The prevalence and distribution of Anaplasma phagocytophilum genotypes in Ixodes ricinus nymphs collected from farm- and woodland sites in Ireland.

Despite the economic importance of grass-based livestock production in Ireland and the fact that many veterinarians and farmers regard tickborne fever (TBF) as an increasingly important disease, especially in sheep, little is currently known about the prevalence and genetic diversity of its causative agent, Anaplasma phagocytophilum. In the present study, 1376 nymphal Ixodes ricinus ticks collected from woodland, farmland, bog and limestone pavement habitats were screened for A. phagocytophilum using TaqMan PCR. Positive samples were further analysed by conventional nested PCR targeting the 16S rRNA, msp4 and groEL loci. Overall 4.5% I. ricinus nymphs were found to be infected. The genetic heterogeneity was comparable to that reported elsewhere in Europe, with greater genetic diversity of 16S variants in ticks collected from farmland than from woodland. All isolates belonged to groEL ecotype I indicating that rodents and birds do not contribute to the epidemiology of tickborne fever in Ireland. In the 16S and groEL loci, a number of the Irish isolates matched European sequences from humans, horses and dogs. The 16S sequences that were identical to human isolates from Europe also matched Ap-ha, the most common human pathogenic strain in the USA. Three isolates also matched published sequences from horses in the msp4 locus. No isolate matched human, equine and canine sequences in all 3 loci. Our results represent the first molecular characterization of Irish A. phagocytophilum isolates.

Mutational and biochemical findings in adults with persistent hypophosphatasemia.

A majority of adults with persistently low serum alkaline phosphatase values carry a pathogenic or likely pathogenic variant in the ALPL gene and also have elevated alkaline phosphatase substrate values in serum and urine. These adults may fall within the spectrum of the adult form of hypophosphatasia. INTRODUCTION: The primary objective of this study was to determine what proportion of adults with persistently low serum alkaline phosphatase values (hypophosphatasemia) harbor mutations in the ALPL gene or have elevated alkaline phosphatase (ALP) substrates. Some adults with persistent hypophosphatasemia share clinical and radiographic features with the adult form of hypophosphatasia (HPP). In HPP, ALPL mutations result in persistent hypophosphatasemia and ALP substrate accumulation in plasma (pyridoxal-5-phosphate (PLP)) and urine (phosphoethanolamine (PEA)). METHODS: Biochemical analyses, including serum ALP activity, bone-specific ALP, plasma PLP, and urine PEA, were performed in adults with persistent hypophosphatasemia. Mutational analyses were performed using PCR and Sanger sequencing methods. Gene variants were classified as pathogenic (P), likely pathogenic (LP), variants of uncertain significance (VUS), likely benign (LB), and benign (B). P and LP variants were further grouped as "Positive ALPL variants" and LB and B grouped as "Negative ALPL variants." RESULTS: Fifty subjects completed all mutational and biochemical analyses. Sixteen percent carried only Negative ALPL variants. Of the remaining 42 subjects, 67% were heterozygous for a P variant, 19% for an LP variant, and 14% for a VUS. Biochemical results were highly inter-correlated and consistent with the expected inverse relationship between ALP and its substrates. Subjects harboring Positive ALPL variants showed lower ALP and BSAP and higher PLP and PEA values compared with subjects harboring only Negative ALPL variants. Approximately half of all subjects harboring Positive ALPL variants or ALPL VUS showed elevations in plasma PLP, and three quarters showed elevations in urine PEA. CONCLUSION: Adults with persistent hypophosphatasemia frequently harbor ALPL mutations and have elevated ALP substrates. These adults may fall within the spectrum of the adult form of hypophosphatasia. Clinicians should take note of persistent hypophosphatasemia in their patients and be cautious in prescribing bisphosphonates when present.

Clinician approach to diagnosis of stress fractures including bisphosphonate-associated fractures.

Stress fractures are repetitive strain injuries that occur in normal bones and in abnormal bones. Stress fractures share many features in common but differences depend on the status of the underlying bone. This review article for clinicians addresses aspects about stress fractures with particular respect to fatigue fractures, Looser zones of osteomalacia, atypical Looser zones, atypical femoral fractures associated with bisphosphonate therapy and stress fractures in Paget's disease of bone.

