Integrating hepatitis C treatment into multidrug-resistant TB care.

BACKGROUND: Direct-acting antivirals (DAAs) are not widely used for patients with chronic hepatitis C virus (HCV) infection and multidrug- or rifampicin-resistant TB (MDR/RR-TB). We describe the implementation aspects of a new integrated model of care in Armenia and the perceptions of the healthcare staff and patients. METHODS: We used qualitative methods, including a desktop review and semi-structured individual interviews with healthcare staff and with patients receiving HCV and MDR/RR-TB treatment. RESULTS: The new integrated model resulted in simplified management of HCV and MDR/RR-TB at public TB facilities. Training on HCV was provided for TB clinic staff. All MDR/RR-TB patients were systematically offered HCV testing and those diagnosed with HCV, offered treatment with DAAs. Treatment monitoring was performed by TB staff in coordination with a hepatologist. The staff interviewed had a positive opinion of the new model. They suggested that additional training should be provided. Most patients were fully satisfied with the care received. Some were concerned about the increased pill burden. CONCLUSION: Integrating HCV treatment into MDR/ RR-TB care was feasible and appreciated by patients and staff. This new model facilitated HCV diagnosis and treatment among people with MDR/RR-TB. Our results encourage piloting this model in other settings.

CONTEXTE: Les antiviraux à action directe (DAA) sont peu prescrits aux patients atteints d'hépatite C (HCV) chronique et de TB multirésistante ou résistante à la rifampicine (MDR/RR-TB). Nous décrivons la mise en place d'un nouveau modèle de soins intégrés en Arménie, ainsi que l'opinion du personnel soignant et des patients. MÉTHODES: Nous avons utilisé des méthodes qualitatives, comprenant un examen électronique de la documentation et des entretiens individuels semi-structurés avec le personnel soignant et les patients sous traitement pour HCV et MDR/RR-TB. RÉSULTATS: Le nouveau modèle intégré a permis de simplifier la prise en charge du HCV et de la MDR/RR-TB dans les centres de soins publics de la TB. Une formation sur le HCV a été dispensée au personnel des centres antituberculeux. Tous les patients atteints de MDR/RR-TB se sont vu systématiquement proposer un test de dépistage du HCV, et un traitement par DAA a été proposé à ceux dont le résultat était positif. Le suivi du traitement a été réalisé par le personnel des centres antituberculeux, conjointement à un hépatologue. Les membres du personnel interrogés avaient une opinion positive du nouveau modèle et suggéraient de dispenser d'autres formations. La plupart des patients étaient pleinement satisfaits des soins reçus, mais certains étaient inquiets au vu du nombre accru de comprimés à prendre. CONCLUSION: L'intégration du traitement du HCV aux soins de la MDR/RR-TB s'est avérée possible et a été appréciée par les patients et le personnel soignant. Ce nouveau modèle a facilité le diagnostic et le traitement du HCV chez les patients atteints de MDR/RR-TB. Ce modèle devrait être testé dans d'autres contextes.

HIV-1 drug resistance testing at second-line regimen failure in Arua, Uganda: avoiding unnecessary switch to an empiric third-line.

