Towards precision medicine for anxiety disorders: objective assessment, risk prediction, pharmacogenomics, and repurposed drugs.

Anxiety disorders are increasingly prevalent, affect people's ability to do things, and decrease quality of life. Due to lack of objective tests, they are underdiagnosed and sub-optimally treated, resulting in adverse life events and/or addictions. We endeavored to discover blood biomarkers for anxiety, using a four-step approach. First, we used a longitudinal within-subject design in individuals with psychiatric disorders to discover blood gene expression changes between self-reported low anxiety and high anxiety states. Second, we prioritized the list of candidate biomarkers with a Convergent Functional Genomics approach using other evidence in the field. Third, we validated our top biomarkers from discovery and prioritization in an independent cohort of psychiatric subjects with clinically severe anxiety. Fourth, we tested these candidate biomarkers for clinical utility, i.e. ability to predict anxiety severity state, and future clinical worsening (hospitalizations with anxiety as a contributory cause), in another independent cohort of psychiatric subjects. We showed increased accuracy of individual biomarkers with a personalized approach, by gender and diagnosis, particularly in women. The biomarkers with the best overall evidence were GAD1, NTRK3, ADRA2A, FZD10, GRK4, and SLC6A4. Finally, we identified which of our biomarkers are targets of existing drugs (such as a valproate, omega-3 fatty acids, fluoxetine, lithium, sertraline, benzodiazepines, and ketamine), and thus can be used to match patients to medications and measure response to treatment. We also used our biomarker gene expression signature to identify drugs that could be repurposed for treating anxiety, such as estradiol, pirenperone, loperamide, and disopyramide. Given the detrimental impact of untreated anxiety, the current lack of objective measures to guide treatment, and the addiction potential of existing benzodiazepines-based anxiety medications, there is a urgent need for more precise and personalized approaches like the one we developed.

HBP/O-GlcNAcylation Metabolic Axis Regulates Bone Resorption Outcome.

Osteoclasts play a key role in the regulation of bone mass and are highly active metabolically. Here we show that a metabolic reprogramming toward the hexosamine biosynthetic pathway (HBP) is required not only for osteoclast differentiation but also to determine the bone resorption mode during physiological and pathological bone remodeling. We found that pharmacological inhibition of O-GlcNAc transferase (OGT) significantly reduced protein O-GlcNAcylation and osteoclast differentiation. Accordingly, genetic deletion of OGT also inhibited osteoclast formation and downregulated critical markers related to osteoclasts differentiation and function (NFATc1, αvintegrin, cathepsin K). Indeed, cells treated with OSMI-1, an OGT inhibitor, also reduced nuclear translocation of NFATc1. Furthermore, the addition of exogenous N-acetylglucosamine (GlcNAc) strongly increased osteoclast formation and demineralization ability. Strikingly, our data show for the first time that O-GlcNAcylation facilitates an aggressive trench resorption mode in human cells. The incubation of osteoclasts with exogenous GlcNAc increases the percentage of erosion by trench while having no effect on pit resorption mode. Through time-lapse recording, we documented that osteoclasts making trenches moving across the bone surface are sensitive to GlcNAcylation. Finally, osteoclast-specific Ogt-deficient mice show increased bone density and reduced inflammation-induced bone loss during apical periodontitis model. We show that osteoclast-specific Ogt-deficient mice are less susceptible to develop bacterial-induced periapical lesion. Consistent with this, Ogt-deleted mice showed a decreased number of tartrate-resistant acid phosphatase-positive cells lining the apical periodontitis site. In summary, here we describe a hitherto undiscovered role of the HBP/O-GlcNAcylation axis tuning resorption mode and dictating bone resorption outcome.

Hear us! Accounts of people treated with injectables for drug-resistant TB.

