator (1D zero-lag autocorrelator), to allow performance comparisons under identical conditions. Clutter-suppressed in vitro data sets from a steady-flow system are used to document the effect of the range gate and ensemble length, noise level and angle of insonation on the precision of the velocity estimates. The same data sets are used to examine issues related to the estimation of the Doppler signal's power. The first-order statistics of power estimates from regions corresponding to flow and noise are determined experimentally and the ability of power-based thresholding to separate flow signals from noise is characterized by means of ROC analysis. In summary, the results of the in vitro evaluation show that the proposed 2D-autocorrelation form of processing is consistently better than the corresponding 1D-autocorrelation techniques, in terms of both velocity and power estimation. Therefore, given their relatively modest implementation requirements, the 2D-autocorrelation algorithms for velocity and power estimation appear to represent a superior, yet realistic, alternative to conventional Doppler processing for color flow mapping     

A monitoring, feedback, and triggering system for reproducible breath-hold MR imaging

OBJECTIVE: To evaluate the diagnostic accuracy and clinical usefulness of high-resolution transvaginal duplex Doppler ultrasound in postpartum and post-abortion patients with excessive hemorrhage who are suspected of having residual trophoblast. METHODS: Forty-eight women with excessive hemorrhage referred for possible residual trophoblastic tissue were evaluated by transvaginal duplex Doppler ultrasonography. Based on two-dimensional imaging, the patients were divided prospectively into groups: women who had an empty uterus with a normal uterine cavity, those with a pure endometrial fluid collection and no echogenic foci, those who had a mixed endometrial fluid collection with foci of echogenicity, and those with intracavitary heterogeneous material with mixed echo patterns of fluid and solid components. In each group, Doppler studies were performed and the resistance index (RI) was calculated. The two-dimensional patterns and Doppler results were correlated with clinical and pathologic follow-up. RESULTS: Twenty-eight subjects had a normal uterine cavity and seven had a pure endometrial fluid collection; all were treated conservatively and none showed later clinical evidence of residual trophoblastic tissue. In 13 women, residual trophoblast was strongly suggested from the images of two-dimensional ultrasonography: Five showed an endometrial fluid collection with some echogenic foci, and eight exhibited intracavitary mixed echogenic material. All underwent curettage, and residual trophoblastic tissue was found in ten of the 13. The mean (+/- standard deviation) RI to flow in the myometrial arteries was 0.54 +/- 0.15 in women without residual trophoblast and 0.35 +/- 0.1 in those with residual trophoblastic tissue (P < .01). CONCLUSION: Our experience suggests that transvaginal duplex Doppler ultrasonography is an effective noninvasive method for evaluating patients with excessive postpartum and post-abortion hemorrhage who are suspected of having residual trophoblastic tissue. Its use enhances the positive preoperative diagnosis of residual trophoblastic tissue and may reduce unnecessary curettage procedures.     

The importance of geriatrics to family medicine: a position paper by the Group on Geriatric Education of the Society of Teachers of Family Medicine

The role of geriatrics and geriatricians in family medicine remains unsettled. Despite a rapidly aging population, a tremendous shortage now exists of faculty with interest and expertise in geriatrics. Relatively few family practice residents choose to enter geriatric fellowship programs, and federal funding for such programs has been reduced. Despite accreditation requirements, residency programs are not always able to provide the range of geriatric experiences needed to properly prepare graduates to provide care for the broad range of older patients. Medical students' exposure to geriatrics remains limited. The Group on Geriatric Education of the Society of Teachers of Family Medicine believes that family medicine faculty must recognize and be committed to the notion that geriatrics is integral to family medicine. Both undergraduate and residency training programs should emphasize experience with geriatric patients in multiple settings. In particular, the nursing home should not be the main focus of geriatric training. The small number of certified geriatric faculty will be able to provide leadership, but a broad range of faculty must become involved in teaching geriatrics. Faculty development activities and continuing education programs to foster the necessary expertise will be essential to the accomplishment of this task.     

SURFACE TENSION AND BUOYANCY DRIVEN INSTABILITIES IN A LAYER OF LIQUID TIN HEATED FROM BELOW

The linear theory of Pearson (1958) and Nield (1964) is modified here to study liquid tin and include the finite thermal resistances of the bounding layers of boron nitride, copper and air (∼10^-2 torr) in the experiments of Ginde et al. (1989). The magnitude of the ΔT_c across the layer of liquid tin required for the onset of convection depends on the ratios of the thermal conductivities and thicknesses of the supporting layers of boron nitride and copper to those of the tin.

According to our theory surface tension contributes more than buoyancy to the instability observed experimentally. The critical ΔT_c observed required for the onset of convection in the layer of tin, is up to 25% lower than that predicted, which shows the layer is less stable than the theory indicates. Thus the surface of the tin was uncontaminated, or a significantly larger observed critical ΔT_c would be expected.

The boundary condition on the thermal fluctuations at the base of the supporting layer of copper does not appear to be important in these experiments. However, the thermal resistance of the boron nitride would have to be assumed to be unrealistically large to obtain agreement within experimental error with the theory.