Contributions of empirical research to medical ethics

Empirical research pertaining to cardiopulmonary resuscitation (CPR), clinician behaviors related to do-not-resuscitate (DNR) orders and substituted judgment suggests potential contributions to medical ethics. Research quantifying the likelihood of surviving CPR points to the need for further philosophical analysis of the limitations of the patient autonomy in decision making, the nature and definition of medical futility, and the relationship between futility and professional standards. Research on DNR orders has identified barriers to the goal of patient involvement in these life and death discussions. The initial data on surrogate decision making also points to the need for a reexamination of the moral basis for substituted judgment, the moral authority of proxy decision making and the second-order status of the best interests standard. These examples of empirical research suggest that an interplay between empirical research, ethical analysis and policy development may represent a new form of interdisciplinary scholarship to improve clinical medicine.     

VRCTC-310--a novel compound of purified animal toxins separates antitumor efficacy from neurotoxicity

Two purified animal venom toxins, crotoxin and cardiotoxin, have been combined to produce a unique natural product (VRCTC-310) currently under investigation as an antitumor agent by the National Cancer Institute. In vitro, it has demonstrated cytotoxic disease specificity and a unique mechanism of action when submitted to COMPARE analysis. In vivo, tolerance was developed to the neurotoxic properties of crotoxin which allowed comparison of several schedules of fixed and escalating daily i.m. doses to mice bearing s.c. Lewis Lung carcinoma. An 83% inhibition of tumor growth was achieved using an escalating dose schedule starting at 1.8 mg/kg and reaching 6.3 mg/kg/day on day 20. Although some irritation around the sites of i.m. injection was noted, animal weight loss was negligible and there were no other signs of adverse toxicity. This natural product represents a new, membrane interactive anticancer agent which produces a unique spectrum of cytotoxicity in vitro and which has demonstrated interesting in vivo antitumor efficacy.     

Assessment of the patient with cleft lip and palate. A developmental approach

Children with cleft lip and palate require interdisciplinary team care from infancy through adolescence. An understanding of developmental stages allows the cleft palate team to adapt and integrate its services into the rapidly changing life of the child. This article discusses the maturational, developmental stages of childhood and the services the child with cleft lip and palate and the child's family deserve through each stage. Health care providers in all settings may continue to provide appropriate care for all patients with cleft lip and palate, despite the challenges of a changing health care environment, by emphasizing the needs of the child in all developmental stages.     

Calbindin D28K regulation in precociously matured chick egg shell gland in vitro

Egg shell calcification in the hen uterus (egg shell gland, ESG) depends primarily on intestinal absorption of dietary Ca2+ as well as ESG Ca2+ transport into the shell. Intestinal Ca2+ absorption is linked to vitamin D-induced calbindin D28K (D28K) concentration. The ESG also contains D28K, and Ca2+ transport into the shell appears to be linked to D28K gene expression, but until this report, there was no direct proof that ESG D28K was or was not vitamin D-dependent. To address this issue, highly developed ESG from estradiol (E2)-injected, severely vitamin D-depleted chicks were cultured in serum-free medium with excellent viability. Addition of the vitamin D-hormone, 1,25(OH)2 vitamin D3 (1,25), to the culture medium increased ESG D28K levels as much as 70%. E2 alone had no effect, but E2 plus 1,25 further increased ESG D28K levels up to 160%. By contrast, progesterone (P4) prevented the 1,25-stimulated increase in D28K, while having no effect on basal D28K level. Of considerable interest, thapsigargin (THAPS), which increases intracellular Ca2+ concentration ([Ca2+]i) in many cell types, stimulated D28K synthesis in a concentration-dependent manner in the complete absence of 1,25 and independent of the [Ca2+] of the medium. These results are the first direct evidence that ESG D28K is under direct control of 1,25 and that both gonadal steroid hormones, E2 and P4, may be coregulators. Further, the effects of THAPS suggest that [Ca2+]i itself may also regulate D28K. This new in vitro model clearly represents a unique opportunity to study the regulation of the ESG calcium transport mechanism under stringently defined conditions.     