BACKGROUND: WHO drug-resistant TB (DR-TB) treatment recommendations now emphasize all-oral regimens, recommending against certain injectable agents and deprioritizing others due to inferior safety and efficacy. Despite increasing focus on patient-centered care, we are not aware of systematic attempts to qualitatively document patients' perspectives on injectable agents. This may inform implementation of WHO guidelines, emphasizing the importance of consultation with affected communities. METHODS: Testimonies were provided by TB survivors who experienced hearing loss from treatment with injectable agents. Testimonies were submitted in writing in response to minimal, standardized, open-ended prompts. Participants provided a signed consent form (with options to participate anonymously or as a named co-author), and later gave input into the overall shape and recommendations of the article. RESULTS: Fourteen TB survivors in 12 countries contributed testimonies. The following common themes emerged: lack of access to appropriate testing, information, treatment, or a collaborative treatment environment; the power of supportive care and social environments; stigma and isolation from TB treatment itself and resultant disability; and inaccessibility of cochlear implants. CONCLUSIONS: Survivor testimonies indicate strong preferences for avoidance of injectable agents, supporting rapid implementation of revised WHO guidelines, as well as for quality and supportive care for both TB and disabilities.

CONTEXTE: Les recommandations de l'OMS pour le traitement de la TB pharmacorésistante (DR-TB) mettent désormais l'accent sur les schémas thérapeutiques entièrement par voie orale, préconisant de ne pas utiliser certains agents injectables et de ne plus donner la priorité à d'autres en raison d'une innocuité et d'une efficacité inférieures. Malgré l'attention accrue portée aux soins centrés sur le patient, nous ne connaissons aucune étude systématique ayant cherché à documenter de manière qualitative le point de vue des patients sur les agents injectables. Ce travail pourrait guider la mise en place des directives de l'OMS, en mettant l'accent sur l'importance de consulter les communautés concernées. MÉTHODES: Des personnes ayant survécu à une TB et ayant connu une perte d'audition due à un traitement par agents injectables ont apporté leurs témoignages. Les témoignages ont été soumis par écrit en réponse à des questions courtes, ouvertes et standardisées. Les participants ont signé un formulaire de consentement (avec possibilité de participer de manière anonyme ou en tant que coauteur nommé) et ont ensuite contribué au format général et aux recommandations de l'article. RÉSULTATS: Quatorze personnes ayant survécu à une TB provenant de 12 pays ont apporté leur témoignage. Les thématiques suivantes ont été fréquemment mentionnées : manque d'accès aux tests, informations et traitements appropriés ou à un environnement thérapeutique collaboratif ; importance des soins de soutien et de l'environnement social ; stigmatisation et isolement dus au traitement antituberculeux et handicaps qui en résultent ; et inaccessibilité aux implants cochléaires. CONCLUSIONS: Le témoignage des personnes ayant survécu à une TB indique qu'elles préfèrent nettement éviter les agents injectables, allant ainsi dans le sens d'une mise en place rapide des directives révisées de l'OMS, et qu'elles préfèrent des soins de qualité et de soutien pour la TB mais aussi pour les handicaps qui en résultent.

IPT in people living with HIV in Myanmar: a five-fold decrease in incidence of TB disease and all-cause mortality.

SETTING: Myanmar, a country with a high human immunodeficiency virus-tuberculosis (HIV-TB) burden, where the tuberculin skin test or interferon-gamma release assays are not routinely available for the diagnosis of latent tuberculous infection. OBJECTIVE: To assess the effect of isoniazid (INH) preventive therapy (IPT) on the risk of TB disease and mortality among people living with HIV (PLHIV). DESIGN: A retrospective cohort study of routinely collected data on PLHIV enrolled into care between 2009 and 2014. RESULTS: Of 7177 patients (median age 36 years, interquartile range 31-42; 53% male) included in the study, 1278 (18%) patients received IPT. Among patients receiving IPT, 855 (67%) completed 6 or 9 months of INH. Patients who completed IPT had a significantly lower risk of incident TB than those who never received IPT (adjusted hazard ratio [aHR] 0.21, 95%CI 0.12-0.34) after controlling for potential confounders. PLHIV who received IPT had a significantly lower risk of death than those who never received IPT (PLHIV who completed IPT, aHR 0.25, 95%CI 0.16-0.37; those who received but did not complete IPT, aHR 0.55, 95%CI 0.37-0.82). CONCLUSION: Among PLHIV in Myanmar, completing a course of IPT significantly reduced the risk of TB disease, and receiving IPT significantly reduced the risk of death.

