Stigma against tuberculosis may hinder non-household contact investigation: a qualitative study in Thailand.

SETTING: A northern province in Thailand. OBJECTIVES: To explore experiences and perspectives on tuberculosis (TB) contact investigations in non-household contacts. DESIGN: Focus group discussions and in-depth interviews with eight groups: three groups of former TB patients (teachers, students and hospital staff) and five groups of representatives from congregate settings such as schools and workplaces. Data were analysed using the modified grounded theory. RESULT: Annual health check-ups at the workplace contributed to the early detection of active TB in teachers. Former TB patients were highly exposed to non-household contacts, but contact investigations were limited to household contacts only. Barriers and facilitators for non-household contact investigations are associated with five factors, including information, awareness and knowledge about TB; stigma; empathy; health system response and informing non-household contacts about TB exposure. Stigma may be the main barrier to investigations among non-household contacts because TB patients tend to withhold information about their diagnosis from colleagues. Lack of knowledge and misperceptions regarding TB transmission contributed to stigma. Empathy with other people encouraged TB patients to inform non-household contacts. CONCLUSION: Non-household contact investigations are not performed despite the risk of TB transmission. To promote contact investigations in congregate settings, interventions to overcome TB stigma and improve public knowledge about TB transmission are required.

Permanent employment or public assistance may increase tuberculosis survival among working-age patients in Japan.

OBJECTIVES: To measure the effect of employment and health insurance status on the survival of working age tuberculosis (TB) patients in Japan. METHODS: Retrospective cohort analysis of new smear-positive pulmonary TB patients aged 15-59 years registered in the Japanese national TB surveillance system between 2007 and 2010. We performed univariate and multivariate Cox proportional hazard model analysis. The survival curves for employment and health insurance status were calculated using Kaplan-Meier analysis. RESULTS: Of 9097 patients studied, 267 (2.9%) died of TB within 12 months. After adjustment with a multivariate model, employment and health insurance status were independently associated with increased risk of TB death: unemployment (HR 2.80, 95%CI 2.11-3.72), absence of insurance (HR 1.48, 95%CI 1.02-2.15). The analysis of survival curves indicated that those with public assistance had almost the same survival rate as insured patients in the unemployed group. Permanent workers (employed >30 days) had the highest survival rates, followed by casual workers (employed <30 days) and the unemployed in the insured group. CONCLUSION: Patients with permanent jobs had better survival rates than unemployed patients and casual workers. Despite being unemployed, receiving public assistance could improve survival. Health measures are required for the unemployed and casual workers.

Leaving the street and reconstructing lives: impact of DOTS in empowering homeless people in Tokyo, Japan.

SETTING: Since 2000, the Public Health Centre (PHC) in Shinjuku, an area of Tokyo with one of the largest homeless populations in Japan, has been implementing PHC-based DOTS treatment for homeless tuberculosis (TB) patients, with much epidemiological success. Anecdotal evidence indicates that homeless patients treated under DOTS have experienced various positive changes. However, this experience has not yet been systematically analysed. OBJECTIVE: To explore the changes experienced by homeless TB patients, and to discuss the possible role of PHC-based DOTS treatment in effecting these changes. DESIGN: A qualitative study via in-depth interviews with 18 ex-homeless patients who completed DOTS-based treatment at Shinjuku City PHC. The data were analysed using the interpretive content analysis method. RESULTS: The various changes experienced by the participants were categorised into five sub-categories of empowerment, including improved mental health and interpersonal relationships. Some of these changes were attributable to the participants undergoing PHC-based DOTS, which, by addressing their various emotional needs, helped to trigger patient empowerment. Based on our findings, a model of empowerment using PHC-based DOTS was constructed. CONCLUSION: PHC-based DOTS not only successfully controlled TB, it also empowered homeless patients by addressing their emotional needs. The interpersonal skills of the nurses played a critical role in this process.

High tuberculosis treatment success in Kabul, Afghanistan despite high patient transfers out.

