The utility of multidimensional assessments of physical health in patient care

Practitioners rely on a variety of measures of a patient's physical condition, including physiologic and clinician assessments. Occasionally, patient self-report data are collected. What insight into the physical health and functioning of patients does each of these types of information yield? This study suggests that each type of information provides a somewhat different insight into a patient's physical condition and that a combination of physiologic, clinician, and patient self-assessments can provide a more thorough assessment of a patient's condition. Using data from a clinical study of patients with heart failure, the Studies of Left Ventricular Dysfunction (SOLVD), measures of these three types of physical health assessments are compared as predictors of hospitalization. Results indicate that the self-report measures performed as well as or better than the physiologic or clinician assessments as predictors of hospitalization. The self-report measures have the added advantage of being inexpensive, noninvasive, and easily obtained over time, allowing for assessments of change. These findings suggest that, while related, each type of measure captures a different aspect of patient physical health and functioning.     

Identification of cell surface and secreted proteins essential for tumor cell survival using a genetic suppressor element screen

Survival factors play critical roles in regulating cell growth in normal and cancer cells. We designed a genetic screen to identify survival factors which protect tumor cells from apoptosis. A retroviral expression library of random cDNA fragments was constructed from cancer cells and used to transduce the colon carcinoma cell line HCT116. Recipient cells were functionally selected for induction of caspase 3-mediated apoptosis. Analyses of over 10,000 putative genetic suppression elements (GSEs) sequences revealed cognate gene candidates that are implicated in apoptosis. We further analysed 26 genes encoding cell surface and secreted proteins that can potentially serve as targets for therapeutic antibodies. Tetracycline-inducible GSEs from several gene candidates induced apoptosis in stable HCT 116 cell lines. Similar phenotypes were caused by RNAi derived from the same genes. Our data suggest requirement for the cell surface targets IGF2R, L1CAM and SLC31A1 in tumor cell growth in vitro, and suggests that IGF2R is required for xenograft tumor growth in a mouse model.     

Ribosomal DNA-directed PCR for identification of Achromobacter (Alcaligenes) xylosoxidans recovered from sputum samples from cystic fibrosis patients

The opportunistic human pathogen Achromobacter (Alcaligenes) xylosoxidans has been recovered with increasing frequency from respiratory tract culture of persons with cystic fibrosis (CF). However, confusion of this species with other closely related respiratory pathogens has limited studies to better elucidate its epidemiology, natural history, and pathogenic role in CF. Misidentification of A. xylosoxidans as Burkholderia cepacia complex is especially problematic and presents a challenge to effective infection control in CF. To address the problem of accurate identification of A. xylosoxidans, we developed a PCR assay based on a 16S ribosomal DNA sequence. In an analysis of 149 isolates that included 47 A. xylosoxidans and several related glucose-nonfermenting species recovered from CF sputum, the sensitivity and specificity of this PCR assay were determined to be 100 and 97%, respectively. The availability of this assay will enhance identification of A. xylosoxidans, thereby facilitating study of the pathogenic role of this species and improving infection control efforts in CF.     

Increased risk of lethal graft-versus-host disease-like syndrome after transplantation into NOD/SCID mice of human mobilized peripheral blood stem cells, as compared to bone marrow or cord blood

We tested the ability of human cells from different hematopoietic tissues to generate graft versus host disease-like syndrome (GVHD) in sublethally irradiated non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice. Tissue sources of human hematopoietic cells were: (1) bone marrow (BM), (2) nonmobilized peripheral blood (PB), (3) mobilized peripheral blood stem-progenitor cells (PBSC), and (4) cord blood (CB). To avoid interindividual donor variation, part of this study was done using BM, PB, and PBSC donated by a single healthy adult volunteer. A total of 179 NOD/SCID mice received graded human hematopoietic cell doses [5-500 x 10(6) mononuclear cells (MNC), containing 2-325 x 10(6) CD3(+) T cells, per mouse] from individual donors. Mice were observed for the development of GVHD and sacrificed 60 days after transplantation (earlier if ill). Mice were analyzed quantitatively by flow cytometry for human hematopoietic cell types and histologically, especially for human T lymphocytes infiltrating BM. No mouse transplanted with the tested doses of human CB or BM cells developed GVHD (experimentally defined as >10% human T lymphocytes infiltrating the mouse BM). For PB and PBSC, the frequencies of death, death with GVHD, and GVHD were directly related to the dose and source of human cells. Because PB cells contaminate harvested BM, the results from infused BM and PB were next combined for further analysis (BM/PB). The relative risks (hazard ratios estimated from the proportional hazards model) for death with GVHD, for each 10 human T cell dose increase, were 1.15 for BM/PB (p < 0.0001) and 1.47 for PBSC (p < 0.0001). In this in vivo xenogeneic model, the average T cell from human PBSC generated GVHD more potently than did the average T cell from human BM/PB, and the average CB T cell had a much lower GVHD potential. These results suggest that the potential for clinical GVHD from an HLA-disparate donor graft is likely to be quantitatively dependent both on the total number of T lymphocytes in the donor graft and the tissue source of the graft. Quantitative criteria for optimal T cell content of allogeneic donor hematopoietic grafts from different sources are discussed.     