Early disease course is unaltered in mucopolysaccharidosis type IIIA (MPS IIIA) mice lacking α-synuclein.

BACKGROUND: Sanfilippo syndrome (mucopolysaccharidosis type IIIA; MPS IIIA) is an inherited paediatric-onset neurodegenerative disorder caused by the lysosomal deficiency of sulphamidase with subsequent accumulation of heparan sulphate. The pathological mechanisms responsible for clinical disease are unknown; however, intraneuronal accumulation of aggregation-prone proteins such as α-synuclein, phosphorylated tau and amyloid precursor protein suggests inefficient intracellular trafficking and lysosomal degradation. AIM: To investigate the contribution the accumulating α-synuclein plays in early symptom emergence that is, impaired cognition, reduced anxiety and motor deficits, first detectable between 3-5 months of age. METHODS: We have crossed congenic MPS IIIA mice with α-synuclein-deficient (Sncatm1Rosl /J) mice and evaluated phenotype and brain disease lesions. RESULTS: In a battery of behavioural tests performed on mice aged 12-22 weeks, we were unable to differentiate α-synuclein-deficient MPS IIIA mice from those with one or both copies of the α-synuclein gene; all three affected genotypes were significantly impaired in test performance when compared to wild-type littermates. Histological studies revealed that the rate, location and nature of deposition of other proteinaceous lesions, the disruption to endolysosomal protein expression and the inflammatory response seen in the brain of α-synuclein-deficient MPS IIIA mice reflected that seen in MPS IIIA mice homo- or heterozygous for α-synuclein. CONCLUSION: Deletion and/or deficiency of α-synuclein does not influence clinical and neuropathological disease progression in murine MPS IIIA, demonstrating that in and of itself, this protein does not initiate the cognitive and motor symptoms that occur in the first 5 months of life in MPS IIIA mice.

Towards precision medicine for pain: diagnostic biomarkers and repurposed drugs.

We endeavored to identify objective blood biomarkers for pain, a subjective sensation with a biological basis, using a stepwise discovery, prioritization, validation, and testing in independent cohorts design. We studied psychiatric patients, a high risk group for co-morbid pain disorders and increased perception of pain. For discovery, we used a powerful within-subject longitudinal design. We were successful in identifying blood gene expression biomarkers that were predictive of pain state, and of future emergency department (ED) visits for pain, more so when personalized by gender and diagnosis. MFAP3, which had no prior evidence in the literature for involvement in pain, had the most robust empirical evidence from our discovery and validation steps, and was a strong predictor for pain in the independent cohorts, particularly in females and males with PTSD. Other biomarkers with best overall convergent functional evidence for involvement in pain were GNG7, CNTN1, LY9, CCDC144B, and GBP1. Some of the individual biomarkers identified are targets of existing drugs. Moreover, the biomarker gene expression signatures were used for bioinformatic drug repurposing analyses, yielding leads for possible new drug candidates such as SC-560 (an NSAID), and amoxapine (an antidepressant), as well as natural compounds such as pyridoxine (vitamin B6), cyanocobalamin (vitamin B12), and apigenin (a plant flavonoid). Our work may help mitigate the diagnostic and treatment dilemmas that have contributed to the current opioid epidemic.

Treatment outcome of tuberculosis patients detected using accelerated vs. passive case finding in Myanmar.

