Pesticides and Parkinson's disease: Current and future perspective.

Inappropriate use of pesticides has globally exposed mankind to a number of health hazards. Still their production is rising at the rate of 11 % annually and, has already exceeded more than 5 million tons in 2000 (FAO 2017). Plenty of available data reveals that pesticides exposures through agricultural use and food-preservative residue consumption may lead to neurodegenerative disorders like Parkinson's and Alzheimer's diseases. Parkinson's disease (PD) is a progressive motor impairment and a neurodegenerative disorder, considered as the leading source of motor disability. Pesticides strongly inhibit mitochondrial Complex-I, causing mitochondrial dysfunction and death of dopaminergic neurons in the substantia nigra (SN), thus leading to pathophysiologic implications of PD. Current medical treatment strategies, including pharmacotherapeutics and supportive therapies can only provide symptomatic relief. While complementary and alternative medicines including traditional medicine or acupuncture are considered as beneficial ways of treatment with significant clinical effect. Medically non-responding cases can be treated by surgical means, 'Deep Brain Stimulation'. Cell therapy is also an emerging and promising technology for disease modeling and drug development in PD. Their main aim is to replace and/or support the lost and dying dopaminergic neurons in the SN. Recently I/II clinical phase trial (Japan) have used dopaminergic progenitors generated from induced pluripotent stem (iPS) cells which can unveil a successful cell therapy to treat PD symptoms efficiently. This review focuses on PD caused by pesticides use, current treatment modalities, and ongoing research updates. Since PD is not a cell-autonomous disease rather caused by multiple factors, a combinatorial therapeutic approach may address not only the motor-related symptoms but also non-motor cognitive-behavioral issues.

Population-based resistance of Mycobacterium tuberculosis isolates to pyrazinamide and fluoroquinolones: results from a multicountry surveillance project.

BACKGROUND: Pyrazinamide and fluoroquinolones are essential antituberculosis drugs in new rifampicin-sparing regimens. However, little information about the extent of resistance to these drugs at the population level is available. METHODS: In a molecular epidemiology analysis, we used population-based surveys from Azerbaijan, Bangladesh, Belarus, Pakistan, and South Africa to investigate resistance to pyrazinamide and fluoroquinolones among patients with tuberculosis. Resistance to pyrazinamide was assessed by gene sequencing with the detection of resistance-conferring mutations in the pncA gene, and susceptibility testing to fluoroquinolones was conducted using the MGIT system. FINDINGS: Pyrazinamide resistance was assessed in 4972 patients. Levels of resistance varied substantially in the surveyed settings (3·0-42·1%). In all settings, pyrazinamide resistance was significantly associated with rifampicin resistance. Among 5015 patients who underwent susceptibility testing to fluoroquinolones, proportions of resistance ranged from 1·0-16·6% for ofloxacin, to 0·5-12·4% for levofloxacin, and 0·9-14·6% for moxifloxacin when tested at 0·5 µg/mL. High levels of ofloxacin resistance were detected in Pakistan. Resistance to moxifloxacin and gatifloxacin when tested at 2 µg/mL was low in all countries. INTERPRETATION: Although pyrazinamide resistance was significantly associated with rifampicin resistance, this drug may still be effective in 19-63% of patients with rifampicin-resistant tuberculosis. Even though the high level of resistance to ofloxacin found in Pakistan is worrisome because it might be the expression of extensive and unregulated use of fluoroquinolones in some parts of Asia, the negligible levels of resistance to fourth-generation fluoroquinolones documented in all survey sites is an encouraging finding. Rational use of this class of antibiotics should therefore be ensured to preserve its effectiveness. FUNDING: Bill & Melinda Gates Foundation, United States Agency for International Development, Global Alliance for Tuberculosis Drug Development.