Haploidentical bone marrow stem cell transplantation in human severe combined immunodeficiency.

From May 1992 to March 1993, 50 infants with severe combined immunodeficiency (SCID) were given bone marrow transplants at Duke University Medical Center. None received chemotherapy for conditioning or for graft-versus-host disease (GVHD) prophylaxis. Forty-one received haploidentical parental marrow depleted of T cells by soybean lectin and sheep red blood cell resetting, and nine received HLA-identical marrow. Forty (80%) survived from 1 week to almost 11 years posttransplantation, including nine of nine (100%) HLA-identical marrow recipients and 31 of 41 haploidentical recipients. T-cell function was present within 2 weeks after transplantation of unfractionated HLA-identical marrow, but not until 3 to 4 months after T-cell-depleted haploidentical marrow stem cells. All 37 patients who are more than 4 months posttransplantation have good T-cell function, and all but one have 100% donor T cells. B-cell function developed slowly or not at all in some recipients of haploidentical marrow. Fourteen (four HLA-identical and 10 haploidentical recipients) have some donor B cells; 19 patients are receiving intravenous immune globulin (IVIG) therapy.

Cost-effectiveness of donepezil in the treatment of mild or moderate Alzheimer's disease.

OBJECTIVE: To demonstrate the use of cost-effectiveness analysis to assess the economic impact of donepezil in the treatment of mild or moderate AD. BACKGROUND: Cost-effectiveness analyses show the relationship between resources used (costs) and health benefits achieved (effects) for an intervention compared with an alternative strategy. METHODS: We developed a model to estimate the incremental cost-effectiveness of donepezil compared with no treatment. We determined costs per quality-adjusted life-years gained, a measurement that enhances the comparability of diverse studies. The model projects the progression of AD patients into more severe disease stages and into nursing homes. Data from a randomized clinical trial of donepezil were used to assess the drug's impact on the 6-week probabilities of progression. Data on the costs and health-related quality of life associated with different disease stages and settings were taken from published estimates and our companion cross-sectional study, respectively. RESULTS: Donepezil costs are partially offset by a reduction in the costs of care due to enhancement in cognitive functioning and the delay to more costly disease stages and settings. The magnitude of this cost offset and of the effect of donepezil on health-related quality of life depends on the model's assumptions about the duration of the drug effect, where controlled data are lacking. If the drug effect exceeds 2 years, the model predicts that for mild AD the drug would pay for itself in terms of cost offsets. CONCLUSIONS: The results of the cost-effectiveness model presented here suggest that donepezil may be cost-effective but additional controlled data on long-term drug efficacy are needed.

Egg hypersensitivity and measles-mumps-rubella vaccine administration.

Because reports have described egg-sensitive individuals in whom anaphylaxis developed after measles vaccination, current recommendations include delaying administration of egg-derived vaccines until skin testing can be performed. Specifically, the 1988 Red Book recommends skin testing via scratch, prick, or puncture with 1:10 dilution of the vaccine and, if the result is negative, intradermal testing is suggested. The purpose of this study was to evaluate the likelihood of reaction to measles-mumps-rubella (MMR) vaccine in patients with documented egg sensitivity and to delineate the efficacy of skin-prick testing (SPT) to MMR as a predictor of hypersensitivity to the vaccine. Egg sensitivity was documented by initial SPT to egg and then, if possible, double-blind placebo-controlled food challenge (DBPCFC). Patients with a positive DBPCFC to egg or a history of anaphylactic egg sensitivity had a SPT with the MMR vaccine and then were given the MMR vaccine. Additionally, children with atopic dermatitis who had been previously proven egg sensitive via DBPCFCs were evaluated retrospectively for sensitivity to the MMR vaccine. Sixteen children with a history of egg sensitivity underwent SPT to egg, with a positive result 3 mm greater than the negative control found in 12 patients. Eight of these children had a positive DBPCFC to egg. The SPT to MMR vaccine was negative in all 16 children; vaccine administration followed with no resultant systemic problems. Three children had a local reaction at the site of injection. Twelve additional children with atopic dermatitis and egg sensitivity were reviewed. Each child had a positive SPT and DBPCFC to egg.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical manifestations of inherited glaucoma in the beagle.

