Pharmacokinetics of hydroxocobalamin in smoke inhalation victims

PURPOSE: This study was performed to describe the clinicopathologic features of a group of patients with posttraumatic unilateral focal choroidal granulomatous inflammation. METHODS: Enucleated eyes with focal choroidal granulomatous inflammation without clinical signs of contralateral ocular inflammation were identified. Clinical and pathologic features were recorded. RESULTS: Six enucleated eyes that had been injured by projectiles had focal uveal granulomatous inflammation of the posterior choroid. Four eyes had uvea attached to or incarcerated into the wound. Two eyes had foreign material associated with the granulomatous inflammation, and two eyes had a disrupted lens with lens-induced inflammation. Two eyes exhibited the focal granulomatous inflammation at the site of a choroidal rupture. None of the six enucleated eyes contained Dalen-Fuchs' nodules. CONCLUSIONS: Focal choroidal granulomatous inflammation may occur as a result of penetrating ocular trauma. The origin of this condition is unknown, although it likely represents a reaction to a foreign body.     

Atypical mycobacterial pulmonary disease and bronchial obstruction in HIV-negative children

Atypical mycobacterial infection in HIV-negative children usually presents with cervical lymphadenopathy. We report on 10 children who are HIV-negative and who presented with pulmonary disease, in whom either culture-proven atypical mycobacterium infection (four), positive avian Mantoux test (five), or lack of response to human tuberculosis treatment (one) had been observed. One case was subsequently diagnosed as chronic granulomatous disease and illustrates that children with atypical mycobacterial pulmonary infection should have their immune status fully investigated. Bronchial obstruction was observed in eight cases, and of these, endobronchial disease was found in six children. The diagnosis of atypical mycobacterial disease is difficult, and a negative avian Mantoux test does not exclude the diagnosis. The availability of clarithromycin and rifabutin has offered new therapeutic options in treating atypical mycobacterial pulmonary infection, but management of these cases can be prolonged and difficult.     

Protection by CD4 or CD8 T cells against pulmonary Mycobacterium bovis bacillus Calmette-Guérin infection

Mice deficient in CD8 T cells demonstrated levels of Th1 cytokines and granulomatous responses in the lungs very similar to those demonstrated by normal control mice and were fully capable of controlling pulmonary mycobacterial infection by Mycobacterium bovis BCG as assessed at day 37 postinfection. In comparison, mice deficient in CD4 T cells had similar levels of interleukin-12 (IL-12) and tumor necrosis factor alpha but lower levels of gamma interferon in the lungs and were still able to mount tissue granulomatous responses and control pulmonary mycobacterial infection. In contrast, IL-12(-/-) mice with impaired CD4 and CD8 T-cell responses had a markedly weakened control of infection, whereas SCID mice deficient in all T cells succumbed to such pulmonary mycobacterial infections.     

Lack of both types 1 and 2 cytokines, tissue inflammatory responses, and immune protection during pulmonary infection by Mycobacterium bovis bacille Calmette-Guérin in IL-12-deficient mice

Understanding of key cytokines and the nature of protective immune responses in pulmonary mycobacterial diseases remains a task of paramount importance. In this study, both wild-type (wt) and IL-12-deficient (IL-12(-/-)) mice were infected by airways inoculation of live Mycobacterium bovis bacille Calmette-Guérin (BCG). The type 1 cytokines IL-12, IFN-gamma, and TNF-alpha, but not the type 2 cytokines IL-4 and granulocyte macrophage (GM)-CSF, markedly increased in the lung and peripheral blood of wt mice postinfection, which resulted in the development of intense granulomatous responses and the effective control of mycobacterial infection in the lung. In contrast, IL-12(-/-) mice demonstrated a lack of both types 1 and 2 cytokines in the lung and blood and a severely impaired tissue immune-inflammatory response lacking not only macrophages and neutrophils but CD4 and CD8 T cells and NK cells in the lung throughout the entire course of study. Total lung mononuclear cells isolated from these mice, in contrast to wt mice, had an impaired recall immune response to Ag challenge in vitro. These impaired responses resulted in an uncontrolled local growth and systemic spread of bacilli. Our findings reveal that IL-12 plays an irreplaceable role in the initiation of Th1 responses, and the loss of its function cannot be compensated for by alternative mechanisms in the lung. This cytokine, together with IFN-gamma and TNF-alpha, and granulomatous inflammation are critically required for the effective control of pulmonary mycobacterial infection. Our results also indicate that the absence of type 1 cytokines does not necessarily favor a Th2 response.     