OBJECTIVES: The number of patients on second-line antiretroviral therapy is growing, but data on HIV drug resistance patterns at failure in resource-constrained settings are scarce. We aimed to describe drug resistance and investigate the factors associated with extensive resistance to nucleoside/nucleotide reverse transcriptase inhibitors (NRTI), in patients failing second-line therapy in the HIV outpatient clinic at Arua Regional Referral Hospital, Uganda. METHODS: We included patients who failed on second-line therapy (two consecutive viral loads ≥1000 copies/mm3 by SAMBA-1 point-of-care test) and who had a drug resistance test performed between September 2014 and March 2017. Logistic regression was used to investigate factors associated with NRTI genotypic sensitivity score (GSS) ≤1. RESULTS: Seventy-eight patients were included: 42% female, median age 31 years and median time of 29 months on second-line therapy. Among 70 cases with drug resistance test results, predominant subtypes were A (47%) and D (40%); 18.5% had ≥1 major protease inhibitor mutation; 82.8% had ≥1 NRTI mutation and 38.5% had extensive NRTI resistance (NRTI GSS ≤1). A nadir CD4 count ≤100/ml was associated with NRTI GSS ≤1 (OR 4.2, 95% CI [1.3-15.1]). Thirty (42.8%) patients were switched to third-line therapy, composed of integrase inhibitor and protease inhibitor (60% darunavir/r) +/- NRTI. A follow-up viral load was available for 19 third-line patients at 12 months: 84.2% were undetectable. CONCLUSIONS: Our study highlights the need for access to drug resistance tests to avoid unnecessary switches to third-line therapy, but also for access to third-line drugs, in particular integrase inhibitors. Low nadir CD4 count might be an indicator of third-line drug requirement for patients failing second-line therapy.

Cardiac tamponade as a first manifestation of possible systemic lupus erythematosus in a 3-year-old female child.

Cardiac manifestations of pediatric systemic lupus erythematosus (SLE) usually occur as an initial manifestation of the disease or within six months after the diagnosis of SLE. Pericarditis is the most frequent cardiac manifestation of SLE, but pericardial effusion causing tamponade, which has a very serious prognosis, rarely occurs, and it is even less frequent for the pericardial tamponade to be the presenting feature of SLE. In the present case which is the youngest case in the literature we report a 3 year old girl who presented to the emergency room with solely pericardial effusion causing tamponade, bilateral pleural effusion and diagnosed "possible SLE" based on American College of Rheumatology criteria.

Antiretroviral therapy for HIV prevention: many concerns and challenges, but are there ways forward in sub-Saharan Africa?

Scientists from the WHO have presented a theoretical mathematical model of the potential impact of universal voluntary HIV testing and counselling followed by immediate antiretroviral therapy (ART). The results of the model suggests that, in a generalised epidemic as severe as that in sub-Saharan Africa (SSA), HIV incidence may be reduced by 95% in 10 years and that this approach may be cost effective in the medium term. This offers a 'ray of hope' to those who have thus far only dreamed of curbing the HIV/AIDS epidemic in SSA, as until now the glaring truth has been pessimistic. When it comes to ART, approximately 7 of 10 people who clinically need ART still do not receive it. From an epidemic point of view, for every person placed on ART an estimated four to six others acquire HIV. The likelihood of achieving the targets of the Millennium Development Goals for 2015 and universal ART access by 2010 are thus extremely low. A new window of opportunity may have now opened, but there are many unanswered feasibility and acceptability issues. In this paper, we highlight four key operational challenges linked to acceptability and feasibility and discuss possible ways forward to address them.

[Violence as occupational hazard for primary medical care personnel].

Poll covered 179 medical professionals (internists, dentists, nurses and nuns, midwives, laboratory workers). Objective was to define frequency and type of violence directed to primary care personnel at the workplace. Most the questionees (95.5%) reported verbal violence, 33% of the questionees--physical violence, and 8.9%--sexual harassment from patients and their relatives.

Orthostatic heart rate variability analysis in idiopathic Parkinson's disease.

OBJECTIVES: We evaluated time and spectral analyses of 24-h heart rate variability (HRV) and the heart rate responses to passive tilt in patients with idiopathic Parkinson's disease (IPD) in order to investigate cardiovascular autonomic functions. MATERIAL AND METHODS: Twenty-three subjects with IPD without autonomic symptoms and 15 age-matched healthy controls were enrolled. Frequency- and time-domain HRV parameters were studied during resting and passive head-up tilt (HUT) test. RESULTS: All time-domain parameters were found to be low in patients with IPD. In patients with IPD, both low frequency (LF) and high frequency (HF) decreased during HUT period and no significant change in LF to HF ratio was noted. Both time- and frequency-domain HRV indices showed no correlation with age, disease severity and duration, and with l-dopa medication. CONCLUSION: The results indicate that impairment of autonomic nervous system function in IPD without autonomic symptoms is frequent, and does not show clear association with clinical stage and the age of the patients.

