[Determinants of low birth weight among newborns to HIV-infected mothers not eligible for antiretroviral treatment in Africa]. / Déterminants du faible poids de naissance chez des enfants nés de mères séropositives pour le VIH, non éligibles au traitement antirétroviral, en Afrique.

BACKGROUND: Low birth weight (LBW) increases the risk of infant death, but little is known about its rate and determinants among babies born to HIV-infected mothers in sub-Saharan Africa. METHODS: This study was conducted in South Africa, Burkina Faso, Uganda and Zambia, during the recruitment process of the PROMISE-PEP (ANRS 12174) clinical trial. The study sample included 1196 subjects screened between August 2009 and December 2011, respectively 254 in South Africa, 221 in Burkina Faso, 197 in Uganda and 524 in Zambia, all ineligible for antiretroviral therapy. Data were collected during ANRS12174 clinical trial antenatal and postnatal screening visits, and during an inclusion visit for completion of an electronic case report form (eCRF). RESULTS: The mean (±SD) age of mothers was 27±5years and their mean CD4 count was 576±195cells/µL. Most mothers lived in a couple (78.7%), had no employment (72.3%) and had a good level of education (74% had gone to school). Male newborns predominated (51.7%). The mean birth weight was 3043g±435g, and 7.8% ([95%CI: 6.3%-9.3%]) of newborns weighed less than 2500g. In univariate analyses, being married or cohabiting, body mass index, WHO HIV disease stage II, female newborn and low gestational age were associated with risk of LBW. In multivariate regression model, low gestational age (aOR=3.74, P<0.0001) and female newborn (aOR=1.63, P=0.04) were significantly associated with LBW. CONCLUSION: The risk factors for LBW found in HIV-infected women ineligible for antiretroviral therapy were the same as in the general population. There was no evidence of additional risk factors associated with HIV infection.

Faecal calprotectin in HIV-infected, HAART-naïve Ugandan children.

OBJECTIVES: Calprotectin is a calcium- and zinc-binding protein and a marker in faeces of gastrointestinal inflammation. Reference values have been established in children older than 4 years. The aim of the present study was to determine the concentration of faecal calprotectin (FC) in human immunodeficiency virus (HIV)-infected, highly active antiretroviral therapy-naïve Ugandan children and compare it with the reference value. METHODS: We tested 193 HIV-infected children ages 0 to 12 years in a hospital-based survey for FC. A standardised interview with sociodemographic information and medical history was used to assess risk factors. A cluster of differentiation 4 (CD4) cell percentage was prevalent in all of the children. RESULTS: The median FC concentrations decreased with increasing age, as in healthy children. The median concentration was 208 mg/kg in infants 0 to 1 year, 171 mg/kg among toddlers 1 to 4 years, and 62 mg/kg for children 4 to 12 years. Children with advanced disease and a low CD4 cell percentage had significantly higher FC concentrations than those with a high CD4 cell percentage. Children older than 4 years with diarrhoea had significantly higher FC concentrations compared with those without diarrhoea. CONCLUSIONS: HIV-infected children older than 4 years had a median FC concentration above the reference value, and gut inflammation in the children with elevated values is likely. Children with more advanced disease had increased FC concentrations regardless of age.

A prospective study on neonatal mortality and its predictors in a rural area in Burkina Faso: can MDG-4 be met by 2015?

OBJECTIVE: To measure the neonatal mortality rate (NMR) and investigate its predictors in a rural area of Burkina Faso. STUDY DESIGN: A cohort of infants born in 24 villages in Banfora region was followed until the children were 6 months old. We estimated the risk of neonatal death and used logistic regression to identify its predictors. RESULT: Among 864 live births followed to day 28, there were 40 neonatal deaths, a NMR of 46.3 per 1000 live births (95% confidence intervals (CI): 22 to 70). Multivariable regression identified twin birth (OR=11.5, 95% CI: 4.5 to 29.8), having a nulliparous mother (odds ratio (OR)=4.3, 95% CI: 1.5 to 12.1), and birth into a polygynous household (OR=2.1, 95% CI: 1.0 to 4.7) as main predictors of neonatal death. CONCLUSION: The burden of neonatal mortality in rural Burkina Faso is very high and the observed NMRs in a predominantly rural country suggest that it is unlikely Burkina will meet fourth Millennium Development Goal (MDG-4) by 2015.