Differential amygdala activation in schizophrenia during sadness

Mycobacterium avium subspecies paratuberculosis (M. paratuberculosis) is the etiologic agent of paratuberculosis (Johne's disease), a chronic granulomatous enteritis in ruminants. Currently, there is a need for improved diagnostic tests because of the lack of methods for accurate, rapid and reliable detection of M. paratuberculosis infection. A M. paratuberculosis gene (hspX) was cloned, sequenced, and a 30 bp species-specific oligonucleotide was synthesized. As an internal control to identify mycobacterial strains, a 33 bp Mycobacterium genus-specific oligonucleotide was synthesized based on the conserved 5' terminus of the mycobacterial recA gene. Dioligonucleotide hybridization (dOH) analysis identified 28/28 (100%) mycobacterial strains and specifically identified 14/14 (100%) reference (ATCC 19698), bovine, ovine and human isolates of M. paratuberculosis. The M. paratuberculosis-specific oligonucleotide distinguished M. paratuberculosis isolates from related mycobacteria, including all closely related members of the Mycobacterium avium complex (MAC) tested in this study. The members of MAC tested in this study included Mycobacterium avium subspecies avium (M. paratuberculosis, Mycobacterium avium subspecies silvaticum (M. silvaticum) and Mycobacterium intracellulare strains. Hybridization was not observed with DNA extracted from a selected group of other bacterial pathogens. The experiments indicate that the dOH analysis is a useful diagnostic tool to detect mycobacterial infection, specifically M. paratuberculosis. The dOH method could be a good alternative to existing assays and will be adapted for specific identification of M. paratuberculosis from faecal samples, mixed bacteriologic cultures, tissue specimens and whole blood.     

Bioavailability and pharmacokinetic disposition of tacrine in elderly patients with Alzheimer''s disease

PURPOSE: The Baerveldt glaucoma implant is an aqueous shunting device with large surface area that is installed through a single-quadrant conjunctival incision. A rabbit model of the Baerveldt implant was created to obtain serial histology and clinical information over 1 year. METHODS: Modified versions of the Baerveldt implant (110 or 160 mm2) were implanted in 18 normal New Zealand white rabbit eyes. The rabbits were examined periodically and their intraocular pressures (IOPs) recorded. They were killed at monthly intervals to obtain histology of the bleb capsules. RESULTS: Thin capsules were present at 1 month, which consisted of lamellar collagen deposition surrounded by a granulomatous reaction with multinucleate giant cells. Inflammatory cells (probably macrophages) were scattered on the inner bleb surface. The granulomatous reaction resolved after 4 months. Subsequently, capsule thickness and cellularity remained relatively stable, although the collagen stroma became less compact over time. Sixteen rabbit eyes had initial IOP reductions of > or = 3 mm Hg compared with fellow eyes, which persisted up to 4 weeks postoperatively. Seven eyes (39%) exhibited a hypertensive phase (IOP exceeded that of fellow eye by > or = 3 mm Hg) from 2 weeks to 3 months postoperatively. CONCLUSION: The Baerveldt explant is surrounded by a fibrous capsule that matures over time. The bleb histology in the rabbit model is similar to that described with the Molteno implant in primates and humans, except for the eventual development of a fibroblastic inner lining in the rabbit model. This contrasts with primate and human models, in which the inner lining remains an open mesh.     

