Initial steps taken by nine primary care practices to implement alcohol screening guidelines with hypertensive patients: the AA-TRIP project.

Many medical conditions are caused or exacerbated by heavy drinking, necessitating alcohol screening and discussion in primary care practices. This is particularly true of hypertension, the most common primary diagnosis in the United States, which has been linked to the regular consumption of 3 or more standard alcoholic beverages a day. The Accelerating Alcohol Screening-Translating Research into Practice (AA-TRIP) project was designed to improve detection and management of alcohol problems in primary care patients with hypertension. Medical providers are being trained using the Practice Partner Research Network's- Translating Research into Practice (PPRNet-TRIP) quality improvement model. This includes a multi-method intervention (electronic medical records, on-site academic detailing, practice feedback reports and annual network meetings) to help practices increase adherence to clinical guidelines. Qualitative analyses of initial steps taken by nine primary care practices toward the routine implementation of alcohol screening guidelines are presented. Organizational factors and provider and patient characteristics all influenced the method and consistency of alcohol screening and intervention. Perceived time constraints, patient sensitivity to questions about alcohol, and possible stigma associated with a diagnosis of alcoholism were also relevant barriers requiring problem solving.     

MEASUREMENT OF SURGICAL COSTS: A CLINICAL ANALYSIS

Because of reduced health care funding it is becoming necessary for surgeons to take a greater interest in the costs of individual operations. This study reports costs directly measurable to the patient, and also the indirect costs of hospital overheads, an operating suite and teaching, which were 37, 10 and 15%, respectively (62%), of hospital budget. A scheme has been developed which could give surgeons a standard to report direct costs. Pre-admission, ward, operating room, recovery, intensive care and post-admission are defined as cost periods and the modalities of staff, equipment (capital, maintenance and replacement), imaging, laboratory and consumables apply to each. This strategy was applied to assess open cholecystectomy (OC) and laparoscopic cholecystectomy (LC) as an example. The direct costs for OC were $3706 and LC $2868, a difference of $838; the indirect and direct costs were OC $6004 and LC $4646, a difference of $1358. Thus indirect cost magnified the difference between the operations. Bed stay, density of nursing and use of disposable instruments were the major influences on direct costs. The individual cost advantage of a shorter bed stay may be countervailed by an increased hospital activity. The main patient benefit of new operations may be improved quality of life and more rapid return to work with prevention of salary losses. A method has been developed to define costs of a particular surgical operation with the purpose of stimulating surgeons' interest in this topic and developing a common style of reporting. This method should help clinicians dealing with hospital finances and waiting lists. Indirect costs are a hidden substantial cost of surgery. Considerably more attention needs to be paid to indirect costs in controlling surgical budgets.     

A cation binding motif stabilizes the compound I radical of cytochrome c peroxidase.

Cytochrome c peroxidase reacts with peroxide to form compound I, which contains an oxyferryl heme and an indolyl radical at Trp-191. The indolyl free radical has a half-life of several hours at room temperature, and this remarkable stability is essential for the catalytic function of cytochrome c peroxidase. To probe the protein environment that stabilizes the compound I radical, we used site-directed mutagenesis to replace Trp-191 with Gly or Gln. Crystal structures of these mutants revealed a monovalent cation binding site in the cavity formerly occupied by the side chain of Trp-191. Comparison of this site with those found in other known cation binding enzymes shows that the Trp-191 side chain resides in a consensus K+ binding site. Electrostatic potential calculations indicate that the cation binding site is created by partial negative charges at the backbone carbonyl oxygen atoms of residues 175 and 177, the carboxyl end of a long alpha-helix (residues 165-175), the heme propionates, and the carboxylate side chain of Asp-235. These features create a negative potential that envelops the side chain of Trp-191; the calculated free energy change for cation binding in this site is -27 kcal/mol (1 cal = 4.184J). This is more than sufficient to account for the stability of the Trp-191 radical, which our estimates suggest is stabilized by 7.8 kcal/mol relative to a Trp radical in solution.     

Infection-induced airway fibrosis in two rat strains with differential susceptibility.

Chronic infections play a significant role in the morbidity and mortality of patients with chronic airflow limitation. By stimulating airway inflammation, persistent infection has the potential to cause airway fibrosis. However, in patient this condition is most typically found in lungs damaged by other factors, such as smoking, abnormal secretions, or barotrauma. We report the characterization of Mycoplasma pulmonis infection-induced lung fibrosis in two immunocompetent rat strains with no preexisting lung disease. The fibrosis was predominantly in the airways, as demonstrated by the findings for infected animals of increased airway inflammation, airway fibrosis, and airway wall thickness, which correlated with the collagen content of the lungs. Also, the physiological alterations were the opposite of those found in interstitial fibrosis, with a positive correlation between lung compliance and collagen content. The airway fibrosis was noted earlier and to a greater extent in Lewis rats than in Fisher rats, and this result apparently was related to regulation of the inflammatory response. Airway wall thickness, airway inflammation, and airway fibrosis are commonly reported in tissue specimens from patients with chronic airway diseases and have been shown to correlate with airflow limitation in patients with chronic obstructive pulmonary disease. Thus, this model may be useful in furthering our understanding of the role of chronic infection and airway inflammation in airflow obstruction.     

