Validity of parental recall of children's fracture: implications for investigation of childhood osteoporosis.

UNLABELLED: Fracture history is an important component of osteoporosis diagnosis in children. One in six parentally reported lifetime fractures in children were not confirmed on review of radiographs. Care should be taken to avoid unnecessary investigations for possible osteoporosis due to parental over-reporting of soft tissue injuries as fractures. INTRODUCTION: The diagnosis of osteoporosis in children requires either a vertebral compression fracture, or a significant fracture history (defined as ≥2 long bone fractures <10 years or ≥3 long bone fractures <19 years, excluding high impact fractures) and low bone mineral density. As children with frequent fractures might benefit from further evaluation, we determined whether parental reports of lifetime fracture were accurate compared to radiological reports and if they appropriately selected children for further consideration of osteoporosis. METHODS: Parents of children (<18 years) with a musculoskeletal injury completed a questionnaire on their child's fracture history, including age, site and mechanism of previous fracture(s). Radiological reports were reviewed to confirm the fracture. RESULTS: Six hundred sixty parents completed the questionnaire and reported 276 previous fractures in 207 children. An injury treated at our hospital was recorded in 214 of the 276 parentally reported fractures. Thirty-four of 214 (16 %) were not a confirmed fracture. An injury was recorded for all parentally reported fractures in 150 children, but for 21 % children, there were inaccurate details (no evidence of fracture, incorrect site or forgotten fractures) on parent report. Eighteen of 150 children had a significant fracture history on parental report alone, but following review of radiology reports, 2 of 18 (11 %) did not have clinically significant fracture histories. CONCLUSIONS: Approximately one in six fractures reported by parents to have occurred in their child's lifetime had not resulted in a fracture. One in nine children with a significant fracture history could have been investigated unnecessarily.

Cytotoxic T lymphocyte and natural killer cell responses to non-typeable Haemophilus influenzae.

Cytotoxic T lymphocytes (CTL) and natural killer (NK) cells have a key role in host defence against infectious pathogens, but their response to bacteria is not well characterized. Non-typeable Haemophilus influenzae is a major cause of respiratory tract infection including otitis media, sinusitis, tonsillitis and chronic bronchitis (especially in chronic obstructive pulmonary disease and bronchiectasis). This bacterium is also present in the pharynx of most healthy adults. The primary factor that may determine whether clinical disease occurs or not is the nature of the lymphocyte response. Here we examined the CTL cell and NK cell responses to nontypeable H. influenzae in healthy control subjects and in subjects who had bronchiectasis and recurrent bronchial infection with this bacterium. Cells were stimulated with live H. influenzae and intracellular cytokine production and release of cytotoxic granules measured. Control subjects had significantly higher levels of interferon gamma production by both CTL and NK cells, while levels of cytotoxic granule release were similar in both groups. The main lymphocyte subsets that proliferated in response to H. influenzae stimulation were the CTL and NK cells. The results suggest that CTL and NK cell responses may be important in preventing disease from nontypeable H. influenzae infection.

Systemic humoral immunity to non-typeable Haemophilus influenzae.

Non-typeable Haemophilus influenzae (NTHi) is a major cause of respiratory but rarely systemic infection. The host defence to this bacterium has not been well defined in patients with chronic airway infection. The aim of this study was to assess the effect of humoral immunity in host defence to NTHi. Responses were measured in control and bronchiectasis subjects who had recurrent bronchial infection. Antibody and complement-mediated killing was assessed by incubating NTHi with serum and the role of the membrane-attack complex and classical/alternate pathways of complement activation measured. The effect of one strain to induce protective immunity against other strains was assessed. The effect of antibody on granulocyte intracellular killing of NTHi was also measured. The results showed that both healthy control subjects and bronchiectasis patients all had detectable antibody to NTHi of similar titre. Both groups demonstrated effective antibody/complement-mediated killing of different strains of NTHi. This killing was mediated through the membrane-attack complex and the classical pathway of complement activation. Immunization of rabbits with one strain of NTHi resulted in protection from other strains in vitro. Antibody activated granulocytes to kill intracellular bacteria. These findings may explain why NTHi rarely causes systemic disease in patients with chronic respiratory mucosal infection and emphasize the potential importance of cellular immunity against this bacterium.

