Cortical Bone Porosity: What Is It, Why Is It Important, and How Can We Detect It?

There is growing recognition of the role of micro-architecture in osteoporotic bone loss and fragility. This trend has been driven by advances in imaging technology, which have enabled a transition from measures of mass to micro-architecture. Imaging trabecular bone has been a key research focus, but advances in resolution have also enabled the detection of cortical bone micro-architecture, particularly the network of vascular canals, commonly referred to as 'cortical porosity.' This review aims to provide an overview of what this level of porosity is, why it is important, and how it can be characterized by imaging. Moving beyond a 'trabeculocentric' view of bone loss holds the potential to improve diagnosis and monitoring of interventions. Furthermore, cortical porosity is intimately linked to the remodeling process, which underpins bone loss, and thus a larger potential exists to improve our fundamental understanding of bone health through imaging of both humans and animal models.

Synthesis of nitrogen analogues of salacinol and their evaluation as glycosidase inhibitors.

The syntheses of two nitrogen analogues (11 and 12) of the naturally occurring sulfonium ion, salacinol (7) are described. The latter compound is one of the active principles in the aqueous extracts of Salacia reticulata that are traditionally used in Sri Lanka and India for the treatment of diabetes. The synthetic strategy relies on the nucleophilic attack of a 1,4-dideoxy-1,4-imino-D- or L-arabinitol at the least hindered carbon of 2,4-O-benzylidene D- or L-erythritol-1,3-cyclic sulfate. The nitrogen analogues bear a permanent positive charge and serve as mimics of the sulfonium ion. We reasoned that these ammonium derivatives should function in a manner similar to that of known glycosidase inhibitors of the alkaloid class such as castanospermine (4) and deoxynojirimycin (5). Enzyme inhibition assays indicate that salacinol (7) is a weak (K(i) = 1.7 mM) inhibitor of glucoamylase, whereas compounds 11 and 12 inhibit glucoamylase with K(i) values in the range approximately 10-fold higher. The nitrogen analogues 11 and 12 showed no significant inhibitory effect of either barley alpha-amylase (AMY1) or porcine pancreatic alpha-amylase (PPA) at concentrations of 5 mM. In contrast, salacinol (7) inhibited AMY1 and PPA in the micromolar range, with K(i) values of 15 +/- 1 and 10 +/- 2 microM, respectively.

A new class of glycosidase inhibitor: synthesis of salacinol and its stereoisomers.

Salacinol (4) is one of the active principles in the aqueous extracts of Salacia reticulata that are traditionally used in Sri Lanka and India for the treatment of diabetes. The syntheses of salacinol (4), the enantiomer of salacinol (5), and a diastereomer (7) are described. The synthetic strategy relies on the selective nucleophilic attack of 2,3,5-tri-O-benzyl-1,4-anhydro-4-thio-D- or L-arabinitol at C-1 of 2,4-O-benzylidene D- or L-erythritol-1,3-cyclic sulfate. The work serves to resolve the ambiguity about the exact structure of salacinol and establishes conclusively the structure of the natural product.

PrePare: a program of enhanced prenatal services within health-maintenance organization settings.

This paper presents the conceptual framework and implementation strategies of a relationship-focused behavioral intervention for pregnant women and their families. The program, PrePare ('Prenatal Parenting'), was designed as a prenatal precursor to the pediatric health care model, Healthy Steps. PrePare includes preventive intervention elements that address parents' universal concerns about pregnancy and parenthood, as well as specific activities to support optimum pregnancy health and reduce high-risk behaviors. As described here, the program is embedded within a large not-for-profit health-maintenance organization (HMO). Delivery of the prenatal component is carried out by Healthy Steps interventionists through three home visits and telephone follow-up during mothers' second and third trimesters of pregnancy. An evaluation of program outcomes is underway. The design compares three groups of families, those who receive PrePare followed by Healthy Steps, Healthy Steps alone and a usual HMO-practice comparison. It is hypothesized that initiating expanded services during the prenatal period will lead to increases in reported patient satisfaction, provider satisfaction and organizational efficiency within the health care delivery system.

Conformational preferences in glycosylamines. implications for the exo-anomeric effect.

