PTH and bone material strength in hypoparathyroidism as measured by impact microindentation.

PTH levels might be associated with bone material strength as measured by impact microindentation. Resistance to microfracture is decreased in hypoparathyroidism and appears to be associated with more severe disease and to improve with PTH replacement. INTRODUCTION: PTH is a key regulator of bone structure and remodeling. When PTH is absent in hypoparathyroidism (HypoPT), bone mass is increased and remodeling is decreased. In addition to bone structure and remodeling, bone material properties contribute to fracture resistance. Yet little is known about the relationship between PTH and bone material properties. Impact microindentation provides a clinical assessment of microfracture resistance, measured as the bone material strength index (BMSi). METHODS: Case-control cross-sectional study of PTH levels and in vivo BMSi measurement by impact microindentation at the anterior tibia in HypoPT patients (n = 17) and in controls matched for age, sex, and menopausal status (n = 17), with follow-up in a subgroup of HypoPT patients (n = 5) after recombinant human parathyroid hormone (1-84) [rhPTH(1-84)] treatment. RESULTS: BMSi was positively associated with PTH levels in controls (r = 0.58, p = 0.02) and was 11% lower (p = 0.01) in HypoPT patients as compared with controls. In HypoPT, lower BMSi was associated with a trend toward greater supplemental calcium doses (p = 0.07). BMSi increased after rhPTH(1-84) treatment in the HypoPT patients who underwent repeat microindentation. CONCLUSIONS: PTH levels might be associated with bone material strength, although other factors might be contributory. In HypoPT, resistance to microfracture is decreased and may be associated with greater supplemental calcium doses and might increase with PTH replacement. It remains to be determined whether changes in bone remodeling and microarchitecture contribute to the effects of PTH on microfracture resistance.

An actuatable soft reservoir modulates host foreign body response.

The performance of indwelling medical devices that depend on an interface with soft tissue is plagued by complex, unpredictable foreign body responses. Such devices-including breast implants, biosensors, and drug delivery devices-are often subject to a collection of biological host responses, including fibrosis, which can impair device functionality. This work describes a milliscale dynamic soft reservoir (DSR) that actively modulates the biomechanics of the biotic-abiotic interface by altering strain, fluid flow, and cellular activity in the peri-implant tissue. We performed cyclical actuation of the DSR in a preclinical rodent model. Evaluation of the resulting host response showed a significant reduction in fibrous capsule thickness (P = 0.0005) in the actuated DSR compared with non-actuated controls, whereas the collagen density and orientation were not changed. We also show a significant reduction in myofibroblasts (P = 0.0036) in the actuated group and propose that actuation-mediated strain reduces differentiation and proliferation of myofibroblasts and therefore extracellular matrix production. Computational models quantified the effect of actuation on the reservoir and surrounding fluid. By adding a porous membrane and a therapy reservoir to the DSR, we demonstrate that, with actuation, we could (i) increase transport of a therapy analog and (ii) enhance pharmacokinetics and time to functional effect of an inotropic agent. The dynamic reservoirs presented here may act as a versatile tool to further understand, and ultimately to ameliorate, the host response to implantable biomaterials.

Trends in Dental Implant Use in the U.S., 1999-2016, and Projections to 2026.

Dental implants have become an increasingly popular treatment choice for replacing missing teeth. Yet, little is known about the prevalence and sociodemographic distribution of dental implant use in the United States. To address this knowledge gap, we analyzed data from 7 National Health and Nutrition Examination Surveys from 1999 to 2016. We estimated dental implant prevalence among adults missing any teeth for each survey period overall as stratified by sociodemographic characteristics. We calculated absolute and relative differences from 1999-2000 to 2015-2016 and fit logistic regression models to estimate changes over time. We also used multivariable logistic regression to estimate independent associations of sociodemographic covariates with the presence of any implant. We projected the proportion of patients treated with dental implants into the year 2026 under varying assumptions of how the temporal trend would continue. There has been a large increase in the prevalence of dental implants, from 0.7% in 1999 to 2000 to 5.7% in 2015 to 2016. The largest absolute increase in prevalence (12.9%) was among individuals 65 to 74 y old, whereas the largest relative increase was ~1,000% among those 55 to 64 y old. There was an average covariate-adjusted increase in dental implant prevalence of 14% per year (95% CI, 11% to 18%). Having private insurance (vs. none or public insurance) or more than a high school education (vs. high school or less) was each associated with a 2-fold increase in prevalence, with an almost 13-fold (95% CI, 8 to21) increase for older adults. Dental implant prevalence projected to 2026 ranged from 5.7% in the most conservative scenario to 23% in the least. This study demonstrates that dental implant prevalence among US adults with missing teeth has substantially increased since 1999. Yet access overall is still very low, and prevalence was consistently higher among more advantaged groups.