The diagnostic value of digital rectal examination in primary care for palpable rectal tumour.

BACKGROUND: Accurate digital rectal examination (DRE) enables the early diagnosis of palpable rectal tumour. We aimed at evaluating the diagnostic value of DRE performed by general practitioners (GPs), with respect to detecting the presence of a palpable rectal tumour. METHOD: All patients diagnosed to have a palpable rectal tumour via a 14-day cancer referral system between May and December 2006 were identified from the colorectal database. Patients referred by GPs during the same period as having a palpable rectal tumour were also identified by reviewing the 14-day cancer referrals. Sensitivity, specificity, positive and negative predictive value of a DRE in primary care were calculated by using these data. RESULTS: Between May and December 2006, 1069 patients were referred to the University Hospital of North Staffordshire to the 14-day urgent colorectal cancer referral service. Of these, 108 patients were referred as having a 'palpable rectal tumour'. Only 32 of the 108 were found to have a rectal lesion on examination in the hospital. Ten tumours were missed by GPs' DREs. CONCLUSION: Digital rectal examination in primary care for palpable rectal tumour has a sensitivity of 0.762, specificity of 0.917, positive predictive value of 0.296 and negative predictive value of 0.988. It is an inaccurate procedure and a poor predictor for palpable rectal tumour.

Chronic consumption of rebaudioside A, a steviol glycoside, in men and women with type 2 diabetes mellitus.

This trial evaluated the effects of 16 weeks of consumption of 1000mg rebaudioside A (n=60) a steviol glycoside with potential use as a sweetener, compared to placebo (n=62) in men and women (33-75 years of age) with type 2 diabetes mellitus. Mean+/-standard error changes in glycosylated hemoglobin levels did not differ significantly between the rebaudioside A (0.11+/-0.06%) and placebo (0.09+/-0.05%; p=0.355) groups. Changes from baseline for rebaudioside A and placebo, respectively, in fasting glucose (7.5+/-3.7mg/dL and 11.2+/-4.5mg/dL), insulin (1.0+/-0.64microU/mL and 3.3+/-1.5microU/mL), and C-peptide (0.13+/-0.09ng/mL and 0.42+/-0.14ng/mL) did not differ significantly (p>0.05 for all). Assessments of changes in blood pressure, body weight, and fasting lipids indicated no differences by treatment. Rebaudioside A was well-tolerated, and records of hypoglycemic episodes showed no excess vs. placebo. These results suggest that chronic use of 1000mg rebaudioside A does not alter glucose homeostasis or blood pressure in individuals with type 2 diabetes mellitus.

The hemodynamic effects of rebaudioside A in healthy adults with normal and low-normal blood pressure.

Rebaudioside A and stevioside are steviol glycosides extracted from the plant Stevia rebaudiana Bertoni and are used in several countries as food and beverage sweeteners. This randomized, double-blind trial evaluated the hemodynamic effects of 4weeks consumption of 1000mg/day rebaudioside A vs. placebo in 100 individuals with normal and low-normal systolic blood pressure (SBP) and diastolic blood pressure (DBP). Subjects were predominantly female (76%, rebaudioside A and 82%, placebo) with a mean age of approximately 41 (range 18-73) years. At baseline, mean resting, seated SBP/DBP was 110.0/70.3mmHg and 110.7/71.2mmHg for the rebaudioside A and placebo groups, respectively. Compared with placebo, rebaudioside A did not significantly alter resting, seated SBP, DBP, mean arterial pressure (MAP), heart rate (HR) or 24-h ambulatory blood pressures responses. These results indicate that consumption of as much as 1000mg/day of rebaudioside A produced no clinically important changes in blood pressure in healthy adults with normal and low-normal blood pressure.

