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Recent advances in vitamin D research indicate that this vitamin, a secosteroid hormone, has beneficial effects on several body systems other than the musculoskeletal system. Both 25 dihydroxy vitamin D [25(OH)2D] and its active hormonal form, 1,25-dihydroxyvitamin D [1,25(OH)2D] are essential for human physiological functions, including damping down inflammation and the excessive intracellular oxidative stresses. Vitamin D is one of the key controllers of systemic inflammation, oxidative stress and mitochondrial respiratory function, and thus, the aging process in humans. In turn, molecular and cellular actions form 1,25(OH)2D slow down oxidative stress, cell and tissue damage, and the aging process. On the other hand, hypovitaminosis D impairs mitochondrial functions, and enhances oxidative stress and systemic inflammation. The interaction of 1,25(OH)2D with its intracellular receptors modulates vitamin D–dependent gene transcription and activation of vitamin D-responsive elements, which triggers multiple second messenger systems. Thus, it is not surprising that hypovitaminosis D increases the incidence and severity of several age-related common diseases, such as metabolic disorders that are linked to oxidative stress. These include obesity, insulin resistance, type 2 diabetes, hypertension, pregnancy complications, memory disorders, osteoporosis, autoimmune diseases, certain cancers, and systemic inflammatory diseases. Vitamin D adequacy leads to less oxidative stress and improves mitochondrial and endocrine functions, reducing the risks of disorders, such as autoimmunity, infections, metabolic derangements, and impairment of DNA repair; all of this aids a healthy, graceful aging process. Vitamin D is also a potent anti-oxidant that facilitates balanced mitochondrial activities, preventing oxidative stress-related protein oxidation, lipid peroxidation, and DNA damage. New understandings of vitamin D-related advances in metabolomics, transcriptomics, epigenetics, in relation to its ability to control oxidative stress in conjunction with micronutrients, vitamins, and antioxidants, following normalization of serum 25(OH)D and tissue 1,25(OH)2D concentrations, likely to promise cost-effective better clinical outcomes in humans.

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During the last two decades, Sri Lanka, located close to the equator, has experienced an escalating incidence of chronic kidney disease (CKD) of unknown aetiology (CKDue) in dry zonal areas. Similar incidences of unusual CKDs have been reported in the dry zonal, agricultural areas of several other equatorial countries. In Sri Lanka, the incidence of CKDue is highest in the North Central Province (NCP), where approximately 45 % of the country's paddy fields are located. However, in recent years, the disease has spread into areas adjacent to as well as distant from the NCP. The cause of CKD in Sri Lanka is unknown, and may likely due to interactions of different potential agents; thus, CKD is of multi-factorial origin (CKD-mfo). These factors include, the negative effects from overuse of agrochemicals. Nevertheless, the potential interactions and synergism between probable agents have not been studied. This systematic review discusses the proposed hypotheses and causes of CKD-mfo in Sri Lanka, and ways to decrease the incidence of this disease and to eradicate it, and provide some recommendations. During the past decade, a number of groups have investigated this disorder using different methodologies and reported various correlations, but failed to find a cause. Research has focussed on the contamination of water with heavy metals, agrochemicals, hard water, algae, ionicity, climate change, and so forth. Nevertheless, the levels of any of the pollutants or conditions reported in water in NPC are inconsistent not correlated with the prevalence of the disease, and are too low to be the sole cause of CKD-mfo. Meanwhile, several nephrotoxins prevalent in the region, including medications, leptospirosis, toxic herbs, illicit alcohol, locally grown tobacco, and petrochemicals, as well as the effects of changed habits occured over the past four decades have not been studied to date. Taken together, the geographical distribution and overall findings indicate that combinations of factors and/or their interactions are likely to precipitate CKD-mfo, which kills more than 5,000 people annually in Sri Lanka; most victims are middleaged male farmers. Much anecdotal evidence from this region suggests that consumption of contaminated water is the most likely source of this deadly disease. Although the aetiology is unknown, prevention of this ''environmentally acquired'' disease seems relatively straightforward. Solutions include (a) preventing environmental pollution, (b) stopping the irresponsible use and decreasing the usage of agrochemicals, and encouraging the use of environmentally friendly agricultural methods, (c) taking proper precautions when using agrochemicals and safe disposal of their containers, (d) changing the risky behaviour of farmers and educating them to preserve the environment, and (e) providing clean potable water to all affected regions. Implementing a well-coordinated, in-depth, region-wide, broad-based research study together with a long-term effective surveillance programme across the country i...

Peripheral inflammation induced with a knee joint injection of a mixture of kaolin/carrageenan (k/c) produces primary and secondary hyperalgesia. Inflammatory pain is thought to involve a variety of transmitters released from nerve terminals, including amino acids, substance P (SP) and calcitonin gene-related peptide (CGRP). In the present study, mice deficient in the calcitonin/alpha CGRP gene (CGRP(-/-)) displayed normal responses to noxious stimuli. However, the CGRP knockout mice failed to demonstrate development of secondary hyperalgesia after induction of knee joint inflammation in two tests that assess central sensitization, through testing at sites remote from the primary insult. Nociceptive behavioral responses were assessed using the hot-plate test and paw withdrawal latency (PWL) to radiant heat applied to the hindpaw. The CGRP(-/-) mice showed no signs of secondary hyperalgesia after development of knee joint inflammation, while the expected significant decrease in the PWL was observed in the CGRP(+/+) mice as control. The CGRP(-/-) mice also had a prolonged rather than a shortened response latency in the hot-plate test 4 h after knee joint injection of k/c. Immunohistological study showed that CGRP-like immunoreactivity (CGRP-LI) was absent in the spinal cord and dorsal root ganglia taken from the CGRP(-/-) mice. These results indicate that endogenous CGRP plays an important role in the plastic neurogenic changes occurring in response to peripheral inflammatory events including the development of nociceptive behaviors.

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