SETTING: Several projects involving accelerated or active case finding (ACF) of tuberculosis (TB) cases are being implemented in Myanmar. However, there is a concern that patients detected using ACF have poorer TB treatment outcomes than those detected using passive case finding (PCF). OBJECTIVE: To assess differences in the demographics, clinical profile and treatment outcomes of patients detected using ACF and PCF. DESIGN: Retrospective cohort study of TB patients diagnosed and enrolled for treatment during 2014-2016. RESULTS: Of 16 048 patients enrolled, 2226 (16%) were detected using ACF; the treatment success rate (cured and completed) was 88%. A higher proportion of cases detected using ACF were aged 55 years, human immunodeficiency virus (HIV) negative and sputum smear-positive pulmonary TB. After adjusting for differences in demographic and clinical characteristics, we found that treatment outcomes in patients detected using ACF and PCF were not significantly different (adjusted relative risk [aRR] 0.89, 95%CI 0.78-1.00). Male sex, age  55 years, patients with a previous history of TB and HIV positivity were independently associated with unsuccessful outcomes. CONCLUSION: ACF detected a significant proportion of TB cases in study townships; treatment outcomes in cases detected using ACF and those detected using PCF were similar. More tailored interventions are needed to improve treatment outcomes in patients at a higher risk of unsuccessful treatment outcomes.

IPT during HIV treatment in Myanmar: high rates of coverage, completion and drug adherence.

Setting: A southern Myanmar district providing isoniazid preventive therapy (IPT) in one of the last countries to formally recommend it as part of human immunodeficiency virus (HIV) care. Objective: To assess coverage and adherence and the feasibility of IPT scale-up in a routine care setting in Myanmar. Design: A retrospective analysis of people living with HIV (PLHIV) screened for tuberculosis (TB) and enrolled in IPT over a 3-year period (July 2011-June 2014) using clinical databases. Results: Among 3377 patients under HIV care and screened for TB, 2740 (81.1%) initiated IPT, with 2651 (96.8%) completing a 6- or 9-month course of IPT; 83 (3.1%) interrupted treatment for different reasons, including loss to follow-up (n = 41), side effects (n = 15) or drug adherence issues (n = 9); 6 (0.2%) died. Among the IPT patients, 33 (1.2%) were diagnosed with TB, including 9 (0.3%) while on IPT and 24 (0.9%) within 1 year of completion of therapy. Among the PLHIV who completed IPT, one case of isoniazid resistance was detected. Conclusion: Scaling up IPT in Myanmar HIV settings is feasible with high rates of drug adherence and completion, and a low rate of discontinuation due to side effects. IPT scale-up should be prioritised in HIV clinical settings in Myanmar.

Contexte : Un district du sud du Myanmar fournissant le traitement préventif par isoniazide (IPT) dans l'un des derniers pays à le recommander formellement comme élément de la prise en charge de l'infection par le virus de l'immunodéficience humaine (VIH).Objectif : Evaluer la couverture, l'adhérence et la faisabilité d'une accélération de l'IPT dans un contexte de soins de routine au Myanmar.Schéma : Analyse rétrospective de personnes vivant avec le VIH (PVVIH) dépistés pour la tuberculose (TB) et enrôlés dans l'IPT sur une période de 3 ans, de juillet 2011 à juin 2014, grâce à des bases de données cliniques.Résultats : Sur 3377 patients pris en charge pour le VIH et dépistés pour la TB, 2740 (81,1%) ont mis en route le TPI, dont 2651 (96,8%) ont achevé un traitement préventif de 6 ou 9 mois ; 83 (3,1%) ont interrompu leur traitement pour différentes raisons incluant les pertes de vue (n = 41), les effets secondaires (n = 15) ou des problèmes d'adhérence au médicament (n = 9), et six (0,2%) sont décédés. Parmi les patients IPT, 33 (1,2%) ont eu un diagnostic de TB, dont 9 (0,3%) pendant la prophylaxie et 24 (0,9%) dans l'année qui a suivi la fin de l'IPT. Un cas de résistance à l'isoniazide a été détecté parmi les PVVIH qui ont achevé l'IPT.Conclusion: L'accélération de l'IPT dans les structures VIH du Myanmar est faisable, avec un taux élevé d'adhérence au médicament et d'achèvement et un taux faible d'arrêt du traitement dû à des effets secondaires. L'accélération de l'IPT devrait être considérée comme une priorité dans les structures cliniques VIH du Myanmar.

