Prediction of incident vertebral fracture using CT-based finite element analysis.

Prior studies show vertebral strength from computed tomography-based finite element analysis may be associated with vertebral fracture risk. We found vertebral strength had a strong association with new vertebral fractures, suggesting that vertebral strength measures identify those at risk for vertebral fracture and may be a useful clinical tool. INTRODUCTION: We aimed to determine the association between vertebral strength by quantitative computed tomography (CT)-based finite element analysis (FEA) and incident vertebral fracture (VF). In addition, we examined sensitivity and specificity of previously proposed diagnostic thresholds for fragile bone strength and low BMD in predicting VF. METHODS: In a case-control study, 26 incident VF cases (13 men, 13 women) and 62 age- and sex-matched controls aged 50 to 85 years were selected from the Framingham multi-detector computed tomography cohort. Vertebral compressive strength, integral vBMD, trabecular vBMD, CT-based BMC, and CT-based aBMD were measured from CT scans of the lumbar spine. RESULTS: Lower vertebral strength at baseline was associated with an increased risk of new or worsening VF after adjusting for age, BMI, and prevalent VF status (odds ratio (OR) = 5.2 per 1 SD decrease, 95% CI 1.3-19.8). Area under receiver operating characteristic (ROC) curve comparisons revealed that vertebral strength better predicted incident VF than CT-based aBMD (AUC = 0.804 vs. 0.715, p = 0.05) but was not better than integral vBMD (AUC = 0.815) or CT-based BMC (AUC = 0.794). Additionally, proposed fragile bone strength thresholds trended toward better sensitivity for identifying VF than that of aBMD-classified osteoporosis (0.46 vs. 0.23, p = 0.09). CONCLUSION: This study shows an association between vertebral strength measures and incident vertebral fracture in men and women. Though limited by a small sample size, our findings also suggest that bone strength estimates by CT-based FEA provide equivalent or better ability to predict incident vertebral fracture compared to CT-based aBMD. Our study confirms that CT-based estimates of vertebral strength from FEA are useful for identifying patients who are at high risk for vertebral fracture.

The associations between QCT-based vertebral bone measurements and prevalent vertebral fractures depend on the spinal locations of both bone measurement and fracture.

UNLABELLED: We examined how spinal location affects the relationships between quantitative computed tomography (QCT)-based bone measurements and prevalent vertebral fractures. Upper spine (T4-T10) fractures appear to be more strongly related to bone measures than lower spine (T11-L4) fractures, while lower spine measurements are at least as strongly related to fractures as upper spine measurements. INTRODUCTION: Vertebral fracture (VF), a common injury in older adults, is most prevalent in the mid-thoracic (T7-T8) and thoracolumbar (T12-L1) areas of the spine. However, measurements of bone mineral density (BMD) are typically made in the lumbar spine. It is not clear how the associations between bone measurements and VFs are affected by the spinal locations of both bone measurements and VF. METHODS: A community-based case-control study includes 40 cases with moderate or severe prevalent VF and 80 age- and sex-matched controls. Measures of vertebral BMD, strength (estimated by finite element analysis), and factor of risk (load:strength ratio) were determined based on QCT scans at the L3 and T10 vertebrae. Associations were determined between bone measures and prevalent VF occurring at any location, in the upper spine (T4-T10), or in the lower spine (T11-L4). RESULTS: Prevalent VF at any location was significantly associated with bone measures, with odds ratios (ORs) generally higher for measurements made at L3 (ORs = 1.9-3.9) than at T10 (ORs = 1.5-2.4). Upper spine fracture was associated with these measures at both T10 and L3 (ORs = 1.9-8.2), while lower spine fracture was less strongly associated (ORs = 1.0-2.4) and only reached significance for volumetric BMD measures at L3. CONCLUSIONS: Closer proximity between the locations of bone measures and prevalent VF does not strengthen associations between bone measures and fracture. Furthermore, VF etiology may vary by region, with VFs in the upper spine more strongly related to skeletal fragility.

Identification of prevalent vertebral fractures using CT lateral scout views: a comparison of semi-automated quantitative vertebral morphometry and radiologist semi-quantitative grading.

