Lathyrism in Spain: Lessons from 68 publications following the 1936-39 Civil War.

After the end of the Spanish Civil War (1936-1939), an estimated 1,000 patients presented with lathyrism due to their excessive and prolonged consumption of grasspea (Lathyrus sativus L.) against the backdrop of poverty, drought, and famine. Based on 68 scientific communications between 1941 and 1962 by qualified medical professionals, the disease emerged in different geographical locations involving selective populations: (1) farmers from extensive areas of central Spain, traditionally producers and consumers of grasspea; (2) immigrants in the industrial belt of Catalonia and in the Basque Country, areas with little or no production of grasspea, which was imported from producing areas; (3) workers in Galicia, an area where the legume is neither produced nor consumed, who were seasonally displaced to high-production areas of grasspea in Castille; and (4) inmates of overcrowded postwar Spanish prisons. Original reports included failed attempts by Carlos Jiménez Díaz (1898-1967) to induce experimental lathyrism, the neuropathology of lathyrism in early stages of the disease in two patients, as reported by Carlos Oliveras de la Riva (1914-2007), and the special susceptibility of children to develop a severe form of lathyrism after relatively brief periods of consumption of the neurotoxic seed of L. sativus. In the Spanish Basque Country, L. cicera L. (aizkol) was cultivated exclusively as animal fodder. Patients who were forced to feed on this plant developed unusual manifestations of lathyrism, such as axial myoclonus and severe neuropsychiatric disorders, unknown in other regions of the country and previously unreported. The postwar epidemic of lathyrism in Spain represents the most extensively studied outbreak of this self-limiting but crippling upper motor neuron disease.

Lathyrane diterpenes from Euphorbia lathyris and the potential mechanism to reverse the multi-drug resistance in HepG2/ADR cells.

P-glycoprotein (P-gp) plays a significant role in multi-drug resistance (MDR) of cancer cells, resulting in the failure of cancer chemotherapy. Lathyrane diterpene was a class of promising MDR modulator. The phytochemical investigation on the seeds of Euphorbia lathyris L. aff ;orded four new lathyrol-type diterpenoids (1-4), together with seventeen known ones (5-23). The structures of these compounds were elucidated by using 1D and 2D NMR spectroscopy. All the compounds were evaluated reversing MDR activity in HepG2/ADR cells. Compounds 2-4, 7-9, 11, 13-14, 16, 18-19, and 2 1-2 3 at 20 µM was able to reverse MDR of HepG2/ADR cells to adriamycin (reversal fold: 10.05-448.39). In the investigation of reversing the MDR mechanism, the most potent compound 21 facilitated the accumulation of intracellular adriamycin in HepG2/ADR cells in the time-dependent model. Although 21 neither affected the P-gp distribution nor expression in HepG2/ADR cells, the amount of P-gp monomer was induced by 21 and verapamil. Compound 21 has also activated the P-gp coupled ATPase activity in a dose-dependent model. The molecular docking analysis implied that 21 had lower binding energy than verapamil and adriamycin. The present data demonstrated that lathyrane diterpenes may act as a class of high-affinity P-gp substrate and was effluxed by P-gp monomer to reverse the MDR.

Historical setting and neuropathology of lathyrism: Insights from the neglected 1944 report by Oliveras de la Riva.

Lathyrism is a central motor system disorder recognized since antiquity resulting from prolonged dietary dependence on the grasspea (Lathyrus sativus). The neuropathology underlying the characteristic spastic paraparesis of lathyrism is sketchy. Described here is a landmark but little-known Spanish-language neuropathological study of two patients with lathyrism of recent onset. Due to erroneous interpretations of Filimonov's influential work in 1926, it was assumed that spastic paraparesis of lathyrism was explained by destruction of Betz's pyramidal cells in the motor cortex. Contrary to present understanding, Betz cells and anterior horn cells were preserved, and pathological findings dominated by myelin loss were largely limited to pyramidal tracts in the lumbar cord. Thickening of the adventitia of capillaries and arterioles, together with proliferation of perivascular astrocytes, was found along the length of the spinal cord. Oliveras de la Riva proposed that the segmental spinal pathology arose because distal regions of elongate pyramidal tract axons are distant from their trophic center in the motor cortex, a view not far from the current distal axonopathy concept of lathyrism. In addition, we review the historical circumstances of Filimonov's work in Russia, a summary of the epidemic of lathyrism in Spain following its Civil War (1936-1939), and some historical aspects of the Cajal Institute in Madrid, where Oliveras de la Riva's work was carried out under the supervision of Fernando de Castro, one of Cajal's favorite students.

