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1.  Caloric restriction leads to high marrow adiposity and low bone mass in growing mice 
Introduction
The effects of caloric restriction (CR) on the skeleton are well studied in adult rodents, and include lower cortical bone mass but higher trabecular bone volume. Much less is known about how CR affects bone mass in young, rapidly growing animals. This is an important problem because low caloric intake during skeletal acquisition in humans, as in anorexia nervosa, is associated with low bone mass, increased fracture risk, and osteoporosis in adulthood. To explore this question, we tested the effect of caloric restriction on bone mass and microarchitecture during rapid skeletal growth in young mice.
Methods
At 3 wks of age we weaned male C57Bl/6J mice onto 30% caloric restriction (CR, 10% Kcal/fat) or normal diet (N, 10% Kcal/fat). Outcomes at 6 (N=4/group) and 12 wks of age (N=8/group) included body mass, femur length, serum leptin and IGF-1, whole body bone mineral density (WBBMD, g/cm2), cortical and trabecular bone architecture at the midshaft and distal femur, bone formation and cellularity, and marrow fat measurement.
Results
Compared to N, CR mice had 52% and 88% lower serum leptin and 33% and 39% lower serum IGF-1 at 6 and 12 wks of age (p<0.05 for all). CR mice were smaller, with lower bone mineral density, trabecular and cortical bone properties. Bone formation indices were lower, while bone resorption indices were higher (p<0.01 for all) in CR vs. N. Despite having lower %body fat, bone marrow adiposity was dramatically elevated in CR vs. N (p<0.05).
Conclusion
Caloric restriction in young, growing mice is associated with impaired skeletal acquisition, low leptin and IGF-1 levels, and high marrow adiposity. These results support the hypothesis that caloric restriction during rapid skeletal growth is deleterious to cortical and trabecular bone mass and architecture, in contrast to potential skeletal benefits of CR in aging animals.
doi:10.1002/jbmr.82
PMCID: PMC3127399  PMID: 20229598
caloric restriction; bone density; body composition; leptin; mice; marrow fat; bone; mouse
2.  Platelet–leukocyte interaction and platelet activation in migraine: a link to ischemic stroke? 
Objectives: Migraine has been identified as an independent risk factor for ischemic stroke. Both neurogenic inflammation and platelet activation have been linked to the pathophysiology of migraine. Increased platelet activation results in up-regulation of specific binding to leukocytes which promotes pro-inflammatory leukocyte secretion and their tethering to endothelium, a mechanism that has been demonstrated in stroke and which could provide a link to migraine. We aimed to determine whether platelet–leukocyte aggregation is increased in migraine patients outside an acute attack.
Methods: Seventy two patients with migraine according to IHS criteria were compared to a control group (n = 72). Whole blood flow cytometry was used to quantify the activation dependent P selectin on the platelet, and to assess the fraction of platelets bound to the different leukocyte subsets.
Results: Migraine patients showed significantly more platelet–leukocyte aggregates compared to the control subjects (p = 0.003). This effect was driven by an increased polymorphonuclear cell–platelet aggregation (p = 0.003) whereas platelet aggregation with monocytes and lymphocytes was not. Platelet activation was also increased (p = 0.001).
Conclusions: In migraine pro-inflammatory platelet adhesion to leukocytes occurs during the headache free interval similar to that seen in acute coronary and cerebrovascular syndromes. This may suggest a link between migraine and stroke on a cellular level.
doi:10.1136/jnnp.2003.019638
PMCID: PMC1739108  PMID: 15201354
3.  Orbital arteriovenous malformation mimicking cavernous sinus dural arteriovenous malformation 
AIMS—Orbital arteriovenous malformations (OAVM) are rare, mostly described with high flow characteristics. Two cases are reported with an OAVM of distinct haemodynamic abnormality. The clinical, angiographic features, and the management considerations are discussed.
METHODS—Case review of two patients with dural AVM (DAVM) who presented to referral neuro-ophthalmology and endovascular services because of clinical symptoms and signs consistent with a cavernous sinus dural AVM.
RESULTS—In each patient, superselective angiography revealed a small slow flow intraorbital shunt supplied by the ophthalmic artery. The transarterial and transvenous endovascular approaches to treat the malformation were partially successful. Although, the abnormal flow was reduced, complete closure of the DAVM could not be accomplished without significant risk of iatrogenic injury. Neither patient's vision improved after intervention.