UNLABELLED: We compared vertebral fracture assessment by semi-automated quantitative vertebral morphometry measurements with the conventional semi-quantitative (SQ) grading using lateral CT scout views. The semi-automated morphometry method showed good to excellent agreement with the visual SQ grading by radiologists for identification of vertebral fractures. INTRODUCTION: Semi-automated quantitative vertebral morphometry (QM) measurements may enhance management of osteoporosis patients by providing an efficient means to identify vertebral fractures (VFx). We compared identification of prevalent VFx by semi-automated QM to SQ grading. METHODS: A non-radiologist performed semi-automated QM from CT lateral scout views in 200 subjects (102 men, 98 women, 65.8 ± 8.9 years) selected from the Framingham Heart Study Multidetector CT Study. VFx were classified in the QM approach based on using Genant's criteria for deformities, and compared with conventional SQ grading performed by experienced radiologists as the gold standard. The kappa (k) statistics, percent agreement (% Agree), sensitivity (SE), specificity (SP), positive predictive value (PPV), and negative predictive value (NPV) were computed. RESULTS: Among 200 subjects, 57 had mild and 41 had moderate or severe VFx by visual SQ grading. Per-person analyses showed excellent agreement between the two methods, with k = 0.780. The % Agree ranged from 86.7% to 91.2%, the SE was 81.3%-96%, and the SP was 86.5%-92%. Among 2,588 vertebrae analyzed, 107 had mild and 49 had moderate or severe VFx by visual SQ grading. Per-vertebra analyses revealed good agreement, with k = 0.580. Agreement between the methods tended to be highest in L1-L4 region. Agreement and validity measures were higher when only moderate and severe fractures were included. CONCLUSION: The semi-automated quantitative vertebral morphometry measurements from CT lateral scout views provided good to excellent agreement with the standard SQ grading for assessment of prevalent vertebral fractures.

Physical exam is not an accurate predictor of injury in geriatric patients with low-energy blunt trauma - A retrospective cohort study.

Background: When evaluating trauma patients, many centers perform computed tomography of the head, cervical spine, chest, abdomen, and pelvis, the so-called "pan-scan." Here, we evaluate the utility of physical exam against pan-scan in geriatric patients who sustained ground-level falls. Methods: We performed a single-centered retrospective cohort review of consecutive patients from the trauma registry of a large, urban Level 1 trauma center. Inclusion criteria were registration during the 2019 calendar year, age ≥65, mechanism of fall from either sitting or standing, and performance of "pan-scan" at time of assessment. The sensitivity, specificity, positive and negative predictive values of the physical exam for significant injuries were calculated. The effect of such injuries on disposition from the emergency department and hospital were determined. Results: An initial query for patients age ≥65 yielded 1280 patients. After exclusion of patients who did not undergo pan-scan or who had GCS <14, 751 patients were included in analysis. Median age was 84 years old. 351 patients had at least one injury identified on pan-scan. Physical exam was determined to have a sensitivity of 0.69 when compared to pan-scan as a gold standard. Patients with injury identified on CT scan had significantly more admissions, mortalities, and ICU and OR requirements. Conclusion: Approximately half of all patients were found to have at least one injury on pan-scan. Physical examination was insensitive at identifying such injuries which ultimately altered patient management, disposition, and outcomes. Pan-scan is recommended in this vulnerable population.

Intra-and inter-reader reliability of semi-automated quantitative morphometry measurements and vertebral fracture assessment using lateral scout views from computed tomography.

