Binding of lipopeptide to CD14 induces physical proximity of CD14, TLR2 and TLR1

Lipoproteins or lipopeptides (LP) are bacterial cell wall components detected by the innate immune system. For LP, it has been shown that TLR2 is the essential receptor in cellular activation. However, molecular mechanisms of LP recognition are not yet clear. We used a FLAG-labeled derivative of the synthetic lipopeptide N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2R,S)-propyl]-(R)-cysteinyl-seryl-(lysyl)(3)-lysine (Pam(3)CSK(4)) to study the roles of CD14, TLR2 and TLR1 in binding and signaling of LP and their molecular interactions in human cells. The activity of Pam(3)CSK(4)-FLAG was TLR2 dependent, whereas the binding was enabled by CD14, as evaluated by flow cytometry and confocal microscopy. Using FRET and FRAP imaging techniques to study molecular associations, we could show that after Pam(3)CSK(4)-FLAG binding, CD14 and Pam(3)CSK(4)-FLAG associate with TLR2 and TLR1, and TLR2 is targeted to a low-mobility complex. Thus, LP binding to CD14 is the first step in the LP recognition, inducing physical proximity of CD14 and LP with TLR2/TLR1 and formation of the TLR2 signaling complex.     

The status of women at one academic medical center. Breaking through the glass ceiling

Despite recent gains in admission to medical school and in obtaining junior faculty positions, women remain underrepresented at senior academic ranks and in leadership positions in medicine. This discrepancy has been interpreted as evidence of a "glass ceiling" that prevents all but a few exceptional women from gaining access to leadership positions. We analyzed data from Columbia University College of Physicians & Surgeons, New York, NY, for all faculty hired from 1969 through 1988 and found that the likelihood of promotion on the tenure track was 0.40 for women and 0.48 for men (ratio, 0.82; 95% confidence interval, 0.56 to 1.20); on the clinical track the likelihood of promotion was 0.75 for women and 0.72 for men (ratio, 1.04; 95% confidence interval, 0.56 to 1.94). Additional analysis of current faculty showed that in the academic year 1988-1989 the proportion of women at each tenure track rank at the College of Physicians & Surgeons equaled or exceeded the national proportion of women graduating from medical school, once allowance was made for the average time lag necessary to attain each rank. On the clinical track women were somewhat overrepresented, particularly at the junior rank. National data that describe medical school faculty, which combine tenure and clinical tracks, showed that in 1988 women were proportionately represented at each rank once the lead time from graduation was considered. We conclude that objective evidence shows that women can succeed and are succeeding in gaining promotions in academic medicine.     

A questionnaire to assess the generic and disease-specific health outcomes of patients with chronic hepatitis C

A 69-item questionnaire measuring generic functioning and well-being and disease-specific health outcomes was developed and tested using the pre-treatment data from patients with chronic hepatitis C (CHC) participating in two randomized trials of interferon -2b (n = 157). The questionnaire included all eight scales from the SF-36 and measures of nine other generic and disease-specific health concepts. Psychometric tests confirmed the assumptions underlying the construction and scoring of all generic and disease-specific scales. Cross-sectional tests of known groups validity showed that CHC patients scored worse on the generic scales than patients with other chronic conditions and worse than a healthy general population. The generic and disease-specific scale scores were lower in the presence of physical findings of CHC, as hypothesized, but only the physical functioning and bodily pain scales were linked to cirrhosis or extreme alanine aminotransferase (ALT) ratios. This instrument will be useful in studies of health outcome among patients with CHC, a condition whose health burden appears to have been underestimated in studies to date.     

Concurrent carboplatin and iodine-125 brachytherapy for recurrent glioblastoma multiforme