Exaggerated interictal cerebrovascular reactivity but normal blood flow velocities in migraine without aura.

Interictal cerebrovascular reactivity and blood flow velocities were tested in 23 patients with migraine without aura and 10 age- and sex-matched healthy controls by using the breath holding index (BHI). The mean systolic, diastolic and mean velocities and pulsatility indices were not different in the controls and patients. The BHI was found to be significantly greater (P=0011) in the patients (1.64 +/- 0.33) compared with the controls (1.26 +/- 0.37), showing an exaggerated reactivity to hypercapnia in migraineurs. Reactivity to pCO2 theoretically depends on pre-existing arteriolar tone and thereby on baseline velocity. Our finding of similar blood flow velocities in controls and patients suggests that the underlying cause for this high reactivity may not be an increased vasotonus but an increased sensitivity to changes in blood CO2 levels.

Efficacy of amodiaquine for uncomplicated Plasmodium falciparum malaria in Harper, Liberia.

In the face of spreading chloroquine and sulfadoxine-pyrimethamine (SP) resistance, amodiaquine remains a cheap and efficacious alternative for treating uncomplicated Plasmodium falciparum malaria in many settings. In Harper, south-eastern Liberia, a previous study we conducted showed very high levels of resistance to both chloroquine and SP. In 2001, in an effort to look for possible alternatives, we measured in the same setting the efficacy of amodiaquine in a 28-d study in vivo, with results corrected by polymerase chain reaction genotyping to distinguish recrudescences from reinfections. In total, 107 children were included in the study and received a 3-d supervised course of 25 mg/kg amodiaquine. Of these, 81 were analysable at day 28. The overall failure rate was 19.8% (95% CI 11.7-30.1%) considering both parasitological and clinical outcomes. These results provide hitherto missing data on amodiaquine in Liberia, and confirm that the drug may still be efficacious in settings where chloroquine and SP are failing. We recommend the introduction of amodiaquine in association with artesunate as a first-line antimalarial in Harper.

High Plasmodium falciparum resistance to chloroquine and sulfadoxine-pyrimethamine in Harper, Liberia: results in vivo and analysis of point mutations.

In Liberia, little information is available on the efficacy of antimalarials against Plasmodium falciparum malaria. We measured parasitological resistance to chloroquine and sulfadoxine-pyrimethamine (SP) in Harper, south-west Liberia in a 28-d study in vivo. A total of 50 patients completed follow-up in the chloroquine group, and 66 in the SP group. The chloroquine failure rate was 74.0% (95% confidence interval [95% CI] 59.7-85.4%) after 14 d of follow-up and 84.0% (95% CI 70.9-92.8%) after 28 d (no polymerase chain reaction [PCR] analysis was performed to detect reinfections in this group). In the SP group, the failure rate was 48.5% (95% CI 36.2-61.0%) after 14 d and 69.7% (95% CI 57.1-80.4%) after 28 d, readjusted to 51.5% (95% CI 38.9-64.0%) after taking into account reinfections detected by PCR. Genomic analysis of parasite isolates was also performed to look for point mutations associated with resistance. Genotyping of parasite isolates revealed that all carried chloroquine-resistant K-76T mutations at gene pfcrt, whereas the triple mutation (S108N, N511, C59R) at dhfr and the A437G mutation at dhps, both associated with resistance to SP, were present in 84% and 79% of pretreatment isolates respectively. These results seriously question the continued use of chloroquine and SP in Harper and highlight the urgency of making alternative antimalarial therapies available. Our study confirms that resistance to chloroquine may be high in Liberia and yields hitherto missing information on SP.

Biochemical evidence of crossed cerebellar diaschisis in terms of nitric oxide indicators and lipid peroxidation products in rats during focal cerebral ischemia.