UNLABELLED: Intra-and inter-reader reliability of semi-automated quantitative vertebral morphometry measurements was determined using lateral computed tomography (CT) scout views. The method requires less time than conventional morphometry. Reliability was excellent for vertebral height measurements, good for height ratios, and comparable to semi-quantitative grading by radiologists for identification of vertebral fractures. INTRODUCTION: Underdiagnosis and undertreatment of vertebral fracture (VFx) is a well-known problem worldwide. Thus, new methods are needed to facilitate identification of VFx. This study aimed to determine intra- and inter-reader reliability of semi-automated quantitative vertebral morphometry based on shape-based statistical modeling (SpineAnalyzer, Optasia Medical, Cheadle, UK). METHODS: Two non-radiologists independently assessed vertebral morphometry from CT lateral scout views at two time points in 96 subjects (50 men, 46 women, 70.3 ± 8.9 years) selected from the Framingham Heart Study Offspring and Third Generation Multi-Detector CT Study. VFxs were classified based solely on morphometry measurements using Genant's criteria. Intraclass correlation coefficients (ICCs), root mean squared coefficient of variation (RMS CV) and kappa (k) statistics were used to assess reliability. RESULTS: We analyzed 1,246 vertebrae in 96 subjects. The analysis time averaged 5.4 ± 1.7 min per subject (range, 3.2-9.1 min). Intra-and inter-reader ICCs for vertebral heights were excellent (>0.95) for all vertebral levels combined. Intra-and inter-reader RMS CV for height measurements ranged from 2.5% to 3.9% and 3.3% to 4.4%, respectively. Reliability of vertebral height ratios was good to fair. Based on morphometry measurements alone, readers A and B identified 51-52 and 46-59 subjects with at least one prevalent VFx, respectively, and there was a good intra-and inter-reader agreement (k = 0.59-0.69) for VFx identification. CONCLUSIONS: Semi-automated quantitative vertebral morphometry measurements from CT lateral scout views are convenient and reproducible, and may facilitate assessment of VFx.

Reliability of vertebral fracture assessment using multidetector CT lateral scout views: the Framingham Osteoporosis Study.

UNLABELLED: Two radiologists evaluated images of the spine from computed tomography (CT) scans on two occasions to diagnose vertebral fracture in 100 individuals. Agreement was fair to good for mild fractures, and agreement was good to excellent for more severe fractures. CT scout views are useful to assess vertebral fracture. INTRODUCTION: We investigated inter-reader agreement between two radiologists and intra-reader agreement between duplicate readings for each radiologist, in assessment of vertebral fracture using a semi-quantitative method from lateral scout views obtained by CT. METHODS: Participants included 50 women and 50 men (age 50-87 years, mean 70 years) in the Framingham Study. T4-L4 vertebrae were assessed independently by two radiologists on two occasions using a semi-quantitative scale as normal, mild, moderate, or severe fracture. RESULTS: Vertebra-specific prevalence of grade ≥ 1 (mild) fracture ranged from 3% to 5%. We found fair (κ = 56-59%) inter-reader agreement for grade ≥ 1 vertebral fractures and good (κ = 68-72%) inter-reader agreement for grade ≥ 2 fractures. Intra-reader agreement for grade ≥ 1 vertebral fracture was fair (κ = 55%) for one reader and excellent for another reader (κ = 77%), whereas intra-reader agreement for grade ≥ 2 vertebral fracture was excellent for both readers (κ = 76% and 98%). Thoracic vertebrae were more difficult to evaluate than the lumbar region, and agreement was lowest (inter-reader κ = 43%) for fracture at the upper (T4-T9) thoracic levels and highest (inter-reader κ = 76-78%) for the lumbar spine (L1-L4). CONCLUSIONS: Based on a semi-quantitative method to classify vertebral fractures using CT scout views, agreement within and between readers was fair to good, with the greatest source of variation occurring for fractures of mild severity and for the upper thoracic region. Agreement was good to excellent for fractures of at least moderate severity. Lateral CT scout views can be useful in clinical research settings to assess vertebral fracture.

The APOA1/C3/A4/A5 cluster and markers of allostatic load in the Boston Puerto Rican Health Study.