Memory for pain and affect in chronic pain patients

Radioligand binding studies were performed to determine the effect of various cations on the characteristics of [3H]glibenclamide binding to its high-affinity receptor in rat cerebral cortex membranes. Mg2+ was shown specifically to reduce radioligand binding to membranes pretreated with 5 mM EDTA. CaCl2 enhanced [3H]glibenclamide binding whilst MnCl2, KCl and NaCl were without significant effect. 2 mM MgCl2 induced a statistically significant rightward shift in the dissociation constant for glibenclamide obtained from both saturation and competition studies. These results suggest that Mg2+ may participate in the regulation of the sulphonylurea receptor in the rat cerebral cortex.     

A common mutation in the FACC gene causes Fanconi anaemia in Ashkenazi Jews

The biaxial mechanical properties of right ventricular free wall (RVFW) myocardium were studied. Tissue specimens were obtained from the sub-epicardium of potassium-arrested hearts and different stretch protocols were used to characterize the myocardium's mechanical response. To assess regional differences, we excised tissue specimens from the conus and sinus regions. The RVFW myocardium was found to be consistently anisotropic, with a greater stiffness along the preferred (or averaged) fiber direction. The anisotropy in the conus region was more pronounced than in the sinus region. A comparison with studies of left ventricle (LV) midwall myocardium revealed that, 1) the fiber direction stiffnesses are greater in the RVFW than in the LV, 2) the degree of anisotropy is greater in the RVFW than in the LV.     

IL-1 in gingival crevicular fluid following closed root planing and papillary flap debridement

Interleukin (IL)-1 alpha and beta are cytokines which can mediate inflammatory, bone resorbing, and reparative effects in the periodontium, but few longitudinal data exist exploring their role following periodontal therapy. This study examined gingival crevicular fluid (GCF) concentrations of IL-1 alpha and IL-1 beta at sites with shallow sulci (SS) or inflamed moderate/advanced pockets (M/AP) before and 6 months after treatment with closed scaling/root planing (SC/RP) or papillary flap debridement (PFD), all in the same subject (n = 14 patients). No significant differences were noted in IL-1 alpha or beta concentrations (determined with two-site enzyme-linked immunosorbent assays) between SS and M/AP sites at baseline. While both therapies improved clinical parameters of periodontal disease, IL-1 alpha concentration increased significantly (p < 0.05) in M/AP-PFD sites 6 months after treatment, but were unchanged in other groups. IL-1 beta concentrations were numerically lower after therapy, except for a significant increase (p < 0.05) in M/AP-PFD sites. These data suggest that surgical wound healing in an inflamed, plaque-infected site (M/AP-PFD) results in prolonged production of IL-1, which may be a reflection of the extent of tissue trauma and delayed wound healing. In spite of increased IL-1 levels, these sites demonstrated significant short-term improvement in clinical attachment level (+ 1.8 mm, p < or = 0.001) postoperatively.     

T cell responses to synthetic peptides of herpes simplex virus type 1 glycoprotein D in naturally infected individuals

To locate T cell determinants of glycoprotein D (gD) of herpes simplex virus type 1 (HSV-1), proliferation assays of lymphocytes obtained from 10 healthy HSV-seropositive individuals were performed using 34 overlapping gD peptides as antigens. Despite large differences between individual responses to the peptides both in number of stimulating peptides and gD regions, three regions (1-54, 110-214, and 290-314) induced a response in 50% or more of the HSV-seropositives. T cells were less frequently stimulated by peptides of region 210-294. No correlation was found between serological data and proliferative responses to the peptides. The diversity in T cell response to the peptides suggests a lack of immunodominance, implying that a single peptide/region of gD, or a combination of peptides, will not be sufficient to serve as a basis for a future HSV-1 vaccine.