OBJECTIVES: Cerebral hypoperfusion in the contralateral cerebellar hemisphere after stroke is interpreted as a functional and metabolic depression, possibly caused by a loss of excitatory afferent inputs on the corticopontocerebellar pathway terminating in the cerebellar gray matter. This phenomenon is defined as crossed cerebellar diaschisis and can be diagnosed clinically by positron emission tomography, single-photon emission computed tomography, brain magnetic resonance imaging and electroencephalography in terms of regional cerebral blood flow or metabolic rate of oxygen measurements. MATERIALS AND METHODS: In the present study, nitric oxide indicators (nitrite and cyclic guanosine monophosphate) and lipid peroxidation products (malondialdehyde and conjugated dienes) were measured in rat cerebral cortices and cerebella after permanent right middle cerebral artery occlusion in order to assess the crossed cerebellar diaschisis. RESULTS: Nitrite values in ipsilateral cortex were significantly higher than those in contralateral cortex at 10 (P < 0.001) and 60 (P < 0.05) min of ischemia but no significant changes were observed in both cerebellum compared to the 0 min values. In both cerebral cortex and cerebellum cGMP levels at 10 and 60 min were significantly increased (P < 0.001). This increase was marked in ipsilateral cortex and contralateral cerebellum when compared with opposite cortex and cerebellum (P < 0.001). MDA values in ipsilateral cortex were significantly higher than those in contralateral cortex at 60 min of ischemia (P < 0.05). Contralateral cerebellar MDA values were found significantly higher than those in ipsilateral cerebellum at 0 (P<0.001) and 60 (P < 0.05) min of ischemia. In ipsilateral cortex, conjugated diene values at 0, 10, 60 min of ischemia were higher than those in contralateral cortex. On the other hand 0, 10, 60 min conjugated diene levels in contralateral cerebellum were significantly higher than those in ipsilateral cerebellum (P < 0.001). CONCLUSION: These findings support the interruption of the corticopontocerebellar tract as the mechanism of the crossed cerebellar diaschisis.

Trial of oral fumagillin for the treatment of intestinal microsporidiosis in patients with HIV infection. ANRS 054 Study Group. Agence Nationale de Recherche sur le SIDA.

OBJECTIVE: Intestinal microsporidiosis caused by Enterocytozoon bieneusi is a cause of chronic diarrhoea in patients with HIV infection for which there is no current therapy. This study was designed to assess the safety and efficacy of oral fumagillin in this infection. DESIGN: A dose-escalation trial. METHODS: Twenty-nine HIV-infected patients with E. bieneusi infection were consecutively enrolled in the trial. Oral doses of fumagillin were given to four groups of patients for 14 days: 10 mg/day (group 1), 20 mg/day (group 2), 40 mg/day (group 3), and 60 mg/day (group 4). Patients were seen at weeks 1, 2, 4 and 6 to assess safety and efficacy. Efficacy was assessed primarily by the clearance of microsporidia from stools and follow-up duodenal biopsies. RESULTS: Thirteen patients complained of abdominal cramps, vomiting or diarrhoea during the study, and three patients had fumagillin withdrawn because of adverse events. Thrombocytopenia, neutropenia and hyperlipasaemia were the most frequent biological adverse events. Twenty-one out of 29 patients transiently cleared microsporidia from their stools during the study. By week 6, however, all patients in groups 1, 2 and 3 had parasitic relapse. Interestingly, eight out of 11 (72%) patients treated with 60 mg/day (group 4) apparently cleared microsporidia from their gastrointestinal tract and gained weight. No parasitic relapse was documented in these eight patients during a mean follow-up of 11.5 months. CONCLUSION: Treatment with fumagillin at 60 mg/day for 14 days has promise as an effective oral treatment for E. bieneusi infections.

Effects of Plasmodium vivax malaria in pregnancy.