Attention deficit and hyperactivity disorder among school children in Kinshasa, Democratic Republic of Congo.

OBJECTIVES: To estimate the prevalence and determinants of attention deficit and hyperactivity disorder (ADHD) symptoms among school children in Kinshasa, an African urban setting. METHODS: The 18-items of the Disruptive Behaviour Disorder rating scale (DBD), which is based on the Diagnostic and Statistical Manual for mental disorders 4(th) edition (DSM-IV), were used to investigate the presence of ADHD symptoms. Parents interviews, using a questionnaire specially designed for the study, were performed to identify socio-demographic characteristics. All children were subject to a clinical examination. RESULTS: The estimated prevalence of DSM-IV ADHD symptoms was 6%. Those with family health problems, younger age at start of primary school, good nutritional status and poor school performance more often had DSM-IV ADHD symptoms. CONCLUSION: ADHD symptoms are as common among school children in Kinshasa as elsewhere. The socio-demographic factors described as risk factors for ADHD in high-income countries were not identified in this study.

Neuro-ophthalmological disorders in HIV infected subjects with neurological manifestations.

AIMS: To determine the frequency and features of neuro-ophthalmological manifestations in neurologically symptomatic HIV infected patients and to assess whether or not the visual evoked potential (VEP) features in these patients differ from those of neurologically asymptomatic HIV infected patients. METHODS: Neuro-ophthalmological evaluation was performed in 166 neurologically symptomatic confirmed HIV positive patients, of whom 75 with normal ophthalmological examination were further studied by means of VEPs. The VEPs values were compared to those obtained from 53 other confirmed HIV positive subjects with neither ophthalmological nor neurological manifestations, who served as a comparison group and to the references values of our laboratory. RESULTS: An abnormal neuro-ophthalmological examination was noted in 99/166 patients (60%). Eye movement disorders were present in 99 patients (51%). Visual field defects were detected in 39% of the patients. Optic neuropathy was noted in 31%, papilloedema in 27% and ocular motor nerve palsies in 26% of the patients. Toxoplasmosis and cryptococcosis were the most frequent associated pathologies, though in some patients the HIV itself was the presumed cause. VEPs were abnormal in 57% and 42% of patients with and without neurological manifestations, respectively. Compared to asymptomatic patients, symptomatic patients had a significantly increased mean latency; however, both groups had significant increase in mean latency compared to reference values. CONCLUSION: Neuro-ophthalmological manifestations are common in neurologically symptomatic HIV infected patients. Subclinical dysfunction in the visual pathways is a common phenomenon in both HIV infected patients with and without neurological symptoms, but neurologically symptomatic patients seem to have more damage in their visual pathways.

Visual evoked potentials in konzo, a spastic paraparesis of acute onset in Africa.

AIM: To assess whether or not visual evoked potentials (VEPs) are abnormal in konzo, a para/tetraparesis of sudden onset, and to correlate the findings to the clinical picture of the disorder. METHODS: VEPs were recorded in 23 patients (9 men and 14 women, mean age: 23 +/- 10 years) suffering from konzo, and 38 healthy subjects (20 men and 18 women, mean age: 27 +/- 15 years). The mean P100 latencies and peak-to-peak N75-P100 amplitudes of each eye were measured and compared in the two groups. The mean interocular P100 latency and amplitude differences were calculated and also compared. RESULTS: VEPs were abnormal in 11/23 patients (48%) consisting of P100 prolongation (7 subjects), absence of P100 wave (2 subjects) or an atypical waveform (2 subjects). The mean P100 latency value of the konzo group was significantly increased as compared with the mean (+ 2.5 SD) of the reference values from healthy subjects (p < 0.05). There was a statistically significant decrease of amplitude in konzo patients compared to normal subjects (p < 0.05) with, however, only 2 patients outside the 95% confidence limits. Six patients (27%) had abnormal VEPs despite normal visual acuity. These abnormalities were symmetric and a relation could be found between neither the duration nor the severity of the disease and the VEP perturbation. CONCLUSION: The main features of these abnormalities are delayed P100 latency and decreased amplitude. These findings indicate involvement of visual pathways and seem to suggest the presence of axonal loss in the prechiasmal visual pathways in konzo. This study provides evidence that the neurodamage in konzo extends to the visual pathways.