Use of a performance algorithm improves utilization of vertebral fracture assessment in clinical practice.

SUMMARY: A performance algorithm can be successfully used by bone density technologists at the time of a bone density test to identify patients with an indication for vertebral fracture assessment (VFA). Doing so appropriately increases physician prescription of fracture prevention medication. INTRODUCTION: Densitometric spine imaging (vertebral fracture assessment, VFA) can identify prevalent vertebral fracture but is underutilized. We developed an algorithm by which DXA technologists identify patients for whom VFA should be performed. Following this algorithm, VFA was performed in patients whose lowest T-score (lumbar spine, total hip, or femoral neck) was between -1.5 and -2.4 inclusive and with one of the following: age, ≥ 65 years; height loss, ≥ 1.5 in.; or current systemic glucocorticoid therapy. Our main objectives were to assess change in VFA utilization at two other healthcare organizations after algorithm implementation, and to estimate the association of VFA results with prescription of fracture prevention medication. METHODS: The proportions of patients with an indication for VFA who had one performed before and after algorithm implementation were compared. Logistic regression was used to estimate the multivariable-adjusted association of VFA results with subsequent prescription of fracture prevention medication adjusted for healthcare organization (study site). RESULTS: After algorithm introduction, appropriate VFA use rose significantly Patients with a VFA positive for vertebral fracture had an odds ratio of 3.2 (95 % C.I., 2.1- 5.1) for being prescribed new fracture prevention medication, adjusted for age, sex, prior clinical fracture, use of glucocorticoid medication, femoral neck bone mineral density T-score, and study site. CONCLUSIONS: An algorithm to identify those for whom VFA is indicated can successfully be implemented by DXA technologists. Documentation of vertebral fracture increases prescription of fracture prevention medication for patients who otherwise lack an apparent indication for such therapy.

Acute hypophosphatasemia.

UNLABELLED: The temporal evolution of a low serum alkaline phosphatase value may relate to its cause. Precipitous lowering of serum alkaline phosphatase below the lower range of normal is uncommon and may indicate severe physiologic stress and increased short-term mortality. INTRODUCTION: The differential diagnosis of a low serum alkaline phosphatase (ALP) value (hypophosphatasemia) is wide ranging, anecdotal, and unfamiliar. The temporal evolution of hypophosphatasemia may relate to its cause. The purpose of this study is to report conditions and circumstances associated with precipitous lowering of serum ALP below the lower range of normal. METHODS: Marshfield Clinic IRB approved use of their electronic medical record to search for subjects with at least two serum ALP values ≤ 40 U/L (normal 40-125 U/L). When the temporal evolution of the qualifying ALP values indicated a precipitous lowering from usually normal serum ALP values, the subject was deemed to have acute hypophosphatasemia. Thirty years of laboratory data and 10 years of clinical narrative were analyzed. Associated diagnoses, clinical circumstances, and short-term mortality were recorded. RESULTS: A total of 458,767 subjects had 2,584,051 serum ALP values, and 5,190 (1.1 %) subjects had at least two serum values ≤ 40 U/L. A detailed review of 1,276 subjects selected on the basis of their lowest ALP value and age identified 190 subjects with acute hypophosphatasemia. Acute hypophosphatasemia was recorded during periods of major trauma/surgery, multisystem failure, acute anemia, blood product transfusions (often massive), apheresis, hypomagnesemia, and acute caloric restriction. Twenty-eight subjects (15 %) died within 35 days of their nadir serum ALP. CONCLUSION: Acute hypophosphatasemia is associated with profound illness or physiologic stress and followed by increased short-term mortality. The temporal evolution of hypophosphatasemia may relate to its cause.

The effect of teriparatide compared with risedronate on reduction of back pain in postmenopausal women with osteoporotic vertebral fractures.