The National Tuberculosis (TB) Institute has the highest patient transfer-out rate in Afghanistan, but the result and treatment outcome of transferred patients were unknown in 2009. This operational research investigated the characteristics and treatment outcome of all transferred-out patients living in Kabul province. We analysed the 1-year TB register of the Institute (n = 1180 cases) and visited 24 health centres to review their TB registers. The results show the transfer-out rate was 52.6%. Of the transferred cases, 58.6% were women and 61.8% pulmonary TB cases (smear-positive 70.6%). The arrival rates of transfer-out patients at health centres in Kabul province were 87.6% for both men and women. Males aged 21-40 years were the most likely to be nonarrivals (OR = 8.91; 95% CI: 1.55-66.7). Treatment success rates in female and male patients were 84.4% and 77.5% respectively and default rates were 7.8% and 18.3%. Strategies to reduce the non-arrival to health centres and treatment interruption in male patients aged 20-40 years are warranted.

High tuberculosis treatment success in Kabul, Afghanistan despite high patient transfers out

The National Tuberculosis [TB] Institute has the highest patient transfer-out rate in Afghanistan, but the result and treatment outcome of transferred patients were unknown in 2009. This operational research investigated the characteristics and treatment outcome of all transferred-out patients living in Kabul province. We analysed the 1-year TB register of the Institute [n= 1180 cases] and visited 24 health centres to review their TB registers. The results show the transfer-out rate was 52.6%. Of the transferred cases, 58.6% were women and 61.8% pulmonary TB cases [smear-positive 70.6%]. The arrival rates of transfer-out patients at health centres in Kabul province were 87.6% for both men and women. Males aged 21-40 years were the most likely to be non-arrivals [OR = 8.91; 95% CI: 1.55-66.7]. Treatment success rates in female and male patients were 84.4% and 77.5% respectively and default rates were 7.8% and 18.3%. Strategies to reduce the non-arrival to health centres and treatment interruption in male patients aged 20-40 years are warranted

Informed patient consent for defaulter tracing: should we obtain it?

Active default tracing is an integral part of tuberculosis (TB) programmatic control. It can be differentiated into the tracing of defaulters (patients not seen at the clinic for > or =2 months) and 'late patients' (late for their scheduled appointments). Tracing is carried out to obtain reliable information about who has truly died, transferred out or stopped treatment, and, if possible, to persuade those who have stopped treatment to resume. This is important because, unlike routine care for non-communicable diseases, TB has the potential for transmission to other members of the community, and therefore presents the issue of the rights of the individual over the rights of the community. For this reason, default or 'late patient' tracing (defined together as default tracing in this article) has been incorporated into standard practice in most TB programmes and, in many industrialised countries, it is also a part of public health legislation. In resource-poor countries with limited access to phones or e-mails, default tracing involves active home visits. In this Unresolved Issues article, we discuss the need for patient consent within both the programmatic and the research context; we describe how this subject arose during operational research training at the Research Institute of Tuberculosis in Japan; we provide comments from individuals who are experienced and skilled at international and national TB control; and finally we offer some conclusions about the way forward. This is not an easy subject, and we welcome open debate on the issue.

Transplantation of neural progenitors enhances production of endogenous cells in the impaired brain.

Grafting of neural progenitors has been shown to reverse a wide variety of neurobehavioral defects. While their role of replacing injured cells and restoring damaged circuitries has been shown, it is widely accepted that this cannot be the only mechanism, as therapy can occur even when an insufficient number of transplanted cells are found. We hypothesized that one major mechanism by which transplanted neural progenitors exert their therapeutic effect is by enhancing endogenous cells production. Consequently, in an allographic model of transplantation, prenatally heroin-exposed genetically heterogeneous (HS) mice were made defective in their hippocampal neurobehavioral function by exposing their mothers to heroin (10 mg kg(-1) heroin on gestation days 9-18). Hippocampal damage was confirmed by deficient performance in the Morris maze (P<0.009), and decreased production of endogenous cells in the dentate gyrus by 39% was observed. On postnatal day 35, they received an HS-derived neural progenitors transplant followed by repeated bromodeoxyuridine injections. The transplant returned endogenous cells production to normal levels (P<0.006) and reversed the behavioral defects (P<0.03), despite the fact that only 0.0334% of the transplanted neural progenitors survived and that they differentiated mainly to astrocytes. An immunological study demonstrated the presence of macrophages and T cells as a possible explanation for the paucity of the transplanted cells. This study suggests one mechanism for the therapeutic action of neural progenitors, the enhancement of the production of endogenous cells, pointing to future clinical applications in this direction by use of neural progenitors or by analogous cell-inducing techniques.