BACKGROUND AND AIMS: The APOA1/C3/A4/A5 cluster encodes key regulators of plasma lipids. Interactions between dietary factors and single nucleotide polymorphisms (SNPs) in the cluster have been reported. Allostatic load, or physiological dysregulation in response to stress, has been implicated in shaping health disparities in ethnic groups. We aimed to determine the association between polymorphisms in the APOA1/C3/A4/A5 cluster with allostatic load parameters, alone, and in interaction with dietary fat intake in Puerto Ricans adults. METHODS AND RESULTS: Data on demographic and anthropometric measures, lifestyle behaviors, and medication use, as well as blood and urine samples for biomarker analysis, were obtained from participants of the Boston Puerto Rican Health Study (n=821, age 45-75 y). The 12 polymorphisms analyzed were not associated with allostatic load parameters. Significant interactions were observed between dietary fat intake and APOA1-75 in association with waist circumference (WC), (P=0.005), APOC3-640 with diastolic blood pressure (DBP), (P=0.003), and APOA4 N147S and APOA5 S19W with systolic blood pressure (SBP), (P=0.001 and P=0.002, respectively). Puerto Ricans homozygous for the common allele of APOA1-75, APOA4 N147S and APOA5 S19W had lower WC and SBP when consuming <31% of total fat from energy, than participants with the minor allele. Participants heterozygous for APOC3-640 had lower DBP at total fat intake ≥31% from energy. CONCLUSION: SNPs in APOA1/C3/A4/A5, as modulated by dietary fat intake, appear to influence allostatic load parameters in Puerto Ricans.

Polymorphisms in the endothelial nitric oxide synthase gene and bone density/ultrasound and geometry in humans.

Nitric oxide (NO), produced by endothelial cells, is a signaling molecule synthesized from l-arginine by nitric oxide synthases (NOS). NO is known to reduce the ratio of receptor activator of nuclear factor KappaB (RANKL)/osteoprotegerin (OPG), leading to decreased osteoclastogenesis and a reduction in bone resorption. Endothelial nitric oxide synthase (eNOS or NOS3) is the predominant constitutive isoform of nitric NOS within bone. Recently, a NOS3 polymorphism, Glu298Asp, previously implicated in osteoporosis, failed to demonstrate an association with bone mineral density (BMD), although there was some indication of an association with selected geometry indices. Since a single polymorphism does not capture all of the potential variants in a given gene, we investigated a broader coverage of the NOS3 gene with bone density/ultrasound and geometry indices in a sample of unrelated individuals from the Framingham Offspring Study. Our results indicated that the Glu298Asp polymorphism was not associated with BMD but suggested some haplotype-based associations in the linkage disequilibrium (LD) region that included the Glu298Asp polymorphism with several geometry indices. Although our findings exhibited several associations with selected bone density/ultrasound and geometry indices, the nominally significant associations are regarded as primarily hypothesis generating and suggest that replication in other samples is needed. Thus, NOS3 genetic variation does not appear to be a major contributor to adult bone density/ultrasound and geometry in our sample.

Proximal hip geometry is linked to several chromosomal regions: genome-wide linkage results from the Framingham Osteoporosis Study.

INTRODUCTION: Femoral geometry contributes to bone strength and predicts hip fracture risk. The purpose of this study was to evaluate heritability (h(2)) of geometric indices of the proximal hip and to perform whole-genome linkage analyses of these traits, adjusted for body size. METHODS: DXA scans of the proximal femur from 1473 members of 323 pedigrees (age range 31-96 years) from the population-based Framingham Osteoporosis Study were obtained. Using the hip structural analysis program, we measured femoral neck length (FNL, cm) and neck-shaft angle (NSA); subperiosteal width (WID, cm), cross-sectional area (CSA, cm(2)); and section modulus (Z, cm(3)) at the narrowest section of the neck (NN), intertrochanteric (IT) and femoral shaft (S) regions. Linkage analyses were performed for the above indices with a set of 636 markers using variance components maximum likelihood method. RESULTS: Substantial genetic influences were found for all geometric phenotypes, with h(2) values between 0.28 (NSA) and 0.70 (IT_WID). Adjustment for height and BMI did not alter h(2) of NSA and FNL but decreased h(2) of the cross-sectional indices. We obtained substantial linkage (multipoint LOD >3.0) for S_Z at 2p21 and 21q11 and S_WID at Xq25-q26. Inclusion of height and BMI as covariates resulted in much lower LOD scores for S_Z, whereas linkage signals for S_Z at 4q25, S_CSA at 4q32 and S_CSA and S_Z at 15q21 increased after the adjustment. Linkage of FNL at 1q and 13q, NSA at 2q and NN_WID at 16q did not change after the adjustment. CONCLUSION: Suggestive linkages of bone geometric indices were found at 1q, 2p, 4q, 13q, 15q and Xq. The identification of significant linkage regions after adjustment for BMI and height may point to QTLs influencing femoral bone geometry independent of body size.