UNLABELLED: The effect of teriparatide and risedronate on back pain was tested, and there was no difference in the proportion of patients experiencing a reduction in back pain between groups after 6 or 18 months. Patients receiving teriparatide had greater increases in bone mineral density and had fewer vertebral fractures. INTRODUCTION: This study aimed to understand the effect of teriparatide in reducing back pain in patients with prevalent back pain and vertebral fracture compared to risedronate. METHODS: In an 18-month randomized, double-blind, double-dummy trial, we investigated the effects of teriparatide (20 µg/day) vs. risedronate (35 mg/week) in postmenopausal women with back pain likely due to vertebral fracture. The primary objective was to compare the proportion of subjects reporting ≥30% reduction in worst back pain severity from baseline to 6 months as assessed by a numeric rating scale in each treatment group. Pre-specified secondary and exploratory outcomes included assessments of average and worst back pain at additional time points, disability and quality of life, bone mineral density, incidence of fractures, and safety. RESULTS: At 6 months, 59% of teriparatide and 57% of risedronate patients reported ≥30% reduction in worst back pain and there were no differences between groups in the proportion of patients experiencing reduction in worst or average back pain at any time point, disability, or quality of life. There was a greater increase from baseline in bone mineral density at the lumbar spine (p = 0.001) and femoral neck (p = 0.02) with teriparatide compared to risedronate and a lower incidence of vertebral fractures at 18 months (4% teriparatide and 9% risedronate; p = 0.01). Vertebral fractures were less severe (p = 0.04) in the teriparatide group. There was no difference in the overall incidence of adverse events. CONCLUSIONS: Although there were no differences in back pain-related endpoints, patients receiving teriparatide had greater skeletal benefit than those receiving risedronate.

The utility of BMD Z-score diagnostic thresholds for secondary causes of osteoporosis.

UNLABELLED: This very large dual X-ray absorptiometry (DXA) cohort confirmed a significant, inverse relationship between bone mineral density (BMD) Z-scores and the presence of secondary causes of osteoporosis but receiver operating characteristic (ROC) curves indicate that Z-score diagnostic thresholds (such as -2.0) discriminate poorly between the presence and absence of secondary causes of osteoporosis. INTRODUCTION: BMD Z-score diagnostic thresholds have been proposed to detect secondary causes of osteoporosis. To determine the sensitivity and diagnostic utility of such thresholds, we analyzed comprehensive BMD and personal health information data from a large, multispecialty group practice. METHODS: Adult subjects were assigned their lowest axial BMD Z-score and ICD-9 diagnosis codes for secondary causes of osteoporosis when cited at least twice in their electronic medical record. Multiple logistic regression was used to model the prevalence of matching ICD-9 codes as a function of Z-score. ROC curves were used to investigate various Z-score cut points for sensitivity and specificity. RESULTS: Eighteen thousand six hundred seventy-four subjects were analyzed. Secondary causes of osteoporosis were identified in 31% of men and 16% of women. The frequency of secondary causes varied with age and between genders and varied inversely with Z-score. No inflection point was observed in this relationship to suggest a useful clinical decision threshold. The difference in mean Z-score of those with and without a secondary cause of osteoporosis was biologically slight (±0.3). Low Z-score diagnostic thresholds were insensitive to the presence of secondary causes of osteoporosis and provided relatively poor predictive value. CONCLUSIONS: This DXA cohort confirmed a significant inverse relationship between Z-score and the presence of secondary causes of osteoporosis but diagnostic Z-score thresholds discriminate poorly between the presence and absence of secondary causes of osteoporosis. If only patients with very low Z-scores are evaluated for secondary causes of osteoporosis the diagnostic specificity may be high but most cases will be missed.

The role of cigarette smoking and statins in the development of postmenopausal osteoporosis: a pilot study utilizing the Marshfield Clinic Personalized Medicine Cohort.

