Pulmonary aspiration: new therapeutic approaches in the experimental model

BACKGROUND: Acute lung injury caused by gastric aspiration is a frequent occurrence in unconscious patients. Acute respiratory distress syndrome in association with gastric aspiration carries a mortality of up to 30% and accounts for up to 20% of deaths associated with anesthesia. Although the clinical condition is well known, knowledge about the exact inflammatory mechanisms is still incomplete. This study was performed to define the role of alveolar macrophages in this inflammatory response. In addition, potentially modifying effects of intratracheally applied nuclear factor kappaB inhibitor pyrrolidine dithiocarbamate were investigated. METHODS: Rat alveolar macrophages were depleted by intratracheal administration of clodronate liposomes, and lung injury was evaluated 6 h after instillation of 0.1N hydrochloric acid. In a second set of experiments, pyrrolidine dithiocarbamate was intratracheally instilled 3 h after hydrochloric acid application, and injury parameters were determined. RESULTS: Depletion of alveolar macrophages resulted in decreased production of inflammatory mediators in acid aspiration (23-80% reduction of messenger RNA or protein of inflammatory mediators; P < 0.05) and consequently also in diminished neutrophil recruitment (36% fewer neutrophils; P < 0.01). Treatment with pyrrolidine dithiocarbamate was highly effective in decreasing neutrophil recruitment (66%; P < 0.01) and vascular permeability (80%; P < 0.001). CONCLUSIONS: These data suggest that alveolar macrophages play an essential role in the inflammatory response of acid-induced lung injury. For the first time, attenuation of acid-induced lung injury with an inhibitor, applied after the onset of injury, is shown.     

The Appalachian Rural Health Project in Chautauqua County,N.Y., 1973–78

The Appalachian Regional Commission awarded a 5-year grant to the Chautauqua County Department of Health to establish primary health care services to medically underserved rural areas of the county. Four clinics were opened at various stages as the project grew.What began as an open system multidisciplinary approach to the delivery of primary health care changed abruptly to a closed system in March 1976, when the county medical society members voiced a strong objection to the rural health project. Among other assertions, the medical society claimed that the clinics of the project were “too costly and unnecessary as they now exist.” Equally strong voices of community people demanded that the project be allowed to operate. An unprecedented public hearing was held and, as a result, a compromise plan was developed that permitted the medical services of the clinics to be continued, but most of the multidisciplinary components devoted to social development were eventually dropped.By September 30, 1978, when the project grant ended, three of the four clinics had been taken over on a private basis by physicians who had previously been assigned to the clinics and supported by the project.The effects of grassroots support and power of the people in a community in determining their health rights and needs were demonstrated and documented in this pioneer program. It is anticipated that the Chautauqua County experience may be a helpful model in planning other projects that attempt to institute change in the health care delivery system in underserved rural areas.     

Association of clinical progression in classic Kaposi's sarcoma with reduction of peripheral B lymphocytes and partial increase in serum immune activation markers

OBJECTIVE: To evaluate various immunologic markers in the peripheral blood of patients with early and advanced classic Kaposi's sarcoma (CKS). DESIGN: Cross-sectional study. SETTING: A major referral center for skin and venereal diseases. PATIENTS: Sixty-eight patients with histologically confirmed CKS staged according to a modified version of the Mitsuyasu-Groopman classification in stage I-II (cutaneous involvement only) and stage IV (skin and systemic involvement). MAIN OUTCOME MEASURES: Concentrations of neopterin and beta2-microglobulin, titer of anti-human herpesvirus 8 antibodies, number of natural killer cells, and numbers of total lymphocytes, B lymphocytes, T lymphocytes, and their subsets in peripheral blood. RESULTS: The median values of beta2-microglobulin and neopterin were elevated in patients with CKS in stage IV (median, 3.679 microg/mL [312.72 nmol/L] and 14.0 nmol/L, respectively) compared with patients in stage I-II (median, 2.406 microg/mL [204.51 nmol/L] and 6.5 nmol/L, respectively). A statistically significant reduction in total lymphocyte and B-lymphocyte counts was observed in patients with advanced-stage CKS (1679/microL and 79/microL, respectively) compared with patients in earlier stages of the disease (2142/microL and 224/microL, respectively). The human herpesvirus 8 antibody titer, determined by latent immunofluorescent assay, decreased from stage I-II to stage IV, although not at a statistically significant level (P = .14). CONCLUSION: The evolution of CKS from the early stages of the disease to the more advanced may be associated with a partial activation of the immune system and a gradual decrease in the number of total and B lymphocytes.     