Changing eating patterns of American children: a view from 1996

Whipple's disease (WD) is an uncommonly diagnosed infection caused by the recently characterized bacillus, Tropheryma whippelii. The association of WD with pericarditis and endocarditis is widely recognized, although less attention has been paid to the myocardium as a site of disease. Although the disease was uniformly fatal before antibiotic therapy, current treatment usually results in cure. We report two patients whose deaths were directly related to cardiac involvement by WD and whose underlying disease escaped diagnosis for years. The first, a 60-year-old white woman, suffered a cardiovascular collapse, and lymphocytic myocarditis was demonstrated at autopsy. The second, a 48-year-old black man, had a lengthy history of progressive cardiac failure that terminated in arrhythmia. Extensive myocardial fibrosis, with lymphocytic and granulomatous inflammation, was demonstrated at autopsy. The presence of T. whippelii was confirmed by electron microscopic examination in both cases and by polymerase chain reaction in one. Patients with WD might harbor an undiagnosed lymphocytic or granulomatous myocarditis, and this diagnosis should be considered in the evaluation of cardiac failure.     

Extraocular muscle involvement in sarcoidosis

BACKGROUND: Sarcoidosis is a granulomatous inflammatory disease that may have a variety of ocular and orbital manifestations. The most common ocular manifestation is uveitis, and the most common orbital manifestation is dacryoadenitis. Extraocular muscle involvement in sarcoidosis has rarely been reported. The authors report a case of sarcoidosis involving the extraocular muscles of a 15-year-old boy with bilateral, painful, external ophthalmoplegia and enlargement of all extraocular muscles on computed tomography (CT) scan. RESULTS: Lateral rectus muscle biopsy and transbronchial lung biopsy showed noncaseating granulomas characteristic of sarcoidosis. Cultures and serologic studies excluded fungal and mycobacterial diseases. Treatment with oral corticosteroids improved symptoms and signs. CONCLUSIONS: The authors report the first case of sarcoidosis in a patient with symptomatic extraocular muscle involvement, and only the third case in which extraocular muscle involvement has been shown histologically.     

Allergic granulomatous angiitis associated with cerebral infarction, myo-pericarditis and acute respiratory failure due to eosinophilic pneumonia

We encountered a 23-year-old woman with allergic granulomatous angiitis (AGA) associated with cerebral infarction, myo-pericarditis, and acute respiratory failure due to extended eosinophilic pneumonia. She underwent emergency treatment at our hospital because of right hemiparesis and impaired consciousness. AGA was suspected because the patient had a history of bronchial asthma accompanied by pulmonary infiltrations with eosinophilia, and presented with diffuse pulmonary infiltrates, pericardial effusion, diffuse hypokinesis of myocardium, cerebral infarction and marked peripheral eosinophlia. Pulmonary eosinophilia was confirmed by examination of broncho-alveolar lavage fluid. Myocardial tissue biopsy specimens revealed fibrous granulation indicative of myocarditis. The patient responded well to corticosteroid therapy.     

Disseminated candidiasis (moniliasis) in a dog. A case report

A case of systemic candidiasis (Candida albicans) in a 1 1/2 year old dog is reported. Clinically, the first manifestation was enlargement of a superficial inguinal lymph node. Later several peripheral lymph nodes were affected and a fistulous opening appeared, communicating with an inflammatory process in the right humerus. Necropsy revealed gross lesions in the kidneys, pancreas and multiple lymph nodes. In addition, microscopic lesions were observed in the myocardium and the bone marrow of the right humerus. The lesions, which contained large fungal colonies, were mainly granulomatous with numerous multinuclear giant and epitheloid cells, but necrosis and suppuration were also evident. The site of invasion is not known. However, a previous perianal and abdominal dermatitis, which was treated locally with antibiotics and corticoids, could possibly have been a mycotic infection.     

Sarcoidosis in children. Epidemiology in Danes, clinical features, diagnosis, treatment and prognosis