Neuro-ophthalmologic findings in konzo, an upper motor neuron disorder in Africa.

PURPOSE: To investigate the neuro-ophthalmological manifestations in konzo, a non-progressive symmetric spastic para/tetraparesis of acute onset associated with consumption of insufficiently processed bitter cassava roots combined with a low protein intake. METHODS: Twenty-one Congolese konzo patients underwent neuro-ophthalmological investigations including visual acuity testing, assessment of light pupillary reflexes, evaluation of ocular motility and deviation, direct ophthalmoscopy, and visual field perimetry. Objective refraction including retinoscopy and keratometry, and slit-lamp biomicroscopy were also done. RESULTS: Five patients had visual impairment, and 14 had temporal pallor of the optic disc. Fourteen presented visual field defects, the most frequent being concentric constriction and peripheral defects. Overall, 11 subjects had symptoms qualifying for the diagnosis of optic neuropathy. Two had spontaneous pendular nystagmus in primary position of gaze. Visual field defects and pallor of the optic discs were found in mild, moderate and severe forms of konzo. No correlation was found between the severity of the motor disability of konzo and the extent of visual field loss. CONCLUSIONS: Konzo was associated with optic neuropathy and a few patients had nystagmus. Although the etiopathogenesis of this optic neuropathy remains to be elucidated, the symmetry of the involvement suggests a toxic origin. We suggest that cyanide causes the neuro-ophthalmological damage in konzo. However, the optic neuropathy in konzo patients does not resemble the features of the epidemic optic neuropathy in Tanzania, Cuba or Nigeria, Leber's hereditary optic neuropathy, tobacco amblyopia or vitamin B deficiency.

Impairments, disabilities and handicap pattern in konzo--a non-progressive spastic para/tetraparesis of acute onset.

PURPOSE: To assess impairments, disabilities and handicap pattern in konzo. METHOD: The study included 17 konzo subjects, of which three were males and 14 females (mean age 21, median 18 years). A detailed neurological examination was performed on all subjects. Subsequently, an assessment of impairments, disabilities and handicap was done with a constructed rating scale partially based on the ICIDH-2 framework. RESULTS: The overall disablement picture in all subjects consisted of motor dysfunction in lower limbs leading to limitations in walking and movement activities, and restrictions in mobility. Hip mobility was severely impaired in most cases (15/17). Although konzo subjects showed normal muscle power in upper limbs (13/17), they had impaired fine motor function (10/17). CONCLUSION: Further studies are needed to assess the effectiveness of the WHO criteria for konzo in defining its forms. The applicability of the ICIDH-2 framework in this study demonstrates the possibility of its use as a common language among researchers in the field of motor disorders. However, a revision is suggested of its taxonomy, and a definition of operational criteria to clarify the content of different qualifiers provided to assess the level of functioning or disability.

High cassava production and low dietary cyanide exposure in mid-west Nigeria.

OBJECTIVE: To investigate if high cassava production levels indicate high consumption and high dietary cyanide exposure in three villages situated within the area of Nigeria with higher cassava production than predicted by a geographic model for cassava production in Africa. DESIGN: Exploratory assessment of: cassava production and processing by qualitative research methods and quantification of residual cyanogens in products; cassava consumption by food frequency and weighed food records and dietary cyanide exposure by urinary thiocyanate and linamarin. SETTING: Rural communities of Afuze, Ebue and Ofabo in mid-west Nigeria. SUBJECTS: 110 subjects from 42 households in three villages for food frequency interviews; 118 subjects in nine Ofabo households for weighed food records. RESULTS: Cassava cultivation was reported to have increased in the preceding 20 years. It was consumed daily by 37 (88%) households, but its mean contribution to daily energy intake was only 13% The range of residual cyanogens in cassava foods was 0 to 62 mg HCN equivalent/kg dry weight (dw). Ten samples (19%) had levels above the 10 mg HCN equivalent/kg dw FAO/WHO safety limit. Mean urinary thiocyanate and linamarin were 51 and 20 micromol/L, indicating low cyanogen intake and dietary cyanide exposure. CONCLUSION: High cassava production levels did not result in high consumption and high dietary cyanide exposure levels, therefore cassava production levels cannot be used to predict consumption or cyanide exposure levels in the study area. A large part of the production is explained by intensive sales.

