Bone marrow transplantation in chronic granulomatous disease

We present a 5-year-old boy with a severe form of X-linked chronic granulomatous disease and hypersensitivity to sulphamides preventing prophylaxis with trimethoprim-sulphomethoxazole. Bone marrow transplantation was performed after preconditioning with busulphan and cyclophosphamide. The immediate post-transplant period was without complications. Complete chimerism was demonstrated and post-transplant oxidative metabolism was normal. The patient is asymptomatic 30 months after the graft. CONCLUSION: Bone marrow transplantation in cases of chronic granulomatous disease is controversial, although it could be useful in selected very severe cases in which prophylactic therapy is problematic.     

Genitourinary involvement in chronic granulomatous disease of childhood

A second case of symptomatic renal involvement of chronic granulomatous disease of childhood is reported, and all previous cases of documented genitourinary lesions in this disease are reviewed. Although frequent infections of other organ systems are a well recognized part of chronic granulomatous disease, involvement of the urinary tract has been rarely reported. The nature of the few cases described suggests that extensive insidious destruction occurs before urinary tract involvement is clinically suspected.     

Type IIB von Willebrand''s disease: gene mutations and clinical presentation in nine families from Denmark, Germany and Sweden

Type IIB of von Willebrand's disease (vWD) is a variant in which the structurally abnormal von Willebrand factor (vWF) shows an increased affinity for the platelet vWF receptor, glycoprotein Ib (GPIb). This may sometimes give rise to platelet aggregation and thrombocytopenia in vivo. In 20 patients from nine unrelated families with type IIB vWD from Denmark, Germany and Sweden we studied the molecular defect by amplification and direct sequencing of parts of exon 28 which encode for the vWF domain that interacts with platelet GPIb. Three different point mutations were identified one of which has not previously been reported. Fifteen patients from five families were heterozygous for the Arg543-->Trp substitution. The mutation had occurred independently in all five families and in two of them represented a de novo mutation. In one of these families the father, though asymptomatic and with normal laboratory test results, carried the mutation in heterozygous form. In three families, four affected members were found to be heterozygous for the Arg543-->Cys substitution. The mutations were of different origin at least in two of the families. The third substitution, Val551-->Leu, which has not previously been described, was found in one patient and was due to a de novo mutation. In most of the patients spontaneous thrombocytopenia had been recorded on at least one occasion. Five of the patients with the Arg543-->Trp substitution and the one with the Val555-->Leu substitution had all had bleeding associated with thrombocytopenia in the neonatal period of early infancy.     

The molecular basis of chronic granulomatous disease

CGD is a rare inherited immunodeficiency syndrome, caused by the phagocytes' inability to produce (sufficient) reactive oxygen metabolites. This dysfunction is due to a defect in the NADPH oxidase, the enzyme responsible for the production of superoxide. It is composed of several subunits, two of which, gp91phox and p22phox, form the membrane-bound cytochrome b558, while its three cytosolic components, p47phox, p67phox and p40phox, have to translocate to the membrane upon activation. This is a tightly and intricately controlled process that involves, among others, several low-molecular weight GTP-binding proteins. Gp91phox is encoded on the X-chromosome and p22phox, p47phox and p67phox on different autosomal chromosomes, and a defect in one of these components leads to CGD. This explains the variable mode of inheritance seen in this syndrome. Clinically CGD manifests itself typically already at a very young age with recurrent and serious infections, most often caused by catalase-positive pathogens. Modern treatment options, including prophylaxis with trimethoprim-sulfamethoxazole and rIFN-gamma as well as early and aggressive anti-infection therapy, have improved the prognosis of this disease dramatically. CGD, as a very well-characterized inherited affection of the hematopoietic stem cells, is predestined to be among the first diseases to profit from the advances in cutting-edge therapeutics, such as gene therapy and in utero stem cell transplantation.     

Phagocytic NADPH oxidase and its role in chronic granulomatous disease

Case-control and cohort studies support the hypothesis that postmenopausal oestrogen-replacement therapy reduces the risk of atherosclerotic disease manifestations. The evidence for a cardioprotective effect of such a therapy is, however, incomplete because randomized prospective studies are missing. Because it may be almost impossible to conduct placebo-controlled trials in the future, other study designs will be needed to minimize selection bias. Further work is required to define the optimal dose and administration schedule of oestrogen and to determine whether addition of progestogens alters the beneficial effect of oestrogen on the cardiovascular system. Such studies may also provide mechanistic insight into the interaction between lipoprotein metabolism and haemostasis and its relation to the atherosclerotic disease process.     