Skin color, aging, and plasma L-dopa levels

Although plasma levels of L-dopa are derived substantially from catecholamine-synthesizing tissues, melanocytes--which produce L-dopa as part of the melanin synthetic cascade--also may be a source of circulating L-dopa. We compared plasma L-dopa levels in albino subjects and in Caucasian and Black normal volunteers and patients with essential hypertension. DOPA levels were similar among the subject groups. Among Caucasian normal volunteers, L-dopa levels were negatively correlated with subject age (r = -0.30, P less than 0.05), whereas norepinephrine levels tended to increase with subject age (r = 0.25, 0.05 less than P less than 0.10), so that the L-dopa:norepinephrine ratio was highly negatively correlated with subject age (r = -0.50, P less than 0.01). Skin pigmentation does not contribute importantly to plasma L-dopa levels in humans. In contrast with levels of norepinephrine, L-dopa levels appear to decrease during normal aging.     

Muscle-derived differentiation factor increases expression of the tyrosine hydroxylase gene and enzyme activity in cultured dopamine neurons from the rat midbrain.

Our earlier work demonstrated that certain populations of brain neurons which do not synthesize catecholamine (CA) neurotransmitters in vivo, will, when grown in culture with muscle-derived differentiation factor (MDF), unexpectedly express the gene for the CA biosynthetic enzyme tyrosine hydroxylase (TH). In this paper, we sought to determine whether MDF could also regulate TH expression in those neurons which normally synthesize CA neurotransmitters. Incubation of cultured dopamine neurons from the ventral midbrain with MDF elevated the levels of TH mRNA and TH enzyme activity 5- to 40-fold higher than that measured in control cultures. Sympathetic neurons were unaffected by a similar MDF treatment. Unlike the 2-day critical period for MDF-responsivity in non-CA neurons. CA neurons remained susceptible to MDF's influence over an extended developmental interval (E14-18), suggesting that MDF may be important for TH gene regulation in brain CA neurons even differentiation is complete. Because of these unique properties, MDF may provide a unique opportunity to explore ways in which the TH gene might be directly manipulated in these cell populations in order to correct the CA imbalances that occur in certain neurological diseases and disorders.     

Metronidazole may inhibit intestinal colonization withClostridium difficile

PURPOSE: Antibiotics suppress normal gut flora, allowing overgrowth of acquired or nativeClostridium difficile, with release of toxins that cause mucosal inflammation. Oral metronidazole is used to treat antibiotic-associated colitis (pseudomembranous colitis). This study was designed to determine whether oral metronidazole, as part of preoperative bowel preparation, prevents or decreases incidence of antibiotic-associated colitis after elective colonic and rectal procedures. METHODS: Eighty-two patients (40 men) were prospectively, randomly assigned to receive one of two oral antibiotic regimens before colorectal surgery. All patients underwent mechanical bowel preparation with polyethylene glycol-electrolyte lavage solution before administration of oral antibiotics. Group 1 (n=42) patients received three doses (1 g/dose) of neomycin and erythromycin. Group 2 (n=40) patients received three doses (1 g/dose) of neomycin and metronidazole. Both groups received one preoperative and three postoperative doses of intravenous cefotetan (2 g/dose). Both groups had stool samples tested forC. difficile toxin in the preoperative and postoperative periods by enzyme-linked immunoabsorbent assay or by tissue culture cytotoxicity. Patients with preoperative stool studies positive forC. difficile were excluded from the study. RESULTS: Treatment groups were not different for age, gender, or surgical procedure. Mean age ±1 standard deviation was 67.6±13.6 (range, 34–94) years in Group 1 and 62.1±13.5 (range, 35–84) years in Group 2 (P=0.069). Mean length of hospital stay ±1 standard deviation was 9.76±4.9 (range, 4–28) days for Group 1 and 8.05±2.6 (range, 3–14) days for Group 2 (P=0.053). Five patients in Group 1 (neomycin and erythromycin) and one patient in Group 2 (neomycin and metronidazole) had positive stool studies forC. difficile. Relative risk of colonization withC. difficile in Group 1 was 4.76 times that in Group 2 (95 percent confidence interval, 0.581, 39). This difference was not statistically significant (P=0.202). There were no significant differences inC. difficile colonization rates with respect to age, length of stay, or gender. CONCLUSIONS: This study suggests that there may be a clinical association between use of metronidazole preoperatively and inhibition of intestinal colonization byC. difficile in this patient population undergoing colonic and rectal surgery.Supported, in part, by the Department of Research at St. Joseph Mercy Hospital, Ann Arbor, Michigan.Poster presentation at the meeting of The American Society of Colon and Rectal Surgeons, Philadelphia, Pennsylvania, June 22 to 26, 1997.