Defense Responses in Grapevine Leaves Against Botrytis cinerea Induced by Application of a Pythium oligandrum Strain or Its Elicitin, Oligandrin, to Roots.

ABSTRACT Pythium oligandrum is known to display antagonistic activities against several species of pathogenic fungi. It also produces an elicitor of plant defense named oligandrin, which belongs to the elicitin family (10-kDa proteins synthesized by Phytophthora and Pythium species). Here, the potential of P. oligandrum or its purified elicitin to limit the progression of B. cinerea on grapevine leaf and the resulting plant-microorganism interactions are described. P. oligandrum or oligandrin were applied to roots, and changes in the ultrastructure and at the molecular level were examined. When B. cinerea was applied to leaves of pretreated plants, leaf invasion was limited and the protection level reached about 75%. On leaf tissues surrounding B. cinerea inoculation, modifications of cuticle thickness, accumulation of phenolic compounds, and cell wall apposition were observed, indicating that grapevine can be considered reactive to elicitins. No macroscopic hypersensitive reaction associated with the elicitation treatment was observed. At the molecular level, the expression of three defense-related genes (LTP-1, beta-1,3-glucanase, and stilbene synthase) was studied. RNAs isolated from B. cinerea-infected leaves of grapevine challenged or not with P. oligandrum or oligandrin were analyzed by real-time reverse transcription-polymerase chain reaction. In grapevine leaves, LTP-1 gene expression was enhanced in response to oligandrin, and RNA transcript levels of beta-1,3-glucanase and stilbene synthase increased in response to all treatments with different magnitude. Taken together, these results open new discussion on the concept of plant reactivity to elicitins, which has until now, been mainly based on plant hypersensitive responses.

Induction of in vitro tumoricidal activity in alveolar macrophages and monocytes from patients with lung cancer.

Human alveolar macrophages (AMs) and blood monocytes were obtained from 65 smoking and nonsmoking normal volunteers and 29 patients with lung cancer. The oxidative metabolic response of these cells was measured by superoxide anion production after incubation with lipopolysaccharide. In addition, tumoricidal activity of AMs and monocytes was assessed against [3H]thymidine-labeled tumor target cells. Smoking was associated with depressed AM superoxide anion responses in normals but not in patients. In contrast, smoking appeared to slightly elevate monocyte superoxide anion activity. AMs and monocytes exposed to lipopolysaccharide or recombinant gamma-interferon showed tumoricidal activity in all groups. Mean cytotoxicity values of smoking patients versus smoking normals and exsmoking patients versus nonsmoking normals were not significantly different. Smoking, however, in both patients and normals was associated with significantly (P less than 0.005) depressed AM cytotoxicity levels (less than 40%) compared to nonsmoking volunteers and exsmoking patients. Activated AMs from cancer patients and normals were cytotoxic against three different tumorigenic cell lines but not against a nontumorigenic line. No correlation between monocyte and AM cytotoxic activity within single individuals was found. We conclude that AM and monocytes from smoking and exsmoking patients can be activated after exposure to immunomodulators; however, smoking may be slightly suppressive to cytotoxic responses. These studies provide a rationale for clinical trials of immunomodulators in patients with lung cancer.

The Emotional Brain as a Predictor and Amplifier of Chronic Pain.

Human neuroimaging studies and complementary animal experiments now identify the gross elements of the brain involved in the chronification of pain. We briefly review these advances in relation to somatic and orofacial persistent pain conditions. First, we emphasize the importance of reverse translational research for understanding chronic pain-that is, the power of deriving hypotheses directly from human brain imaging of clinical conditions that can be invasively and mechanistically studied in animal models. We then review recent findings demonstrating the importance of the emotional brain (i.e., the corticolimbic system) in the modulation of acute pain and in the prediction and amplification of chronic pain, contrasting this evidence with recent findings regarding the role of central sensitization in pain chronification, especially for orofacial pain. We next elaborate on the corticolimbic circuitry and underlying mechanisms that determine the transition to chronic pain. Given this knowledge, we advance a new mechanistic definition of chronic pain and discuss the clinical implications of this new definition as well as novel therapeutic potentials suggested by these advances.