The conformational preferences about the C-N bond in N-(4-methoxyphenyl)-2,3,4,6-tetra-O-acetyl-alpha (1) and beta-D-glucopyranosylamine (2), in the solid state and in solution, have been investigated. The crystal structure of the axially substituted alpha anomer (1) indicates a conformational preference about the C-1-N bond in which nN-->sigma*C-O exo-anomeric interactions may be expressed, although this conformational preference is not displayed in solution. The solution conformation relieves steric interactions that result from expression of the exo-anomeric effect in the solid-state conformation. The conformational preference in the equatorially substituted beta anomer (2) both in solution and in the solid state is similar and permits expression of nN-->sigma*C-O exo-anomeric interactions. The structural data for 1 and 2 indicate significant differences in O-5-C-1-N-1 bond angles but insignificant differences in each of the O-5-C-1 or C-1-N-1 bond lengths. The J(C-1-H-1 coupling constants in 1 and 2 indicate a greater coupling constant for the alpha anomer that is consistent with a dominant nO-->sigma*C-H orbital interaction in the beta anomer that weakens the C-1-H-1 bond.

Methodologic issues in pediatric outcomes research.

Clinicians, health services researchers, and third-party payers, among others, are justifiably interested in the outcomes of pediatric medical care and are, therefore, supportive of research in this area. Pediatric populations pose some unique methodologic challenges for health services researchers. To date, however, many of the approaches, models, and techniques used in pediatric outcomes research have been imported uncritically from experience with adult populations. As a result, some of the most interesting and salient aspects of pediatric outcomes research have yet to be fully developed. These include the following: 1) the problems posed by the dynamics of childhood development, 2) an emphasis on health supervision, 3) the need to see children within the context of a family system and to appreciate the interrelatedness of child health domains, 4) the measurement of the effects of interventions that span sectors, and 5) the paucity of available data sources. This article reviews these problematic areas and argues for a broad conceptual definition of pediatric health, a systems approach to assessing outcomes, and increased interdisciplinary collaboration.

Synthesis of thio-linked disaccharides by 1-->2 intramolecular thioglycosyl migration: oxacarbenium versus episulfonium ion intermediates.

The conversion of 1,1'-thio-linked glucopyranosyl alpha-D-mannopyranosides to 1,2-thio-linked methyl sophorosides or methyl kojibiosides is described. The method involves the 1-->2-migration of the thioglucopyranosyl portion of the nonreducing disaccharide with inversion of configuration at C-2 of the mannopyranose ring and concomitant formation of the methyl glucopyranoside. The thioglucosyl migration does not occur when electron-withdrawing benzoate protecting groups are present. The rearrangement occurs with retention of configuration in the migrating thioglucoside but the methyl glycoside is formed as a mixture of alpha- and beta-isomers. This is attributed to a mechanism involving an oxacarbenium-ion intermediate rather than an episulfonium-ion intermediate. The relevance of this work to recent theoretical predictions concerning the relative stability of such intermediates is discussed.

Novel 4-thiogalactofuranosyl-containing disaccharides with nitrogen in the interglycosidic linkage.

The syntheses of three novel disaccharides containing a 4-thiogalactofuranosyl residue as the non-reducing unit and a nitrogen in the interglycosidic linkage are described. Acid-catalyzed condensation reactions of 4-thio-alpha/beta-D-galactofuranose with either methyl 3-amino-3-deoxy-alpha-D-mannopyranoside, methyl 2-amino-2-deoxy-alpha-D-mannopyranoside, or methyl 2-acetamido-6-amino-2,6-dideoxy-beta-D-glucopyranoside gave methyl 3-amino-3-deoxy-3-N-(4-thio-alpha/beta-D-galactofuranosyl)-alpha-D-manno pyranoside, methyl 2-amino-2-deoxy-2-N-(4-thio-alpha/beta-D-galactofuranosyl)-alpha-D-manno pyranoside, or methyl 2-acetamido-6-amino-2,6-dideoxy-6-N-(4-thio-alpha/beta-D-galactofuranosy l)-beta-D-glucopyranoside.

Synthesis of galactofuranosyl-containing oligosaccharides corresponding to the glycosylinositolphospholipid of Trypanosoma cruzi.