Marco de referencia: Un distrito del sur de Birmania que provee el tratamiento preventivo con isoniazida (IPT). Birmania es uno de los últimos países que incluyó esta profilaxis en las recomendaciones formales de atención de la infección por el virus de la inmunodeficiencia humana (VIH).Objetivo: Evaluar la cobertura, el cumplimiento terapéutico y la factibilidad de ampliar la escala de aplicación del IPT en un entorno de tratamiento corriente en Birmania.Método: Fue este un análisis retrospectivo de personas con infección por el VIH, en quienes se practicó la detección sistemática de la tuberculosis (TB) y se registraron para recibir el IPT. Se obtuvo la información a partir de las bases de datos clínicos durante un período de 3 años, de julio del 2011 hasta junio del 2014.Resultados: De los 3377 pacientes que recibían atención por infección por el VIH, con investigación sistemática de la TB, 2740 iniciaron el TPI (81,1%) y 2651 completaron un esquema de 6 o 9 meses de profilaxis (96,8%). Ochenta y tres pacientes interrumpieron por razones diversas el tratamiento (3,1%), entre ellas, la pérdida durante el seguimiento (n = 41), los efectos secundarios (n = 15) o los problemas de cumplimiento terapéutico (n = 9) y seis pacientes fallecieron (0,2%). De los pacientes que recibieron IPT, en 33 se diagnosticó TB (1,2%), en 9 de ellos durante la profilaxis (0,3%) y en 24 casos durante el primer año después de haber completado el esquema (0,9%). Se detectó un caso de resistencia a isoniazida en las personas infectadas por el VIH que completaron el IPT.Conclusiôn: La ampliación de escala del IPT en los entornos de atención de la infección por el VIH es factible en Birmania y se pueden alcanzar altas tasas de cumplimiento terapéutico y compleción del esquema, con una baja tasa de interrupción debida a efectos colaterales. Es importante dar prioridad a la ampliación de escala del IPT en los medios de atención de la infección por el VIH en el país.

Rifampicin-resistant tuberculosis patients in Myanmar in 2016: how many are lost on the path to treatment?

SETTING: Regional tuberculosis (TB) centres of the Yangon and Mandalay Regions of Myanmar, which account for 65% of all notified rifampicin-resistant tuberculosis (RR-TB) cases countrywide. OBJECTIVE: To determine 1) initial loss to follow-up (LTFU), 2) treatment delay, and 3) factors associated with initial LTFU and treatment delay among RR-TB patients residing in the Yangon and Mandalay regions diagnosed using Xpert® during January-August 2016. DESIGN: This was a retrospective cohort study. Each diagnosed patient was tracked in the drug-resistant TB treatment registers of the Yangon and Mandalay regional treatment centres for January-December 2016 using patient name, age, sex, township and date of diagnosis. If the diagnosed patient was not found in the treatment register by 31 December 2016, he/she was considered 'initial LTFU'. RESULTS: Of the 1037 RR-TB patients diagnosed, 310 (30%) experienced initial LTFU, which was significantly higher among patients aged 55 years and among those diagnosed in the Mandalay Region. A treatment delay of >1 month was observed in 440 (70%) patients (median delay 41 days). Delay was uniformly high across patient subgroups, and was not associated with any factor. CONCLUSION: Initial LTFU and treatment delays among RR-TB patients were high. Future studies using qualitative research methods are needed to ascertain the reasons for this observation.

Clinical, virological and epidemiological characterization of dengue outbreak in Myanmar, 2015.