Insulin resistance, oxidative stress, hypertension, and leukocyte telomere length in men from the Framingham Heart Study.

Insulin resistance and oxidative stress are associated with accelerated telomere attrition in leukocytes. Both are also implicated in the biology of aging and in aging-related disorders, including hypertension. We explored the relations of leukocyte telomere length, expressed by terminal restriction fragment (TRF) length, with insulin resistance, oxidative stress and hypertension. We measured leukocyte TRF length in 327 Caucasian men with a mean age of 62.2 years (range 40-89 years) from the Offspring cohort of the Framingham Heart Study. TRF length was inversely correlated with age (r = -0.41, P < 0.0001) and age-adjusted TRF length was inversely correlated with the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) (r =-0.16, P = 0.007) and urinary 8-epi-PGF(2alpha) (r = -0.16, P = 0.005) - an index of systemic oxidative stress. Compared with their normotensive peers, hypertensive subjects exhibited shorter age-adjusted TRF length (hypertensives = 5.93 +/- 0.042 kb, normotensives = 6.07 +/- 0.040 kb, P = 0.025). Collectively, these observations suggest that hypertension, increased insulin resistance and oxidative stress are associated with shorter leukocyte telomere length and that shorter leukocyte telomere length in hypertensives is largely due to insulin resistance.

Anti-microbial stewardship: antibiotic use in well-appearing term neonates born to mothers with chorioamnionitis.

OBJECTIVE: To determine if implementation of a protocol based on a neonatal early-onset sepsis (EOS) calculator developed by Kaiser Permanente would safely reduce antibiotic use in well-appearing term infants born to mothers with chorioamnionitis in the unique setting of an Observation Nursery. STUDY DESIGN: Data obtained from a retrospective chart review of well-appearing term infants born between 2009 and 2016 were entered into the EOS calculator to obtain management recommendations. RESULTS: Three hundred and sixty-two infants met the study criteria. Management according to the EOS calculator would reduce antibiotic use from 99% to 2.5% (P<0.0001) of patients. Average length of therapy would also decrease from 2.08 to 0.05 days (P<0.0001). One infant, who remained asymptomatic, had Enterococcus bacteremia and received a 7-day course of broad-spectrum antibiotics. CONCLUSIONS: Culture-positive sepsis in asymptomatic neonates born to mothers with chorioamnionitis is rare. Management according to the EOS calculator would markedly reduce the potential complications of antibiotic use. These data should initiate re-examination of existing protocols for management of this cohort of patients.

Adjuvant tamoxifen: predictors of use, side effects, and discontinuation in older women.

PURPOSE: To identify predictors of adjuvant tamoxifen use, side effects, and discontinuation in older women. PATIENTS AND METHODS: We followed a cohort of 303 women > or = 55 years of age diagnosed with stage I or stage II breast cancer for nearly 3 years. Data were collected from women's surgical records and from computer-assisted telephone interviews at 5, 21, and 33 months after primary tumor therapy. RESULTS: Two hundred ninety-two (96%) of 303 patients in the study provided information about tamoxifen use. Tamoxifen use was reported by 189 patients (65%); 26 (15%) discontinued use during the follow-up period. Patients who were 65 to 74 years of age (relative to those 55 to 64 years of age), had stage II disease, were estrogen receptor-positive, saw a greater number of breast cancer physicians, and had better perceptions of their abilities to discuss treatment options with physicians had greater odds of tamoxifen use. Those who had better physical function, had received standard primary tumor therapy, and had obtained helpful breast cancer information from books or magazines had lesser odds of tamoxifen use. Patients > or = 75 years of age (relative to those 55 to 64 years of age) and patients with better emotional health had significantly lesser odds of reporting side effects. Patients who were estrogen receptor-positive were less likely to stop taking tamoxifen; patients who experienced side effects were more likely to stop taking tamoxifen. CONCLUSION: Deviations from a prescribed course of adjuvant tamoxifen occur relatively frequently. The clinical consequences of this deviation need to be identified.