Inherited glaucoma was exhibited in 55 beagles. The glaucomatous process was divided into early (6 to 12 months of age), moderate (13 to 30 months of age), and advanced (31 months of age). In early glaucoma the tridocorneal angles, as judged by gonioscopy, were open and without anomalies, intraocular pressure was elevated, and the tonographic facility of aqueous outflow was decreased. With moderate glaucoma, the tridocorneal angles were typically open; intraocular pressure was elevated, facility of aqueous outflow was decreased; and variable optic disc cupping and focal disinsertion of the zonules from the lens were seen. Advanced glaucoma exhibited narrow to closed tridocorneal angles, decreased facility of aqueous outflow, elevated intraocular pressure, lens dislocation, optic disc atrophy, and finally phthisis bulbi. The beagle in the early and moderate stages of glaucoma, before angle closure and lens dislocation, is an animal model for studies in open-angle glaucoma.

The effect of topical pilocarpine on intraocular pressure and pupil size in the normotensive and glaucomatous beagle.

Topical 1, 2, and 4 percent pilocarpine were evaluated in the normotensive and glaucomatous beagles, comparing intraocular pressure (IOP), pupillary size, and time. In normotensive beagles pilocarpine produced maximal decreases of 25 percent (5.5 mm. Hg) at 1 percent concentration; 34 percent (7.26 mm. Hg) at 2 percent concentration; and 25 percent (6.9 mm. Hg) at 4 percent concentration. The maximum reductions in IOP after pilocarpine instillation in the glaucomatous beagle were 30 percent (9.1 mm. Hg) at 1 percent concentration; 44 percent (14.92 mm. Hg) at 2 percent concentration; and 31 percent (10.89 mm. Hg) at 4 percent concentration. The glaucomatous beagles responded with a greater reduction of IOP than did the normotensive beagles.

Cost-effectiveness considerations in the treatment of heterozygous familial hypercholesterolemia with medications.

When used for the primary prevention of coronary heart disease in persons with heterozygous familial hypercholesterolemia (hFH), a hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitor is projected to be effective and to have very favorable cost-effectiveness ratios at low-to-medium doses. For example, 20 mg of lovastatin per day is estimated to save lives and save money in all men ages 35-44 years with hFH and in women ages 35-44 years with hFH and any other risk factor. The estimated incremental cost effectiveness of 40 mg compared with 20 mg of lovastatin for individuals with hFH ages 35-44 years was less than $45,000 per year of life saved in men with > or = 1 other risk factors and women with > or = 2 other risk factors. The estimated incremental cost-effectiveness ratio of 80 mg compared with 40 mg/day was substantially higher ($100,000 or more per year of life saved) even in the highest risk persons. The estimated cost-effectiveness ratios for primary prevention in hFH were reasonably similar to the favorable ratios for secondary prevention in the general population but substantially better than the estimated ratios for primary prevention in other adults with high cholesterol levels. Any national recommendations regarding the use of medications for individuals with hFH must include cost considerations. Our analyses support the use of low-to-moderate doses of high-cost medications for primary prevention in these patients.

Skin testing and food challenges in allergy and immunology practice.

Skin tests by prick technique offer considerable guidance in the diagnosis of food allergy. Negative prick skin tests are powerful evidence against food allergy. Positive food skin tests are slightly to moderately predictive of reaction to a food on DBPCFC. Oral food challenge is necessary for confirmation of food allergy, except where the history is overwhelmingly convincing. Open, incremental food challenge as described is diagnostic if negative, but only 50% of all positive open challenges are confirmed on blinded challenge. DBPCFC can be designed for any food with simple blinding techniques. The technique of DBPCFC can be modified for investigation of atypical symptoms.

Study of the feline and canine populations in the greater Las Vegas area.