Toxicity and safety study of concurrent carboplatin chemotherapy and iodine-125 (I-125) brachytherapy. I-125 brachy therapy has an established albeit limited role in surgically accessible recurrent gliomas. Carboplatin has anti-tumoral; activity against gliomas and demonstrated sensitization of tumor to radiotherapy. In 15 patients (age range 30-77 years; median 53) with recurrent glioblastoma multiforme, stereotactically placed catheters were afterloaded with I-125 sources. A median 50 Gy minimum treatment volume dose was delivered during a 100 h period in conjunction with continuous infusion carboplatin (100 mg/m(2)/20 h x 5). Tumor volumes ranged from 13 to 63 cm(3) (median, 32 cm(3)). Early complications included: headache (n=7), transient exacerbations of pre existing neurologic deficits (n=5), seizures (n=2), nausea/vomiting (n=2), myelosuppression (n=2) and a catheter site wound CSF leak (n=1). Late complications included: steroid dependency (n=10), carcinomatous meningitis in association with hydrocephalus (n=1) and radiation-induced necrosis requiring reoperation (n=6). All patients were evaluable with a median survival of 10 months. In 12 patients, best clinical and neuroradiographic response was stable disease all of whom died of recurrent tumor (local recurrence in 11; CSF dissemination in 1). In 3 patients best response was either complete (n=2) or partial (n=1) all of whom are alive with a median follow-up of 31 months. I-125 brachytherapy with concurrent carboplatin chemotherapy is associated with an acceptable level of toxicity, has anti-tumoral activity and warrants further investigation in carefully selected patients with recurrent gliomas.     

5-A-DAY: dietary behavior and the fruit and vegetable intake of Latino children.

OBJECTIVES. The purpose of the study was to examine children's intake of fruits and vegetables in relation to the recent national "5-A-DAY" campaign. METHODS. Four 24-hour dietary recalls per child collected from 205 mothers of 4- to 5-year-old urban Latino children were used to analyze average 5-A-DAY fruit and vegetable consumption and examine associations between 5-A-DAY consumption, nutrient intakes, and eating patterns. RESULTS. The reported mean servings per day of fruits and vegetables, as defined by 5-A-DAY criteria, were 1.8 and 1.0, respectively, with only 6.8% (n = 14) of the children averaging five or more servings per day. Fruit juice accounted for 36% of 5-A-DAY servings. There were significant linear trends in intake of vitamins A and C, potassium, iron, cholesterol, protein, and fiber across quintiles of 5-A-DAY intake. There were no differences among quintiles in intake of saturated or total fat or in servings from most non-5-A-DAY food groups. CONCLUSIONS. Latino children's intake of fruits and vegetables falls far short of current recommendations. Fruit juice accounted for a disproportionate amount of 5-A-DAY intake in this population. Sensible 5-A-DAY interventions should take into consideration the existing eating patterns of the target population.     

Low Prenatal Weight Gain Among Adult WIC Participants Delivering Term Singleton Infants: Variation by Maternal and Program Participation Characteristics

Objective: To determine the association of maternal and prenatal WIC program participation characteristics with low prenatal weight gain among adult women delivering liveborn, singleton infants at term. Methods: WIC program data for 19,017 Black and White Alabama women delivering in 1994 were linked with birth certificate files to examine the association of anthropometric, demographic, reproductive, hematologic, behavioral and program participation characteristics with low prenatal weight gain. Results: One third (31.0%) had low prenatal weight gain as defined by the Institute of Medicine. The incidence of low weight gain was increased among women who had < 12 years of education, were single, Black, anemic, had low or normal pre-pregnancy body mass index (BMI), increased parity, interpregnancy intervals 24 months, used tobacco or alcohol, or entered prenatal care or WIC programs after the first trimester. After adjusting for selected maternal characteristics, the adjusted odds ratios (AOR) for low weight gain were increased with short interpregnancy intervals (AOR 1.21 to 2.20); tobacco use (AOR 1.16 to 1.40), anemia (AOR 1.20 to 1.25), and second trimester entry into prenatal care (AOR 1.14 to 1.20); the size of the AORs and 95% confidence intervals varied by BMI and racial subgroup. Conclusions: The results of this study suggest that WIC interventions targeting low prenatal weight gain be focused on risk factors present not only during pregnancy, but during the pre- and interconceptional periods as well. Interventions should target low BMI, tobacco use, and anemia, and include attention to nutrition screening and risk reduction among women in postpartum and family planning clinic settings.     

Heel pain in children. Diagnosis and treatment

Heel pain in children is common, and its evaluation is challenging. Medical history and physical examination may be unrevealing owing to children's limited communication skills. Often, advanced laboratory and imaging studies are required to make an accurate diagnosis. The most common causes of heel pain in children are apophysitis, enthesopathy, and overuse syndromes such as tendinitis. Juvenile rheumatoid arthritis is relatively uncommon. In very active children, occult fractures must also be evaluated. Pain unrelated to activity may indicate tumors, infection, or congenital problems. In general, heel pain in children is treated nonoperatively. For fractures in particular, children are less likely than adults to receive surgical treatment.     