Assessment of in vitro pharmacological effect of Neotropical Piperaceae in GABAergic bioassays in relation to plants traditionally used for folk illness by the Yanesha (Peru).

ETHNOPHARMACOLOGICAL RELEVANCE: A previous pilot ethnobotanical and ethnopharmacological study with the Q'echi׳ Maya identified the family Piperaceae, as an important taxonomic group traditionally used for the treatment of epileptic and culture-bound anxiety disorders and possessing activity in the GABA system. Following that lead, a botanical survey was conducted in Peru, where 47 species of Piperaceae were collected including 21 plants traditionally used for folk illnesses by the Yanesha of Peru, an indigenous Amazonian group. MATERIALS AND METHODS: Two high throughput bioassays were used to quantify the in vitro activity of botanical extracts on the GABA system. RESULTS: Plant extracts demonstrated moderate to high affinity to the γ-aminobutyric acid benzodiazepine (GABA-BZD) receptor. In addition, extracts demonstrated low to moderate activity in the inhibition of the GABA-transaminase, with select plants exhibiting significant activity. Plants indicated by the Yanesha showed comparable activity to the other Piperaceae plants collected. Piper cremii was the most active plant in the GABA-BZD receptor assay, and Drymaria cordata (Caryophyllaceae) in the GABA-T assay. CONCLUSION: The study provides evidence that there is a pharmacological basis behind the use of plants in the treatment of susto and mal aire in both Central and South America, and we propose that the possible mechanism of action includes an interaction with the GABA-T enzyme and/or the GABAA-BZD receptor.

White-spot lesions and gingivitis microbiotas in orthodontic patients.

White-spot lesions (WSL) associated with orthodontic appliances are a cosmetic problem and increase risk for cavities. We characterized the microbiota of WSL, accounting for confounding due to gingivitis. Participants were 60 children with fixed appliances, aged between 10 and 19 yrs, half with WSL. Plaque samples were assayed by a 16S rRNA-based microarray (HOMIM) and by PCR. Mean gingival index was positively associated with WSL (p = 0.018). Taxa associated with WSL by microarray included Granulicatella elegans (p = 0.01), Veillonellaceae sp. HOT 155 (p < 0.01), and Bifidobacterium Cluster 1 (p = 0.11), and by qPCR, Streptococcus mutans (p = 0.008) and Scardovia wiggsiae (p = 0.04) Taxa associated with gingivitis by microarray included: Gemella sanguinis (p = 0.002), Actinomyces sp. HOT 448 (p = 0.003), Prevotella cluster IV (p = 0.021), and Streptococcus sp. HOT 071/070 (p = 0.023); and levels of S. mutans (p = 0.02) and Bifidobacteriaceae (p = 0.012) by qPCR. Species' associations with WSL were minimally changed with adjustment for gingivitis level. Partial least-squares discriminant analysis yielded good discrimination between children with and those without WSL. Granulicatella, Veillonellaceae and Bifidobacteriaceae, in addition to S. mutans and S. wiggsiae, were associated with the presence of WSL in adolescents undergoing orthodontic treatment. Many taxa showed a stronger association with gingivitis than with WSL.

Three-dimensional head shape quantification for infants with and without deformational plagiocephaly.

OBJECTIVE: The authors developed and tested three-dimensional (3D) indices for quantifying the severity of deformational plagiocephaly (DP). DESIGN: The authors evaluated the extent to which infants with and without DP (as determined by clinic referral and two experts' ratings) could be correctly classified. PARTICIPANTS: Infants aged 4 to 11 months, including 154 with diagnosed DP and 100 infants without a history of DP or other craniofacial condition. After excluding participants with discrepant expert ratings, data from 90 infants with DP and 50 infants without DP were retained. MEASUREMENTS: Two-dimensional (2D) histograms of surface normal vector angles were extracted from 3D mesh data and used to compute the severity scores. OUTCOME MEASURES: Left posterior flattening score (LPFS), right posterior flattening score (RPFS), asymmetry score (AS), absolute asymmetry score (AAS), and an approximation of a previously described 2D measure, the oblique cranial length ratio (aOCLR). Two-dimensional histograms localized the posterior flatness for each participant. ANALYSIS: The authors fit receiver operating characteristic curves and calculated the area under the curves (AUC) to evaluate the relative accuracy of DP classification using the above measures. RESULTS: The AUC statistics were AAS = 91%, LPFS = 97%, RPFS = 91%, AS = 99%, and aOCLR = 79%. CONCLUSION: Novel 3D-based plagiocephaly posterior severity scores provided better sensitivity and specificity in the discrimination of plagiocephalic and typical head shapes than the 2D measurements provided by a close approximation of OCLR. These indices will allow for more precise quantification of the DP phenotype in future studies on the prevalence of this condition, which may lead to improved clinical care.

