Predicting non-completion of treatment for latent tuberculous infection: a prospective survey

Treatment of latent tuberculosis (TB) infection (LTBI) is essential for the elimination of TB in the United States, but treatment is often not completed. Little is known about patients' reasons for not completing treatment. We hypothesized that certain health beliefs, lifestyle, and clinic- and regimen-related barriers to provision of care could predict non-completion of LTBI treatment. METHODS: We administered a survey in English, Chinese, or Spanish to patients with LTBI at the first TB clinic visit. Using chi(2) and logistic regression analysis, we assessed demographics, TB risk factors, and survey responses as predictors of non-completion of 6 mo of isoniazid. RESULTS: 217 patients, 90% foreign-born, completed the survey, and 28.6% of which finished at least 6 mo of isoniazid under usual clinic conditions. Multivariate analysis identified two independent predictors of non-completion: low risk perception of progressing to active TB without LTBI treatment (odds ratio [OR], 0.31 [0.13-0.72], 95% confidence interval [CI]), p = 0.007, accounting for 20% of non-completers, and not wanting venipuncture (OR, 0.43 [0.22-0.85], 95% CI), p = 0.015, accounting for 37% of non-completers. Another 18% shared both predictors; thus these two predictors accounted for 75% of non-completers in total. CONCLUSIONS: Patients assess LTBI treatment risks and inconveniences relative to low perceived benefits at treatment outset. Predictors of LTBI treatment non-completion are identifiable at the first visit. Targeting TB high-risk individuals, minimizing inconveniences, further education, and use of diagnostic tests with improved specificity for TB may address these concerns.     

Cyclooxygenase-2 expression and effect of celecoxib in gastric adenomas of trefoil factor 1-deficient mice

Expression of cyclooxygenase-2 (Cox-2) is elevated in gastric adenocarcinomas and precursor lesions leading to this disease. Mice deficient for trefoil factor 1 (TFF1) develop a pyloric adenoma with full penetrance. Because inhibition of Cox-2 suppresses tumor growth in several animal models, we studied expression of Cox-2 and effect of a selective Cox-2 inhibitor celecoxib in gastrointestinal tissues of the TFF1-deficient mice. Cox-2 mRNA and protein were strongly expressed in the pyloric adenomas of the TFF1(-/-) mice as detected by in situ hybridization and immunohistochemistry. Nonneoplastic gastrointestinal tissues of wild-type or TFF1(-/-) mice expressed low or nondetectable levels of Cox-2. Celecoxib (1600 ppm p.o. for 3 months) caused ulceration and inflammation of the adenoma in all treated TFF1(-/-) mice (n = 7). This effect of the drug was adenoma specific, because no histological alterations were observed in the non-neoplastic gastric or intestinal tissues in the TFF1(-/-) or wild-type mice receiving the drug treatment. All untreated TFF1(-/-) mice had an adenoma (n = 7), but none demonstrated the combination of ulceration and inflammation. Our data show that Cox-2 is expressed in gastric adenomas of the TFF1(-/-) mice and suggest that inhibition of Cox-2 disturbs the integrity of the adenoma by promoting ulceration and inflammation. These findings support the effort to initiate clinical studies to investigate the effect of Cox-2 inhibitors as a chemotherapeutic modality for dysplasias of the stomach.     

Shunting procedures in the management of intracranial cerebrospinal fluid cysts in infancy and childhood

Summary Widely diverging opinions on the optimal therapy for intracranial cerebrospinal fluid cysts (CSF), mainly arachnoid cysts and the Dandy-Walker cysts, exist. Excision of the cyst walls in the treatment of the Dandy-Walker cyst has been replaced by shunting procedures, but the recommended method for primary treatment of arachnoid cysts in childhood is still cyst wall excision. Membrane excision is, however, often complicated by recurrence, subsequently requiring shunting-procedures. In a series of 19 cases primary shunting of intracranial CSF cysts proved to be a reliable method. In those cases where hydrocephalus (ventricular dilatation) is present at the time of the primary operation the ventricles should be shunted as well as the cyst. The catheter from the ventricle and that from the cyst should be connected to the same valve, otherwise an increased risk of intracranial herniation exists. The prognosis for infants and children suffering from intracranial CSF cysts is in general good; in 17 out of 19 cases mental development was normal and in 15 out of 19 motor development was normal. The risk of permanent motor damage seems to be particularly high when an arachnoid cyst is located on the quadrigeminal plate.     