Relations of plasma fibrinogen level in children to measures of obesity, the (G-455-->A) mutation in the beta-fibrinogen promoter gene, and family history of ischemic heart disease: the Columbia University BioMarkers Study.

Higher plasma fibrinogen levels are associated with increased risk of myocardial infarction in adults, but little is known about factors that influence fibrinogen levels in childhood. The authors examined the associations of measures of obesity, presence of the (G-455-->A) allele in the beta-fibrinogen promoter gene, and family history of early onset of ischemic heart disease with plasma fibrinogen levels in children. Children (n = 299) were recruited during 1994-1997 from 276 families living in a racially mixed area of New York City. The mean age of the study children was 9.9 years; 79% were Hispanic. The frequency of the (G-455-->A) allele was lower in Hispanics than in non-Hispanic Whites (15.5% vs. 28.3% in children (p < 0.01) and 13.9% vs. 28.3% in parents (p < 0.001)). Graded relations of children's plasma fibrinogen levels were found with tertiles of body mass index (weight (kg)/height (m)2) and sum of skinfolds (tests for linear trend: p < 0.001). Plasma fibrinogen levels in the children were not related to race/ethnicity, presence of the (G-455-->A) allele, or family history. Multiple linear regression analyses adjusting plasma fibrinogen levels for age, sex, race/ethnicity, the (G-455-->A) allele, and family history of early onset of heart disease showed a significant association with either body mass index or sum of skinfolds (p < 0.001 for both models) but not with the other variables.     

Cardiorespiratory variables and sensation during stimulation of the left vagus in patients with epilepsy

We studied physiological and sensory effects of left cervical vagal stimulation in six adult patients receiving this stimulation as adjunctive therapy for intractable epilepsy. Stimulus strength varied among subjects from 0.1 to 2.1 microCoulomb (microC) per pulse, delivered in trains of 30-45 s at frequencies from 20 to 30 Hz; these stimulation parameters were standard in a North American study. The stimulation produced no systematic changes in ECG, arterial pressure, breathing frequency tidal volume or end-expiratory volume. Five subjects experienced hoarseness during stimulation. Three subjects with high stimulus strength (0.9-2.1 microC) recalled shortness of breath during stimulation when exercising; these sensations were seldom present during stimulation at rest. No subjects reported the thoracic burning sensation or cough previously reported with chemical stimulation of pulmonary C fibers. Four of six subjects (all those receiving stimuli at or above 0.6 microC) experienced a substantial reduction in monthly seizure occurrence at the settings used in our studies. Although animal models of epilepsy suggest that C fibers are the most important fibers mediating the anti-seizure effect of vagal stimulation, our present findings suggest that the therapeutic stimulus activated A fibers (evidenced by laryngeal effects) but was not strong enough to activate B or C fibers.     

Co-occurrence of mood and personality disorders: a report from the Collaborative Longitudinal Personality Disorders Study (CLPS)

The purpose of this study was to examine the relationship of subtypes and particular clinical features of mood disorders to co-occurrence with specific personality disorders. Five hundred and seventy-one subjects recruited for the Collaborative Longitudinal Personality Disorders Study (CLPS) were assessed with the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) and the Diagnostic Interview for DSM-IV Personality Disorders (DIPD-IV). Percent co-occurrence rates for current and lifetime mood disorders with personality disorders were calculated. Logistic regression analyses examined the effects of clinical characteristics of depressive disorders (e.g., age at onset, recurrence, symptom severity, double depression, and atypical features) on personality disorder co-occurrence. In comparison with other DSM-IV personality disorders, avoidant, borderline, and dependent personality disorders (PDs) were most specifically associated with mood disorders, particularly depressive disorders. Severity and recurrence of major depressive disorder and comorbid dysthymic disorder predicted co-occurrence with borderline and to a lesser extent research criteria depressive personality disorders. The results are consistent with the view that a mood disorder with an insidious onset and recurrence, chronicity, and progression in severity leads to a personality disorder diagnosis in young adults.