Persistence of oral Candida albicans carriage in healthy Portuguese schoolchildren followed for 3 years.

Little is known about carriage of Candida albicans, the predominant pathogenic yeast in oral infection, in children. We cultured buccal mucosal and gingival swabs from 150 Portuguese children to investigate the prevalence of C. albicans at baseline (before dental treatment), post-treatment, and 12, 24, and 36 months post-baseline. The children, aged 8 to 11 years at baseline, had no systemic disease or clinical symptoms of oral candidiasis. At each successive visit, respectively, 47, 32, 21, 27, and 28% of children were C. albicans positive, resulting in an almost 50% reduction in prevalence from baseline to post-treatment (P < 0.0005). Children who carried C. albicans at one visit had 3 to 20 times greater odds of carrying C. albicans at another visit. C. albicans was cultured from 12 children at all time-points and from 10 children at four time-points. Children with oral C. albicans frequently maintained carriage over time, even with regular dental care.

Serologic evidence of herpes simplex virus 1 infection and oropharyngeal cancer risk.

In vitro and animal models suggest that the herpes simplex virus 1 (HSV1) may contribute to the development of oropharyngeal squamous cell carcinoma (OSCC). To determine whether the risk of OSCC is related to infection with HSV1 in humans, we recruited 260 patients from 18 to 65 years old who were newly diagnosed with OSCC between 1990-1995 while residing in three western Washington State counties. For comparison, we recruited at random 445 controls frequency matched to cases on age and sex. Participants completed in-person interviews and provided serum samples that were tested for antibody response to HSV1. After adjusting for sex, cigarette smoking, alcohol consumption, age, and income, HSV1 antibody positivity was associated with a slightly increased risk of OSCC [adjusted odds ratio (OR), 1.3; 95% confidence interval (CI), 0.9-2.0]. The adjusted association between HSV1 antibody positivity and OSCC risk among those who were current cigarette smokers (OR, 4.2; CI, 2.4-7.1) was stronger than would be predicted based on the additive combination of smoking alone (OR, 2.3; CI, 1.2-4.2) and HSV1 seropositivity alone (OR, 1.0; CI, 0.6-1.7). There was suggestive evidence that the association between HSV1 infection and OSCC was similarly modified by evidence of HPV infection but no evidence of effect modification with alcohol consumption. This population-based study suggests that HSV1 may enhance the development of OSCC in individuals who are already at increased risk of the disease because of cigarette smoking or HPV infection.

Risk of recurrent coronary events in relation to use and recent initiation of postmenopausal hormone therapy.

BACKGROUND: The finding from the Heart and Estrogen/Progestin Replacement Study (HERS) of increased coronary risk restricted to the first year after starting postmenopausal hormone therapy raises new questions about the role of hormone therapy in women with coronary heart disease. We assessed the risk of recurrent myocardial infarction or coronary heart disease death associated with the use and recent initiation of hormone therapy in women who survived a first myocardial infarction. METHODS: The setting for this population-based inception cohort study was Group Health Cooperative, a health maintenance organization. We studied 981 postmenopausal women who survived to hospital discharge after their first myocardial infarction between July 1, 1986, and December 31, 1996. We obtained information on hormone use from the Group Health Cooperative computerized pharmacy database and identified recurrent coronary events by medical record review. RESULTS: During median follow-up of 3.5 years, there were 186 recurrent coronary events. There was no difference in the risk of recurrent coronary events between current users of hormone therapy and other women (adjusted relative hazard [RH], 0.96; 95% confidence interval [CI], 0.62-1.50). Relative to the risk in women not currently using hormones, there was a suggestion of increased risk during the first 60 days after starting hormone therapy (RH, 2.16; 95% CI, 0.94-4.95) and reduced risk with current hormone use for longer than 1 year (RH, 0.76; 95% CI, 0.42-1.36). CONCLUSION: These results are consistent with the findings from the HERS, suggesting a transitory increase in coronary risk after starting hormone therapy in women with established coronary heart disease and a decreased risk thereafter.