Current scenario of consumption of Lathyrus sativus and lathyrism in three districts of Chhattisgarh State, India.

Lathyrism is a disease caused by excessive consumption of grass pea, Lathyrus sativus especially under conditions of severe drought. Grass pea contains 3-N-oxalyl-L-2, 3-diaminopropanoic acid (ß-ODAP) a putative neurotoxin which acts through excitatory mechanism causing Neurolathyrism. Due to awareness of the disease, availability of food and levels of consumption of L. sativus there is reduction in lathyrism cases where higher consumption of L. sativus is reported in India. The present study was undertaken with the objective to assess the current scenario of consumption of L. sativus, incidence of cases of lathyrism, ß-ODAP, protein and amino acids content in L. sativus pulse collected from three districts (Bilaspur, Durg and Raipur) of Chattisgarh state. For this purpose, a total of 17,755 (13,129 rural and 4626 urban) individuals from 151 villages and 60 wards from urban area were covered for clinical examination. Out of total 5769 households (HHs) covered during the survey, 1602 HHs were cultivators, 1791 HHs non-cultivators and 2376 agricultural and other labourers. A one day 24-hour re-call diet survey was carried out in 5758 HHs (4549 rural and 1209 urban). A total of 360 split grass pea (SGP) samples were collected to estimate ß-ODAP, protein and amino acids content. Results of the study revealed that an average consumption of SGP was 20.9 gm/CU/day in Bilaspur and no consumption was reported among urban population of Raipur. Only nine old cases of lathyrism were found during the study. The mean ß-ODAP content in SGP was 0.63 ±â€¯0.14, 0.65 ±â€¯0.13 and 0.65 ±â€¯0.14 gm/100 gm, whereas the protein content was 27.0 ±â€¯2.39, 27.0 ±â€¯1.99 and 26.7 ±â€¯1.90 gm/100 gm in samples collected from Bilaspur, Durg and Raipur districts respectively. Arginine content was high in SGP and sulphur containing amino acids (cysteine and methionine) were less than other amino acids. In conclusion, the consumption of SGP was lower in these three districts with lower ß-ODAP content than earlier reports, thus the lower prevalence of lathyrism in the districts surveyed.

Journey from food toxins to food safety: Transition over a century in service of nation.

Since the first report of lathyrism in 1926, the ICMR-National Institute of Nutrition (NIN) at Hyderabad, India, has made tremendous contributions in the field of food toxins/food safety for the benefit of the people. The present article highlights the Institute's work on various food toxins/foodborne diseases since its inception and discusses the important contributions made in the context of public health protection that formed the basis for several national policies on their prevention and control. The investigations on food toxins, in the initial decades, were limited to the description of lathyrism and its endemicity. Subsequently, the horizon was broadened to include the problem of mycotoxins and mycotoxicosis, which had received global attention and variety of other disease outbreaks investigations leading to total food safety transition in the forthcoming decades. Important contributions in epidemiological investigations, reproduction of the disease in experimental animals, surveillance and monitoring studies, development of methods for detection of food toxins and contaminants, evolving strategies for prevention and control and developing the concept of risk assessment and risk management for addressing food safety issues in the country are discussed.

Exercise increases pyridinoline cross-linking and counters the mechanical effects of concurrent lathyrogenic treatment.