Hospital-based surveillance was conducted at two widely separated regions in Myanmar during the 2015 dengue epidemic. Acute phase serum samples were collected from 332 clinically diagnosed dengue patients during the peak season of dengue cases. Viremia levels were measured by quantitative real-time PCR and plaque assays using FcγRIIA-expressing and non-FcγRIIA-expressing BHK cells to specifically determine the infectious virus particles. By serology and molecular techniques, 280/332 (84·3%) were confirmed as dengue patients. All four serotypes of dengue virus (DENV) were isolated from among 104 laboratory-confirmed patients including two cases infected with two DENV serotypes. High percentage of primary infection was noted among the severe dengue patients. Patients with primary infection or DENV IgM negative demonstrated significantly higher viral loads but there was no significant difference among the severity groups. Viremia levels among dengue patients were notably high for a long period which was assumed to support the spread of the virus by the mosquito vector during epidemic. Phylogenetic analyses of the envelope gene of the epidemic strains revealed close similarity with the strains previously isolated in Myanmar and neighboring countries. DENV-1 dominated the epidemic in 2015 and the serotype (except DENV-3) and genotype distributions were similar in both study sites.

Impact on regional recurrence and survival of axillary surgery in women with node-negative primary breast cancer.

BACKGROUND: This study examined whether axillary lymph node dissection (ALND) with removal of many normal lymph nodes resulted in a reduced rate of axillary recurrence and better survival, as reported in recent studies. METHODS: The follow-up analyses were based on 8657 patients with node-negative primary breast cancer treated solely by surgery. Median follow-up was 9 years. RESULTS: The number of lymph nodes removed correlated with a reduction in the rate of subsequent axillary recurrence (from 2.1 to 0.4 per cent; P = 0.037), local recurrence (from 7.4 to 3.8 per cent; P < 0.001) distant metastases (from 15.0 to 10.3 per cent; P < 0.001) and death as first event (from 7.5 to 5.5 per cent; P = 0.012). CONCLUSION: When ALND is indicated, at least ten axillary lymph nodes should be retrieved. The role of ALND as primary treatment has decreased significantly during the past decade. The findings leave the concept of the sentinel node biopsy intact, as a highly specific procedure compared to ALND.

A phase II clinical trial does not show that high dose simvastatin has beneficial effect on markers of bone turnover in multiple myeloma.

Several studies have evaluated the impact of low dose statin (20-80 mg/day) on bone metabolism with inconclusive results despite promising data of preclinical studies. In this study, we investigated the effect of high dose simvastatin (HD-Sim) on biochemical markers of bone turnover and disease activity in six heavily pretreated patients with multiple myeloma (MM). These patients were treated with simvastatin (15 mg/kg/day) for 7 days followed by a rest period of 21 days in two 4-week cycles. Endpoints were changes in the level of biochemical markers of (i) osteoclast activity (tartrate resistant acid phosphatase, TRACP); (ii) bone resorption (collagen fragments CTX and NTX); (iii) bone formation (osteocalcin and aminoterminal propeptide of type I collagen PINP); (iv) cholesterol; (v) regulators of bone metabolism [osteoprotegerin (OPG) and Dickkopf-1 (DKK-1)] and (vi) disease activity (monoclonal proteins or free light chains in serum). TRACP activity in serum and levels of collagen fragments (NTX) in urine increased for all patients temporarily during the 7 days of treatment with HD-Sim indicating that osteoclasts may have been stimulated rather than inhibited. The other markers of bone metabolism showed no change. None of the patients showed any reduction in free monoclonal light chains or monoclonal proteins in serum during treatment with HD-Sim. In spite of the fact that bone turn over effects of HD-Sim may have been blunted by concomitant treatment of patients with other drugs we observed a transient increase in markers of osteoclast activity. This sign of a transient stimulation of osteoclast activity suggests that HD-Sim may be harmful rather than beneficial for MM patients. For this reason and because of gastro-intestinal side effects the study was stopped prematurely.

Cellular stress triggers the human topoisomerase I damage response independently of DNA damage in a p53 controlled manner.

