Stimulation of bone formation in vivo by phosphate supplementation

The effect of phosphate supplementation on bone remodeling was assessed in six mature, healthy beagle dogs. The phosphate supplement was given in divided doses orally, daily for 12 weeks in the form of a neutral potassium phosphate preparation. The dose averaged 108 mg P/kg per day, which is double the normal canine phosphorus intake. Bone remodeling was assessed by measurement, at sacrifice, of areas of cortical bone containing different colorcoded tetracyclines which had been continuously administered during 12-week control and treatment periods; remodeling was assessed kinetically during the control and treatment periods by replicate studies employing⁴⁷Ca intravenously.Both techniques demonstrated that the principal effect of phosphate supplementation was a significant stimulation of bone formation. Within cortical bone, formation was doubled, from an average of 2.7% to 5.3% per year. The major location of new bone deposits was endosteal. Whole skeletal mineral accretion, measured kinetically, increased 45% above an average control value of 0.154 g/day. These studies suggest that, in the adult dog, normal plasma phosphate levels are suboptimal for new bone formation.Even with this short duration of administration, phosphate produced microscopic calcification of the renal parenchyma. However, there was no biochemical evidence of renal functional impairment.     

Patterns of substance use among patients in an urban psychiatric emergency service

Data from patients visiting an urban psychiatric emergency service in California were examined to document incidence and patterns of substance use and ethnic differences among users. A total of 392 patients were randomly assigned to receive a drug screen (N = 198) or to receive usual care (N = 194). Forty-four percent of the mandatorily screened patients had positive screens for any substances: 37 percent were positive for any drugs, and 7 percent were positive for alcohol only. Cocaine was present in 62 percent of the drug-positive screens. Blacks were two and a half times more likely than whites to have positive screens for drugs and five times more likely to have positive screens for cocaine.     

A chimeric opioid peptide with mixed μ agonist/δ antagonist properties

Abstract: There is evidence to indicate that opioid compounds with mixed μ agonist/δ antagonist properties are analgesics with low propensity to produce tolerance and physical dependence. A chimeric peptide containing the potent and selective μ agonist H‐Dmt‐D‐Arg‐Phe‐Lys‐NH₂ ([Dmt¹]DALDA) (Dmt = 2′,6′‐dimethyltyrosine) and the potent and selective δ antagonist H‐Tyr‐TicΨ[CH₂‐NH]Cha‐Phe‐OH (TICP[Ψ]) (Cha = cyclohexylalanine), connected ‘tail‐to‐tail’ via a short linker, was synthesized using a combination of solid‐phase and solution techniques. The resulting peptide, H‐Dmt→D‐Arg→Phe→Lys‐NH‐CH₂‐CH₂‐NH‐Phe←Cha[NH‐CH₂]ΨTic←Tyr‐H, showed the expected μ agonist/δ antagonist profile in the guinea‐pig ileum and mouse vas deferens assays. Its μ and δ receptor binding affinities were in the low nanomolar range, as determined in rat brain membrane binding assays.     

Involvement of deprivation and environmental lead in neural tube defects: a matched case-control study

OBJECTIVE: To analyse the prevalence of neural tube defects in small geographical areas and seek to explain any spatial variations with reference to environmental lead and deprivation. SETTING: The Fylde of Lancashire in the north west of England. DESIGN: Cases were ascertained as part of a prospective survey of major congenital malformations in babies born in the Fylde to residents there between 1957 and 1981. A matched case-control analysis used infants with cardiovascular system, alimentary tract, and urinary system malformations as controls. Conditional logistic regression was used to assess the effects of more than 10 micrograms/l lead in drinking water and the Townsend deprivation score. RESULTS: The prevalence of neural tube defects in 1957-73 was higher in Blackpool, Fleetwood, and North Fylde, whereas the three control groups showed no significant spatial variation. In 1957-81 mothers living in electoral wards with either a higher proportion of houses with more than 10 micrograms/l lead in the water or a higher deprivation score had a greater risk of having a baby with a neural tube defect. For spina bifida and cranium bifidum alone, this was also true. For anencephaly, deprivation was less important although the effect of lead was still seen. In some neural tube defects, lead may act independently of other possible factors associated with deprivation. It seemed unlikely that lead levels changed significantly during the survey. The percentage of houses with 10 micrograms/l or more of lead in the water in 1984-5 was similar to that found in Great Britain 10 years previously. CONCLUSION: There is evidence to suggest that lead is one cause of neural tube defects, especially anencephaly. This could link the known preventive actions of hard water and folic acid. Calcium is a toxicological antagonist of lead. One cause of a deficiency of folic acid is impaired absorption secondary to zinc deficiency, which may be produced or exacerbated by lead.     