Association between the PPARA L162V polymorphism and plasma lipid levels: the Framingham Offspring Study.

Peroxisome proliferator activated receptor (PPAR) alpha is a member of the nuclear receptor superfamily that regulates key proteins involved in fatty acid oxidation, extracellular lipid metabolism, hemostasis, and inflammation. A L162V polymorphism at the PPARA locus has been associated with alterations in lipid and apolipoprotein concentrations. We studied the association among lipids, lipoproteins, and apolipoproteins and the presence of the L162V polymorphism in 2373 participants (1128 men and 1244 women) in the Framingham Offspring Study. The frequency of the less common allele (V162) was 0.069. The V162 allele was associated with increased serum concentrations of total and LDL cholesterol in men (P=0.0012 and P=0.0004, respectively) and apolipoprotein B in men (P=0.009) and women (P=0.03 after adjustment for age, body mass index, smoking, and use of beta-blockers, diuretics or estrogens). Apolipoprotein (apo) C-III concentrations were higher in carriers of the V162 allele. The association of the L162V polymorphism on LDL cholesterol concentration was greatest in those who also carried the E2 allele at the APOE locus and the G allele at the APOC3 3238C>G polymorphism. This suggests that alterations in triglyceride-rich lipoprotein metabolism may be involved in the generation of the increase in LDL cholesterol observed with the L162V PPARA polymorphism.

Association of the Sst-I polymorphism at the APOC3 gene locus with variations in lipid levels, lipoprotein subclass profiles and coronary heart disease risk: the Framingham offspring study.

Apolipoprotein (apo) CIII participates in the regulation of the metabolism of triglyceride-rich lipoproteins and it is a major component of chylomicrons and VLDL. The APOC3 gene is on chromosome 11q23 and is highly polymorphic. The less common allele (S2) of the SstI polymorphism on the 3' untranslated region of the APOC3 gene has been previously associated with increased triglycerides, total cholesterol (TC), and apoCIII levels and cardiovascular risk on several, but not all, studies. The aim of this study was to examine the association of this polymorphism with plasma lipid levels, lipoprotein subfractions and coronary heart disease (CHD) risk in a population-based study: The Framingham Offspring Study. The frequency of the S2 allele was 0.086, consistent with previous reports in Caucasian populations. In men, the S2 allele was associated with lower concentrations of high-density lipoprotein cholesterol (HDL-C; P<0.04) and HDL2-C (P<0.02) and a significant increase in apoCIII non-HDL (P<0.05). TG levels were higher in men carriers of the S2 allele, but this association did not reach statistical significance (P=0.30). Conversely, in women, the S2 allele was associated with increased TC (P<0.03), low-density lipoprotein cholesterol (LDL-C; P<0.03), and ApoB levels (P<0.04). Lipoproteins subfractions were also examined using nuclear magnetic resonance (NMR) spectroscopy. S2 male carriers had significantly lower concentrations of large LDL and a significant reduction in LDL particle size (P<0.04). In women, there was a significant increase in intermediate LDL particles (P<0.05) with no significant effect on lipoprotein diameters. We also examined the associations between the S2 allele and biochemical markers of glucose metabolism. In men, the S2 allele was associated with elevated fasting insulin concentrations (P<0.04), whereas no significant associations were observed in women. Despite the described associations with lipid and glucose metabolism related risk factors, we did not find any significant increase in CHD risk associated with the S2 allele in this population.

Arecoline a muscarinic cholinergic agent conditions central pathways that modulate natural killer cell activity.

The central nervous system plays an active role in the regulation of the immune system. Modulation of immune activities appears to be in part under the control of the hypothalamic-pituitary-adrenal (HPA) axis. We investigated the effect of a muscarinic cholinergic agonist, arecoline, which stimulates the secretion of corticotropin-releasing hormone (CRF) and adrenocorticotropic hormone (ACTH) on the immune system. In this report we demonstrate that peripherally administered arecoline or ACTH can increase activity of pre-activated NK cells. Second, we show that central administration of arecoline at a dose too low to alter peripheral events is sufficient to induce a significant increase in the activity of pre-activated natural killer (NK) cells. Finally, we demonstrate by using a Pavlovian conditioning paradigm that the pairing of a novel odor (camphor) with administration of arecoline can be used to alter NK cell activity. Subsequent to the conditioning trial, exposure to the odor alone is sufficient to raise NK cell activity. From these observations, we infer that the pathway(s) that are conditioned reside in sites located within the CNS and the conditioned response is evoked in the peripheral compartment (NK cell activity).