Effect of TPN on bone marrow kinetics--therapeutic implications

Stimulation of tumor and host tissue proliferation occurs with nutritional support of the tumor-bearing host. This study was performed to determine the effect of parenteral nutrition on bone marrow cytokinetics in tumor-bearing animals. Forty-three Lewis/Wistar rats with subcutaneous mammary tumor implants (AC-33) were protein-depleted for 8 days, underwent superior vena cava cannulation and were randomized to receive intravenous saline or total parenteral nutrition (TPN). Animals receiving TPN were sacrificed after 2, 6, 12, 24, and 48 hr and bone marrow cells were harvested for cell cycle analysis by flow cytometry. Compared to control animals, a significant increase in bone marrow cells in S (DNA synthetic) phase was demonstrated after 24 hr of TPN. The ratio of sensitive/resistant bone marrow cells to chemotherapy specific for cells actively synthesizing DNA was increased after 24 hr of TPN. This alteration in bone marrow cytokinetics was transient and distinct from the previously documented stimulation of tumor growth kinetics. The potential therapeutic implications of differentially stimulating host tissue and tumor growth kinetics with TPN are discussed.     

Maternal transmission of immunity to Eimeria maxima: western blot analysis of protective antibodies induced by infection.

Infection of breeding hens with Eimeria maxima induces production of parasite-specific antibodies which are transferred, via the egg yolk, to hatchling chicks. These antibodies (immunoglobulin G) are highly protective, mediating up to a 97% reduction in oocyst excretion in challenged hatchlings. However, the degree of maternally derived immunity transferred by the hens to their offspring declines with increasing time after infection of the hens. This decline in immunity is directly related to declining immunoglobulin G titers. However, sera from highly protected hatchlings recognize only a very few E. maxima proteins on Western blots (immunoblots). In particular, a 230-kDa protein band is outstanding for its association with maternally derived immunity to E. maxima in hatchlings. This band was excised from a sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) preparative gel of crude merozoite protein extract. The SDS-PAGE cutout was emulsified in Freund's adjuvant and injected, intramuscularly, into six breeding hens on two occasions, 2 weeks apart. Eggs were collected from these hens 28 to 39 days after the second injection, and the hatchlings from these eggs were challenged with 150 sporulated oocysts of E. maxima. Subsequent oocyst excretion in these hatchlings was, on average, 54% lower than oocyst excretion by control chicks but only 37% lower (significant at P < 0.05) than that by chicks from hens sham immunized with Freund's adjuvant. The latter result is apparently due to the ability of the adjuvant to induce production of antibodies which recognize Eimeria spp. and thereby transfer some degree of protection to hatchlings. These experiments indicate that protective, maternally derived immunoglobulin G antibodies may be useful for the identification of putative anticoccidial vaccine candidates.     

Respiratory failure produced by severe procainamide intoxication in a patient with preexisting peripheral neuropathy caused by amiodarone

We describe a patient in whom respiratory failure, due to extreme neuromuscular weakness, was produced by procainamide intoxication superimposed on a peripheral neuropathy secondary to long-term amiodarone therapy. Respiratory failure reversed rapidly after procainamide was discontinued, and the serum level fell to a therapeutic range.     

Epidermal growth factor receptors and adenylate cyclase activity in human thyroid tissues

Thyroid stimulating hormone (TSH) and epidermal growth factor (EGF) are growth factors for some thyroid cells in cultures. We have previously found more EGF receptors in neoplastic human thyroid tissues than in normal thyroid tissues. We have also found a higher TSH-stimulated adenylate cyclase (AC) activity in neoplastic human thyroid tissues than in normal thyroid tissues. To clarify the relationship between the effect of EGF and TSH on thyroid tissue, we measured the binding of EGF and TSH and the basal, TSH-stimulated and forskolin-stimulated adenylate cyclase activity in 49 normal, hyperplastic and neoplastic human thyroid tissues (5 normal, 2 Hashimoto thyroiditis, 5 Graves' disease, 14 multinodular goiters, 9 follicular adenomas, S follicular carcinomas, 8 papillary carcinomas, and 1 undifferentiated carcinoma). Specific binding of EGF and TSH were measured by radioreceptor assays using competitive inhibition of radio-labeled ligand by unlabeled ligand. Basal, maximally (300 mU/ml) TSH-stimulated, and maximally (100 mM) forskolin-stimulated adenylate cyclase activities were also measured in the same membrane particulate fractions from the thyroid tissues. We found: neoplastic thyroid tissues bind more labeled EGF than nonneoplastic thyroid tissues; follicular adenomas and carcinomas have higher EGF binding than other thyroid tissues; a weak but significant correlation between specific EGF binding and specific TSH binding, and between specific EGF binding and TSH-stimulated adenylate cyclase activity of the thyroid membrane preparations. These findings are consistent with the hypothesis that TSH stimulates an increase in thyroid EGF receptors by increasing intracellular cAMP. The higher binding of EGF and the higher TSH-stimulated AC activity may explain why thyroid neoplasms grow to a larger size than normal thyroid tissues.