Heroin neuroteratogenicity: targeting adenylyl cyclase as an underlying biochemical mechanism.

Prenatal heroin exposure evokes neurochemical and behavioral deficits that in part, reflect disruption of septohippocampal cholinergic function. In earlier studies, we found that cholinergic synaptic defects involve changes in proteins, like protein kinase C, that are essential to receptor-mediated signaling. In the current study, we determined whether heroin targets another signaling protein, adenylyl cyclase (AC), which regulates the production of cAMP. Mice exposed to prenatal heroin showed subsequent postnatal elevations of AC activity that lasted into adulthood. The effect was most robust with stimulants that activate AC directly (forskolin, Mn(2+)), indicating increased expression of AC itself; we also identified shifts in catalytic properties suggestive of a change in the AC isoform. Superimposed on the overall induction of AC, there were transient deficits in the responses to stimulants working through G-proteins (NaF) or G-protein coupled receptors (isoproterenol, a beta-adrenoceptor agonist), indicating alterations at other steps in the signaling pathway. Effects on the regulation of AC activity were seen in brain regions with widely disparate maturational timetables and also occurred in regions, like the cerebellum, that are sparse in cholinergic input. These results suggest that the expression and/or function of signaling proteins distal to neurotransmitter receptors represent a major target for neurobehavioral teratogenesis by heroin; the fact that these targets are shared by otherwise unrelated neuroteratogens may account for a common set of neurochemical and behavioral anomalies in response to prenatal exposure to drugs or environmental chemicals.

Hormonal regulation of peripheral benzodiazepine receptor binding properties is mediated by subunit interaction.

The peripheral benzodiazepine receptor (PBR) is composed of three subunits with molecular masses of 18, 30, and 32 kDa. Many physiological functions have been attributed to the PBR, including regulation of steroidogenesis. Furthermore, the PBR itself is under hormonal regulation. In the current study, we investigated the role of female gonadal sex hormones in the regulation of PBR expression in steroidogenic and nonsteroidogenic tissues. To accomplish this, adult female rats were pharmacologically castrated using chronic administration of the gonadotropin-releasing hormone agonist decapeptyl (triptorelin-D-Trp(6)-LHRH). Half of these rats received 17beta-estradiol as hormone replacement, while a control group received daily injections of vehicle only. We found that PBR binding capacity dropped by 40 and 48% in ovaries and adrenals, respectively, following decapeptyl administration, as opposed to no change in the kidney. This down-regulation of PBR densities was prevented by estradiol replacement. We did not find evidence for transcriptional, posttranscriptional, and translational mechanisms in this decapeptyl-induced down-regulation. In contrast, immunoprecipitation of the PBR complex, using antibodies against the 18- and 32-kDa subunits of the complex, demonstrated that there were changes in PBR subunit interactions, consistent with the down-regulation of PBR binding capacity. These findings represent a novel hormone-dependent posttranslational regulatory mechanism.

The relationship between neural alterations and behavioral deficits after prenatal exposure to heroin.