Outbreak-specific monovalent/bivalent vaccination to control and eradicate virulent ovine footrot

Footrot is a contagious disease of small ruminants which is caused by the bacterium Dichelobacter nodosus. In its virulent form there are severe economic losses and a very significant animal welfare issue. Sheep and goats can be vaccinated for treatment and prevention of the disease. There are 10 different serogroups of D. nodosus (A–I and M) and immunity is serogroup-specific. When all 10 serogroups are presented together in a vaccine, protection persists for only a few months due to “antigenic competition”. Consequently we evaluated the use of sequential monovalent or bivalent vaccines to control/eliminate/eradicate virulent footrot in a longitudinal intervention study on 12 commercial farms in southeast Australia with flock sizes of approximately 1200–4200 sheep. Overall, virulent footrot was eradicated from 4 of the flocks, 2 of which had 2 serogroups, and the others 4 or 5 serogroups. Where there were only 1 or 2 serogroups (3 farms) the clinical response was rapid and dramatic; prevalence was reduced from 45 to 50% before vaccination to 0% (2 farms) or 0.4% (1 farm) after one round of vaccination. In the remaining 9 flocks there were more than 2 serogroups and successive bivalent vaccines were administered leading to eradication of virulent footrot on 2 farms over 4 years and control of the disease on all but 3 of the others. Of the latter farms, 1 discontinued, and 2 initially had poor response to vaccine due to misdiagnosis of serogroup ‘M’, which was previously unknown in Australia. Control was achieved after administration of a serogroup M vaccine. These results provide clear evidence for control, elimination and eradication of virulent footrot by outbreak-specific vaccination in Australia.     

Multiple in silico tools predict phenotypic manifestations in congenital thrombotic thrombocytopenic purpura

Congenital thrombotic thrombocytopenic purpura (cTTP) is a rare, recessively inherited genetic disorder with varying clinical presentation that is caused by ADAMTS13 mutations. Several studies have found limited associations between ADAMTS13 mutations and cTTP phenotype. The use of in silico tools that examine multiple mutation characteristics may better predict phenotype. We analysed 118 ADAMTS13 mutations found in 144 cTTP patients reported in the literature and examined associations of several mutation characteristics, including N‐terminal proximity, the evolutionary conservation of the affected amino acid position, as well as amino acid charge/phosphorylation and genetic codon usage to disease phenotype. Structure‐altering mutations were examined for their impact on ADAMTS13 function based on existing ADAMTS13 crystallographic data (AA 77‐685). Our in silico data indicate that: (i) The position of the mutation in the N‐ or C‐terminus, (ii) evolutionary conservation and (iii) codon usage of the affected mutation position are associated with disease parameters, such as age of onset, organ damage and fresh frozen plasma prophylaxis. In conclusion, the usage of multiple in silico tools presents a promising strategy in refining predictions for the diverse presentation of cTTP. Enhancing our utilization of in silico tools to find genotype‐phenotype associations will create better‐tailored approaches for individual patient treatment.     

Studies of the antidiarrheal action of clonidine. Effects on motility and intestinal absorption

Clonidine, an alpha 2-adrenergic agonist, has been reported to stimulate the rate of electrolyte absorption in vitro, to alter intestinal motility in vivo, and to have antidiarrheal effects in animals. Experiments were performed in 8 healthy volunteers in order to evaluate the antidiarrheal effect of clonidine in humans. When diarrhea was induced by intragastric infusion of 2700 ml of balanced electrolyte solution over 90 min, oral administration of 0.3 mg of clonidine reduced the volume of rectal effluent by 48% (from 1233 +/- 62 to 640 +/- 77 ml, p less than 0.001), a clear-cut antidiarrheal effect. Clonidine increased total gut volume significantly (from 987 +/- 91 to 1830 +/- 142 ml, p less than 0.001), suggesting that clonidine exerted its antidiarrheal effect by altering gut motility, i.e., increasing the capacity of the gut and slowing the transit of fluid through the intestine. In other experiments, the net absorption rate of the whole gut during steady state total gut perfusion was measured. The rate of absorption of fluid was transiently stimulated by clonidine by 15% (from 696 +/- 77 to 799 +/- 55 ml/h, p less than 0.02), indicating an additional effect on mucosal cell function. These studies indicate that in this experimental diarrhea model, clonidine has antidiarrheal properties that are due largely to effects on motility of the gut but that clonidine also modestly stimulates the net rate of absorption by intestinal mucosa.     

Intraoperative detection of myocardial ischemia in high-risk patients: electrocardiography versus two-dimensional transesophageal echocardiography

Because acute segmental wall motion abnormalities (SWMAs) of the left ventricle are highly sensitive and specific indicators of myocardial ischemia, this study compared the incidence and significance of ischemia, as detected by two-dimensional transesophageal echocardiography and surface electrocardiography, during anesthesia and surgery in patients at high risk of myocardial ischemia. During surgery, 24 of the 50 patients studied had new SWMAs, whereas only six had ST segment changes. All patients with ST segment changes also had new SWMAs: in three instances, SWMAs occurred before the ST segment change, and in three instances, they occurred simultaneously. All three patients who had intraoperative myocardial infarctions also had persistent intraoperative SWMAs, whereas only one patient had ST segment changes. Ten healthy patients requiring noncardiovascular surgery were monitored similarly; none of these had SWMAs, ST segment changes, or myocardial infarction. This study demonstrates the superiority of two-dimensional transesophageal echocardiography over electrocardiography for the intraoperative detection of myocardial ischemia. Furthermore, when new SWMAs persist to the conclusion of surgery, myocardial infarction is likely to have occurred.