This paper reviews current knowledge of childhood sarcoidosis with regard to the epidemiology in Danes, clinical presentation, diagnostic procedures, treatment and prognosis. Sarcoidosis is a granulomatous disease of unknown aetiology, with multiorgan involvement. The diagnosis is confirmed by the demonstration of epitheloid cell granulomas in tissue biopsy specimens. During the period 1980-92, three cases of childhood sarcoidosis were recorded in Copenhagen County, which has a total population of 610,000. The approximate incidence of clinically recognized sarcoidosis in Danish children younger than 15 y of age was 0.22-0.27/100,000 children per year, corresponding to approximately three new cases in Denmark each year. The true incidence is unknown, since the disease is often asymptomatic and resolves without a clinical diagnosis being made. In children younger than 5 y of age, the disease is characterized by involvement of skin, eyes and joints, whereas in older children involvement of lungs, lymph nodes and eyes predominate. The mainstay of treatment consists of oral corticosteroids. The risk/benefit ratio of using long-term corticosteroids needs to be evaluated in each individual patient. Some patients may benefit from additional therapy with methotrexate. The long-term prognosis is not well established, but it seems to be poorer in children younger than 5 y. Older children appear to have as favourable a prognosis as young adults.     

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.     

Lethal tuberculosis in interleukin-6-deficient mutant mice

Tuberculosis is a chronic infectious disease which causes major health problems globally. Acquired resistance is mediated by T lymphocytes and executed by activated macrophages. In vitro studies have emphasized the importance of macrophage activation for mycobacterial growth inhibition. In vivo, the protective host response is focused on granulomatous lesions in which Mycobacterium tuberculosis is contained. A cellular immune response of the T helper 1 (Th1) type is considered central for control of tuberculosis. Using interleukin-6 (IL-6)-deficient mice, we here demonstrate a crucial role of this pluripotent cytokine in protection against M. tuberculosis but not against Mycobacterium bovis BCG. Infection with M. tuberculosis was lethal for the IL-6-deficient mice at inocula that were still controlled by IL-6-competent mice. Spleen cells from M. tuberculosis-infected IL-6-/- mouse mutants produced elevated levels of IL-4 and reduced levels of gamma interferon compared to the control levels. Cytofluorometric analyses of spleen cells from M. tuberculosis-infected mice revealed more-profound alterations in T-cell ratios in IL-6-/- mice than in control mice. We assume that IL-6 contributes to host resistance by its proinflammatory activity and by its influence on cytokine secretion.     

Mutations of the RET-GDNF signaling pathway in Ondine''s curse

Sarcoidosis is a multi-systemic granulomatous disease of unknown cause. It commonly involves lymph nodes, lungs, eyes, and skin. Cardiac sarcoid may be isolated, or associated with systemic involvement. Cardiac involvement is found in 20-50% of autopsied patients with sarcoidosis. However, it only gives rise to clinical manifestations in about 5% of patients. Cardiac involvement by sarcoid has been reported to manifest as complete heart block, papillary muscle dysfunction, congestive heart failure, pericarditis and/or effusion, conduction abnormality or arrhythmia, chest pain, and sudden death. The most common site of involvement is the interventricular septum base, which when involved may lead to heart block or arrhythmia. We report a case of sudden death in a 33-year-old male with a history of surgically repaired congenital heart disease. Although his congenital heart disease was originally postulated to be important in his death, autopsy examination revealed cardiac sarcoid with prominent involvement of the conduction system.     

Anesthetic management of a patient with the allergic granulomatous angitis (Churg-Strauss syndrome)

We gave anesthesia 4 times to a patient (19-year-old female) with allergic granulomatous angitis (AGA). She had asthma, myopathy and detrimental side effect in her eyes of steroid therapy for AGA. Two of the 4 operations were emergency laparotomy for peritonitis due to colon perforation, and the other 2 operations were elective eye surgeries. General anesthesia was induced with thiamylal (1st operation) or midazolam (2nd-4th operation). Intraoperative anesthesia was maintained with N2O-O2-isoflurane combined with thoracic epidural anesthesia (1st operation) or N2O-O2-sevoflurane (2nd-4th operation). Asthmatic attack, which AGA accompanies frequently, did not occur during these anesthetic managements. The steroid therapy, which is a fundamental means to control the allergic syndrome, might suppress asthma. However, asthmatic attack and systemic vasculitis should be kept in mind in anesthetic management of AGA.     