Role of arcuate nucleus of the hypothalamus in the acquisition of association memory between the CS and US.

A single trial association protocol was used to demonstrate a conditioned increase in natural killer (NK) cell activity. The signals used were odor of camphor as the conditioned stimulus (CS) and polyinosinic-polycytidylic acid (poly I:C) as the unconditioned stimulus (US). This model has been used to dissect the underlying mechanisms of interaction between the central nervous system (CNS) and the immune system (IS) and vice versa. Here, we demonstrate the potential role played by the arcuate nucleus of the hypothalamus in the acquisition of association memory between the CS and the US. Chemical destruction of the arcuate nucleus with monosodium glutamate (MSG) was used for this purpose. Mice with arcuate nucleus lesion prior to the association protocol did not demonstrate a conditioned increase in NK cell activity. However, the lesion has no effect if produced prior to exposure to the CS at recall. These studies demonstrate the significant role played by the hypothalamus (arcuate nucleus) in a conditioned response.

What can we do to improve physical function in older persons with type 2 diabetes?

BACKGROUND: Older persons with type 2 diabetes are at higher risk for functional impairment than are their age-matched counterparts without-diabetes. We therefore sought to identify factors associated with impaired physical function in older persons with type 2 diabetes by using a cross-sectional study design. METHODS: We studied 1238 persons with type 2 diabetes who were 55 years of age or older and enrolled in the Type II Diabetes Patient Outcomes Research Team (PORT) project. Subjects were primary care patients at a large staff model health maintenance organization who had completed a mailed survey that collected information about demographics (age, race, marital status, income, education, gender, and body mass index [BMI]), health behaviors (exercise, smoking, and alcohol), care and control of diabetes (therapy, self-reported glucose control, home glucose monitoring, and disease duration), mood (Center for Epidemiologic Studies--Depression Scale [CES-D]), comorbidity, and the Short-Form-36 health survey (SF-36). We evaluated the bivariate relationships between the PFI- 10, a 10-item measure of physical function from the SF-36, and candidate independent variables from the domains described previously. Variables that were significant at an a level of .10 were entered into a multiple linear regression model. RESULTS: There were eight independent predictors of impaired physical function (all p < .05, R2 = .40). Factors associated with impaired function in order of their relative importance were as follows: a higher comorbidity score, older age, obesity, lack of regular exercise, CES-D score higher than 20, taking insulin, lower formal education, and abstinence from alcohol. CONCLUSIONS: Increased comorbidity and older age are associated with poorer function, as is the severity of diabetes and less formal education. Exercise, lower BMI, and better mood are associated with better function. Therefore, promoting regular exercise and weight loss, in addition to treating depression, are likely to preserve or even improve the functional status of older persons with type 2 diabetes. Moderate alcohol use may be beneficial as well. The extent to which these relationships persist in prospective studies or clinical trials remains to be evaluated.

The internal validity of a dietary pattern analysis. The Framingham Nutrition Studies.

STUDY OBJECTIVES: To examine the internal validity of a dietary pattern analysis and its ability to discriminate clusters of people with similar dietary patterns using independently assessed nutrient intakes and heart disease risk factors. DESIGN AND PARTICIPANTS: Population based study characterising dietary patterns using cluster analysis applied to data from the semiquantitative Framingham food frequency questionnaire collected from 1942 women ages 18-76 years, between 1984-88. SETTING: Framingham, Massachusetts. MAIN RESULTS: Of 1942 women included in the cluster analysis, 1828 (94%) were assigned to one of the five dietary pattern clusters: Heart Healthy, Light Eating, Wine and Moderate Eating, High Fat, and Empty Calorie. Dietary patterns differed substantially in terms of individual nutrient intakes, overall dietary risk, heart disease risk factors, and predicted heart disease risk. Women in the Heart Healthy cluster had the most nutrient dense eating pattern, the lowest level of dietary risk, more favourable risk factor levels, and the lowest probability of developing heart disease. Those in the Empty Calorie cluster had a less nutritious dietary pattern, the greatest level of dietary risk, a heavier burden of heart disease risk factors, and a relatively higher probability of developing heart disease. Cluster reproducibility using discriminant analysis showed that 80% of the sample was correctly classified. The cluster technique was highly sensitive and specific (75% to 100%). CONCLUSIONS: These findings support the internal validity of a dietary pattern analysis for characterising dietary exposures in epidemiological research. The authors encourage other researchers to explore this technique when investigating relations between nutrition, health, and disease.