The oligosaccharide beta-D-Galf-(1-->3)-alpha-D-Manp-(1-->2)-[beta-D-Galf- (1-->3)]-alpha-D-Manp-(1-->2)-alpha-D-Manp corresponds to the terminal end of the glycosylinositolphospholipid oligosaccharide of the protozoan Trypanosoma cruzi, the causative agent of Chagas' disease. Syntheses of methyl or ethylthio glycosides of the terminal disaccharide, trisaccharide, tetrasaccharide, and pentasaccharide corresponding to this structure are described. These syntheses employ the selective activation of a phenyl 1-selenogalactofuranoside or a phenyl 1-selenomannopyranoside donor over ethyl 1-thioglycoside acceptors with NIS-TfOH.

High-risk periods for childhood injury among siblings.

OBJECTIVE: To determine whether the risk of unintentional injury requiring emergency department (ED) or inpatient care in children is transiently increased over a 90-day period after injury to a sibling. DESIGN: Retrospective cohort. SETTING: King County, Washington. Participants. A total of 41 242 children 0 to 15 years of age continuously enrolled in Medicaid and living in King County during the period October 1, 1992 through September 30, 1993 (27 450 child-years). OUTCOME MEASURES: The outcome was an unintentional injury treated in the ED or inpatient setting. Incidence rates and hazard ratios were calculated for children whose sibling had been injured in the previous 90 days, compared with children without such exposure. Multivariate analysis was used to adjust for age, gender, race, sibling group size, and noninjury ED use. RESULTS: . There were 4921 injuries treated only in the ED and 82 hospital admissions. The incidence of ED treated injury was 305 per 1000 child-years among children whose sibling had been injured in the previous 90 days and 174 per 1000 child-years among children without this exposure (relative risk: 1.75; 95% confidence interval: 1.56-1.95). The incidence of injury-related hospitalization was 1.7 per 1000 child-years among children whose sibling had been injured in the previous 90 days, compared with 3.0 per 1000 child-years among children without this exposure (relative risk:.57; 95% confidence interval:.07-2.12). Injury risk peaked in the period 4 to 10 days after a sibling's injury and returned toward, but did not attain, baseline risk over the subsequent 21/2 months. The magnitude of this effect depended on the child's age; the relative risk of injury was higher among older children. CONCLUSIONS: Injuries treated in the ED or inpatient setting appear to cluster within sibling groups over brief periods of time. Shared social or environmental exposures may contribute to this clustering and may be amenable to targeted, time-limited prevention interventions.

A preschool program for safety and injury prevention delivered by home visitors.

OBJECTIVE: To evaluate the feasibility, acceptability, and effectiveness of an injury prevention program delivered by school based home visitors to the families of low income children attending preschool enrichment programs in Washington State. STUDY SAMPLE: The families of children attending preschool Head Start programs in two regions were eligible. A total of 213 families (77.8% of those eligible) from intervention sites, and 149 families (71.9% of those eligible) from concurrent comparison sites, agreed to participate and completed the trial. INTERVENTION: Trained school personnel conducted home safety inspections as part of a planned home visit. Intervention families were offered educational materials as well as smoke detectors, batteries, ipecac, and age appropriate car safety restraints based on results of the home inspection. EVALUATION METHODS: At a repeat home visit three months later, the proportion of families with a positive change in injury prevention knowledge or behavior among those in the intervention group was compared with the proportion in the comparison group. Smoke detector presence and function were observed. RESULTS: Among families without a working smoke detector at baseline, the intervention was associated with an increased probability of having a working detector at follow up (relative risk (RR) 3.3, 95% confidence interval (CI) 1.3 to 8.6). Intervention families were also more likely to report the presence of ipecac in the home (RR 4.7, 95% CI 3.0 to 7.3) at follow up and to have obtained an age appropriate booster seat (RR 4.1, 95% CI 1.9 to 8.8). The program was acceptable to client families and to the home visitors who conducted the intervention. CONCLUSIONS: Among the families of low income children enrolled in preschool enrichment programs, home safety inspections and the distribution of safety supplies by school based home visitors appears to improve knowledge and behavior related to poisoning, smoke detector installation, and car safety seat use over three months of follow up.

Use of a phenyl 1-selenogalactofuranoside as a glycosyl donor for the synthesis of galactofuranosyl-containing disaccharides.