CONCLUSION—A DAVM in the orbit can cause similar clinical symptoms and signs to those associated with a cavernous sinus DAVM. Even with high resolution magnetic resonance imaging, only superselective angiography can identify this small intraorbital slow flow shunt. The location in the orbital apex and the small size precludes a surgical option for treatment. The transarterial and transvenous embolisation options are limited.


doi:10.1136/bjo.84.7.771
PMCID: PMC1723558  PMID: 10873992
4.  Activated parathyroid hormone/parathyroid hormone–related protein receptor in osteoblastic cells differentially affects cortical and trabecular bone 
Journal of Clinical Investigation  2001;107(3):277-286.
Parathyroid hormone (PTH), an important regulator of calcium homeostasis, targets most of its complex actions in bone to cells of the osteoblast lineage. Furthermore, PTH is known to stimulate osteoclastogenesis indirectly through activation of osteoblastic cells. To assess the role of the PTH/PTH-related protein receptor (PPR) in mediating the diverse actions of PTH on bone in vivo, we generated mice that express, in cells of the osteoblastic lineage, one of the constitutively active receptors described in Jansen’s metaphyseal chondrodysplasia. In these transgenic mice, osteoblastic function was increased in the trabecular and endosteal compartments, whereas it was decreased in the periosteum. In trabecular bone of the transgenic mice, there was an increase in osteoblast precursors, as well as in mature osteoblasts. Osteoblastic expression of the constitutively active PPR induced a dramatic increase in osteoclast number in both trabecular and compact bone in transgenic animals. The net effect of these actions was a substantial increase in trabecular bone volume and a decrease in cortical bone thickness of the long bones. These findings, for the first time to our knowledge, identify the PPR as a crucial mediator of both bone-forming and bone-resorbing actions of PTH, and they underline the complexity and heterogeneity of the osteoblast population and/or their regulatory microenvironment.
PMCID: PMC199196  PMID: 11160151
6.  Osteopenia and decreased bone formation in osteonectin-deficient mice 
Journal of Clinical Investigation  2000;105(7):915-923.
Bone continuously remodels in response to mechanical and physiological stresses, allowing vertebrates to renew bone as adults. Bone remodeling consists of the cycled synthesis and resorption of collagenous and noncollagenous extracellular matrix proteins, and an imbalance in this process can lead to disease states such as osteoporosis, or more rarely, osteopetrosis. There is evidence that the extracellular matrix glycoprotein osteonectin or secreted protein acidic and rich in cysteine (BM-40) may be important in bone remodeling. Osteonectin is abundant in bone and is expressed in areas of active remodeling outside the skeleton. In vitro studies indicate that osteonectin can bind collagen and regulate angiogenesis, metalloproteinase expression, cell proliferation, and cell-matrix interactions. In some osteopenic states, such as osteogenesis imperfecta and selected animal models for bone fragility, osteonectin expression is decreased. To determine the function of osteonectin in bone, we used contact x-ray, histomorphometry, and Northern blot analysis to characterize the skeletal phenotype of osteonectin-null mice. We found that osteonectin-null mice have decreased bone formation and decreased osteoblast and osteoclast surface and number, leading to decreased bone remodeling with a negative bone balance and causing profound osteopenia. These data indicate that osteonectin supports bone remodeling and the maintenance of bone mass in vertebrates.
PMCID: PMC377474  PMID: 10749571
7.  Colony-stimulating factor-1 induces cytoskeletal reorganization and c-src-dependent tyrosine phosphorylation of selected cellular proteins in rodent osteoclasts. 
Journal of Clinical Investigation  1997;100(10):2476-2485.
Colony-stimulating factor-1 (CSF-1) stimulates motility and cytoplasmic spreading in mature osteoclasts. Therefore, we examined the cellular events and intracellular signaling pathways that accompany CSF-1-induced spreading in normal osteoclasts. To explore the role c-src plays in these processes, we also studied osteoclasts prepared from animals with targeted disruption of the src gene. In normal osteoclasts, CSF-1 treatment induces rapid cytoplasmic spreading, with redistribution of F-actin from a well-delineated central attachment ring to the periphery of the cell. CSF-1 increases membrane phosphotyrosine staining in osteoclasts and induces the phosphorylation of several cellular proteins in cultured, osteoclast-like cells, including c-fms, c-src, and an 85-kD Grb2-binding protein. Src kinase activity is increased threefold after CSF-1 treatment. In src- cells, no attachment ring is present, and CSF-1 fails to induce spreading or a change in the pattern of F-actin distribution. Although c-fms becomes phosphorylated after CSF-1 treatment, the 85-kD protein is significantly less phosphorylated in src- osteoclast-like cells. These results indicate that c-src is critical for the normal cytoskeletal architecture of the osteoclast, and, in its absence, the spreading response induced by CSF-1 is abrogated, and downstream signaling from c-fms is altered.