Using census data and birth certificates to reconstruct the early-life socioeconomic environment and the relation to the development of Alzheimer's disease.

The early-life environment and its effect on growth and maturation of children and adolescents are associated with several adult chronic diseases, including Alzheimer's disease. Because it is not feasible to collect information prospectively over the average life span, methods to reconstruct the early-life environment of the aged are necessary to evaluate these associations. In a community-based case-control study conducted in the United States, we collected U.S. census records and birth certificates to reconstruct the early-life socioeconomic environment of each elderly subject. Information was found on 82% of the available Alzheimer's disease cases (239 of 292) and 87% of the available controls (245 of 282). We investigated risk of Alzheimer's disease associated with father's occupation, parental age, household size, sibship size, and birth order. Subjects whose fathers were unskilled manual workers or laborers were at higher risk for Alzheimer's disease (odds ratio = 1.80, 95% confidence interval = 1.19--2.73). The risk of Alzheimer's disease was increased with increasing number of people in the household. We also evaluated whether subjects with the apolipoprotein epsilon 4 allele (APOE epsilon 4), a strong genetic risk factor that is not a necessary cause or a sufficient cause by itself for the development of Alzheimer's disease, were at higher risk than subjects who did not carry this allele. Among subjects with the APOE epsilon 4 allele whose fathers held lower-socioeconomic level occupations, the odds of developing Alzheimer's disease were higher (odds ratio = 2.35, 95% confidence interval = 1.07--5.16) compared with subjects without the allele (odds ratio = 1.40, 95% confidence interval = 0.78--2.52). Subjects carrying the APOE epsilon 4 allele alone have a threefold increased risk of Alzheimer's disease (odds ratio = 3.17, 95% confidence interval = 1.99--5.04). Compared with subjects with neither risk factor, subjects with both the genetic and the environmental risk factors (household size of seven or more and father's occupation being manual) had a relatively high risk of Alzheimer's disease (odds ratio = 14.8, 95% confidence interval = 4.9--46). The data suggest that APOE epsilon 4 may modify the associations between father's occupation, other early-life environmental factors, and development of Alzheimer's disease in late life.

The phylogenetic position of Carex section Phyllostachys and its implications for phylogeny and subgeneric circumscription in Carex (Cyperaceae).

Wide speculation surrounds the origin and phylogenetic relationships of the most highly reduced sections in the genus Carex. In order to gain a better understanding of phylogeny in Carex, the relationship of the reduced sect. Phyllostachys to 12 putatively related sections, representing all four subgenera (Primocarex, Indocarex, Carex, Vignea), was inferred from sequences of the ITS (internal transcribed spacer) region of nrDNA. Phylogenetic reconstructions identified two main clades: (1) a "compound" clade composed of sections from subg. Indocarex, Primocarex, and a portion of subg. Carex, and (2) a "reduced" clade consisting of sections from subg. Carex (Phyllostachys) and Primocarex (Filifoliae and Firmiculmes). Subgenus Indocarex was paraphyletic within the "compound" clade supporting classifications that have merged it within a wider subg. Indocarex/Carex/Primocarex line. Subgenus Primocarex was polyphyletic. This result was consistent with theories that extreme reduction has occurred along several different evolutionary lines in Carex. Phylogenetic theories inferred from the presence or abnormal growth of the rachilla were not supported by tree topologies. Difficult sectional circumscriptions, such as the separation of sections Laxiflorae and Careyanae, were strongly upheld by sequence data. The ITS region is an effective tool for defining sectional limits and for estimating relationships among sections in Carex, but does not provide enough phylogenetic information to fully resolve relationships below the sectional level.

Structure of bovine pancreatic cholesterol esterase at 1.6 A: novel structural features involved in lipase activation.

The structure of pancreatic cholesterol esterase, an enzyme that hydrolyzes a wide variety of dietary lipids, mediates the absorption of cholesterol esters, and is dependent on bile salts for optimal activity, is determined to 1.6 A resolution. A full-length construct, mutated to eliminate two N-linked glycosylation sites (N187Q/N361Q), was expressed in HEK 293 cells. Enzymatic activity assays show that the purified, recombinant, mutant enzyme has activity identical to that of the native, glycosylated enzyme purified from bovine pancreas. The mutant enzyme is monomeric and exhibits improved homogeneity which aided in the growth of well-diffracting crystals. Crystals of the mutant enzyme grew in space group C2, with the following cell dimensions: a = 100.42 A, b = 54.25 A, c = 106.34 A, and beta = 104.12 degrees, with a monomer in the asymmetric unit. The high-resolution crystal structure of bovine pancreatic cholesterol esterase (Rcryst = 21.1%; Rfree = 25.0% to 1.6 A resolution) shows an alpha-beta hydrolase fold with an unusual active site environment around the catalytic triad. The hydrophobic C terminus of the protein is lodged in the active site, diverting the oxyanion hole away from the productive binding site and the catalytic Ser194. The amphipathic, helical lid found in other triglyceride lipases is truncated in the structure of cholesterol esterase and therefore is not a salient feature of activation of this lipase. These two structural features, along with the bile salt-dependent activity of the enzyme, implicate a new mode of lipase activation.