Pneumonic tularemia in a patient with chronic granulomatous disease

We report the case of a 14-year-old boy with granulomatous pneumonia caused by Francisella tularensis. In addition, an autosomal recessive form of chronic granulomatous disease was diagnosed. Both F. tularensis and chronic granulomatous disease are associated with pulmonary granulomas. To our knowledge, this is the first report of F. tularensis infection in a patient with chronic granulomatous disease. The relationship between these two processes is discussed.     

Arcuate dermal erythema in a carrier of chronic granulomatous disease

A female carrier of chronic granulomatous disease developed arcuate, erythematous dermal plaques on her back and face. The lesions were clinically and histopathologically suggestive of Jessner benign lymphocytic infiltration of the skin. Some women with relatively fixed arcuate or annular, erythematous, dermal plaques may be carriers of chronic granulomatous disease.     

Secondary hypertension and clinical genetics: usual presentation with unusual diagnosis

A transjugular central venous catheter was inadvertently sutured to the wall of the right atrium in a 63-year-old female during coronary bypass surgery. Using two nitinol Goose Neck snares via a transfemoral and a transjugular approach the catheter was severed into two pieces and retrieved percutaneously.     

Cutaneous purulent aspergillosis in a young man with chronic granulomatous disease

We describe a case of cutaneous purulent aspergillosis in a 19-year-old man with chronic granulomatous disease (CGD) treated successfully with a 6-month regimen of itraconazole. The therapeutic effect of the drug was seen after 1 month of administration. Surgical treatment of the skin lesions, although first planned, was not necessary.     

Ureteral obstruction in a patient with chronic granulomatous disease, receiving combined prophylaxis with IFN-gamma and antibiotics

For a successful take, skin grafts must be immobilized when applying dressings. Surgical beds requiring a stent to maintain contact between the graft and wound bed can be treated with Biobrane (Dow B. Hickam, Inc., Sugarland, Texas), which is held in place with skin staples at the periphery. Moistened gauze is placed over the grafted area, the redundant Biobrane stretched over the gauze, and this top layer again stapled at the periphery. When the stent is no longer needed, the top layer of Biobrane and gauze are removed, leaving a graft adherent to the bed and covered with Biobrane. This allows the surgeon to quickly construct an effective stent.     

Safety and effectiveness of long-term interferon gamma therapy in patients with chronic granulomatous disease

In chronic granulomatous disease (CGD), diminished or absent neutrophil NADPH oxidase function leads to recurrent pyogenic infections and granuloma formation. In a recent randomized, placebo-controlled trail, short-term prophylactic use of recombinant human interferon gamma (rIFN-gamma 1b) reduced the risk of serious infection in CGD patients by 67%, The current study evaluated the safety and effectiveness of long-term rIFN-gamma therapy in CGD patients. Patients were treated three times weekly with rIFN-gamma and evaluated semiannually. Serious infections (requiring hospitalization and parenteral antibiotic therapy), adverse clinical events, and measures of growth and development were noted. Thirty patients were evaluated for 12 months. The total average duration of rIFN-gamma therapy was 2.5 years. Three patients developed a total of four serious infections (0.13 infections per patient year). This rate compare favorably with rates of 1.10 and 0.38 infections per patient year found in the placebo and rIFN-gamma groups, respectively, during a previous study. Common adverse events were fever (23%), diarrhea (13%), and flu-like illness (13%). No serious adverse event was attributable to rIFN-gamma therapy and no obvious effects on growth and development were observed. rIFN-gamma is a safe and effective adjunctive therapy for reducing the frequency and severity of serious infections in CGD patients.     

Prevalence and clinical correlates of psychotic symptoms in Alzheimer''s disease

The Canadian Heart Health Initiative-Ontario Project (CHHIOP) investigates predisposition and capacity in Ontario public health departments to implement community-based heart health promotion activities. The research draws upon diffusion of innovations theory and recent work on ecological approaches to health promotion within which public health agencies are seen to play a central role. Mail-back surveys were completed by heart health staff in all 42 health departments in 1994 and 1996. Predisposition and capacity were measured as the importance and effectiveness ascribed to 18 organizational practices supportive of community heart health activities. Level of implementation was reported for 74 activities spanning a range of risk factors and settings. Predisposition, capacity and implementation scores increased between 1994 and 1996. The findings confirm positive correlations between predisposition and capacity and between capacity and implementation.     

Pseudomonas cepacia pneumonia in a child with chronic granulomatous disease and selective IgA deficiency

A 6 1/2 year-old boy with chronic granulomatous disease (CGD) and selective IgA deficiency developed a chronic progressive pneumonia which failed to respond to several conventional combinations of antimicrobial therapy. On lung biopsy, Pseudomonas cepacia was obtained in pure culture, sensitive to chloramphenicol, tetracycline, kanamycin and nalidixic acid. With specific therapy, he slowly recovered. P. cepacia has not been previously described as a cause of persistent pneumonia in immunodeficient children. The occurrence of CGD and selective IgA deficiency together is a very rare combination of immunodeficiencies.     