Non-tuberculous mycobacterial infection in children with cancer

Reported here is the clinical presentation and management of patients with rapidly growing non-tuberculous mycobacterial infection diagnosed in a paediatric oncology unit. A retrospective analysis that correlated patient isolates with the children's cancer registry revealed two cases of non-tuberculous mycobacterial infection; both had been observed within the last 6 years and were due to Mycobacterium chelonae. The first case was line-associated and the second was a disseminated infection. In both cases the patients were lymphopenic and had had indwelling vascular catheters. Neither patient was neutropenic. The literature on mycobacterial infection in children with cancer is also reviewed.     

New information on the structure of mycobacteria

Recent progress about the mycobacterial structures have been realized and two major structures have been concerned: the genome and the cell wall. From these acquired new knowledge several lines of clinical research and diagnosis application emerged. Cloning and sequencing of several mycobacterial genes led to the development of diagnostic tools (DNA probes, PCR, finger printings of indated mycobacterial strains) and the potential detection of multiding resistant strains of M. tuberculosis. Genetic manipulations involving various mycobacterial genes do open the way for more precise molecular approaches concerning virulence factors involved in the pathophysiological understanding of mycobacterial diseases. Comparative physico-chemical and ultra-structural analysis of the mycobacterial cell wall evoked a highly complexed cell wall structure, constituted of a double lipidic layer linked to the peptidoglycan (PG). The first layer is constituted of mycolic acids that are linked to the PG by arabinogalactan, and to the superficial layer by hydrophobic interactions of glycolipids. The superficial layer is constituted of amphiphatic glycolipids, having a lipidic banal pole and a polysaccharidic apical pole. The knowledge of the mycobacterial cell wall structure opened the way of: the development of immunological diagnostic tools, being now days in clinical evaluation phase, a better approach for host-bacteria relationship study at the cellular level (macrophage, lymphocytes), and the understanding of the mode of action of antimycobacterial drugs such as isoniazid and ethambutol.     

Primary (granulomatous) angiitis of the central nervous system with multiple aneurysms of spinal arteries. Case report

A 55-year-old woman with primary (granulomatous) angiitis of the central nervous system in association with non-Hodgkin's lymphoma (mucosa-associated lymphoid tissue type) presented with an acute spinal subdural hemorrhage secondary to rupture of one of several fusiform inflammatory aneurysms of the spinal cord radicular arteries. The literature on hemorrhagic complications, aneurysms, and spinal cord involvement in granulomatous angiitis is reviewed. Recognition of granulomatous angiitis is important, as the condition may be responsive to immunosuppressive therapy.     

The diagnosis and medical management of pulmonary parenchymal mycobacterial diseases

Pulmonary mycobacterial infections are an increasing clinical problem. The complex task of isolation and identification of the specific mycobacteria requires special stains, cultures, biochemical testing, and nucleic acid probes. Once the organism has been identified, the therapy with multiple drugs will be dictated by the type of organism and its drug susceptibility. An increasing number of patients presenting with drug-resistant tuberculosis or nontuberculous pulmonary mycobacterial infections require individualized, prolonged multi-drug regimens. The thoracic surgeon must be aware of the subtleties of mycobacterial pulmonary infections because diagnosis and failed medical treatment may require surgical intervention.     

Genetic determination of the meso-diaminopimelate biosynthetic pathway of mycobacteria

The increasing incidence of multiple-drug-resistant mycobacterial infections indicates that the development of new methods for treatment of mycobacterial diseases should be a high priority. meso-Diaminopimelic acid (DAP), a key component of a highly immunogenic subunit of the mycobacterial peptidoglycan layer, has been implicated as a potential virulence factor. The mycobacterial DAP biosynthetic pathway could serve as a target for design of new antimycobacterial agents as well as the construction of in vivo selection systems. We have isolated the asd, dapA, dapB, dapD, and dapE genes involved in the DAP biosynthetic pathway of Mycobacterium bovis BCG. These genes were isolated by complementation of Escherichia coli mutations with an expression library of BCG DNA. Our analysis of these genes suggests that BCG may use more than one pathway for biosynthesis of DAP. The nucleotide sequence of the BCG dapB gene was determined. The activity of the product of this gene in Escherichia coli provided evidence that the gene may encode a novel bifunctional dihydrodipicolinate reductase and DAP dehydrogenase.