Analysis of household dogs and cats, based on age-distribution data and on age-specific birth and survival rates, as well as on pet source, indicated that the dog and cat populations are stable and not increasing in size (lambda congruent to 1). Roaming dogs and cats euthanatized at the pound represented about 5.7% and 8.1% of the estimated dog and cat populations, respectively. The death at the pound seems to be effective in checking pet population growth. Among pets acquired, 84% were less than 1 year of age for dogs as compared with 88% for cats. Breeders and pet shops supplied about 7% of cats and 17% of dogs. About 10% of cats and 10% of dogs were acquired at the pound, while 6.4% of dogs and 14% of cats were acquired as stray. About 45% of dogs and 41% of cats were acquired from pet owners. Some dogs (12.46%) and cats (12%) were imported from outside the Las Vegas area. Of dogs and cats below 2 months of age, 33% and 19.5%, respectively, came from breeders or pet shops or were imported from outside the area. Seventeen percent of unspayed female dogs and 16% of unspayed female cats reproduced. The percentages of spayed females were 77 for dogs and 86 for cats. Forty-five percent of the dogs and 48% of the cats were males. Among dogs at the shelter, 2% were neutered and 26% spayed. At the pound, 24% of dogs were small breeds, 24% medium size breeds, and 52% large breeds.(ABSTRACT TRUNCATED AT 250 WORDS)

Ocular hypotensive effects of carbonic anhydrase inhibitors in normotensive and glaucomatous Beagles.

Four carbonic anhydrase inhibitors (acetazolamide, dichlorphenamide, ethoxzolamide, and methazolamide) cause ocular hypotony in normotensive and glaucomatous Beagles. Four dosages of acetazolamide and methazolamide and three dosages of dichlorphenamide and ethoxzolamide were evaluated. The extent of ocular hypotony after these carbonic anhydrase inhibitors was usually greater in glaucomatous Beagles than it was in normotensive Beagles.

Evaluation of a soluble sustained-release ophthalmic delivery unit in the dog.

A 5-mg hydroxypropyl cellulose soluble ocular insert was evaluated by placement in the upper and the lower conjunctival and bulbar nictitating membrane fornices in normal dogs. The insert was easily placed in the conjunctival fornices, but was difficult to place in the bulbar nictitating membrane fornix. The conjunctival inserts did not produce irritation of the cornea and the conjunctiva. Placement of the inserts beneath the nictitating membrane produced local irritation and chemosis. The sites of highest to lowest retention for the insert were upper conjunctival fornix, bulbar nictitating membrane fornix, and lastly, lower conjunctival fornix. Dissolution was nearly complete in 8 hours.

Uveoscleral flow of aqueous humor in the normal dog.

Fluorescein-labeled dextran and sodium fluorescein perfused in the posterior chamber of the normal dog eye egressed through the trabecular meshwork and intrascleral plexus, as well as posteriorly through the ciliary body into the suprachoroidal space and the sclera. Intraocular pressures of 20, 25, 30, and 60 mm of Hg did not produce detectable changes in the fluorescein-labeled dextran movement. Topical 1% atropine and 10% phenylephrine did not affect posterior passage of sodium fluorescein; 2% pilocarpine impeded posterior passage, causing an accumulation of sodium fluorescein and associated fluorescence in the anterior ciliary body.

Cataracts in Chesapeake Bay Retrievers.

Cataracts developed in 13 of 27 related Chesapeake Bay Retrievers. The posterior pole, "Y" sutures, and equatorial cortices of the lens were predominantly affected. In one affected dog, the cataracts had progressed to hypermaturity, permitting restoration of vision. The trait was believed to be dominant, with incomplete penetrance.

Skin testing and food challenges for the evaluation of food allergy.

Skin testing by prick technique has an excellent safety record in the evaluation of food hypersensitivity. Skin prick tests for the common food allergens are excellent tools for identifying those at very low risk of reaction on eating the food but are of variable value in identifying patients who will be positive on challenge. Intradermal skin tests to foods are less safe and appear to add no predictive information. Skin tests to less common food allergens, especially fruits, are less well characterized and may require use of the food item itself as the source of allergen rather than a commercial extract. For a few foods, the CAP system fluorescent enzyme immunoassay (Pharmacia, Peapack, NJ) recently has been shown to have good ability to identify patients at very high probability of reaction on oral challenge. Oral challenge remains the definitive method of demonstrating sensitivity or tolerance to a food. The double-blind, placebo-controlled food challenge is the gold standard of diagnosis, but in many situations, simpler open or single-blind challenge procedures may be substituted. With careful, incremental dosing and a low starting dose, oral challenges for food hypersensitivity have an excellent safety record. Skin prick tests are of little value in the evaluation of adverse food reactions not mediated by IgE. Oral challenge is relied upon in this situation for definitive diagnosis, but challenges may be cumbersome if the time course of the presumed reaction is not rapid.

