Pigs fed cholesterol neonatally have increased cerebrum cholesterol as young adults

Sixty-eight female neonatal pigs selected for seven (Experiment 1) or eight (Experiment 2) generations for high (HG) or low (LG) plasma cholesterol were used to test the hypothesis that neonatal dietary cholesterol fed during the first 4 or 8 wk of postnatal life increases the cholesterol content of the cerebrum in young adulthood following free access to a high-fat (15%), high-cholesterol (0.5%) diet from 8 to 20 or 24 wk of age. Pigs were removed from their dams at 1 d of age and given free access to a sow-milk replacer diet containing 9.5% coconut fat and 0 or 0.5 % cholesterol. All pigs (except four HG and four LG pigs in Experiment 2, which were deprived of cholesterol throughout the study) were fed the high-fat, high-cholesterol diet from 8 wk to termination at 20 or 24 wk of age. Cerebrum weight and cholesterol concentration were higher in pigs fed cholesterol neonatally than in those deprived of cholesterol neonatally in both experiments, but weight and cholesterol concentration were unaffected by genetic line. Cholesterol concentrations in longissimus and semitendinosus muscles and in subcutaneous fat were unaffected by diet or genetic line. We conclude that dietary cholesterol deprivation during the first 4 to 8 wk of life in piglets is associated with lower cholesterol concentration and total content in the young adult cerebrum than in pigs supplemented with cholesterol in early life. These data support previous observations and suggest the possibility of a metabolic need for neonatal dietary cholesterol in normal brain development.     

Phylogenetic analysis of the Bunocotylinae dollfus, 1950 (Digenea: Hemiuridae)

We investigated the functional determinants of the cutaneous expression of elements of the hypothalamic-pituitary-adrenal axis. In the present work, the presence of adrenocorticotropin (ACTH) peptide in skin of C57/BL6 mouse was demonstrated by reversed-phase HPLC analysis combined with specific radioimmunoassay. ACTH concentration that was low in telogen, increased during anagen in two steps: a rapid phase in anagen I, and a slower rise that reached its peak in anagen VI. Immunofluorescence localized the ACTH antigen to the basal layer of epidermis, outer root sheath of hair follicle and subcutaneous muscle of anagen VI skin. At physiological plasma concentration (10-9 M), ACTH selectively stimulated DNA synthesis in dermis, while pharmacological doses (10-7-10-6 M) inhibited DNA synthesis in both dermis and epidermis. In conclusion, we suggest that local production of ACTH may represent a regulatory element in the control of skin functions including hair growth.     

Ligaments and articular contact guide passive knee flexion

The aim of this study was to test the hypothesis that the coupled features of passive knee flexion are guided by articular contact and by the isometric fascicles of the ACL, PCL and MCL. A three-dimensional mathematical model of the knee was developed, in which the articular surfaces in the lateral and medial compartments and the isometric fascicles in the ACL, PCL and MCL were represented as five constraints in a one degree-of-freedom parallel spatial mechanism. Mechanism analysis techniques were used to predict the path of motion of the tibia relative to the femur. Using a set of anatomical parameters obtained from a cadaver specimen, the model predicts coupled internal rotation and ab/adduction with flexion. These predictions correspond well to measurements of the cadaver specimen's motion. The model also predicts posterior translation of contact on the tibia with flexion. Although this is a well-known feature of passive knee flexion, the model predicts more translation than has been reported from experiments in the literature. Modelling of uncertainty in the anatomical parameters demonstrated that the discrepancy between theoretical predictions and experimental measurement can be attributed to parameter sensitivity of the model. This study shows that the ligaments and articular surfaces work together to guide passive knee motion. A principal implication of the work is that both articular surface geometry and ligament geometry must be preserved or replicated by surgical reconstruction and replacement procedures to ensure normal knee kinematics and by extension, mechanics.     

Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer. The Cancer and Leukemia Group B

BACKGROUND: Both total dose and dose intensity of adjuvant chemotherapy are postulated to be important variables in the outcome for patients with operable breast cancer. The Cancer and Leukemia Group B study 8541 examined the effects of adjuvant treatment using conventional-range dose and dose intensity in female patients with stage II (axillary lymph node-positive) breast cancer. METHODS: Within 6 weeks of surgery (radical mastectomy, modified radical mastectomy, or lumpectomy), 1550 patients with unilateral breast cancer were randomly assigned to one of three treatment arms: high-, moderate-, or low-dose intensity. The patients received cyclophosphamide, doxorubicin, and 5-fluorouracil on day 1 of each chemotherapy cycle, with 5-fluorouracil administration repeated on day 8. The high-dose arm had twice the dose intensity and twice the drug dose as the low-dose arm. The moderate-dose arm had two thirds the dose intensity as the high-dose arm but the same total drug dose. Disease-free survival and overall survival were primary end points of the study. RESULTS: At a median follow-up of 9 years, disease-free survival and overall survival for patients on the moderate- and high-dose arms are superior to the corresponding survival measures for patients on the low-dose arm (two-sided P<.0001 and two-sided P = .004, respectively), with no difference in disease-free or overall survival between the moderate- and the high-dose arms. At 5 years, overall survival (average +/- standard error) is 79% +/- 2% for patients on the high-dose arm, 77% +/- 2% for the patients on the moderate-dose arm, and 72% +/- 2% for patients on the low-dose arm; disease-free survival is 66% +/- 2%, 61% +/- 2%, and 56% +/- 2%, respectively. CONCLUSION: Within the conventional dose range for this chemotherapy regimen, a higher dose is associated with better disease-free survival and overall survival.     

Stress (heat shock) proteins: molecular chaperones in cardiovascular biology and disease

Previously we have formulated transmission models of untreated tuberculosis epidemics (Blower et al., Nature, Medicine 1 (1995), 815-821); in this paper, we present time-dependent uncertainty and sensitivity analyses in order to quantitatively understand the transmission dynamics of tuberculosis epidemics in the absence of treatment. The time-dependent uncertainty analysis enabled us to evaluate the variability in the epidemiological outcome variables of the model during the progression of a tuberculosis epidemic. Calculated values (from the uncertainty analysis) for the disease incidence, disease prevalence, and mortality rates were approximately consistent with historical data. The time-dependent sensitivity analysis revealed that only a few of the model's input parameters significantly affected the severity of a tuberculosis epidemic; these parameters were the disease reactivation rate, the fraction of infected individuals who develop tuberculosis soon after infection, the number of individuals that an infectious individual infects per year, the disease death rate, and the population recruitment rate. Our analysis demonstrates that it is possible to improve our understanding of the behavior of tuberculosis epidemics by applying time-dependent uncertainty and sensitivity analysis to a transmission model.     

Biomechanical topography of human articular cartilage in the first metatarsophalangeal joint

The objective of this study was to provide a map of cartilage biomechanical properties, thickness, and histomorphometric characteristics in the human, cadaveric first metatarsophangeal joint, to determine if normal articular cartilage was predisposed topographically to biomechanical mismatches in articulating surfaces. Cartilage intrinsic material properties and thickness were obtained from seven pairs of human, freshly frozen, cadaveric, metatarsophalangeal joints using an automated creep indentation apparatus under conditions of biphasic creep. Eight sites were tested: four on the metatarsal head, two on the proximal phalanx base, and one on each sesamoid bone to obtain the aggregate modulus, Poisson's ratio, permeability, shear modulus, and thickness. Cartilage in the lateral phalanx site of the left metatarsal head had the largest aggregate modulus (1.34 MPa), whereas the softest tissue was found in the right medial sesamoid (0.63 MPa). The medial phalanx region of the right joint was the most permeable (4.56 x 10(-15) meter4/Newton-second), whereas the medial sesamoid articulation of the metatarsal head of the left joint was the least permeable (1.26 x 10(-15) meter4/Newton-second). Material properties and thickness are indicative of the tissue's functional environment. The lack of mismatches in cartilage biomechanical properties of the articulating surfaces found in this study may be supportive of clinical observations that early degenerative changes, in the absence of traumatic events, do not occur at the selected test sites in the human first metatarsophalangeal joint.     

