Motor control and cognition deficits associated with protein carbamoylation in food (cassava) cyanogenic poisoning: Neurodegeneration and genomic perspectives.

A case-control design determined whether konzo, an upper motoneuron disease linked to food (cassava) toxicity was associated with protein carbamoylation and genetic variations. Exon sequences of thiosulfate sulfurtransferase (TST) or mercaptopyruvate sulfurtransferase (MPST), plasma cyanide detoxification rates, and 2D-LC-MS/MS albumin carbamoylation were assessed in 40 children [21 konzo-affected and 19 putatively healthy controls, mean (SD) age: 9.2 (3.0) years] subjected to cognition and motor testing using the Kaufman Assessment Battery and the Bruininks/Oseretsky Test, respectively. Konzo was significantly associated with higher levels of carbamoylated peptides 206-219 (LDELRDEGKASSAK, pep1) after adjusting for age, gender, albumin concentrations and BUN [regression coefficient: 0.03 (95%CI:0.02-0.05), p = 0.01]. Levels of pep1 negatively correlated with performance scores at all modalities of motor proficiency (r = 0.38 to 0.61; all p < 0.01) or sequential processing (memory)(r = - 0.59, p = 0.00) and overall cognitive performance (r = - 0.48, p = 0.00) but positively with time needed for cyanide detoxification in plasma (r = 0.33, p = 0.04). Rare potentially damaging TST p.Arg206Cys (rs61742280) and MPST p.His317Tyr (rs1038542246) heterozygous variants were identified but with no impact on subject phenotypes. Protein carbamoylation appears to be a reliable marker for cassava related neurodegeneration.

Lower sulfurtransferase detoxification rates of cyanide in konzo-A tropical spastic paralysis linked to cassava cyanogenic poisoning.

Using a matched case-control design, we sought to determine whether the odds of konzo, a distinct spastic paraparesis associated with food (cassava) cyanogenic exposure in the tropics, were associated with lower cyanide detoxification rates (CDR) and malnutrition. Children with konzo (N=122, 5-17 years of age) were age- and sex-matched with presumably healthy controls (N=87) and assessed for motor and cognition performances, cyanogenic exposure, nutritional status, and cyanide detoxification rates (CDR). Cyanogenic exposure was ascertained by thiocyanate (SCN) concentrations in plasma (P-SCN) and urine (U-SCN). Children with a height-for-age z-score (HAZNCHS)<-2 were classified as nutritionally stunted. CDR was measured as time required to convert cyanide to SCN, and expressed as ms/µmol SCN/mg protein or as mmolSCN/ml plasma/min. Mean (SD) U-SCN in children with konzo was 521.9 (353.6) µmol/l and was, significantly higher than 384.6 (223.7) µmol/l in those without konzo. Conditional regression analysis of data for age- and sex- matched case-control pairs showed that konzo was associated with stunting (OR: 5.8; 95% CI: 2.7-12.8; p<0.01; N=83 paired groups) and higher U-SCN (OR: 1.1; 95% CI: 1.02-1.20 per 50-µmol increase in U-SCN; p=0.02; N=47 paired groups). After adjusting for stunting and U-SCN, the odds of developing konzo was reduced by 63% (95% CI: 11-85%, p=0.03; N=41 paired groups) for each 5mmol SCN/(ml plasma/min)-increase in CDR. Linear regression analysis indicated a significant association between BOT-2 or KABC-II scores and both the HAZNCHS z-score and the U-SCN concentration, but not the CDR. Our findings provide evidence in support of interventions to remove cyanogenic compounds from cassava prior to human consumption or, peharps, enhance the detoxification of cyanide in those relying on the cassava as the main source of food.

Cyanide and the human brain: perspectives from a model of food (cassava) poisoning.