Congenital immunodeficiency syndromes.

Cogenital abnormalities of innate or acquired immunity, although not common, produce multiple problems for which the surgeon may be consulted. Even if the diagnosis has not been previously made, patients with abnormal situs, congenital heart disease, failure to heal surgical wounds, pneumatoceles, lymphoproliferative disorders, recurrent severe infections, or autoimmune destruction of formed elements of the blood may have one of the disorders discussed above.

Pneumatosis intestinale in children with primary combined immunodeficiency.

We report six episodes of pneumatosis intestinale (PI) in children with primary combined immunodeficiency. PI was generally benign and responded to conservative therapy. Increased risk of infection or disruption of gastrointestinal mucosa are probable predisposing factors. A diagnosis of PI should be considered in children with primary combined immunodeficiency who experience otherwise unexplained gastrointestinal symptoms, particularly in the early post-transplant period.

Complement: function and clinical relevance.

There is a remarkable array of proteins participating in the complement cascade, regulating the activation of the system, or recognizing a fragment of a component as a biologic signal. The classical pathway of complement activation depends on antigen-antibody interaction and is important as an effector arm of acquired humoral immunity to microorganisms. The alternative pathway functions as a form of innate humoral immunity by attacking membranes not having the characteristics of self-membrane. In addition, the alternative path provides amplification after triggering by either path. Absence or dysfunction of many of the components is associated with autoimmune or immunodeficiency disease. Absence of the inhibitor C1INH is associated with the unique syndrome of hereditary angioedema.

Relative impact of targeted versus populationwide cholesterol interventions on the incidence of coronary heart disease. Projections of the Coronary Heart Disease Policy Model.

We used the Coronary Heart Disease Policy Model, a state-transition computer simulation, to assess the absolute and relative effects of two different national cholesterol interventions: a targeted program to identify and treat all individuals with elevated serum cholesterol levels (greater than or equal to 250 mg/dl) versus a populationwide program to reduce everyone's serum cholesterol level. Based on the assumptions inherent in our model, which uses the Framingham Heart Study coefficients, we estimate the targeted program would reduce projected coronary heart disease absolute incidence by 8-10% in men ages 35-54 years and by 1-4% in men ages 55-74 years. Our model suggests that similar reductions in coronary heart disease incidence could be achieved by a 10 mg/dl populationwide reduction in serum cholesterol levels. In women, the targeted program would yield greater relative and absolute benefits and would be equivalent to a approximately 23 mg/dl populationwide reduction in serum cholesterol. We conclude that it would be inadvisable to rely solely on targeted cholesterol reduction programs to reduce national coronary heart disease.

Intravenous immunoglobulin: new clinical applications.

At the present time there are three commercially available intravenous immunoglobulin (IVIG) preparations. There is no distinct therapeutic advantage for any one product over any other. Intravenous immunoglobulin is currently approved for the treatment of antibody deficiency syndromes and for acute and chronic idiopathic thrombocytopenic purpura. In addition, controlled clinical trials have demonstrated efficacy for the treatment of Kawasaki disease and for the prevention of the following infections: sepsis in preterm neonates, sepsis in infants with AIDS, and cytomegalovirus infection in the immune-compromised host. Open (uncontrolled) studies have suggested benefit in the treatment of neonatal sepsis, chronic Epstein-Barr virus infection, and a number of autoimmune diseases. Additional carefully designed studies must be completed before IVIG therapy can be recommended for these latter categories. In published reports, dosage of IVIG and intervals between infusions have varied considerably. For all current indications, the physician must therefore individualize treatment and thoroughly review any recent literature that may clarify guidelines to IVIG therapy. Significant adverse reactions are rare but high cost remains the main obstacle to more routine implementation.