The present studies employ multitudinous approaches in order to overcome the methodological obstacles in the understanding of the relationship between neurochemical alterations and behavioral deficits induced by heroin during prenatal development. Mice were exposed prenatally to heroin via daily subcutaneous injections of 10 mg/kg, on gestation days 9-18. At age 50 days, the heroin-exposed offspring displayed behavioral deficits as assessed in the eight-arm and Morris mazes, pointing to possible alteration in the septohippocampal cholinergic innervations. Biochemically there was increased presynaptic activity of these innervations as attested to by the increased [3H]hemicholinium-3 (HC-3) binding sites and by K+-stimulated inositol phosphate (IP) formation. Postsynaptically, there was global hyperactivation along the different components of the nerve conduction cascade, including an increase in M1 muscarinic receptor Bmax, a general increase in G-proteins (GP) including the most relevant, G subtype, and an increase in IP formation and in basal protein kinase C (PKC) activity. However, there was desensitization of PKC activity in response to cholinergic agonist in the heroin-exposed offspring. Transplantation of normal embryonic cholinergic cells to the impaired hippocampus reversed the behavioral deficits and both the pre- and postsynaptic hyperactivity and resensitized PKC activity. To support and further strengthen the findings of the neural grafting study, correlation of the heroin-induced behavioral deficits with the biochemical alterations, done within individuals, was applied. The results showed high r values for IP formation, basal PKC, and PKC desensitization. The r values for HC-3 binding were statistically significant but relatively low. Taken together, the findings of the neural grafting and correlation studies bring us closer to understanding the relationship between the prenatal heroin-induced biochemical and behavioral changes. However, mammalian models possess the inherent methodological hindrances, stemming from possible maternal effects. To provide a control for these confounding variables, a chick embryo model was applied in which filial imprinting, a behavior related to a specific hyperstriatal nucleus, served as an endpoint. Heroin was administered to developing chick embryos by injecting the eggs (20 mg/kg) on incubation days (ID) 0 or 5. Prehatch exposure to heroin markedly diminished the ability for filial imprinting in the hatched chicks.

Neurobehavioral damage to cholinergic systems caused by prenatal exposure to heroin or phenobarbital: cellular mechanisms and the reversal of deficits by neural grafts.

Despite the basic differences in their underlying biological targets, prenatal exposure to heroin or phenobarbital produces similar syndromes of neurobehavioral deficits, involving defects in septohippocampal cholinergic innervation-related behaviors. At the cellular level, these deficits are associated with cholinergic hyperactivity, characterized by increased concentrations of muscarinic receptors and enhanced second messenger activity linked to the receptors. In the present study, we determined whether the cellular changes are mechanistically linked to altered behavior, using two different approaches: neural grafting and correlations between behavior and biochemistry within the same individual animals. Mice were exposed transplacentally to phenobarbital or heroin on gestation days 9-18 and, as adults, received fetal cholinergic grafts or were sham-operated. Prenatal drug exposure resulted in deficits in behavioral performance tested in the eight-arm radial maze, accompanied by increases in hippocampal M(1)-muscarinic receptor expression and muscarinic receptor-mediated IP formation. Neural grafting reversed both the behavioral deficits and the muscarinic hyperactivity. In the drug-exposed offspring, there was a significant correlation between maze performance and carbachol-induced inositol phosphate (IP) formation. These studies indicate that deficits of cholinergic function underlie the neurobehavioral deficits seen in the hippocampus of animals exposed prenatally to heroin or phenobarbital, and consequently that the observed cholinergic hyperactivity is an unsuccessful attempt to compensate for the loss of cholinergic function. The fact that the damage can be reversed by neural grafting opens up novel approaches to the restoration of brain function after prenatal insults.

Neural grafting reverses prenatal drug-induced alterations in hippocampal PKC and related behavioral deficits.

Administration of heroin or phenobarbital to pregnant mice evokes neurochemical and behavioral deficits consequent to disruption of septohippocampal cholinergic innervation. The present study evaluates the relationship between the drug-induced biochemical changes and the behavioral deficits, applying two different approaches: neural grafting and within-individual correlations of biochemistry and behavior. Mice were exposed transplacentally to phenobarbital or heroin on gestational days 9-18 and tested in adulthood. Drug-exposed mice displayed impaired radial arm maze performance, increases in presynaptic choline transporter sites (monitored with [(3)H]hemicholinium-3 binding), upregulation of membrane-associated protein kinase C (PKC) activity, and desensitization of the PKC response to a cholinergic agonist, carbachol. Grafting of cholinergic cells to the impaired hippocampus reversed the behavioral deficits nearly completely and restored basal PKC activity and the PKC response to carbachol to normal; the drug effects on hemicholinium-3 binding were also slightly obtunded by neural grafting, but nevertheless remained significantly elevated. There were significant correlations between the performance in the eight-arm maze and both basal PKC activity and PKC desensitization, and to a lesser extent, between behavioral performance and hemicholinium-3 binding. Taken together, these findings indicate an inextricable link between the biochemical effects of prenatal drug exposure on the PKC signaling cascade and adverse behavioral outcomes. The ability of neural grafting to reverse both the drug-induced changes in PKC and behaviors linked to septohippocampal cholinergic function suggest a mechanistic link between this signaling pathway and neurobehavioral teratology caused by heroin or phenobarbital.