Identification of specific pathways of communication between the CNS and NK cell system.

The specific signals and pathways utilized by the natural killer (NK) cell system and the central nervous system (CNS) that results in the conditioned response (CR) is not clearly understood. Single trial conditioning of the NK cell activity provides us with a model to probe the mechanisms of communication between two major systems (Immune and CNS) which are involved in the health and disease of the individual. The studies show that the IFN-beta molecules possess the properties attributed to the unconditioned stimulus (US). IFN-beta can penetrate the CNS and evoke the elevation of NK cell activity in the spleen. This unconditioned response (UR) can be linked to a specific conditioned stimulus (CS). Specific odors such as camphor provide a neural pathway for the CS to associate with the US. Evidence is presented that in conditioning there are two locations where memory develops. The CS/US association is made centrally and its memory is stored at a central location, but the memory for the specificity of the odor is presumably stored in the olfactory bulbs. The CS recalls the CR by triggering the olfactory neural pathway which, in turn, signals the hypothalamic-pituitary axis to release mediators that modulate the activity of NK cells in the spleen. These results imply that through conditioning one has direct input into the regulatory hypothalamus that controls the internal environment of the organism and the health and disease of the individual. Consequently, it is not inconceivable that through this approach we might be able to alter the course of a disease process.

Effects of early inhaled beclomethasone therapy on tracheal aspirate inflammatory mediators IL-8 and IL-1ra in ventilated preterm infants at risk for bronchopulmonary dysplasia.

We tested the hypothesis that inhaled beclomethasone therapy for prevention of bronchopulmonary dysplasia (BPD) reduces pulmonary inflammation. As part of a randomized, placebo-controlled trial, interleukin-8 (IL-8) and interleukin-1 receptor antagonist (IL-1ra) concentrations in tracheal aspirates were measured as markers of pulmonary inflammation. On study days 1 (baseline), 8, 15, and day 28 of age, samples were obtained from enrolled infants (birth weights <1,251 g, gestational age <33 week, 3 to 14 days of age) who remained ventilated and had not received systemic glucocorticoid therapy. Cytokine levels (pg/microg of free secretory component of immunoglobulin A) were compared between groups. We determined whether baseline cytokine levels modified treatment effect regarding subsequent need for systemic glucocorticoid therapy or occurrence of BPD (age 28 days). Tracheal aspirates were obtained from 161 infants (77 receiving beclomethasone, 84 receiving placebo). Median IL-8 levels were lower in beclomethasone versus placebo infants on study days 8 (82.9 vs. 209.2, P < 0.01) and 15 (37.4 vs. 77.4, P < 0.03) after controlling for antenatal glucocorticoid therapy and maternal race. Median IL-1ra levels were lower in beclomethasone versus placebo infants only on study day 8 (86.5 vs. 153.3, P < 0.01). Fewer beclomethasone infants with baseline IL-8 levels in the interquartile range required systemic glucocorticoid therapy (beclomethasone 30.6% vs. placebo 65.8%, P < 0.01) or developed BPD (beclomethasone 42.4% vs. placebo 69.4%, P < 0.03). We conclude that early-inhaled beclomethasone therapy was associated with a reduction in pulmonary inflammation after 1 week of therapy. Beclomethasone-treated infants with moderately elevated baseline IL-8 levels received less subsequent systemic glucocorticoid therapy and had a lower incidence of BPD than nontreated infants.