SUMMARY: A cohort of postmenopausal osteoporotic females and controls with normal bone mineral density, the interleukin 6 (IL6) -634G > C (rs1800796) C allele of the promoter region showed association with osteoporosis. The lipoprotein receptor-related protein 5 (LRP5) gene showed association between C135242T C/T alleles and osteoporosis only in smokers, suggesting a role for environmental interaction. INTRODUCTION: A nested case-control study within a population-based cohort was undertaken to assess the relative impact of cigarette smoking, statin use, genetic polymorphisms, and one-way interaction of these factors on development of osteoporosis in postmenopausal women. METHODS: Genotyping of 14 single-nucleotide polymorphisms (SNPs) corresponding to vitamin D receptor gene, estrogen receptor 1, collagen type 1 alpha 1, IL6, transcription growth factor beta, apolipoprotein E, and LRP5 genes was performed in cases (n = 309) with osteoporosis and controls (n = 293) with normal bone mineral density drawn from a homogeneous Caucasian population. SNPs were chosen based on known functional consequences or prior evidence for association and genotyped using matrix-assisted laser desorption ionization time-of-flight technology. RESULTS: Cases differed from controls relative to body mass index, age, and smoking but not statin use. After adjusting for age, the IL6 -634G > C (rs1800796) allele showed association with osteoporosis (odds ratio (OR) for CC + CG = 2.51, p = 0.0047)), independent of statin use or smoking status. On stratification for smoking, association with LRP5 C135242T (rs545382) and osteoporosis emerged (OR 2.8 in smokers for CT alleles, p = 0.03)), suggestive of potential environmental interaction. CONCLUSION: Evidence suggested a role for genetic variation in IL6 and LRP5 in conferring risk for osteoporosis in Caucasian women, with the latter manifest only in smokers.

Short-term dietary compensation in free-living adults.

Evidence suggests that compensatory behaviors operate in infants and pre-school children, such that the high variance characteristic of single eating occasions is much reduced over the day. However, the concept has not been fully explored in adults. The present within-subject, observational study investigated short-term dietary compensation patterns in fifty, weight-stable, normal weight (n=27), overweight (n=14), and obese (n=9) free-living adults (11 M, 39 F; age 30+/-11 y; BMI 26.3+/-5.9). Twenty four-hour diet recalls were obtained for 7 consecutive days, by the multi-pass technique. Each 24-h period was divided into 7 eating occasions. The coefficient of variation for energy intake was calculated for each adult, for each eating occasion, and over each 24-h period. Sub-group variability was assessed by BMI and frequency of consumption of sweetened energy-yielding beverages. The mean coefficient of variation for energy intake for the 7 eating occasions was 110.5%, compared to 28.9% for the day as a whole. Correlations between energy intakes at successive eating events were uniformly negative. No significant differences were noted in the sub-group analyses. Significantly greater variation in energy intake was noted for snacks compared to meals (P<0.0001). These data suggest that adults regulate energy intake over a 24-h period more closely than they do at individual eating occasions, similar to the pattern previously observed in children. Further studies of compensatory responses by larger sub-groups of individuals at risk for weight gain are warranted.

Integrated anti-remodeling and anabolic therapy for the osteoporosis of Hajdu-Cheney syndrome.

Hajdu-Cheney syndrome (MIM 102500) is a rare skeletal dysplasia marked by severe generalized osteoporosis and focal bone loss (acro-osteolysis). Osteoporosis treatment outcome has been reported only once previously. Reported herein is the biochemical and densitometric response to integrated anti-remodeling and anabolic therapy in a woman with Hajdu-Cheney syndrome. Results suggest dissociation of bone formation from bone resorption resulting in dramatic increases in bone mineral density without clinical evidence of activated osteoporosis.

First observation of herpes-like virus particles in northern pike, Esox lucius L., associated with bluespot-like disease in Ireland.

Circular whitish granular lesions, 5-12 mm in diameter, were observed on the skin and fins of a wild northern pike, Esox lucius, caught in a lake in the Republic of Ireland. Histological examination of the lesions revealed hypertrophied cells in the epidermis with deeply basophilic enlarged nuclei and dark-staining granular material in the cytoplasm. Transmission electron microscopy of these cells revealed naked hexagonal herpes-like virus nucleocapsids (97 +/- 7 nm) in their nuclei while the cytoplasm contained multiple aggregates of enveloped viral particles. This is the first report of herpes-like virus particles in northern pike originating outside North America, where esocid herpesvirus-1 (EsHV-1) has previously been reported. Shared clinical, histological, morphological and epidemiological findings suggest that the observed particles in this report may also be EsHV-1.

A prospective randomized study of preoperative nutritional supplementation in patients awaiting elective orthotopic liver transplantation.