Dietary cyanide from insufficiently processed cassava and growth retardation in children in the Democratic Republic of Congo (formerly Zaire).

Dietary cyanide exposure from cyanogenic glucosides in insufficiently processed cassava has been advanced as a contributing factor in child growth retardation. Whether cyanide exposure aggravates children's growth retardation was studied by comparing two populations of children from the northern and the southern zones of the Bandundu region, Democratic Republic of Congo (former Zaire), using dietary interviews, anthropometry and urine analyses. Both populations consumed cassava as their staple diet, but whereas in the north the cassava was well processed, in the south it was inadequately processed. The mean urinary thiocyanate was much higher in the south, whereas mean urinary sulphate excretion was equally low in the two areas. However, the mean urinary SCN/SO4 molar ratio was higher in the south (0.20), indicating that 10-20% of sulphur amino-acids were used for cyanide detoxication. No significant differences were found between the two populations in weight-for-height and weight-for-age indices but the height-for-age index was significantly lower in children from the south, indicating more severe growth retardation in children exposed to dietary cyanide. Because of the preferential use of sulphur amino-acids for cyanide detoxification in the human body, dietary cyanide exposure from cassava may be a factor aggravating growth retardation in Bandundu.

Low dietary cyanogen exposure from frequent consumption of potentially toxic cassava in Malawi.

In a cassava-growing area in Malawi, where roots are processed by soaking and water is available throughout the year, we interviewed 176 women farmers regarding their preferences for cassava cultivars and frequency of cassava consumption. Dietary cyanogen exposure was estimated from urinary levels of linamarin, the cyanogenic glycoside in cassava, and urinary thiocyanate, the main cyanide metabolite. Protection against unplanned harvest by family members, theft and animal spoilage were stated to be very important reasons for growing bitter cassava cultivars by 91%, 90% and 74% of the women, respectively. The mean (+/- SD) number of cultivars grown by each woman was 4.6 (+/- 2.4). The correlation between mean taste and mean danger scores for the 25 most grown cultivars was strong (r > 0.98). The scoring indicated that cultivars belonged to two distinct groups, eight to a group referred to as 'cool' and 17 to a group termed 'bitter'. The dumpling-like porridge (kondowole) made from cassava flour from bitter roots was eaten twice daily by 51% and at least weekly by 81%. The mean (+/- SEM) urinary linamarin was 14 (+/- 1) mumol/L and thiocyanate was 50 (+/- 4) mumol/L, less than a tenth of levels reported from populations eating insufficiently processed bitter cassava roots, and in the same range as in a non-smoking Swedish reference population. We conclude that cyanogenesis is a preferred characteristic of cassava by the studied farmers because it enhances food security. The availability of water and their knowledge about toxicity and processing enables these women farmers to provide a safe staple food from bitter cassava roots.

Geographical and seasonal association between linamarin and cyanide exposure from cassava and the upper motor neurone disease konzo in former Zaire.

High cyanide intake from consumption of insufficiently processed cassava has been advanced as a possible aetiology of the upper motor neurone disease konzo. However, similar neurodamage has not been associated with cyanide exposure from any other source. With an ecological study design, we compared 22 cases of konzo, 57 unaffected household members and 116 members from unaffected households, a total of 195 subjects, in konzo-affected savanna villages with 103 subjects in adjacent non-affected forest villages in the Paykongila area in the Bandundu Region, Zaire. In the dry season, the mean value (+/- SEM) of urinary thiocyanate, the main cyanide metabolite, was higher in the three groups in konzo-affected villages (563 +/- 105, 587 +/- 44 and 629 +/- 47 micromol/l) than in unaffected villages (241 +/- 17 micromol/l). In affected villages in the dry season when konzo incidence was high, mean urinary thiocyanate was also higher than the levels found in the wet season when incidence was low. The wet season values (mean +/- SEM) were 344 +/- 60, 381 +/- 35 and 351 +/- 27 micromol/l. Urinary levels of inorganic sulphate were low in all groups, indicating low intake of the sulphur amino-acids which provide a substrate for cyanide detoxification. These findings support an aetiological role for cyanide in konzo. However, urinary linamarin, the cyanogenic glucoside and source of cyanide in cassava, was more closely associated with the occurrence of konzo. The mean value (+/- SEM) of urinary linamarin in the konzo cases was 632 +/- 105 micromol/l and in their household members 657 +/- 52 micromol/l, which was significantly higher than in members of control households in the same village (351 +/- 28 micromol/l) and in unaffected villages (147 +/- 18 micromol/l). This suggests that a specific neurotoxic effect of linamarin, rather than the associated general cyanide exposure resulting from glucoside breakdown in the gut, may be the cause of konzo.