Threats by fundamentalist leaders to use chemical weapons have resulted in renewed interest in cyanide toxicity. Relevant insights may be gained from studies on cyanide mass intoxication in populations relying on cyanogenic cassava as the main source of food. In these populations, sublethal concentrations (up to 80 µmol/l) of cyanide in the blood are commonplace and lead to signs of acute toxicity. Long-term toxicity signs include a distinct and irreversible spastic paralysis, known as konzo, and cognition deficits, mainly in sequential processing (visual-spatial analysis) domains. Toxic culprits include cyanide (mitochondrial toxicant), thiocyanate (AMPA-receptor chaotropic cyanide metabolite), cyanate (protein-carbamoylating cyanide metabolite), and 2-iminothiazolidine-4-carboxylic acid (seizure inducer). Factors of susceptibility include younger age, female gender, protein-deficient diet, and, possibly, the gut functional metagenome. The existence of uniquely exposed and neurologically affected populations offers invaluable research opportunities to develop a comprehensive understanding of cyanide toxicity and test or validate point-of-care diagnostic tools and treatment options to be included in preparedness kits in response to cyanide-related threats.

Lower serum levels of selenium, copper, and zinc are related to neuromotor impairments in children with konzo.

We assessed the relationship between key trace elements and neurocognitive and motor impairments observed in konzo, a motor neuron disease associated with cassava cyanogenic exposure in nutritionally challenged African children. Serum concentrations of iron, copper, zinc, selenium, and neurotoxic lead, mercury, manganese, cadmium, and cobalt were measured in 123 konzo children (mean age 8.53 years) and 87 non-konzo children (mean age 9.07 years) using inductively coupled plasma mass spectrometry (ICPMS). Concentrations of trace elements were compared and related to performance scores on the Kaufman Assessment Battery for Children, 2nd edition (KABC-II) for cognition and Bruininks-Oseretsky Test, 2nd edition (BOT-2) for motor proficiency. Children with konzo had low levels of selenium, copper, and zinc relative to controls. Selenium concentration significantly correlated with serum 8,12-iso-iPF2α-VI isoprostane (Spearman r=0.75, p<0.01) and BOT-2 scores (r=0.31, p=0.00) in children with konzo. Elemental deficiency was not associated with poor cognition. Mean (SD) urinary level of thiocyanate was 388.03 (221.75) µmol/l in non-konzo compared to 518.59 (354.19) µmol/l in konzo children (p<0.01). Motor deficits associated with konzo may possibly be driven by the combined effects of cyanide toxicity and Se deficiency on prooxidant mechanisms. Strategies to prevent konzo may include dietary supplementation with trace elements, preferentially, those with antioxidant and cyanide-scavenging properties.

Comparison of operational criteria for treatment outcome in gambiense human African trypanosomiasis.

OBJECTIVE: To develop a simple and standard operational decision tool for the diagnosis of relapse after treatment for human African trypanosomiasis (HAT), by evaluating the performance of several criteria currently used by HAT control programs and research projects. METHODS: We identified 10 different criteria for relapse, based on trypanosome presence and/or white blood cell count in cerebrospinal fluid, and compared their specificity, sensitivity and time to diagnosis on a data set containing 63 relapsed and 247 cured T.b. gambiense patients. RESULTS: At any time point, the criterion 'Trypanosomes present and/or a cerebrospinal white blood cell count > or =50/microl' allowed accurate and timely detection of HAT relapse, irrespective of disease stage. This criterion was 13-25% more sensitive (P < or = 0.013) than trypanosome detection alone and was >97% specific. Lumbar punctures at the end of treatment and at 3-month post-treatment provided limited clinical information. CONCLUSIONS: Adequate detection of relapse was possible with a simple criterion but these findings should be validated in a prospective study before adoption in clinical practice.

[Primary resistance of Mycobacterium tuberculosis to anti-tuberculosis drugs in Kinshasa, (DRC)]. / Résistance primaire de Mycobacterium tuberculosis aux anti-tuberculeux à Kinshasa, République Démocratique du Congo.

In a descriptive cross-sectional study carried out in Kinshasa between July 2003 and January 2004, we determined the prevalence of the primary resistance of M. tuberculosis to first-line anti-tuberculosis drugs. The antibiogram was performed with the proportion method on 301 isolats from patients who all had a first episode of pulmonary tuberculosis with positive microscopy (TPM+) and who had not received any anti-tuberculosis treatment before. The primary resistance rate reached 43.5%; it reached 31.6% in 1990. The multi-drug-resistance rate (MDR-TB) notified as resistant to both rifamicine and isoniazide rose to 5.3%. This rate of primary resistance is among the highest in Africa. The emergence of the resistant strains and specially the multi-drug-resistant strains (MDR-TB) in Kinshasa requires a regular assessment of these phenomena which threaten seriously the implementation of the national tuberculosis control programme.