The collagen cross-link profile of bone, associated with bone strength and fracture toughness, is tightly regulated (affecting cross-link quantity, type, lysine hydroxylation and maturity) and may contribute to the improvements in bone quality during exercise. We hypothesized that 1) exercise promotes mature cross-link formation, 2) increased mature cross-linking is accompanied by shifts in lysine hydroxylation, and 3) these changes in collagen cross-link profile have positive effects on mechanical properties. Growing male C57Bl6 mice were treated with 30 min/day of running exercise, 350 mg/kg/day ß-aminopropionitrile (BAPN) injected subcutaneously to inhibit enzymatic collagen cross-linking, or both exercise and BAPN, from 5 to 8 weeks of age. Bone collagen cross-linking profile, mechanical properties, morphology, and mineralization were measured from the tibiae. Cross-link measures, including immature, pyridinoline, pyrrole and pentosidine cross-links, ratios reflecting cross-link maturity and hydroxylation, and mineralization were tested for their importance to mechanical properties across 8 week groups through correlation analyses and step-wise linear regressions. BAPN treatment significantly reduced lysylpyridinoline, pyrrole, hydroxylysinorleucine, and total mature collagen cross-linking, resulting in decreased bone elastic modulus and increased yield strain despite a marginal increase in TMD. Exercise caused a shift toward pyridinoline cross-linking, with increased hydroxylysylpyridinoline and decreased pyrrole cross-linking resulting in total mature cross-linking and estimated tissue level mechanical properties matching sedentary control levels. Exercise superimposed on BAPN treatment increased total mature cross-linking from BAPN to control levels, but did so by increasing pyridinoline, not pyrrole, cross-links. Exercise also counteracted the BAPN effects on modulus and strain, without a change in TMD. Pyrrole cross-linking was the strongest correlate of modulus (r=0.470, p<0.01) and yield strain (r=-0.467, p<0.01). Cross-links with similar levels of telopeptide lysine hydroxylation to pyrrole (lysylpyridinoline and hydroxylysinorleucine) also correlated with modulus and strain to a lesser extent. In conclusion, exercise in growing mice promotes pyridinoline collagen cross-linking in bone, the resulting increase in total mature cross-linking is sufficient to counteract the mechanical effects of concurrent cross-link inhibition, and this responsiveness to loading is a potential means by which exercise might improve bone quality in diseased or otherwise compromised bone.

Lathyrus hirsutus (Caley Pea) intoxication in a herd of horses.

BACKGROUND: Caley Pea (Lathyrus hirsutus) is potentially toxic to horses, but large case series are not reported. OBJECTIVES: To describe the clinical signs of horses intoxicated with Lathyrus hirsutus and speculate on the neuroanatomical lesion localization and pathogenesis based upon the observed clinical signs. ANIMALS: Twenty-two of 25 horses ranging in age from 6 to 34 months were affected. Five affected horses were presented to the OSUCHVS for evaluation and treatment after having been attended at the ranch by a local veterinarian (ALA). An additional horse that had been euthanized was also presented for necropsy. METHODS: A case series is presented. Diagnostic evaluation included: physical examination, complete blood count, serum biochemistry, CSF analysis, EMG, ERG, upper airway endoscopy, muscle biopsy, and serum vitamin E analysis. The grain ration consumed by the affected horses was analyzed for ionophores and cultured for fungi: the hay was examined for toxic plants. RESULTS: Bermuda grass hay consumed by the horses contained large quantities of mature Lathyrus hirsutus. Acute clinical signs conform to earlier descriptions of Lathyrus hirsutus intoxication in cattle. Residual neurologic signs were characterized by incoordination in the rhythmicity of multiple gaits. Evidence of mild neurogenic muscle atrophy was recognized in 1 of 5 horses biopsied. CONCLUSIONS AND CLINICAL IMPORTANCE: Caley Pea intoxication may occur within days of seed pod consumption. The neurologic signs are unique and suggest involvement of the upper motor neuron system and regions of the spinal cord influencing voluntary motor movement. Drought conditions during plant growth may increase the risk of toxicosis.

Lathyrism: has the scenario changed in 2013?

Lathyrism is now rarely seen as a clinical disease in general, medical or neurology outpatient departments, throughout the world. Eating patterns of seeds of Lathyrus sativus are still prevalent focal points in parts of the world. Question arises, why are we not seeing cases of lathyrism? Is it that the disease has changed its profile, with the changing socioeconomic status of the poor or underdeveloped or moderately developed countries? Is it that the seeds of lathyrus are less toxic now? Is it that the body defence against toxins of lathyrus has genetically modified? To find out answers to these interesting questions, an extensive questionnaire-based sampling was done among 1000 subjects from northern India to identify the human behaviour regarding the knowledge, attitude, and practices (KAPs) for L. sativus. Four clinically suspected cases of Lathyrism were also fully worked up. It was concluded that many areas of India are still being fed with lathyrus seeds, but not many cases have appeared. Many questions have to be answered, as to what has reduced the incidence of lathyrism.