PMCID: PMC508448  PMID: 9366562
9.  An outbreak of cholera from food served on an international aircraft. 
Epidemiology and Infection  1996;116(1):9-13.
In February 1992, an outbreak of cholera occurred among persons who had flown on a commercial airline flight from South America to Los Angeles. This study was conducted to determine the magnitude and the cause of the outbreak. Passengers were interviewed and laboratory specimens were collected to determine the magnitude of the outbreak. A case-control study was performed to determine the vehicle of infection. Seventy-five of the 336 passengers in the United States had cholera; 10 were hospitalized and one died. Cold seafood salad, served between Lima, Peru and Los Angeles, California was the vehicle of infection (odds ratio, 11.6; 95% confidence interval, 3.3-44.5). This was the largest airline-associated outbreak of cholera ever reported and demonstrates the potential for airline-associated spread of cholera from epidemic areas to other parts of the world. Physicians should obtain a travel history and consider cholera in patients with diarrhoea who have travelled from cholera-affected countries. This outbreak also highlights the risks associated with eating cold foods prepared in cholera-affected countries.
PMCID: PMC2271246  PMID: 8626007
10.  A cluster of Escherichia coli O157:H7 infections with the hemolytic-uremic syndrome and death in California. A mandate for improved surveillance. 
Western Journal of Medicine  1996;165(1-2):15-19.
In mid-January 1993, an outbreak of Escherichia coli O157:H7 infections associated with eating hamburger patties at a fast-food restaurant chain (chain A) was reported in Washington State. From mid-December to mid-January, 9 cases of E coli O157:H7-associated bloody diarrhea and the hemolytic-uremic syndrome had been reported in San Diego County, California. A total of 34 persons had bloody diarrhea, the hemolytic-uremic syndrome, or E coli O157:H7 organisms isolated from stool during the period November 15, 1992, through January 31, 1993. Organisms of E coli O157:H7 identified from 6 persons were indistinguishable from those of the Washington outbreak strain. Illness was associated with eating at chain A restaurants in San Diego (odds ratio, 13; 95% confidence interval, 1.7, 99) and with eating regular-sized hamburgers (odds ratio, undefined; lower-limit 95% confidence interval, 1.3). Improved surveillance by mandating laboratory- and physician-based reporting of cases of E coli O157:H7 infection and the hemolytic-uremic syndrome might have alerted health officials to this outbreak sooner, which could have resulted in earlier investigation and the institution of measures to prevent more cases.
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PMCID: PMC1307535  PMID: 8855679
11.  A carbamate insecticide: a case study of aldicarb. 
Environmental Health Perspectives  1994;102(Suppl 11):23-27.
Aldicarb, the active ingredient in the insecticide TEMIK, was introduced to the agricultural community over 25 years ago. It has been registered worldwide to control a wide variety of insect, mite, and nematode pests in agriculture. The toxicological research database supporting the registration and use of aldicarb was generated over more than 25 years and contains more than 280 animal studies on 12 species of animals, 2 clinical human trials, and over 20 human monitoring studies. This database, which includes biochemical aspects (metabolism and mode-of-action studies), acute toxicity and special short-term toxicity studies, long-term toxicity studies, and epidemiological observations in humans, serves as the starting point for the evaluation of the risks associated with the acceptance of levels of aldicarb residues in food and drinking water and for the more direct occupational exposure. This article highlights the available toxicological data and reviews worldwide regulation of aldicarb. Included in these discussions is a brief description of the toxicological end point upon which regulatory decisions have been based, namely acetylcholinesterase depression. Aldicarb, the N-methylcarbamic acid ester of 2-methyl-2-(methylthio) propionaldehyde oxime, was the first of a limited group of insecticidal oxime N-methylcarbamates that have properties distinct from N-methylcarbamates which have a phenolic constituent, instead of the oxime moiety. Aldicarb is highly water-soluble (approximately 6000 ppm), nonvolatile, relatively stable under acidic conditions, and is easily degraded under alkaline conditions. These properties are important determinants of its systemic action in plants and of its problematic environmental behavior. Possible environmental hazards involving the chemical include groundwater contamination and (more recently) excessive terminal residues in certain foods.