Cyanide detoxification in rats exposed to acetonitrile and fed a low protein diet.

Different neurological syndromes have been associated with exposure to cyanide. Dietary cyanide exposure from cassava roots combined with a low intake of the sulfur amino acids necessary for cyanide detoxification has been implicated in the causation of konzo, an upper motoneuron disease identified in Africa. We have investigated the effect of a low protein diet on the capacity for cyanide detoxification. Rats were fed normal chow containing 18% protein or a low protein diet with 5% protein. To expose rats to cyanide the drinking water was supplemented with 40 or 80 mM acetonitrile (CH3CN) for up to 4 weeks. Weight gain was monitored and 24-hr urines were collected for analyses of total sulfur, inorganic sulfate, thiocyanate, and 2-aminothiolazine-4-carboxylic acid (ATC). Blood was collected for analyses of cyanide and cyanate. Rats on a normal diet grew throughout the experiment, while those on a low protein diet initially lost weight and then stabilized at a constant weight. Rats exposed to acetonitrile all progressively lost weight, those on a low protein diet at the highest rate. Signs of neurological damage were not observed. Rats not exposed to acetonitrile excreted < 0.2% of sulfur as thiocyanate and those on a low protein diet reduced their total sulfur excretion to one-third that of rats of the normal diet. Rats on the normal diet did not change total sulfur excretion during exposure to acetonitrile, although thiocyanate now contributed more than two-thirds of excreted sulfur. Rats on a low protein diet exposed to acetonitrile increased both total sulfur and thiocyanate excretion to the levels of rats on a normal diet. Rats exposed to acetonitrile had manyfold increases of circulating concentrations of cyanide and cyanate and of urinary excretion of ATC. There was a positive correlation between blood cyanide concentrations and the plasma concentration of cyanate. It is concluded that the rat has a high capacity for detoxification of cyanide. During adaptation to a low protein intake, sulfur is conserved but cyanide detoxification is still possible at the cost of extensive protein catabolism. It is thus possible that subclinical cyanide exposure could interfere with normal growth and development. The observation of a relationship between circulating cyanide on the one hand and circulating cyanate and urinary excretion of ATC on the other highlights the possibility that cyanide metabolites may mediate neurotoxic effects of cyanide.

Dietary determinants of a non-progressive spastic paraparesis (Konzo): a case-referent study in a high incidence area of Zaire.

BACKGROUND: Konzo is an upper motor neuron disease in Africa, characterized by an abrupt onset of a permanent but non-progressive spastic paraparesis. It is named after the local designation in the first report from Zaire. Konzo has been attributed to a metabolic insult from the combined effect of high cyanide and low sulphur intake from several weeks of exclusive consumption of insufficiently processed bitter cassava roots. METHODS: The association between insufficient soaking of cassava roots and konzo is assessed in a matched case-referent study with multivariate conditional logistic regression including 57 case-referent pairs from a rural high incidence community of Zaire. RESULTS: In the multivariate analysis short processing of cassava in the form of only 2 nights soaking yielded an odds ratio of 11.0 (95% confidence interval 1.7-73) when controlling for poverty-related factors and diet. We also show a dose-response relationship for insufficient cassava soaking, both unadjusted and adjusted for potential confounders. CONCLUSIONS: This study supports a causal relationship between insufficient processing of bitter cassava and konzo.

Konzo in the Central African Republic.

We identified a new focus of konzo, an upper motor neuron disease, in a part of western Central African Republic. Interviews and high serum levels of thiocyanate indicate that cyanide exposure from insufficiently processed cassava may cause konzo. Abrupt onset, nonprogressive course, and seronegativity to HTLV-I clearly differentiate konzo from HTLV-I-associated myelopathy in tropical countries.