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1.  Exploring the role of Mycobacterium avium subspecies paratuberculosis in the pathogenesis of type 1 diabetes mellitus: a pilot study 
Gut Pathogens  2013;5:14.
Although the etiology of Type 1 Diabetes mellitus (T1DM) has not been determined, genetic polymorphism in key genes, including SLC11A1, and association with Mycobacterium avium subspecies paratuberculosis (MAP) have been reported. We hypothesize that molecular mimicry between MAP Heat shock protein 65 K (Hsp65) and human Glutamic Acid Decarboxylase 65 K (GAD65) may be the trigger leading to autoimmune destruction of beta cells in patients exposed to MAP.
Peptide sequences of MAP Hsp65 and human GAD65 were investigated for amino acid sequence homology and cross reactivity. A total of 18 blood samples from T1DM and controls were evaluated for the presence of MAP.
Peptide BLAST analysis revealed a 44% overall identity between MAP Hsp65 and GAD65 with 75% positives in a 16 amino acid region. PyMOL 3D-structural analyses identified the same 16 amino acid region as a potential epitope for antibody binding. Preliminary data suggests a cross reactivity between MAP Hsp65, and a healthy rat pancreatic tissue homogenate against plasma from T1DM patients and rabbit polyclonal anti-MAP IgG. Long-term culture of human blood resulted MAP detection in 3/10 T1DM and 4/8 controls whereas MAP IgG was detected in 5/10 T1DM samples and 3/8 non-diabetic controls.
The high degree of homology between GAD65 and MAP Hsp65 in an antigenic peptide region supports a possible mycobacterial role in triggering autoimmune destruction of pancreatic cells in T1DM. Reactivity of T1DM patient sera with MAP Hsp65 supports this finding. Culture of MAP from the blood of T1DM patients is intriguing. Overall, the preliminary data are mixed and do not exclude a possible role for MAP in T1DM pathogenesis. A larger study including well-characterized controls is needed to investigate the intriguing question of whether MAP is associated with T1DM or not?
PMCID: PMC3686596  PMID: 23759115
Type 1 diabetes; Mycobacterium avium subspecies paratuberculosis; Hsp65; GAD65; Crohn’s disease
3.  Detection of Mycobacterium avium ss. Paratuberculosis in Blau Syndrome Tissues 
Autoimmune Diseases  2010;2010:127692.
Background and Aim of the Work. Blau syndrome is an inherited granulomatous inflammatory disorder with clinical findings of uveitis, arthritis, and dermatitis. Although rare, Blau syndrome shares features with the more common diseases sarcoidosis and Crohn's disease. The clinical findings of Blau syndrome are indistinguishable from juvenile sarcoidosis; the mutations of Blau syndrome are on the same gene of chromosome 16 (CARD15) that confers susceptibility to Crohn's disease. The product of this gene is part of the innate immune system. Mycobacterium avium ss. paratuberculosis (MAP) is the putative cause of Crohn's disease and has been implicated as a causative agent of sarcoidosis. Methods. Archival tissues of individuals with Blau syndrome were tested for the presence of MAP. Results. DNA evidence of MAP was detected in all of the tissues. Conclusions. This article finds that MAP is present in Blau syndrome tissue and postulates that it has a causal role. The presence of MAP in Blau syndrome—an autosomal dominant, systemic inflammatory disease—connects genetic and environmental aspects of “autoimmune” disease.
PMCID: PMC2989750  PMID: 21152214
4.  Metabolism of rifabutin and its 25-desacetyl metabolite, LM565, by human liver microsomes and recombinant human cytochrome P-450 3A4: relevance to clinical interaction with fluconazole. 
Rifabutin and fluconazole are often given concomitantly as therapy to prevent opportunistic infections in individuals infected with the human immunodeficiency virus. Recent reports have shown increased levels of rifabutin and its 25-desacetyl metabolite, LM565, in plasma when rifabutin is administered with fluconazole. Since fluconazole is known to inhibit microsomal enzymes, this study was undertaken to determine if this rifabutin-fluconazole interaction was due to an inhibition of human hepatic enzymes. The metabolism of both rifabutin and LM565 was evaluated in human liver microsomes and recombinant human cytochrome P-450 (CYP) 3A4 in the presence of fluconazole and other probe drugs known to inhibit CYP groups 1A2, 2C9, 2D6, 2E1, and 3A. The concentrations of rifabutin (1 microg/ml), LM565 (1 microg/ml), and fluconazole (10 and 100 microg/ml) used were equal to those observed in plasma after the administration of rifabutin and fluconazole at clinically relevant doses. High-performance liquid chromatography was used to assess the metabolism of rifabutin and LM565. Rifabutin was readily metabolized to LM565 by human microsomes, but the reaction was independent of NADPH and was not affected by the P-450 inhibitors. No rifabutin metabolism by recombinant CYP 3A4 was found to occur. LM565 was also metabolized by human microsomes to two products, but metabolism was dependent on NADPH and was affected by certain P-450 inhibitors. In addition, LM565 was readily metabolized by the recombinant CYP 3A4 to the same two products found with its metabolism by human microsomes. Therefore, rifabutin is metabolized by human microsomes but not via cytochrome P-450 enzymes, whereas LM565 is metabolized by CYP 3A4.