Coronary arterial involvement and QT dispersion in Kawasaki disease.

For the early detection of myocardial ischemia in patients with severe involvement of the coronary arteries after Kawasaki disease, a method with high sensitivity and low cost is desirable because these patients require frequent follow-up and diagnostic tests. For this purpose, electrocardiographic, echocardiographic, Holter, and stress testing or angiography are repeated. However, these tests have some limitations due to cost, convenience, or sensitivity. It is uncertain that increased QT dispersion would exactly indicate progression of myocardial ischemia after Kawasaki disease, but this is the first study to present that QT dispersion of > or = 60 ms had higher sensitivity for detection of severe involvement of coronary artery after Kawasaki disease. This study is limited due to the small number of patients; larger prospective studies are required to clarify the usefulness of QT dispersion analysis in detecting the progression of myocardial ischemia after Kawasaki disease.

Neonatal catecholaminergic ventricular tachycardia--a case report.

A case of neonatal catecholaminergic ventricular tachycardia is reported. Episodes of fetal tachycardia were detected in a female baby and just after birth, sustained monomorphic ventricular tachycardia of complete left bundle branch block pattern and inferior axis were recorded, suggesting a right ventricular outflow origin. Routine examination did not reveal overt heart disease. Ventricular tachycardia was induced by crying or sucking, elicited by isoproterenol infusion, and was suppressed by intravenous injection of ATP or propranolol. The baby's arrhythmia was controlled with oral propranolol. The ventricular tachycardia seemed to be caused by triggered activity.

Frequencies in the Japanese population of HFE gene mutations.

We studied the frequencies of C282Y and H63D mutations in the HFE gene, thought to be responsible for hereditary hemochromatosis (HH), in 504 chromosomes obtained from 252 unrelated Japanese. Allele-specific PCR and PCR-restriction fragment length polymorphism methods revealed that the C282Y mutation was not found and the H63D mutation was low in frequency (at only 0.99%) compared with data from European people. Since most HH is thought to be associated with the HFE gene mutation, the low incidence of these mutations is a likely reason for the rarity of this disease in the Japanese population.

Substance abuse studies and prevention efforts among Arabs in the 1990s in Israel, Jordan and the Palestinian Authority--a literature review.

This paper is the result of a collaborative project of Israeli, Jordanian and Palestinian scientists gathered to reveal the current extent of substance abuse and efforts at prevention among Arabs in Israel, Jordan and the Palestinian Authority territories, in order to identify needs and suggest future collaborative activities and directions for regional cooperation. The article provides data and covers the current state of substance abuse prevention and research among Moslems, Christians and Druze in the trilateral region in the 1990s by reviewing prevention materials and studies published in the professional literature, as well as in reports and Doctoral and Master's theses in Arabic, which have been located in academic libraries and other institutions, in the framework of a comprehensive search. This manuscript is the first to summarize Jordanian and Palestinian findings in the substance abuse domain. The review shows that most of the Israeli research in the Arab sector deals with alcohol use among youth, that the majority of Jordanian studies focus on illicit drug use, that the research among Palestinians is in its infancy, and that comprehensive prevention programs are lacking in the trilateral region. It describes the key results of most of the 12 Israeli studies among Arabs, 11 Jordanian studies and four Palestinian studies. It reveals that drug abuse among Israeli Arab students is probably more prevalent than among Jewish adolescents, that the typical Jordanian drug addict has a higher level of education than the typical Palestinian drug addict, and that the Palestinian is more likely to be a multiple drug user. Recommendations for future activities include organization of a regional collaborative workshop in order to establish data collection systems for basic statistics relevant to drug abuse and development of comprehensive prevention programs, as well as studies in the substance abuse domain concerning knowledge, attitudes and behavior among the general Arab population.

A method of reducing the opioid withdrawal intensity using progressively increasing doses of naloxone.