The structure of the human thyroxine binding globulin (TBG) gene.

A portion of the human X-chromosome (> 5 kb) encoding the translated portion of the thyroxine-binding globulin (TBG) gene was sequenced. The primary templates for sequencing were isolated from a human X-chromosome library (two positive plaques from 400,000 screened initially with a TBG cDNA probe) or were produced by PCR amplification using leucocyte genomic DNA as the amplification template. Potential hormone response elements (HREs) were identified at either end of the gene. These HREs have sequences based on the consensus half-site of thyroid hormone response elements, although it is unclear whether the structures are functional HREs. Other potential regulatory elements also were identified towards the 3' end of the gene.

Limitations of diagnostic criteria and assessment instruments for mental disorders. Implications for research and policy.

During the past 2 decades, psychiatric epidemiological studies have contributed a rapidly growing body of scientific knowledge on the scope and risk factors associated with mental disorders in communities. Technological advances in diagnostic criteria specificity and community case-identification interview methods, which made such progress feasible, now face new challenges. Standardized methods are needed to reduce apparent discrepancies in prevalence rates between similar population surveys and to differentiate clinically important disorders in need of treatment from less severe syndromes. Reports of some significant differences in mental disorder rates from 2 large community surveys conducted in the United States--the Epidemiologic Catchment Area study and the National Comorbidity Survey--provide the basis for examining the stability of methods in this field. We discuss the health policy implications of discrepant and/or high prevalence rates for determining treatment need in the context of managed care definitions of "medical necessity."

Human alveolar macrophage function: differences between smokers and nonsmokers.

Human alveolar macrophages and peripheral blood monocytes were obtained from smoking and nonsmoking normal volunteers. The macrophages and monocytes were incubated in vitro with bacterial lipopolysaccharide (LPS). The oxidative metabolic response of these cells was measured by superoxide anion production. Macrophages from smokers were suppressed in their superoxide anion response to LPS activation as compared to macrophages from nonsmokers. Monocytes from smokers and nonsmokers were not different. The cytotoxic properties of these macrophages and monocytes were assessed by an in vitro 3H-thymidine release assay against various allogeneic target cells. Macrophages and monocytes exposed to LPS were rendered tumoricidal. Macrophages from nonsmokers appeared to generate greater cytotoxic activity than macrophages from smokers. Macrophages from both smokers and nonsmokers were cytotoxic for three different tumorigenic cell lines but not for a nontumorigenic cell line. Monocytes from smokers and nonsmokers were not different in cytotoxic activity. We conclude that macrophages from both smokers and nonsmokers can be activated after exposure to LPS; however, macrophages from smokers may be slightly suppressed in their responses.

Stimulation of the growth hormone (GH)-insulin-like growth factor I axis by daily oral administration of a GH secretogogue (MK-677) in healthy elderly subjects.