PMCID: PMC163826  PMID: 9145845
5.  Measurement of acute phase proteins for assessing severity of Plasmodium falciparum malaria. 
Journal of Clinical Pathology  1991;44(3):228-231.
Seventeen adult patients with acute Plasmodium falciparum malaria, admitted to the Hospital for Tropical Diseases, were studied. Serial measurements of the serum concentration of C-reactive protein, serum amyloid A protein, and percentage parasitaemia were determined, together with initial measurement of serum electrolytes, liver function, haemoglobin, white cell and platelet counts. Initial C-reactive protein and serum amyloid A concentrations were increased (C-reactive protein mean 49.0 mg/l serum amyloid A 28 mg/l) falling towards the normal range by the seventh day of treatment. There was a significant correlation between the pretreatment parasite count and clinical and laboratory markers of inflammation. C-reactive protein and serum amyloid A concentrations correlated inversely with the serum sodium. These results indicate that measurement of acute phase reactants such as C-reactive protein and serum amyloid A may prove valuable in assessing the severity of P falciparum malaria, and in following the response to antimalarial treatment.
PMCID: PMC496944  PMID: 1707416
7.  Oesophageal tuberculosis: four cases. 
Gut  1981;22(3):234-236.
Four Asian patients presented with dysphagia. In each case the oesophagus was involved by adjacent tuberculous subcarinal glands. The lungs were clear and symptoms of systemic illness were minimal. Findings at oesophagoscopy were non-specific and early diagnosis rested on a high index of suspicion and a strongly positive Mantoux test. Bacteriological proof was obtained early in only two of the cases.
PMCID: PMC1419516  PMID: 7227859
8.  Rapid screening for bacteriuria using a particle counter, pulse-height analyser, and computer. 
Journal of Clinical Pathology  1981;34(2):194-198.
A system for the rapid screening of urines for the presence of bacteriuria has been devised using a Coulter Counter Model ZBI linked to a multichannel pulse-height analyser (Coulter "Channelyser") with computer analysis of the output. In a series of 215 urines containing growth of a single pathogen of more than 100 x 10(6)/l (greater than 100 000/ml) satisfactory level of sensitivity (99.1%) was obtained using only two different amplification settings by means of a brief treatment (5-10 seconds) of the undiluted specimen with low intensity ultrasound; 85-90% of mixed growths of 10 x 10(6)/l (greater than 10 000/ml) were detected. Sonication did not improve the results in this group. Specimens showing abnormal cyturia of more than 10 x 10(6)/l (greater than 10 000/ml) but no growth on culture were positive in 33% of cases without the use of ultrasound but in 72% after sonication.
PMCID: PMC1146452  PMID: 7014646
9.  Contemporary mediastinal tuberculosis. 
Thorax  1980;35(5):392-396.
Mediastinal lymphadenopathy is a prominent feature of adult tuberculosis in immigrant groups in the United Kingdom. Chest radiography of 95 tuberculous immigrants showed mediastinal gland enlargement in 29 cases, whereas none of the 42 Europeans showed this feature. An analysis has been made of the distribution of the disease in all groups together with a more detailed evaluation of mediastinal involvement in the immigrants. Pericardial effusions were seen in eight patients together with the following three unusual complications: (1) broncho-oesophageal fistula; (2) bronchial erosion; (3) superior mediastinal obstruction.
PMCID: PMC471298  PMID: 7434292
10.  Particle size distribution analysis for the rapid detection of microbial infection of urine. 
Journal of Clinical Pathology  1979;32(4):386-390.
The accuracy and practicality of particle size distribution analysis for rapid screening of urine specimens are assessed. Six hundred urines were subjected simultaneously to routine bacteriological examinations and particle size distribution analysis using a Coulter Counter (ZBI) linked to a C1000 Channelyzer. There was complete agreement in the results of 593 (98.8%) specimens. Characteristic profiles of various bacterial species in infected specimens were consistently obtained. This system can easily be linked to any existing computer reporting in a district hospital laboratory, and the results of negative specimens (70--80%) can be obtained within 5--10 minutes.
PMCID: PMC1145678  PMID: 376561

Results 1-11 (11)