The 'human topoisomerase I (htopoI) damage response' was reported to be triggered by various kinds of DNA lesions. Also, a high and persistent level of htopoI cleavage complexes correlated with apoptosis. In the present study, we demonstrate that DNA damage-independent induction of cell death using colcemid and tumor necrosis factor alpha is also accompanied by a strong htopoI response that correlates with the onset of apoptotic hallmarks. Consequently, these results suggest that htopoI cleavage complex formation may be caused by signaling pathways independent of the kind of cellular stress. Thus, protein interactions or signaling cascades induced by DNA damage or cellular stress might lead to the formation of stabilized cleavage complexes rather than the DNA lesion itself. Finally, we show that p53 not only plays a key role in the regulation of the htopoI response to UV-C irradiation but also to treatment with colcemid.

Reliability and validity of two oral health related quality of life measures in Myanmar adolescents.

OBJECTIVE: To assess two Oral Health Related Quality of Life (OHQoL) measures and the levels of oral impacts among 14-year-old students in Yangon Division, Myanmar. DESIGN: Cross-sectional validation study. Setting High schools in Yangon Division. PARTICIPANTS: A multi-stage stratified random cluster sample of 543 students. OUTCOME MEASURES: Prevalence, extent (number of impacts) and total score as recorded using the Oral Impacts on Daily Performance (OIDP) and the short form of the Oral Heath Impact Profile (OHIP-14). Psychometric measures of validity and reliability. RESULTS: 15.8% and 53.0% of participants had an impact using OIDP and OHIP-14 respectively. The extents and total scores were low among those with impacts. Both measures had good reliability (Cronbach's alpha 0.72 for OIDP and 0.86 for OHIP-14). The presence of dental caries was associated with summary measures of OHIP-14 but not with OIDP. The most frequent cause of impact was dental caries. CONCLUSIONS: Both OIDP and OHIP-14 had reasonable reliability but OHIP-14 had superior construct validity. OHIP-14 appears to be more useful as an instrument to discriminate between groups with and without impacts in population surveys.

A human topoisomerase I cleavage complex is recognized by an additional human topisomerase I molecule in vitro.

Several recent studies have shown that human topoisomerase I (htopoI) can recognize various DNA lesions and thereby form a covalent topoisomerase I-DNA complex, which is known to be detrimental to cells. We have investigated whether htopoI recognizes another htopoI that is covalently trapped on a DNA substrate. For this purpose we created an artificial DNA substrate containing a specific topoisomerase I binding sequence, where the enzyme was trapped in the covalently bound form. We demonstrate that, in vitro, free htopoI stimulates the formation of an additional cleavage complex immediately upstream of the covalently bound topoisomerase I. The predominant distance between the two cleavage sites is 13 nt. In addition we find that these two enzymes may form direct protein-protein contacts and we propose that these may be mediated through the formation of a dimer by domain swapping involving the C-terminal and the core domains. Finally, we discuss the possibility that the double cleavage reaction may be the initial step for the removal of the recognized cleavage complex.

Intestinal obstruction after appendectomy.

BACKGROUND: The frequency of intestinal obstruction varies in the literature (0.2-10.7%) and requires evaluation in a proper design. METHODS: From 1978 to 1985, 1951 patients underwent appendectomy; 58 patients were excluded because of appendectomy per occasionem, 156 because of previous laparotomy, and 190 because of simultaneous major surgery. Three foreigners were lost to follow-up. The cohort was linked to the Danish National Inpatient Register for identification of cases, defined by intestinal obstruction requiring surgical intervention. RESULTS: The follow-up period was long (median, 3563 days; range, 2-5113). Twenty-one patients developed intestinal obstruction. The cumulated incidence was 0.33% after 30 days, 0.79% after 1 year, and 1.51% after 14 years. Female sex as compared with male sex (RR = 3.91; 95% confidence limits (CL), 1.25-12.0) and removal of a removal of a normal appendix as compared with an inflamed appendix (RR = 4.0; 95% CL, 1.28-12.5) carried a significantly higher risk of intestinal obstruction. CONCLUSION: Intestinal obstruction after open appendectomy is rare.