Inhibition of acyl coenzyme A:cholesterol acyltransferase blocks esterification but not uptake of cholesterol in Caco-2 cells.

The effects of cholesterol esterase (CEase) and acyl coenzyme A:cholesterol acyltransferase (ACAT) inhibitors on the uptake and esterification of cholesterol in Caco-2 cells were examined. CEase increased the uptake of [3H]cholesterol from bile salt mixed-micelles by 2.5- to 3.0-fold and its esterification by greater than 25-fold. Inhibition of cellular ACAT activity with CL277082 or CP113818 had little or no effect on cholesterol uptake measured in the presence or absence of CEase. The subsequent esterification of [3H]cholesterol was reduced greater than 90% by each ACAT inhibitor. Similar results were obtained in cells in which ACAT activity was induced by preincubation either with 25-hydroxycholesterol and mevalonic acid or with CEase and bile salt mixed-micelles containing 100 micromol/L cholesterol. Neither ACAT inhibitor had an effect on CEase-mediated synthesis or hydrolysis of cholesteryl oleate in vitro. Thus, the uptake of cholesterol from bile salt mixed-micelles in the presence or absence of CEase was not regulated by the level of cellular ACAT expression. The subsequent esterification of exogenous sterol was not due to CEase, but was completely dependent on ACAT activity. The dissociation of cholesterol uptake from ACAT activity suggests that the factors controlling the transfer of sterol from extracellular media to the cell are different from the factors regulating the cellular level of cholesterol esterification.

Phosphatidylcholine hydrolysis is required for pancreatic cholesterol esterase- and phospholipase A2-facilitated cholesterol uptake into intestinal Caco-2 cells.

Pancreatic secretion is required for efficient cholesterol absorption by the intestine, but the factors responsible for this effect have not been clearly defined. To identify factors involved and to investigate their role in cholesterol uptake, we studied the effect of Viokase(R), a porcine pancreatic extract, on cholesterol uptake into human intestinal Caco-2 cells. Viokase is capable of facilitating cholesterol uptake into these cells such that the level of uptake is 5-fold higher in the presence of solubilized Viokase. This stimulation is time-dependent and is dependent on the presence of bile salt. However, bile salt-stimulated pancreatic cholesterol esterase, which has been proposed to mediate cholesterol uptake, is not fully responsible. The major cholesterol transport activity was purified and identified as pancreatic phospholipase A2. Anti-phospholipase A2 antibodies abolished virtually all of the phospholipase A2 and cholesterol transport activity of solubilized Viokase. We demonstrate that both phospholipase A2 and cholesterol esterase increase cholesterol uptake by hydrolyzing the phosphatidylcholine that is used to prepare the cholesterol-containing micelles. In the absence of cholesterol esterase or phospholipase A2, uptake of cholesterol from micelles containing phosphatidylcholine is not as efficient as uptake from micelles containing phospholipase A2-hydrolytic products. These results indicate that phospholipase A2 may mediate cholesterol absorption by altering the physical-chemical state of cholesterol within the intestine.

Forecasting the peak of gastrointestinal nematode infection in lambs.

The pattern of sheep nematode infective larvae on pasture shows a marked midsummer peak arising largely from the ewe peri-parturient egg output. Records of larval pattern over a nine-year period were examined in relation to meteorological data, and a correlation was demonstrated between the time of the summer peak and cumulative rainfall. A "wet score" was allocated to 12-hourly rainfall figures, and a "critical index" of 440 units of wetness was shown to be necessary before the larval peak was reached. A "warning index" of 350 to 380 wetness units is suggested which would allow a prediction to be made of the onset of major infection in lambs.

Simultaneous measurements of clear air turbulence at the tropopause by high-power radar and instrumented aircraft.

Large amplitude Kelvin-Helmholtz billows observed by radar at a height of almost 11 km are shown to have been associated with clear air turbulence which produced a vertical aircraft acceleration of 0.65g.