Aging is associated with declining activity of the GH axis, possibly contributing to adverse body composition changes and increased incidence of cardiovascular disease. The stimulatory effects on the GH-insulin-like growth factor I (IGF-I) axis of orally administered MK-677, a GH-releasing peptide mimetic, were investigated. Thirty-two healthy subjects (15 women and 17 men, aged 64-81 yr) were enrolled in a randomized, double blind, placebo-controlled trial. They received placebo or 2, 10, or 25 mg MK-677, orally, once daily for 2 separate study periods of 14 and 28 days. At baseline and on day 14 of each study period, blood was collected every 20 min for 24 h to measure GH, PRL, and cortisol. Attributes of pulsatile GH release were assessed by 3 independent algorithms. MK-677 administration for 2 weeks increased GH concentrations in a dose-dependent manner, with 25 mg/day increasing mean 24-h GH concentration 97 +/- 23% (mean +/- SE; P < 0.05 vs. baseline). This increase was due to an enhancement of preexisting pulsatile GH secretion. GH pulse height and interpulse nadir concentrations increased significantly without significant changes in the number of pulses. With 25 mg/day MK-677 treatment, mean serum IGF-I concentrations increased into the normal range for young adults (141 +/- 21 microgram/L at baseline, 219 +/- 21 micrograms/L at 2 weeks, and 265 +/- 29 micrograms/L at 4 weeks; P < 0.05). MK-677 produced significant increases in fasting glucose (5.4 +/- 0.3 to 6.8 +/- 0.4 mmol/L at 4 weeks; P < 0.01 vs. baseline) and IGF-binding protein-3. Circulating cortisol concentrations did not change, and PRL concentrations increased 23%, but remained within the normal range. Once daily treatment of older people with oral MK-677 for up to 4 weeks enhanced pulsatile GH release, significantly increased serum GH and IGF-I concentrations, and, at a dose of 25 mg/day, restored serum IGF-I concentrations to those of young adults.

Trends in the evolution of the euglenid pellicle.

Trends in the evolution of the euglenid pellicle were described using phylogenetic methods on 18S rDNA, morphological, and combined data from 25 mostly phototrophic taxa. The tree topology from a total-evidence analysis formed a template for a synthetic tree that took into account conflicting results derived from the partitioned datasets. Pellicle character states that can only be observed with the assistance of transmission and scanning electron microscopy were phylogenetically mapped onto the synthetic tree to test a set of previously established homology statements (inferences made independently from a cladogram). The results permitted us to more confidently infer the ancestral-derived polarities of character state transformations and provided a framework for understanding the key cytoskeletal innovations associated with the evolution of phototrophic euglenids. We specifically addressed the character evolution of (1) the maximum number of pellicle strips around the cell periphery; (2) the patterns of terminating strips near the cell posterior end; (3) the substructural morphology of pellicle strips; (4) the morphology of the cell posterior tip; and (5) patterns of pellicle pores on the cell surface.

Coherent backscatter enhances reflection confocal microscopy.

When thin optically transparent specimens are grown on reflective substrates, contrast in reflection confocal microscopy is markedly enhanced. This enhanced contrast allows for the visualization of the thin filopodia and organelles contained within the neuritic processes of PC12 cells in culture. The characteristics of this contrast enhancement suggest that it arises because of interference between light scattered from the specimen and coherently backscattered illumination reflected off the substrate. This technique provides a method for visualizing living cells or other similarly transparent objects on opaque substrates in a nondestructive manner.

High prevalence of genital tract papillomavirus infection in female adolescents.

To investigate clinical condyloma, abnormal cervical cytologic findings, and evidence of human papillomavirus infections, 89 adolescent girls were examined. Cellular DNAs extracted from exfoliated cervical cells were examined for human papillomavirus genomic sequences by Southern transfer hybridization using 32P-labeled human papillomavirus DNA probes. Human papillomavirus sequences were detected in 12 (13%) young women, abnormal cytologic specimens in 21 (24%), and vulvar condylomas in 12 (13%). The human papillomavirus types identified included HPV-6/11 (four instances), which is known to be associated with benign lesions, and HPV-16, -18, and -31 (eight instances) which are considered to have oncogenic potential. Two young women were infected with both HPV-16 and -31. Human papillomavirus sequences were found in 48% of the young women with abnormal cytologic findings and in 3% of patients with normal cytologic findings (P less than .0001). Condylomatous changes in the cervical smear were associated with the presence of HPV-6/11 and mild dysplasia with the presence of HPV-16, -18, and -31. The presence of vulvar condylomas correlated with condylomatous changes in the cervical smear and with the recovery of HPV-6/11 from the cervical epithelium. The results indicate that the prevalence of human papillomavirus infections in this population is high and that a majority of the infections are with viruses associated with lower genital tract malignancies.

Heritable susceptibility for colitis in mice induced by IL-10 deficiency.