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Resumen La hormona estimuladora de tiroides (TSH) y el factor de crecimiento epidermal (EGF) son factores de crecimiento para algunas células tiroideas en cultivo tisular. Previamente hemos informado el hallazgo de más receptores de EGF en tejidos tiroideos neoplásicos humanos que en tejidos tiroideos normales. Con el objeto de clarificar la relación entre el efecto del EGF y de la TSH sobre el tejido tiroideo, realizamos la determinacion de la ligación del EGF y de la TSH y de la actividad basai y de la actividad estimulada por TSH y forskolina de la adenilato-ciclasa (AC) en 49 especímenes de tejido tiroideo humano (5 normales, 2 tiroiditis de Hashimoto, 5 enfermedad de Graves, 14 bocios multinodulares, 9 adenomas foliculares, 5 carcinomas foliculares, 8 carcinomas papilares, y 1 carcinoma indiferenciado). La ligadura especifica del EGF y de la TSH fue medida mediante determinaciones de receptores utilizando inhibición competitiva radiomarcada. También se determinó la actividad basai y la actividad estimulada por forskolina de la adenilato-ciclasa en las mismas fracciones de tejidos tiroideos. Se registraron los siguientes hallazgos: los tejidos neoplásicos ligan más EGF marcado que los tejidos tiroideos no neoplásicos; los adenomas foliculares y los carcinomas poseen una capacidad de ligación del EGF mayor que los otros tejidos tiroideos; hay una débil pero significativa correlación entre la ligación especifíca del TGF y la de la TSH, y entre la ligación específica del EGF y la actividad estimulada por TSH de la adenilato-ciclasa en las preparaciones de membrana tiroidea. Estos hallazgos aparecen consistentes con la hipótesis de que la TSH estimula un aumento en los receptores de EGF mediante el incremento de la cAMP intracelular. La aumentada ligación de EGF y la incrementada actividad estimulada de TSH pueden explicar el por qué los neoplasmas tiroideos crecen hasta un tamaño mayor que los tejidos tiroideos normales.

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Résumé La thyroid stimulating hormone (TSH) et l'epidermal growth factor (EGF) sont des facteurs de croissance agissant sur certaines cellules thyroïdes en culture. Nous avons trouvé qu'il y avait plus de récepteurs EGF dans le tissu thyroïde humain néoplasique que dans le tissu thyroïdien normal. Nous avons également montré qu'il y avait plus d'activité d'adenylate cyclase stimulée par la TSH dans le tissu thyroïden néoplasique par rapport au tissu normal. Pour clarifier le rapport entre les effets de l'E.GF et la TSH sur le tissu thyroïden, nous avons mesuré l'activité de liaison d'EGF, de TSH et l'activité adénulate cyclase de base, stimulée par la TSH, et par la forskoline chez 49 patients ayant du tissu normal, hyperplasique ou néoplasique (5 normaux, 2 thyroïdites de Hashimoto, 5 maladies de Basedow, 14 goîtres multinodulaires, 9 adénomes folliculaires, 5 cancers folliculaires, 8 cancers papillaires, et 1 cancer indifférencié). Les liaisons spécifiques d'EGF et de TSH ont été mesurées par le dosage des récepteurs nucléaires par la méthode de déplacement des ligands marqués par des ligands froids (non marquées). Les activités adénylate cyclase de base, maximale (300 mU/mL), stimulée par la TSH (300 mU/mL) et la forskoline (100 mM) ont été également mesurées dans les mêmes fractions de particules membranaires provenant des tissus thyroïdens. Nous avons trouvé que: les tissus néoplasiques se liaient davantage avec l'EGF que les tissus non néoplasiques; les adénomes folliculaires et les cancers avaient un index de liaison plus élevé que les autres tissus thyroïdens; et il y avait une corrélation faible mais significative entre la liaison spécifique EGF et TSH, et entre la liaison spécifique EGF et l'activité adénylate cyclase des préparations de membrane thyroïdienne. Ces résultats sont en faveur de l'hypothèse selon laquelle la TSH provoque une augmentation des récepteurs EGH de la thyroïde en augmentant la concentration intracellulaire d'AMP cyclique. Le degré de liaison d'EGF élevé, et l'augmentation de l'activité stimulée par la TSH peuvent expliquer la croissance accélérée des tissus néoplasiques par rapport à celle des tissus normaux.

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Presented at the International Association of Endocrine Surgeons in Toronto, Ontario, Canada, September, 1989.

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Supported in part by the Medical Research Service of the Veterans Administration Medical Center, San Francisco, California and the Affirmative Action Faculty Development Grant of the University of California, San Francisco, California.     

Assessment of life stress events: the etiology and measurement of traumatic stress disorder.

The impact of stressful life events on health has been of considerable interest from a cross-cultural perspective. Examined herein is the etiology and onset of post-traumatic stress disorder with careful review of the diagnostic criteria, current measures used and clinical dimensions of PTSD. Also examined from a cross-cultural perspective is how psychological trauma may be processed by victims of trauma and subsequent approaches both pharmacological and psychotherapeutic to the treatment of post-traumatic stress disorder.