Outpatient management with oral corticosteroid therapy for obstructive conditions in chronic granulomatous disease

We report the outpatient management of three patients with X-linked chronic granulomatous disease, two of whom had episodes of gastric outlet obstruction and another, urinary bladder obstruction. These obstructive conditions were successfully treated with 2-week courses of orally administered corticosteroids with or without the addition of orally administered clindamycin. There were no infectious or other adverse reactions.     

The biochemical basis of nitroblue tetrazolium reduction in normal human and chronic granulomatous disease polymorphonuclear leukocytes

Normal human polymorphonuclear leukocytes (PMN) placed in anaerobic chambers reaching pO2's of less than 5 mm Hg fail to generate O2-, iodinate ingested particles, and stimulate glucose-1-14C oxidation through the hexose monophosphate shunt. The observation that anaerobic cells are incapable of generating O2- or reducing nitroblue tetrazolium (NBT) to formazan supports the idea that NBT reduction in phagocytizing PMN is due exclusively to oxygen-dependent O2- generating oxidase which is deficient in chronic granulomatous disease leukocytes, despite their hyperphagocytic capacity.     

Prevalence of bronchial hyper-responsiveness in the southern, central and northern parts of Sweden

Studies have suggested that there is a higher prevalence of asthma in northern Sweden than in southern Sweden. Bronchial hyper-responsiveness (BHR) has been shown to be associated with asthma. The aim of this study was to explore the prevalence of bronchical hyper-responsiveness in different parts of Sweden. As part of the European Community Respiratory Health Survey (ECRHS), interviews, skin prick tests, lung function tests and methacholine provocation tests of the airways were performed in 1448 randomly selected subjects in southern, central and northern Sweden. The Mefar dosimeter was used according to the ECRHS protocol. The responsiveness was calculated both as the PD20 and as the dose response slope (DRS). BHR was defined as a PD20 of < or = 1.6 mg. Atopy was defined as at least one skin prick test of > or = 3 mm. The prevalence of BHR was 12.7%, 10.6% in men and 15.0% in women. No difference in prevalence was found between the three different regions of Sweden. The prevalence of BHR was higher in women than in men and higher in smokers than in non-smokers. Using multiple logistic regression, with BHR as the dependent variable, atopy, being female, having a low FEV1 (% predicted) and smoking (both own and passive) increased the odds of having BHR, while age and the region of Sweden did not influence BHR. Defining BHR as a PD20 of < or = 1.0 mg or a PD20 of < or = 2.0 mg did not change this. Multiple regression using log DRS as the dependent variable produced the same result. Both BHR and increasing DRS were associated with self-reported wheezing, attacks of shortness of breath during the daytime at rest or after strenuous activity, being awakened by a feeling of tightness in the chest or an attack of shortness of breath. In subjects without self-reported asthma, BHR was associated with self-reported wheezing and attacks of shortness of breath after strenuous activity. In conclusion, we found that the prevalence of BHR in the three investigated areas was 12.7%. We found a trend towards a higher prevalence of BHR in the most northerly of the study areas, but the difference between the areas was not statistically significant. BHR and DRS were associated with atopy, smoking, female sex and FEV1 (% predicted). The reporting of symptoms from the airways was associated with the degree of bronchical responsiveness.     

Pantothenic acid, coenzyme A, and human chronic ulcerative and granulomatous colitis

To investigate further an apparent relationship between chronic ulcerative and granulomatous colitis and pantothenic acid deficiency, colonic tissues obtained at the time of colectomy in 29 patients with these disorders were assayed for pantothenic acid and for coenzyme A (CoA) activity. For comparison, normal colonic tissues free of pathological lesions were obtained from 31 patients having colectomy for carcinoma or diverticulitis. Plasma, red blood cells, and colonic mucosa were assayed microbiologically for free and total pantothenic acid. The activity of CoA in colonic mucosa was determined by assaying the acetylation of sulfanilamide. Concentrations of free, bound, and total pantothenic acid in blood and in colonic mucosa did not differ between the two groups of patients. Bound pantothenic acid increased linearly with total pantothenic acid. Colonic mucosa concentrated free pantothenic acid to about 50 times the level of blood, and pantothenic acid in red cells was similar to the concentration in plasma. Compared to normal gut mucosa, CoA activity was markedly low in mucosa from patients with chronic ulcerative or granulomatous disease despite the presence of normal amounts of free and bound pantothenic acid. A block in the conversion of bound pantothenic acid to CoA in diseased mucosa is suggested.