PMCID: PMC1566767  PMID: 7737038
12.  Evaluation of a screening test for detecting urinary tract infection in newborns and infants. 
Journal of Clinical Pathology  1991;44(12):1029-1030.
The results of a study of a screening test for urinary tract infection (UTI) in infants under 18 months is reported. Two hundred and forty three urine specimens were tested in the laboratory using AMES Multistix 8SG reagent strips read by photometer. The strips included three potential markers for urinary tract infection: leucocyte esterase, nitrite, and protein. The predictive value of a positive result (PPV) was low. The predictive value of negative test (NPV) when combining the screen of leucocyte esterase, nitrite, and protein was 99.4% with no difference between boys and girls. The test for leucocyte esterase had a 97.6% negative predictive value. An examination of the results by age confirms the good NPV in all age groups. Paediatricians should find Multistix 8SG strips a useful aid in the diagnosis of urinary tract infection in infants, and that costly culture of samples with negative strip tests can be avoided.
PMCID: PMC494975  PMID: 1791205
13.  Physician management of hypercholesterolemia. A randomized trial of continuing medical education. 
Western Journal of Medicine  1994;161(6):572-578.
To determine the effect of continuing medical education (CME) on compliance with the recommendations of the National Cholesterol Education Program Expert Panel on high serum cholesterol levels in adults, we randomly assigned primary physicians in 174 practices to 3 groups, 2 that underwent either standard or intensive CME and a control group. The standard CME group was offered a free 3-hour seminar on high serum cholesterol levels; the intensive CME group was offered in addition follow-up seminars and free office materials. After 18 months, we audited 13,099 medical records from the 140 practices that remained in the study. There were no significant differences (P > .15) in screening for high serum cholesterol or compliance with guidelines between the groups receiving continuing medical education (51% screening; 33% compliance) and the control group (57% screening; 37% compliance). In the prespecified subgroup of patients with hypercholesterolemia, there was a trend toward a modest benefit from the continuing medical education interventions: compliance was 21% in the control group, 23% in the standard CME group, and 27% in the intensive CME group (P = .07 overall). These results emphasize the need for better ways to change behavior in practicing physicians and the importance of studying the implementation of preventive health recommendations.
PMCID: PMC1022738  PMID: 7856157
14.  Firearms in New Mexico. 
Western Journal of Medicine  1994;161(2):137-139.
To determine the prevalence of firearm ownership and storage practices in New Mexico, we did a random-digit-dialing survey of New Mexico residents in October 1991. Of 200 households surveyed, 79 (40%) had 1 or more firearms in the home. Rural households were more likely than urban households to have firearms (44% versus 30%), and households with annual incomes of greater than $25,000 were more likely to have a firearm than households with incomes of $25,000 or less (41% versus 33%). Household firearm ownership did not vary with the presence of young (< 15 years old) children (38% with children versus 41% without). Handguns were generally owned for self-protection, and rifles were owned for hunting. Of households with firearms, 24% stored them unsafely (unlocked and loaded or unloaded but with ammunition nearby), including 21% of households with young children. Of the households with handguns only, 40% stored these firearms unsafely compared with 13% of those with rifles only. The prevalence of gun ownership in New Mexico is similar to that reported in national surveys; handguns are stored less safely than rifles; and the presence of young children in the home does not appear to improve firearm storage safety.
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PMCID: PMC1022524  PMID: 7941530
15.  Predictors of screening for hypercholesterolemia in a general internal medicine practice. 
Western Journal of Medicine  1993;158(4):359-363.
We compared current practice with the National Cholesterol Education Program (NCEP) guidelines for the detection and evaluation of hypercholesterolemia and analyzed the association of various patient and provider factors with screening. Using a retrospective medical records review of 1,000 randomly selected patients between the ages of 18 and 70 in a university-based general internal medicine practice--faculty, residents (categorical and primary care), and nurse practitioners--we found that 80% of patients were screened for hypercholesterolemia. Patients older than 35 were more likely to be screened than younger patients (87% versus 77%; P = .001), and, among younger patients, nonwhites were less likely to be screened than whites (58% versus 77%; P = .0001). Lipoprotein analysis was done in 60% of the 235 patients in whom it was indicated; older patients were significantly more likely to have these measurements. Among patients taking medications for hypercholesterolemia, 92% had lipoprotein analyses done beforehand. No differences were detected in screening by provider characteristics. We conclude that providers in our practice are appropriately aggressive in screening high-risk patients for hypercholesterolemia. The finding that young whites are screened much more often than nonwhites was surprising. Finally, although there is a high rate of screening overall, many patients with elevated cholesterol levels are not appropriately classified as to their low-density-lipoprotein levels.