Multiple familial trichoepithelioma caused by mutations in the cylindromatosis tumor suppressor gene

The recessive oncogene cylindromatosis (CYLD) mapping on 16q12-q13 is generally implicated in familial cylindromatosis, whereas a gene region for multiple familial trichoepithelioma has been assigned to 9p21. Markers from both chromosome intervals were subjected to linkage analysis in a large family with multiple hereditary trichoepithelioma (TE) from Algeria. Linkage to 9p21 was excluded, whereas CYLD remained as a candidate. Mutation analysis identified a single bp germ-line deletion expected to result in truncation or absence of the encoded protein, which segregated with the multiple TE phenotype. In individual tumors, loss of heterozygosity at 16q or a somatic point mutation in the CYLD gene was detected. Hence, mutations of the tumor suppressor gene CYLD at 16q12-q13 may give rise to familial TE indistinguishable from the phenotype assigned to 9p21.     

Combined modality treatment for locally advanced non-small cell lung cancer: preoperative chemoradiation does not result in a poorer quality of life

The German Lung Cancer Cooperative Group (GLCCG) is assessing the impact of chemoradiation in addition to chemotherapy in the neoadjuvant treatment of stage III NSCLC. After three cycles of cisplatin/etoposide patients receive either hyperfractionated radiotherapy (RT) with concurrent carboplatin/vindesine and then surgery (arm A) versus surgery and then conventional RT (arm B). Quality of life (QL) was assessed throughout therapy using the EORTC QLQ-C30 and EORTC QLQ-LC 13. Of 126 eligible patients, 54 completed treatment. For patients in both treatment arms physical functioning decreased, whereas dyspnoea, fatigue and pain increased from beginning to the end of treatment. For self-assessed QL no statistically significant effect was found in or between the two treatment arms. The combined modality approach with preoperative radio/chemotherapy proves to be feasible in treating locally advanced NSCLC patients without decreasing their subjective QL.     

Molecular characterisation and neuropsychological outcome of 21 patients with profound biotinidase deficiency detected by newborn screening and family studies

Early recognition by newborn screening and oral biotin supplementation may prevent clinical and neurological deficits in profound biotinidase deficiency (residual plasma biotinidase activity <10%). In order to evaluate possible correlations of molecular characteristics, onset and continuation of treatment and clinical outcome, we investigated 21 patients detected by newborn screening and consecutive family investigations. In 18 patients found by newborn screening, the range of biotinidase activities was 0%-9% residual activity. Application of a sensitive HPLC assay enabled us to discriminate five patients with residual biotinidase activities <1%. Two patients with zero activities were homozygous for the G98:d7i3 mutation and three patients with activities <1% carried mutations G98:d7i3, R157H, and Q456H. The mutation spectrum of the remaining patients included T532M, A171T+D444H, V62M,C432W, and D444H. Evaluation of clinical and neuropsychological outcome showed that only patients with biotinidase activities <1% exhibited characteristic clinical symptoms within the first weeks of life whereas five patients with residual activities of 1.2%-4.6% did not develop clinical symptoms even when not treated until 3.5-21 years. In all patients treated with biotin within the first weeks of life, neuropsychological outcome was normal whereas abnormal in three out of five patients tested for IQ and treated after the age of 3.5 years. CONCLUSION: The clinical and molecular spectrum of profound biotinidase deficiency is heterogeneous. Early onset of symptoms is predicted by the presence of zero residual activity as measured by sensitive assays and by homozygosity for the G98:d7i3 mutation. In patients with higher residual activities and variable mutational spectrum, correlation with the onset and severity of symptoms cannot be made.     

Preeclampsia in the parous woman: who is at risk?