The use of personal protective measures in control of malaria in a defined community.

Malaria is one of the main health problems in the non-immune immigrant workers and army personnel of the malaria endemic areas in Myanmar. Due to changes in the vector bionomics and multiresistant strains of P. falciparum, chemoprophylaxis alone is not an effective means of control of malaria in them. So it is envisaged that the combined used of personal protective measures (deltamethrin impregnated bed-nets, scalves and hand-bands) and the chemoprophylaxis will be an effective means of control of malaria in the define group of people. The study also intended to find out the side effects of the deltamethrin and feasibility and acceptability of methods by the users. The study was conducted in Theini Township, Northern Shan State, from March to November 1993. The study population consisted of all ages of both sexes 554 and 440 persons in the test and control groups respectively. At the initial phase of the study, malaria infected persons from both the groups were treated. The experimental group received personal protective measures with impregnation of bed-nets using 25 mg ai/m2 of deltamethrin at 4 monthly intervals and the scarves and hand-bands at twice the concentration of the insecticides at monthly intervals. Chemoprophylaxis was given to both the groups at weekly intervals using age adjusted dosage of Pyrixine tablet (sulfadoxine-pyrimethamine). The parasitological, entomological, and epidemiological indices were collected at two month intervals in both the groups. The study clearly showed the impact of personal protective measures and chemoprophylaxis on malaria infection in the studied subjects. During the study period, the out patient malaria cases of the test group was 6% to 11.2% and that of the control group was 12% to 21.6% in Theini Hospital. The reinfection rate of the test group (0.9 to 4.7%) was also significantly lower than the control group (6.1 to 14.3%) from July to November. Acceptance of the treated bed-nets, scarves and hand-bands was high and good compliance was found in the follow up. The results of the study clearly showed that malaria can be controlled effectively in the defined group of persons for a malaria transmission season by using chemoprophylaxis and personal protective measures.

[Nephropathia epidemica. Hantavirus nephritis--a differential diagnosis in acute abdomen]. / Nephropathia epidemica. Hantavirusnephritis--en differentialdiagnose til akut abdomen.

Nephropathia epidemica (NE) is an infectious disease caused by hantavirus of the Bunyavirus family and carried by little rodents, in Denmark presumably by the bank vole (Clethrionomys glareolus). The disease usually presents with self-limiting renal failure, thrombocytopenia, fever, lower back and/or abdominal pain. As such it might be confused with for example acute abdomen as shown by the two cases given. Final diagnosis is based upon demonstrating antibody formation against hantavirus.

[Liver pathology associated with anabolic androgenic steroids]. / Leverpatologi associeret med anaboliske-androgene steroider.

This review regards the liver damaging side-effects of anabolic-androgenic steroids (AAS). It seems that AAS can cause development of peliosis hepatis, subcellular changes of hepatocytes, hepatocellular hyperplasia and hepatocellular adenomas. On the other hand, it has not been convincingly proved that AAS can cause development of hepatocellular carcinomas when used in usual therapeutical doses. Tumours reported as hepatocellular carcinomas caused by AAS seem to be hyperplastic lesions of a benign nature that are able to regress on withdrawal of the putative agent. The effect of untraditional combinations of AAS and high-dose AAS is not yet known, leaving the possibility of a carcinogenic effect in those cases.

Liver pathology associated with the use of anabolic-androgenic steroids.

This review examines the liver-damaging side effects of anabolic-androgenic steroids (AAS). It seems that AAS can cause development of peliosis hepatis, subcellular changes of hepatocytes, hepatocellular hyperplasia and hepatocellular adenomas. On the other hand, it has not been convincingly proved that AAS can cause development of hepatocellular carcinomas when used in the usual therapeutic doses. Tumours reported as hepatocellular carcinomas caused by AAS seems to be hyperplastic lesions of a benign nature able to regress with withdrawal of the putative agent. The effects of untraditional combinations and high-dose AAS are not yet known, leaving the possibility of a carcinogenic effect in those cases.