The use of acetylated phenyl 1-seleno-beta-D-galactofuranoside as a glycosyl donor for the synthesis of protected D-Galf-beta-(1-->3)-alpha-D-Manp as its methyl or ethylthio glycoside has been demonstrated. Activation of the selenoglycoside over a thioglycoside acceptor by NIS/TfOH is extremely selective and gives the ethylthio disaccharide in 91% yield. The parent disaccharide is found as a terminal and branched unit in the lipopeptidophosphoglycan oligosaccharides of the protozoan Trypanosoma cruzi, the causative agent of Chagas' disease.

Thermal modulation of the toxicokinetics of benzo[a]pyrene in isolated hepatocytes of sablefish (Anoplopoma fimbria), black rockfish (Sebastes melanops), and chub mackerel (Scomber japonicus).

Hepatocytes from sablefish (Anoplopoma fimbria), black rockfish (Sebastes melanops) and chub mackerel (Scomber japonicus) were isolated from 11 degrees C acclimated animals. The uptake, metabolism, and excretion of benzo[a]pyrene (B[a]P) in hepatocytes was measured at 6, 11 and 19 degrees C. Chub mackerel hepatocyte uptake rates were significantly lower (0.012 +/- 0.003 microg/s per g cell) at 11 degrees C than black rockfish (0.028 +/- 0.009 microg/s per g cell) or sablefish (0.032 +/- 0.012 microg/s per g cell) hepatocytes at all temperatures. Hepatocytes metabolized B[a]P to phase I (1-8%) and phase II (92-99%) metabolites. Accumulation of phase II metabolites was lower in chub mackerel hepatocytes (0.016 +/- 0.004 microg/h per g cell), than black rockfish (0.052 +/- 0.012 microg/h per g cell), or sablefish hepatocytes (0.060 +/- 0.015 microg/h per g cell). Phase II metabolite accumulation increased greatest with temperature in chub mackerel hepatocytes (Q10 = 1.94 +/- 0.30), followed by sablefish (Q10 = 1.65 +/- 0.30), and rockfish (Q10 = 1.38 +/- 0.30). Sablefish hepatocytes had higher excretion rates of phase II metabolites (0.010 +/- 0.0023 microg/h per g cell), than mackerel (0.0046 +/- 0.0009 microg/h per g cell) or rockfish hepatocytes (0.0029 +/- 0.0008 microg/h per g cell). Phase II metabolite excretion rates increased with temperature only in sablefish hepatocytes (Q1O = 1.67 +/- 0.76). These differences in toxicokinetics may indicate distinct consequences for various species exposed to xenobiotics.

Use of a phenyl 1-selenogalactofuranoside as a glycosyl donor for the synthesis of galactofuranosyl-containing disaccharides.

The use of acetylated phenyl 1-seleno-beta-D-galactofuranoside as a glycosyl donor for the synthesis of protected D-Galf-beta-(1-->3)-alpha-D-Manp as its methyl or ethylthio glycoside has been demonstrated. Activation of the selenoglycoside over a thioglycoside acceptor by NIS/TfOH is extremely selective and gives the ethylthio disaccharide in 91% yield. The parent disaccharide is found as a terminal and branched unit in the lipopeptidophosphoglycan oligosaccharides of the protozoan Trypanosoma cruzi, the causative agent of Chagas' disease.

Vitamin A therapy for children with respiratory syncytial virus infection: a multicenter trial in the United States.

BACKGROUND: High dose vitamin A therapy is effective in reducing morbidity and mortality associated with measles infection. Children with acute respiratory syncytial virus (RSV) infection have low serum vitamin A concentrations. METHODS: We performed a multicenter, randomized, placebo-controlled trial of high dose vitamin A therapy among 239 children 1 month to 6 years of age to determine whether high dose vitamin A therapy would reduce morbidity associated with RSV infection. RESULTS: There were no differences between the vitamin A and placebo recipients for most clinical outcomes; however, vitamin A recipients had-longer hospital stays than placebo recipients (5.0 days vs. 4.4 days, P = 0.01) after enrollment. This effect was significant for children who were older than 1 year (who also had received the highest doses of vitamin A), particularly among those at low risk for complications of RSV infection and those enrolled during the second study season. Serum retinol levels at enrollment were inversely correlated with severity of illness. CONCLUSIONS: We found no evidence of a beneficial effect of vitamin A for the treatment of RSV infection in children in the United States. There may be groups of children for which vitamin A has an adverse effect, resulting in longer hospital stays.

Falciparum malaria in eastern Thailand: a randomized trial of the efficacy of a single dose of mefloquine.