OBJECTIVE: The purpose of this study was to identify risk factors for preeclampsia in second pregnancies and to determine whether gestational age at delivery in the first pregnancy increases the risk of recurrent preeclampsia. STUDY DESIGN: We conducted a population-based, case-control study using birth certificate data from the Missouri maternally linked cohort. Data from women delivered of their first 2 singleton pregnancies between 1989 and 1997 (2332 cases with preeclampsia in the second pregnancy and 2370 control cases) were analyzed with logistic regression. RESULTS: Significant risk factors for preeclampsia in a second pregnancy include longer birth interval, previous preterm delivery, previous small-for-gestational-age newborn, renal disease, chronic hypertension, diabetes mellitus, obesity, black race, and inadequate prenatal care. Smoking and same paternity are protective. A history of preeclampsia confers the highest risk for preeclampsia in the second pregnancy; the risk is inversely proportional to gestational age at delivery of the first pregnancy: adjusted odds ratio, 15.0; 95% CI, 6.3-35.4 for 20 to 33 weeks; adjusted odds ratio, 10.2; 95% CI, 6.2-17.0 for 33 to 36 weeks; and adjusted odds ratio, 7.9; 95% CI, 6.3-10.0 for 37 to 45 weeks. CONCLUSION: The relative risk of recurrent preeclampsia increases with earlier gestational age at delivery of the first pregnancy that was complicated by preeclampsia.     

Risk factors for outcome and complications of dorsal foraminotomy in cervical disc herniation

BACKGROUND: Dorsal foraminotomy is a standard operative procedure for lateral cervical disc herniation. Factors associated with surgical complications and clinical outcome in dorsal foraminotomy of cervical disc herniation were evaluated in a retrospective cohort study. METHOD: Thirty-nine patients were operated upon for unilateral, monosegmental, mediolateral cervical disc herniation (+/- associated spondylosis) from 1997 to 1999. Preoperative radiologic imaging and surgical reports were analyzed. Motor disfunction, neck irritation, and radicular pain were evaluated. Outcome was ranked according to modified Odom's criteria at 6 weeks and 1 year postoperatively. RESULTS: Six weeks after injury 7 of 39 patients (18%) showed neck irritation. No new neurologic deficit was seen. All patients with preoperative paresis improved; two had early relapses of a medial soft disc prolapse (2/39). Residual radicular pain was seen in 3 of 39 patients (8%) within 30 days postoperatively, necessitating surgical revision. Factors of surgical failure were associated spondylosis (2/3) and residual mediolateral disc protrusion (1/3). In one patient with associated spondylosis, local pain due to a symptomatic fracture of the lateral process of D1 resolved after revision. Duration of preoperative radicular pain was identified as a risk factor for unfavorable outcome. CONCLUSION: In lateral cervical disc herniation, associated spondylosis or medial disc protrusion poses a significant risk of surgical failure and complications of dorsal foraminotomy. Reducing the radicular failure rate by enlarging the bony decompression may lead to local failure. In well-selected patients with a lateral cervical free disc fragment, dorsolateral foraminotomy is successful and safe.     

Clinical evaluation of the Elecsys CA 15-3 test in breast cancer patients

The aim of the present study was to evaluate the clinical performance of the CA 15-3 assay on Elecsys systems in an international multicenter study (11 centers). A total of 1326 single samples (272 apparently healthy individuals, 34 pregnant women, 308 benign diseases, 273 cancers other than breast, 439 breast cancer) and 538 serial samples of 98 breast cancer patients during follow-up were analyzed. 95% of values in healthy individuals were below 25 kU/L, and 88% in benign breast diseases, respectively. In malignant breast disease at primary diagnosis the value distribution of Elecsys CA 15-3, sensitivity at 95% specificity, as well as the areas under the curve in ROC analysis were clearly correlated to tumor stages: UICC I to IV 88 to 25% of values < 25 kU/L, sensitivity 7 to 78%, areas under the curve 0.53 to 0.94. During follow-up, sensitivity/specificity for detection of recurrences were 90%/71%. In metastatic disease clinical progression/response to therapy were indicated in 91%/78% of patients at a specificity of 92%/78%. The findings indicate that the Elecsys CA 15-3 assay is very suitable in routine work for detection of recurrences as well as for therapy control in metastatic breast cancer.