Accelerated pubertal development in patients with shunted hydrocephalus.

OBJECTIVE: To evaluate pubertal development and peripheral concentrations of gonadotrophins and sex hormones in children with shunted hydrocephalus compared with healthy controls. STUDY DESIGN: 114 patients (52 females, 62 males) and 73 healthy controls (35 females, 38 males) aged 5 to 20 years were analysed for stage of puberty, age at menarche, testicular volume, basal serum follicle stimulating hormone (FSH), luteinising hormone (LH), sex hormone binding globulin (SHBG), testosterone and oestradiol concentrations, and free androgen index. RESULTS: Male gonadal and male and female pubic hair development occurred significantly earlier in the patients than in the controls. The mean age at menarche was significantly lower in the female patients than in their controls (11.7 v 13.2 years; p < 0.001), and lower than it had been for their mothers (v 13.1 years; p < 0.001). Relative testicular volume was higher in the male patients than in their controls (1.2 standard deviation score (SDS) v 0.2 SDS; p < 0.001). The prepubertal patients had higher basal LH (0.13 U/l v 0.08 U/l; p < 0.001) and SHBG (132.3 nmol/l v 109.1 nmol/l; p < 0.01) than the controls. Both the prepubertal and pubertal females had significantly higher basal FSH than their controls (1.57 U/l v 1.03 U/l; p < 0.05, and 4.0 U/l v 2.9 U/l; p < 0.01, respectively). CONCLUSIONS: Hydrocephalic children experience accelerated pubertal maturation, reflected in a younger age at menarche in females and an increased testicular volume in males. This may be because of enhanced gonadotrophin secretion, possibly resulting from unphysiological variations in intracranial pressure.     

Increased frequency of IgM antibodies to cow's milk proteins in Hungarian children with newly diagnosed insulin-dependent diabetes mellitus

We investigated the association between serum antibodies to cow’s milk proteins and insulin-dependent diabetes mellitus (IDDM) in Hungarian children. Forty-eight children 1.0–17.1 years of age with newly diagnosed IDDM and 74 control children 1.0–16.0 years of age were studied for serum IgG, IgA and IgM antibodies to cow’s milk, β-lactoglobulin, bovine serum albumin and ovalbumin by enzyme-linked immunosorbent assays. The specificity of IgM antibodies to β-lactoglobulin and bovine serum albumin was controlled by Western blot. The levels of IgG and IgA antibodies to cow’s milk proteins were similar in children with and without IDDM, with the exception of slightly increased levels of IgA antibodies to β-lactoglobulin in diabetic children (P = 0.05). The levels of IgM antibodies to cow’s milk were significantly higher in IDDM patients than in control children (P = 0.0002). Children with IDDM more often had IgM antibodies to β-lactoglobulin (46.3% vs 18.8%; P = 0.002) and bovine serum albumin (87.8% vs 49.3%, P < 0.0001) than control children. Neither the levels of IgG or IgA antibodies to ovalbumin nor the frequency of IgM antibodies to ovalbumin differed between diabetic and control children. Conclusion In Hungarian children, clinical manifestation of IDDM is often associated with IgM antibody response to cow’s milk protein and its fractions, β-lactoglobulin and bovine serum albumin, indicating a loss of immunological tolerance to these proteins. IgG and IgA antibodies to cow’s milk proteins, associated with an early introduction of cow’s milk in diet, seem to play a minor role in the development of childhood IDDM in Hungary. Received: 14 November 1995 Accepted: 3 March 1996     