Severity of inflammatory bowel disease in IL-10 gene-targeted mice is in part determined by genetic background. In the current study, a targeted IL-10 gene was transferred into the C3H/HeJBir substrain, known to exhibit high T-cell and B-cell responses to enteric flora, and to be highly sensitive to colitigenic stress. IL-10-deficient C3H/HeJBir mice developed early onset colitis in contrast to IL-10-deficient C57BL/6J congenic mice. Histopathologic analysis of disease in C3H/HeJBir.Il10-/- and C57BL/6J.Il10-/- mice showed significant differences at all ages studied. Hybrids of these congenic strains (F1.Il10-/-) were produced to study the mode of inheritance as well as subphenotypes that correlated with histopathology. Lesions in F1 mice were intermediate between parental strains. C3H-contributed subphenotypes that correlated best with histopathology were peripheral blood granulocyte percentage, serum amyloid A concentration, spleen weight/body weight ratio, and mesenteric lymph node weight/ body weight ratio. Neither enhanced humoral immunity (secretory IgA, anti-Escherichia coli cellular membrane Ig) characteristic of C3H/HeJBir, nor T-cell percentages in peripheral blood correlated as well. This study represents a necessary step in elucidating murine genetic modifiers controlling colitis sensitivity.

Ultrastructure of Trimastix pyriformis (Klebs) Bernard et al.: similarities of Trimastix species with retortamonad and jakobid flagellates.

Trimastix pyriformis (Klebs 1893) Bernard et al. 1999, is a quadriflagellate, free-living, bacterivorous heterotrophic nanoflagellate from anoxic freshwaters that lacks mitochondria. Monoprotist cultures of this species contained naked trophic cells with anterior flagellar insertion and a conspicuous ventral groove. Bacteria were ingested at the posterior end of the ventral groove, but there was no persistent cytopharyngeal complex. The posterior flagellum resided in this groove, and bore two prominent vanes. A Golgi body (dictyosome) was present adjacent to the flagellar insertion. The kinetid consisted of four basal bodies, four microtubular roots, and associated fibers and bands. Duplicated kinetids, each with four basal bodies and microtubular root templates, appeared at the poles of the open mitotic spindle. Trimastix pyriformis is distinguishable from other Trimastix species on the basis of external morphology, kinetid architecture and the distribution of endomembranes. Trimastix species are most similar to jakobid flagellates, especially Malawimonas jakobiformis, and to species of the retortamonad genus Chilomastix. Retortamonads may have evolved from a Trimastix-like ancestor through loss of "canonical" (easily seen with electron microscopy) endomembrane systems and elaboration of cytoskeletal elements associated with the cytostome/cytopharynx complex.

Education and change in cognitive function. The Epidemiologic Catchment Area Study.

The association between educational attainment and decline in cognitive function over an interval of 1 year was examined for 14,883 subjects 18 years and older in the National Institute of Mental Health Epidemiologic Catchment Area Study. Cognitive function was assessed at both time points by the Mini-Mental State Examination (MMSE); cognitive decline was coded as a dichotomous variable and was defined as 1 if the subject's score had declined 3 or more points from the baseline MMSE score at the 1-year follow-up interview and as 0 otherwise. The association between educational attainment and decline in cognitive function over 1 year was examined in logistic regression models that were stratified by age group (< 65 years, > or = 65 years) and by baseline MMSE level (MMSE > 23, MMSE < or = 23). Covariates included age, baseline MMSE score, ethnicity, residence, lifetime diagnosis of abuse of alcohol or other drugs, and gender. In those with baseline MMSE > 23, education was a significant predictor of cognitive decline, not only in the elderly but also in younger subjects. Among those with baseline MMSE < or = 23, education was not a significant predictor of cognitive decline. The fact that education provides protection against cognitive decline even in those younger than 65 years, in whom the prevalence and incidence of dementia are very low, would seem to indicate that education or its correlates provides protection against processes other than dementia that might produce a decline in test performance in young persons.