Reported are the results of a randomized trial of a single dose of mefloquine (15 mg/kg or 25 mg/kg body weight) for the treatment of uncomplicated multidrug-resistant falciparum malaria. Of the 110 adult patients enrolled in the study 57 were randomly assigned to the 15 mg/kg group and 53 to the 25 mg/kg group. The baseline characteristics of the patients did not differ significantly in the two groups, except that those in the 15 mg/kg group had lower haemoglobin levels. Adverse effects following treatment were commoner in the 25 mg/kg group, but not significantly so. Seven patients (6%) did not complete the 42-day follow-up. The parasitological failure rates in the 15 and 25 mg/kg groups were, respectively, 50% (28/56) and 43% (25/53) on day 28, and 62% (33/53) and 56% (28/50) on day 42. Treatment failures were not correlated with the serum mefloquine concentrations on day 2, and 13 out of 19 patients with serum mefloquine concentrations > 2000 micrograms/l on day 2 showed an R response during the follow-up. The mean ratio between the concentrations of the (SR)-(-) and (RS)-(+) enantiomers of mefloquine on day 2 was 3.37, indicating that there are differences in their pharmacokinetics. Re-treatment of patients who showed an R response with seven days of quinine (30 mg.kg-1.day-1)+tetracycline (25 mg.kg-1.day-1) was successful in 93% of the cases.

PIP: During November-December, 1991, clinicians administered either 15 mg/kg mefloquine or 25 mg/kg mefloquine to 57 and 53 patients, respectively, to treat falciparum malaria. The patients were at the referral hospital in Site 8, a Khmer refugee camp on the border between Thailand and Cambodia. The 2 groups responded essentially the same, except the 15 mg/kg group had a lower mean hemoglobin level than the 25 mg/kg group (9.4 g/dl vs. 10 g/dl; p = .03). Parasitological failure rates on day 28 and 42 were not significantly different between the 2 groups. On day 28, they were 50% for the 15 mg/kg group and 43.4% for the 25 mg/kg group. They were especially high at day 42 (62% and 56%, respectively). Patients in the 25 mg/kg group were more likely to experience adverse effects of mefloquine (13% vs. 7% for vomiting, 26% vs. 19% for diarrhea, and dizziness 74% vs. 70%), but the differences were not significant. The mean serum mefloquine level was basically the same for both groups (2165 mcg/l in 15 mg/kg group and 2284 mcg/l in the 25 mg/kg group). 13 of 19 patients tested had serum mefloquine concentrations greater than 2000 mcg/1 on day 2, yet they experienced parasitological failure. This concentration traditionally indicated successful treatment. People who vomited within an hour of receiving mefloquine had much lower serum mefloquine levels than those who did not vomit (1289 mcg/l vs. 2300 mcg/l; p = .03). Patients who experienced dizziness on day 2 had much higher serum mefloquine levels than those who were not dizzy (2394 mcg/l vs. 1371 mcg/l; p = .006). On day 2, the mean ratio between the levels of the (SR)-(-) and (RS)-(+) enantiomers of mefloquine stood at 3.37, suggesting that differences exist in their pharmacokinetics. The 7-day retreatment regimen with quinine and tetracycline was successful in 93% of the 50 patients who experienced parasitological failure.

Attentional dysfunction in children with encopresis.

Encopresis and attentional dysfunction are common neurobehavioral disorders of childhood. The extent to which these disorders occur in association is unknown. The purpose of this study is to document the comorbidity of attentional dysfunction in a clinically identified population of encopresis patients. We used the Child Behavior Checklist (CBCL) to estimate the prevalence of disordered attention or hyperactivity in a group of children with encopresis seen at a tertiary care facility. Responses to CBCL questionnaires were analyzed to compare scores on the "hyperactive" behavior subscale with published normative data. The number of encopretic respondents with T scores above 70 (> 2 SD above the mean) on a hyperactivity subscale was ascertained for each age and gender cohort. From 347 eligible new clinic patients, responses from 167 were suitable for analysis. Overall, 23.4% of children with encopresis (95% confidence interval: 17.2%-30.5%) had T scores on the hyperactive subscale higher than 70. This prevalence (ten fold greater than expected in the normal population) was similar in both genders and across age groups. This association between attentional dysfunction and encopresis has significance for theories regarding etiology and for practical treatment strategies.