BACKGROUND: Plasmodium vivax is more common than P. falciparum as a cause of malaria in many parts of the tropics outside Africa. P. falciparum infection has harmful effects in pregnancy, but the effects of P. vivax have not been characterised. We investigated the effects of P. vivax infection during pregnancy. METHODS: Since 1986, pregnant Karen women living in camps for displaced people on the western border of Thailand have been encouraged to attend antenatal clinics. Karen women were screened for malaria and anaemia at each week of pregnancy until delivery, and pregnancy outcome recorded. We compared the effects of P. vivax infection on anaemia and pregnancy outcome with those of P. falciparum and no malaria infection in the first pregnancy recorded at the antenatal clinics. FINDINGS: There were 634 first episodes of pure P. vivax malaria in 9956 women. P. vivax malaria was more common in primigravidae than in multigravidae and was associated with mild anaemia and an increased risk of low birthweight (odds ratio 1.64 [95% CI 1.29-2.08], p<0.001). The birthweight was a mean of 107 g (95% CI 61-154) lower in women with P. vivax infection than in uninfected women. By contrast with P. falciparum malaria, the decrease in birthweight was greater in multigravidae. P. vivax malaria was not associated with miscarriage, stillbirth, or with a shortened duration of pregnancy. INTERPRETATION: P. vivax malaria during pregnancy is associated with maternal anaemia and low birthweight. The effects of P. vivax infection are less striking than those of P. falciparum infection, but antimalarial prophylaxis against P. vivax in pregnancy may be justified.

PIP: This article presents the results of a study on the effects of Plasmodium vivax infection during pregnancy. Pregnant Karen women living in open camps to the north and south of Thailand were the subjects of the study. In each camp, the subjects attended weekly antenatal clinics for physical examination and blood screening by microscopy for malaria parasites; the outcome was recorded. The investigators compared the effects of P. vivax infection on anemia and pregnancy outcome women with those of P. falciparum and no malaria infection in the first pregnancy recorded at the clinics. Results showed that P. vivax malaria was more common in primigravidas than in multigravidas and was associated with mild maternal anemia and significantly decreased birth weight by comparison with babies born to women with no evidence of malaria during pregnancy. By contrast with P. falciparum malaria, the decrease in birth weight was greater in multigravidas. The mean birth weight was 107 g lower in women with P. vivax infection than in uninfected women. Infection with P. vivax during pregnancy was not associated with shorter gestation or with an increased rate of miscarriage or stillbirth. The findings suggest that studies of P. vivax, P. malariae, and P. ovale malaria in pregnancy should be encouraged and that chemoprophylaxis against P. vivax malaria in pregnancy may be justified.

Effects of Lamotrigine on brain nitrite and cGMP levels during focal cerebral ischemia in rats.

Glutamate receptor antagonists are protective in animal models of focal cerebral ischemia. Lamotrigine (3,5-diamino-6-[2,3-dichlorophenyl]-1,2, 4-triazine) is an anticonvulsant drug that blocks voltage-gated sodium channels and inhibits the ischemia-induced release of glutamate. Experiments in primary neuronal cultures implicate nitric oxide (NO) as a mediator of glutamatergic neurotoxicity acting via N-Methyl-D-Aspartate (NMDA) receptors. The effect of glutamate release inhibitor, Lamotrigine upon NO and cGMP production has been examined in focal cerebral ischemia in rats. Focal cerebral ischemia was produced by the permanent occlusion of right middle cerebral artery (MCA) in urethane anesthetized rats. A number of indicators of brain NO production (nitrite, cGMP) were determined in ipsilateral and contralateral cerebral cortex and cerebellum after 0, 10, 60 min of focal cerebral ischemia. The same parameters were measured in rats treated with Lamotrigine (20 mg/kg, i.p.) 30 min before or just after the occlusion of the right MCA.

The effects of nitric oxide synthase inhibitor, L-NAME on NO production during focal cerebral ischemia in rats: could L-NAME be the future treatment of sudden deafness?

