Independent effects of food intake and insulin status on insulin-like growth factor-I in young pigs

The successful use of proteins in pharmaceutical and other commercial applications requires close examination of their relative fragility. Because of the resultant enhanced stability, proteins are often formulated in the solid state, even though dehydration tends to alter their structure. Even in the solid form, however, proteins may become inactivated due to various deleterious processes, e.g., aggregation. This review focuses on such mechanisms, with an emphasis on case studies conducted in our laboratory. Proteins which have both disulfide bonds and free thiols may aggregate via thiol-disulfide exchange, and this process may be facilitated by lyophilization-induced structural perturbations. For proteins possessing disulfides but not free thiols, aggregation also may occur when native disulfides are beta-eliminated, thus giving rise to thiol species which can catalyze disulfide scrambling. Other deleterious processes have also been uncovered, including a formaldehyde-mediated aggregation of formalinized vaccines. It is illustrated how knowledge of such deterioration pathways makes possible the rational development of stable solid protein formulations.     

Recent Changes in U.S. Food and Drug Law: Implications for Drug Development

This paper examines in detail the Waxman/Hatch Act and the NDA Rewrite, from both an implementation point of view and from a world-wide research and development perspective. The central theme of these regulatory changes appears to be consistent with U.S. drug policy of the past two decades, i.e., cost containment, primarily, followed by uniformity and efficiency in the regulatory review process. These recent changes, just as the 1962 Drug Ammendments 22 years earlier, will continue to have profound effects upon the sites at which pharmaceutical research and development is carried out.     

Mortality determinants in massive pediatric burns. An analysis of 103 children with > or = 80% TBSA burns (> or = 70% full-thickness)

OBJECTIVE: Survivors and nonsurvivors among 103 consecutive pediatric patients with massive burns were compared in an effort to define the predictors of mortality in massively burned children. SUMMARY BACKGROUND DATA: Predictors of mortality in burns that are used commonly are age, burn size, and inhalation injury. In the past, burns over 80% of the body surface area that are mostly full-thickness often were considered fatal, especially in children and in the elderly. In the past 15 years, advances in burn treatment have increased rates of survival in those patients treated at specialized burn centers. The purpose of this study was to document the extent of improvement and to define the current predictors of mortality to further focus burn care. METHODS: Beginning in 1982, 103 children ages 6 months to 17 years with burns covering at least 80% of the body surface (70% full-thickness), were treated in the authors' institution by early excision and grafting and have been observed to determine outcome. The authors divided collected independent variables from the time of injury into temporally related groups and analyzed the data sequentially and cumulatively through univariate statistics and through pooled, cross-sectional multivariate logistic regression to determine which variables predict the probability of mortality. RESULTS: The mortality rate for this series of massively burned children was 33%. Lower age, larger burn size, presence of inhalation injury, delayed intravenous access, lower admission hematocrit, lower base deficit on admission, higher serum osmolarity at arrival to the authors' hospital, sepsis, inotropic support requirement, platelet count < 20,000, and ventilator dependency during the hospital course significantly predict increased mortality. CONCLUSIONS: The authors conclude that mortality has decreased in massively burned children to the extent that nearly all patients should be considered as candidates for survival, regardless of age, burn size, presence of inhalation injury, delay in resuscitation, or laboratory values on initial presentation. During the course of hospitalization, the development of sepsis and multiorgan failure is a harbinger of poor outcome, but the authors have encountered futile cases only rarely. The authors found that those patients who are most apt to die are the very young, those with limited donor sites, those who have inhalation injury, those with delays in resuscitation, and those with burn-associated sepsis or multiorgan failure.     

Management of recurrent penile cancer following partial or total penectomy

The initial management of localized penile carcinoma determines the probability of recurrence. Although potentially disfiguring, the management of recurrent carcinoma of the penis requires aggressive surgical resection of both the primary lesion and nodal sites to effect the best chance for long-term survival.     

A trimeric, alpha-helical, coiled coil peptide: association stoichiometry and interaction strength by analytical ultracentrifugation

To examine the effects of TNF-alpha on luteal functions, TNF-alpha was injected into the ovary of rabbits on the 7th day of pseudopregnancy (Day 7). The animals were laparotomized under general anesthesia, and 1 x 10(4) IU TNF-alpha dissolved in PBS was injected into the ovary. On Days 8 and 10, the blood progesterone (P) concentration was determined. The mean blood P level was 10.31 ng before the administration of TNF-alpha on Day 7. On Day 8, the mean blood P level was 11.22 ng in the control group, while it was markedly reduced to 1.29 ng in the TNF-alpha administration group. On Day 10, the mean blood P level was 6.80 ng in the control group and 5.49 ng in the TNF-alpha group. These results suggest that the capacity for P secretion of the corpus luteum, which reached a degenerative stage by TNF-alpha administration, can be recovered.     

Random walk models for DNA synapsis by resolvase

During site-specific recombination by resolvase, the protein binds to two sites on a supercoiled DNA molecule and the loaded sites then interact with each other to form a synaptic complex. The kinetics of synapsis show non-exponential behaviour extending over five log units of time and are independent of the length of the DNA molecule and the length of DNA between the sites. In this study, numerical models were developed in order to account for how fluctuations in the structure of supercoiled DNA might lead to the juxtaposition of distant sites in a manner consistent with the experimental data on synapsis by resolvase. Models where the juxtaposition arises from fluctuations around branch points in the superhelix failed to match the data: they yielded non-exponential kinetics but only over two log units of time and they predicted longer synapsis times for both larger DNA molecules and larger inter-site spacings. In another model, one fraction of the juxtaposition events gives rise directly to the productive complex while the remaining fraction initially yields a non-productive complex: the latter molecules undergo no further fluctuations until the abortive synapse dissociates at the end of a delay period. This model again failed to match the experimental data. However, the inclusion of three sorts of non-productive complexes, each with a different delay constant, led to progress curves that concurred with the data. Schemes were also developed to account for the juxtaposition of three sites at a branch point in supercoiled DNA.