Congenital arteriovenous fistula of internal thoracic artery: successfully managed by transcatheter embolization

Spatial contrast sensitivity was measured in kittens aged 6, 9, and 12 months and in adult cats. Cats had to open one of two small windows, which had a photograph of a grid, in order to obtain food reinforcement. The nonreinforced stimulus was a photograph of a uniform field of the same mean luminance. Visual acuity was constant in kittens aged 6 to 12 months. However, six-month-old kittens had low contrast sensitivity at low spatial frequencies (< 0.6 cycles/degree). At the age of nine months, contrast sensitivity over this range increased, though the level seen in adult cats was reached only at the age of 12 months. It is suggested that the increase in contrast sensitivity occurring after the critical developmental period in kittens reflects maturation of higher-order cortical fields involved in the process of recognition.     

Development and validation of an ion-exclusion chromatographic method for the quantitation of organic acids in complex pharmaceutical products

Fusobacterium nucleatum is a Gram-negative anaerobic rod implicated in the pathogenesis of periodontal disease. However, this organism has also been frequently identified in high numbers in healthy adults. These observations suggest that the species may comprise different clonal types, some of which may participate in disease. The purpose of the present investigation was to use restriction endonuclease analysis (REA) and ribotyping to characterize F. nucleatum clonal types isolated from healthy young adults with optimal plaque control and investigate the stability of some of these clonal types. A group comprising 11 dental students and 11 dental outpatients with optimal plaque control was sampled. Clonal stability was investigated by sampling the dental student group at baseline and at 16 months. One hundred and thirty-two clinical isolates of F. nucleatum were successfully recovered from 15/22 individuals. For the positive subjects, 29 different clonal types were identified by REA and ribotyping, each subject and site being colonized by 1-4 clonal types. For the dental students, 9 and 15 different clonal types were identified at baseline and 16 months, respectively. None of the students harboured identical clonal types at both sampling times. Our results show that ribotyping is a useful technique for monitoring the distributions of F. nucleatum clonal types and indicate that healthy individuals with optimal plaque control can be colonized by more than one F. nucleatum clonal type and that these clonal types appear to be unstable.     

Cortical granule exocytosis is triggered by different thresholds of calcium during fertilisation in sea urchin eggs

In sea urchin eggs, fertilisation is followed by a calcium wave, cortical granule exocytosis and fertilisation envelope elevation. Both the calcium wave and cortical granule exocytosis sweep across the egg in a wave initiated at the point of sperm entry. Using differential interference contrast (DIC) microscopy combined with laser scanning confocal microscopy, populations of cortical granules undergoing calcium-induced exocytosis were observed in living urchin eggs. Calcium imaging using the indicator Calcium Green-dextran was combined with an image subtraction technique for visual isolation of individual exocytotic events. Relative fluorescence levels of the calcium indicator during the fertilisation wave were compared with cortical fusion events. In localised regions of the egg, there is a 6s delay between the detection of calcium release and fusion of cortical granules. The rate of calcium accumulation was altered experimentally to ask whether this delay was necessary to achieve a threshold concentration of calcium to trigger fusion, or was a time-dependent activation of the cortical granule fusion apparatus after the 'triggering' event. Calcium release rate was attenuated by blocking inositol 1,4,5-triphospate (InsP3)-gated channels with heparin. Heparin extended the time necessary to achieve a minimum concentration of calcium at the sites of cortical granule exocytosis. The data are consistent with the conclusion that much of the delay observed normally is necessary to reach threshold concentration of calcium. Cortical granules then fuse with the plasma membrane. Further, once the minimum threshold calcium concentration is reached, cortical granule fusion with the plasma membrane occurs in a pattern suggesting that cortical granules are non-uniform in their calcium sensitivity threshold.