PMCID: PMC1022061  PMID: 8317121
16.  Giving answers or raising questions?: the problematic role of institutional ethics committees. 
Journal of Medical Ethics  1989;15(3):137-142.
Institutional ethics committees (IECs) are part of a growing phenomenon in the American health care system. Although a major force driving hospitals to establish IECs is the desire to resolve difficult clinical dilemmas in a quick and systematic way, in this paper we argue that such a goal is naive and, to some extent, misguided. We assess the growing trend of these committees, analyse the theoretical assumptions underlying their establishment, and evaluate their strengths and shortcomings. We show how the 'medical consultation' model is often inappropriately applied to IECs and suggest that IECs must operate under a different framework. Finally, we argue that IECs should be valued for the process they facilitate, and not for the product that they are, often unreasonably, expected to deliver.
PMCID: PMC1375804  PMID: 2795627
17.  Management of hypercholesterolemia. A primary care perspective. 
Western Journal of Medicine  1989;150(5):562-568.
We now have sufficient evidence to recommend an aggressive program of the detection and treatment of hypercholesterolemia. All adult patients should be screened and evaluated, and treatment decisions should be based on their LDL-cholesterol levels and the presence or absence of other risk factors. Diet therapy should be initiated in motivated patients for three to six months progressing from a qualitative to a quantitative approach. Patients with persistent elevations in their LDL-cholesterol levels who accept drug therapy can be begun on a regimen of nicotinic acid, gemfibrizol or bile acid-binding resins, and, when necessary, lovastatin.
PMCID: PMC1026661  PMID: 2741452
18.  Assessing trends in mortality in 121 U.S. cities, 1970-79, from all causes and from pneumonia and influenza. 
Public Health Reports  1988;103(2):120-128.
The Centers for Disease Control receives weekly reports of mortality due to all causes and to pneumonia and influenza from 121 cities and counties in the United States. To assess the epidemiologic applicability of these data, the trends of death rates based on data compiled by the Centers for Disease Control's mortality reporting system (CDC-MRS) from 1970 through 1979 were compared with trends derived from national mortality statistics compiled by the National Center for Health Statistics (NCHS). In general, CDC-MRS trends in death rates from all causes and from pneumonia and influenza followed patterns similar to those shown by mortality statistics for the entire nation. CDC-MRS data were particularly sensitive to annual fluctuations in the nationwide rate of death from pneumonia and influenza among the elderly population. However, because of higher death rates among residents of the CDC-MRS reporting areas, in addition to other ascertainment biases, CDC-MRS death rates--from all causes and from pneumonia and influenza--consistently exceeded NCHS rates for the nation. Moreover, for each age group, trends based on CDC-MRS reflected an underestimate of the rate of decline in mortality observed over time according to NCHS data. It is concluded that despite its limitations, the CDC-MRS provides mortality data that are both timely and useful for epidemiologic purposes.
PMCID: PMC1477970  PMID: 2833763
23.  Phosphorus Necrosis of the Jaw: A Present-day Study 
A historical note on the aetiology of phossy jaw shows that present-day knowledge is little greater than it was a century ago. The varied clinical course of the disease is described together with a report of 10 classical cases not previously reported. Six cases, not amounting to true necrosis but in which healing after dental extraction was delayed, and described, and mention is made of the noticeable differences in the oral state and appearances of tartar of healthy workmen exposed to phosphorus compared with healthy workmen not exposed. But no systematic differences of any kind were found in the incidence of general infections, fractures of bones, haematological findings, and biochemical studies of blood and urine in two groups of healthy men most exposed and least exposed to phosphorous in the same factory. An intensive study in hospital of a case of classical necrosis showed no departure from normal, except delayed healing following bone biopsy from the iliac crest, and a reversed polymorphonuclear/lymphocyte ratio.
In the discussion the time of onset of necrosis after first exposure to phosphorus, clinical and radiological diagnosis, the organisms present, personal susceptibility, the appearance of the sequestra, and regeneration of bone are considered. An up-to-date note on prevention of the disease is given, although this has met with only partial success. Some persons are highly susceptible and, whilst complete protection is impossible in the light of our present knowledge, early diagnosis and modern treatment have robbed the disease of its terrible manifestations of Victorian times and turned it into a minor, although often uncomfortable complaint, with little or no resulting disability.
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PMCID: PMC1038164  PMID: 14449812

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