BACKGROUND: Poor nutritional status is common among patients awaiting orthotopic liver transplantation and is associated with poor outcome. METHODS: This prospective randomized controlled trial examined the effect of pretransplant nutritional supplementation on the outcome of patients undergoing liver transplantation. Of 82 consecutive patients with mid-arm muscle circumference <25th percentile, 42 received enteral supplementation, and the remainder acted as the control group. The supplemented group received a calorie-dense enteral feed taken daily (in addition to diet) until transplantation. Nutritional status was monitored by upper arm anthropometric measurements and handgrip strength. Dietary intake was calculated from 5-day food diaries. RESULTS: Supplementation improved mid-arm circumference, mid-arm muscle circumference, and grip strength. Pretransplant nutritional status was not associated with posttransplant sepsis or major complications. Preoperative grip strength of <85% of normal values was predictive of increased incidence of posttransplant major complications. Supplementation did not affect outcome, although there were more deaths in the control group (seven deaths before and two deaths after transplant) than there were in the supplemented group (two deaths before and three deaths after transplant). There was no difference in overall survival (P = 0.075). CONCLUSIONS: Enteral supplementation improved some parameters of nutritional status pretransplant. Dietary intake of patients in the two groups was similar at transplant. Nutritional supplementation has not increased nutritional intake, although this may reflect the importance of regular dietetic input and support, rather than suggesting that nutritional supplementation is ineffective. Supplementation had no effect on outcome of liver transplantation.

Psychological profiles and motives of adults seeking orthodontic treatment.

Personality profiles and the motivations for seeking orthodontic treatment were investigated in a sample of adult patients. An improvement in dental esthetics was found to be the prime motivating factor, and the decision to seek treatment was usually made by the adult patients themselves. Questionnaires to assess personality traits revealed an atypical group of patients demonstrating neurotic traits. These patients were found to have a significantly different perception of their malocclusion than did the "normal" group of adult patients. Patients with neurotic traits may pose problems for clinicians with regard to expectations both during and at the end of treatment.

Analysis of T cell and B cell function in Peyer's patch and lamina propria of New Zealand Black and DBA/2 mice.

We have analyzed gastrointestinal immune function in both DBA/2 and spontaneously autoimmune New Zealand Black (NZB) mice. We have studied both in vitro proliferation and differentiation of Peyer's patch cells and have measured immunoglobulin (Ig) secretion by cultured jejunal segments. Peyer's patch B cells and T cells from both DBA/2 and NZB mice showed similar proliferative responses to Con A and lipopolysaccharide (LPS), respectively. Unlike NZB splenic B cells, isolated Peyer's patch B cells from NZB mice did not spontaneously secrete Ig of any isotype. Seven-day cultures of equal numbers of Peyer's patch T cells and B cells resulted in similar patterns of secretion of IgA, IgG, and IgM in both strains. The addition of Con A to cultures of DBA/2 Peyer's patch cells consistently resulted in a onefold to threefold increase in IgA secretion after 7 days. Con A stimulation of NZB Peyer's patch cells did not produce any increment in IgA secretion. LPS stimulation of Peyer's patch cells from either strain resulted in a similar increase in IgG secretion with little effect on IgA secretion. The in vivo correlate of this finding was seen in the IgA to IgG ratio of Ig secreted by cultured jejunal fragments. In DBA/2 mice the rates of IgA/IgG varied from 2.36 to 4.85, whereas in NZB mice the ratio never exceeded 0.5. These experiments show that defects on the T cell compartment of NZB mice encompass gut-associated lymphoid tissue. The possible relationship of these findings and previously observed defects in oral tolerance is discussed.

Computer generation of high-energy x-ray dose distributions.

A computer program for the generation of high-energy x-ray dose distributions has been developed. The program takes account of the fact that the x-ray beam profile, as affected by penumbra, wedges, beam blocks, or flattening filters, is one of the prime determinants of the dose distribution. Doses from primary and scattered radiation are calculated separately by using published tissue-air ratio (TAR) and scatter-air ratio (SAR) data. The dose from scattered radiation is determined by dividing the x-ray field into a series of scattered strips and summing the contribution from each. Wedges or beam blocks are taken into account simply by earning their actual coordinates and linear attenuation coefficients. The program may be used to design wedges, beam blocks, or flattening filters prior to fabrication. Complete libraries of dose distribution for 60Co, 2-, 4-, and 6-MV x rays have been generated.