We assessed the withdrawal intensity in acutely morphine-dependent mice using a pretreatment with escalating doses of naloxone. All animals received a single dose of morphine (100 mg/kg) for the induction of acute opioid dependency. Group 1 (control) received three injections of normal saline and then naloxone 0.8 mg/kg. Group 2 received increasing pretreatment doses of naloxone (0.1, 0.2, and 0.4 mg/kg) and a challenge dose of 0.8 mg/kg. Group 3 received three injections of naloxone 0.1 mg/kg and a challenge dose of 0.8 mg/kg. Groups 4 and 5 were used to verify whether ED(50) found in previous studies was comparable with values obtained in the current experiments. The withdrawal intensity was determined by the number of jumps. The mice of group 1 exhibited significantly more jumps after 0.8 mg/kg of naloxone as compared with group 2. The number of jumps in response to naloxone between groups 1 and 2 and groups 2 and 3 was not significantly different. The results show that pretreatment with increasing naloxone doses significantly reduced the withdrawal intensity as compared with the control group; whereas pretreatment with repeated low antagonist did not reduce it significantly.

Brain opioid receptor adaptation and expression after prenatal exposure to buprenorphine.

Previous in vivo studies revealed that buprenorphine can down-regulate mu and up-regulate delta2 and kappa1 opioid receptors in adult and neonatal rat brain. To assess gestational effects of buprenorphine on offspring, pregnant rats were also administered this drug and opioid receptor binding parameters (Kd and Bmax values) were measured by homologous binding assays of postnatal day 1 (P1) brain membranes. Buprenorphine concentrations of 2.5 mg/kg injected into dams elicited an up-regulation of kappa1 opioid receptors as detected with the kappa1-selective agonist 3H-U69593. Parallel studies with the mu-selective agonist [D-ala2, mephe4,gly-ol5] enkephalin revealed a buprenorphine-induced down-regulation in receptor density at 0.3, 0.6 or 2.5 mg/kg drug treatment. A greater down-regulation of mu receptors for P1 males than for their female counterparts was observed. Buprenorphine did not cause a reduction in binding affinity in these experiments. Changes in opioid receptor adaptation induced by buprenorphine were further supported by data from cross-linking of 125I-beta-endorphin to brain membrane preparations. RT-PCR analysis of opioid receptor expression was also estimated in P1 brains. However, significant changes in neither mu nor kappa receptor message were detected in P1 brains as a result of prenatal buprenorphine treatment under the conditions of these experiments. Since buprenorphine is being evaluated in clinical trials for the treatment of heroin abuse, the in utero actions of the drug have ramifications for its use in the treatment of maternal drug abuse.

Pre- and postsynaptic alterations in the septohippocampal cholinergic innervations after prenatal exposure to drugs.

The present study was designed to evaluate possible presynaptic and postsynaptic alterations in the hippocampal cholinergic innervations that account for the hippocampus-related behavioral deficits found after prenatal drug exposure. Mice were prenatally exposed to either phenobarbital or heroin. On postnatal day 50, the hippocampi were removed and protein kinase C (PkC) activity, the amounts of Gi, Go, and Gq guanosine 5'-triphosphate binding proteins (G-proteins), and choline transports were determined. Basal PkC activity was higher than control levels in both phenobarbital and heroin treated mice, by 41% and 35%, respectively. The increase of PkC activity in response to carbachol was impaired in both treatment groups: in control mice, membrane PkC activity in hippocampal slices increased by 40%-50%, while no such response, or even slight reduction in PkC activity, was observed in the drug-exposed offspring. A significant increase was found in Gi and Gq G-proteins (18%-21%) in mice exposed to phenobarbital or to heroin compared with control levels. The amount of choline transporters, determined by hemicholinium binding, increased by 70% compared with the control level in mice prenatally exposed to heroin, and increased by 71% in mice prenatally exposed to phenobarbital. The alterations in basal and carbachol-stimulated hippocampal PkC activity after prenatal drug exposure may be related to an impairment in long-term potentiation (LTP); which plays an important role in hippocampal related behavioral abilities, changes in which are caused by prenatal drug exposure.