Beta-chemokines are induced by Mycobacterium tuberculosis and inhibit its growth

Chemokines (CK) are potent leukocyte activators and chemoattractants and aid in granuloma formation, functions critical for the immune response to Mycobacterium tuberculosis. We hypothesized that infection of alveolar macrophages (AM) with different strains of M. tuberculosis elicits distinct profiles of CK, which could be altered by human immunodeficiency virus (HIV) infection. RANTES, macrophage inflammatory protein-1 alpha (MIP-1 alpha), and MIP-1 beta were the major beta-CK produced in response to M. tuberculosis infection. Virulent M. tuberculosis (H37Rv) induced significantly less MIP-1 alpha than did the avirulent strain (H37Ra), while MIP-1 beta and RANTES production was comparable for both strains. MIP-1 alpha and MIP-1 beta were induced by the membrane, but not cytosolic, fraction of M. tuberculosis. M. tuberculosis-induced CK secretion was partly dependent on tumor necrosis factor alpha (TNF-alpha). AM from HIV-infected individuals produced less TNF-alpha and MIP-1 beta than did normal AM in response to either M. tuberculosis strain. We tested the functional significance of decreased beta-CK secretion by examining the ability of beta-CK to suppress intracellular growth of M. tuberculosis. MIP-1 beta and RANTES suppressed intracellular growth of M. tuberculosis two- to threefold, a novel finding. Thus, beta-CK contribute to the innate immune response to M. tuberculosis infection, and their diminution may promote the intracellular survival of M. tuberculosis.     

Significance of cow's milk protein antibodies as risk factor for childhood IDDM: interactions with dietary cow's milk intake and HLA-DQB1 genotype

Summary Dietary factors are suspected to play an aetiological role in the development of insulin-dependent diabetes mellitus (IDDM). We analysed cow's milk formula, betalactoglobulin, and bovine serum albumin antibodies by an enzyme-linked immunoassay in unselected children with newly diagnosed IDDM and in their non-diabetic siblings and enquired about infant feeding practices by questionnaire. Among 410 diabetic sibling pairs matched for age and sex, by logistic regression analysis – including overall duration of breast-feeding, age at introduction of dairy products, recent consumption of cow's milk and HLA-DQB1 genotype (“high/moderate” vs “low/decreased” risk of IDDM) – bovine serum albumin IgG antibody levels (OR 2.12, 95 %CI 1.25–3.57) and genetic risk (OR 3.81, 95 %CI 2.43–5.17) were positively associated with IDDM; cow's milk formula IgM antibodies were inversely associated with the risk of IDDM (OR 0.50, 95 %CI 0.29–0.87). Of the diabetic sibling pairs, 42 were identical for HLA-DQB1 alleles associated with IDDM risk or protection (DQB1^*0201, *0301, ^*0302 and *0602/03). In these 42 pairs, children with IDDM had higher median levels of bovine serum albumin IgG, of betalactoglobulin IgG, and of cow's milk formula IgG and IgA antibodies than the non-diabetic siblings (p < 0.05). In conclusion, children with IDDM have higher levels of cow's milk protein antibodies than their HLA-DQB1-matched sibling controls, and these high levels of antibodies are independent risk markers for IDDM. [Diabetologia (1998) 41: 72–78] Received: 13 June 1997 and in revised form: 26 August 1997     

Experimental meningococcal meningitis in the infant rat

Experimental infection of the infant rat could be established with intraperitoneal challenge with strains of all three meningococcal groups A, B, and C tested. 5-day-old rats were challenged with 3 different doses (10(2), 10(4), and 10(6) bacteria/animal) and the development of peritonitis, bacteraemia and meningitis detected as a function of time at 3, 6, and 9 h. Mortality was followed up to 24 h. Group B strains caused a rapidly developing and sustained high level bacteraemia and meningitis with all challenge doses. Bacteraemia and meningitis following challenge with MenA and MenC were of somewhat shorter duration and reached lower peak levels. Repeated 'rat passages' of meningococcal strains that had been kept stored for long periods markedly increased their virulence. This study shows that the infant rat model can be applied for studying pathogenesis of meningococcal bacteraemia and meningitis. Previous work from this laboratory has shown it to be suited also for studying antibody-mediated protection from this disease.