Recent evidence in primary neuronal cell culture implicates NO as a mediator of glutamatergic neurotoxicity acting via N-methyl-D-aspartate (NMDA) receptors. In this study, we investigated the effects of inhibition of NOsynthase activity in focal cerebral ischemia in rats. Focal cerebral ischemia was produced by permanent occlusion of right MCA in urethane anesthetized rats. A number of indicators of brain NO production, nitrite and cGMP were determined in ipsilateral and contralateral cerebral cortex and cerebellum after 0, 10 and 60 minutes of focal cerebral ischemia. The same parameters were measured in rats pre- and posttreated with the potent Nitric oxide synthase (NOS) inhibitor, NW-nitro-L-arginine methyl ester (L-NAME).

Inhibitory role of N omega-nitro-L-arginine methyl ester (L-NAME), a potent nitric oxide synthase inhibitor, on brain malondialdehyde and conjugated diene levels during focal cerebral ischemia in rats.

The effect of N omega-nitro-L-arginine methyl ester (L-NAME) on ischemic neuronal damage was studied in a rat model of permanent focal cerebral ischemia in terms of ipsilateral and contralateral cortical and cerebellar tissue lipid peroxides. Forty-five male Swiss Albino rats were assigned to one of four groups; sham operated as control, subjected to right middle cerebral artery occlusion or injection of L-NAME (10 mg/kg i.p.) either 30 min before or just after right middle cerebral artery occlusion. Changes in lipid peroxides were expressed as nanomoles of malondialdehyde and conjugated diene per milligram of protein. Malondialdehyde values following 60 min of ischemia relative to contralateral cortex and conjugated diene levels in 0, 10 and 60 min of ischemia were found to be higher in ipsilateral cortex than in contralateral cortex. On the other hand, contralateral cerebellar malondialdehyde levels after 0 and 60 min of ischemia and conjugated diene levels after 0, 10 and 60 min of ischemia were higher than those in ipsilateral cerebellum. Pharmacological inhibition of nitric oxide synthase by L-NAME before or just after permanent middle cerebral artery occlusion significantly decreased the malondialdehyde and conjugated diene levels in both the cortex and the cerebellum. No significant differences were found in malondialdehyde values between rats that had been pre- and post-treated with L-NAME, but conjugated diene levels in the post-treated group seemed to be significantly lower than those in the pretreated group. On the whole, these results suggest that malondialdehyde and conjugated diene represent early biochemical markers of lipid peroxidation in ischemic tissues, reflecting the radical-mediated tissue damage.

Painful unilateral epileptic seizure.

Two rare cases with focal, paroxysmal pain as the initial manifestation of partial epilepsy have been reported. The pain attacks subsided after treatment with anti-epileptic drugs.

Visual evoked potentials in diabetes mellitus.

25 diabetic patients have been studied in order to investigate the possible effects of the disease on the central nervous system by means of pattern shift visual evoked potentials. Patients with diabetic retinopathy, glaucoma and cataract were excluded from the study. Results obtained from a control group of 30 normal subjects were compared to those of the patient group in which sural nerve conduction velocities have also been determined to see whether there is a correlation between peripheral and central involvement of the nervous system. In diabetic patients latency prolongation in the P100 and N140 components were observed. The N90-N140 interpeak latency was also prolonged. In addition, in patients with longstanding diabetes mellitus the incidence of VEP abnormalities was found to be high. Pathologic changes in VEP latencies did not show any correlation with sural nerve conduction abnormalities.

[Immunoglobulin and complement levels in migraine]. / Migrende immünglobulin ve kompleman düzeyleri.

There is circumstantial evidence to suggest that immune mechanisms are involved in the pathogenesis of migraine. Several workers have noted an increased incidence of allergy in patients with migraine and the disease has also been explained on an allergic basis. In this study the serum levels of IgG, IgA, IgM and C3 of 50 migraineurs are determined and the results were found to be increased realistically when compared by the control group. The results are compared by the literature.