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Loss of the capacities of epidermal stem cells (ESCs) induced by ultraviolet-B (UV-B) irradiation has been widely associated with various skin diseases. Netrin-1, a member of the axonal guidance protein family, has displayed diverse biological functions in different types of cells and tissues, mediated by its specific receptor UNC-5 homolog B (UNC5b). In this study, we examined the physiological functions of netrin-1 and UNC5b in ESCs upon UV-B exposure. Our results indicate that UNC5b is expressed in ESCs, and its expression is upregulated in response to UV-B radiation. We found that treatment with netrin-1 prevented UV-B radiation-induced oxidative stress by reducing the generation of reactive oxygen species (ROS) and expression of NADPH oxidase 4 (NOX-4). Additionally, treatment with netrin-1 improved UV-B radiation-induced mitochondrial dysfunction by increasing mitochondrial membrane potential (MMP) levels and adenosine triphosphate (ATP) production. The presence of netrin-1 attenuated UV-B radiation-induced lactic dehydrogenase (LDH) release. UV-B exposure resulted in the loss of the capacities of ESCs by reducing the expressions of integrin β1 and Krt19, the two major ESC markers. Importantly, this process was prevented by netrin-1. Silencing of UNC5b abolished the effects of netrin-1 on the expression of integrin β1 and Krt19, suggesting that the effects of netrin-1 in maintaining the capacities of ESCs are dependent on UNC5b. Mechanistically, we found that the Wnt/β-catenin signalling may be involved. Our findings suggest that netrin-1 may serve as a therapeutic agent for the treatment of skin diseases.

Autophagy carries out intracellular degradation of cytoplasmic components, which is important for the removal of dysfunctional organelles and for efficient nutrient recycling in eukaryotic cells. Most proteins in plant green tissues are found in chloroplasts, mainly as photosynthetic proteins that constantly accumulate damage caused by sunlight. Our recent study investigated the involvement of autophagy in the turnover of damaged chloroplasts and found that entire photodamaged chloroplasts are transported into the vacuole for degradation via an autophagy process termed chlorophagy. Our previous studies also established that autophagy can also degrade chloroplast components piecemeal: chloroplast stroma is transported for degradation via autophagy vesicles termed Rubisco-containing bodies (RCB). During sugar starvation-induced senescence in darkened leaves, the RCB pathway is preferentially active. By contrast, we observed active chlorophagy without prior induction of RCB production in photodamaged leaves. These distinct responses between the RCB pathway and chlorophagy support the notion that the induction of the partial-type and entire-organelle-type chloroplast autophagy are differentially regulated by individual upstream molecules. This finding further suggests that the two types of autophagy are coordinated to achieve the controlled chloroplast turnover in response to specific conditions.

In yeast and mammals, selective vacuolar delivery and degradation of whole mitochondria, or mitophagy, represents an important quality control system and is achieved by a cargo recognition mechanism enabling selective elimination of dysfunctional mitochondria. As photosynthetic organelles that need light for energy production, plant chloroplasts accumulate sunlight-induced damage. Plants have evolved multiple mechanisms to avoid, relieve, or repair chloroplast photodamage. Our recent study showed that vacuolar degradation of entire chloroplasts, termed chlorophagy, is induced to degrade chloroplasts that are collapsed due to photodamage. Our results underscore the involvement of autophagy in the quality control of endosymbiotic, energy-converting organelles in eukaryotes.

Because the incidence of cutaneous malignant melanoma (CMM) was reported to increase with increasing terrestrial UVR (290-400 nm) doses in the US back in 1975 and a recent publication showed no association exists with UVR exposure at all, we set out to fully elucidate the role of UVR in CMM. To achieve this goal, we analyzed the CMM incidences over latitude and estimated the average personal UVR dose in the US and numerous countries (> 50) on 5 continents around the world. Using data from the International Agency for Research on Cancer in 2005, we performed worldwide analysis of CMM over UVR dose by sex, age group (0-14, 15-29, 30-49, 50-69, 70-85+) and Fitzpatrick skin types I-VI. Surprisingly, increasing UVR doses, which represent erythemally-weighted doses comprised primarily of UVB (290-315 nm) radiation, did not significantly correlate with increasing CMM incidence for people with any skin type anywhere in the world. Paradoxically, we found significant correlations between increasing CMM and decreasing UVB dose in Europeans with skin types I-IV. Both Europeans and Americans in some age groups have significant increasing CMM incidences with decreasing UVB dose, which shows UVB is not the main driver in CMM and suggests a possible role for lower cutaneous vitamin D 3 levels and UVA (315-400 nm) radiation. CMM may be initiated or promoted by UVA radiation because people are exposed to it indoors through windows and outdoors through some sunscreen formulations. Thus, our findings may explain why some broad-spectrum sunscreen formulations do not protect against getting CMM.

Evidence is mounting that vitamin D deficiency is intimately involved in autism. We report on autism prevalence by US state for those aged 6-17 y in 2010 with respect to indices of solar UV-B (UVB) doses. We calculated autism prevalence rates for white, black and Asian Americans by using total prevalence and relative populations of minors for each ethnic group by state. Analyses omit AK and HI (considered extreme cases), WY (no data), along with AZ and ND for black Americans (low numbers) and DC, ME, MT, ND and SD for Asian Americans (low numbers). For white Americans, the regression coefficient for solar UVB doses and autism prevalence ranged from -0.52 in January to -0.57 in October. For black Americans, the regression coefficient for latitude was 0.61, whereas those for solar UVB ranged from -0.55 to -0.61. For Asian Americans, the values for solar UVB ranged from -0.28 to -0.38. The inverse correlation between solar UVB and autism prevalence is similar to that for many types of cancer in the US. The journal literature indicates that adverse effects on fetal brain development during pregnancy due to vitamin D deficiency can explain these findings. However, we cannot rule out a role of vitamin D deficiency in early life. These results add to the evidence that vitamin D deficiency may be an important risk factor for autism and suggest that pregnant women and autistic individuals raise their serum 25-hydroxyvitamin D concentrations above 30 ng/ml.

A large body of evidence indicates that solar ultraviolet-B (UVB) irradiance and vitamin D reduce the risk of incidence and death for many types of cancer. However, most of that evidence comes from midlatitude regions, where solar UVB doses are generally high in summer. Data on cancer standardized incidence ratios (SIRs) by sex and 54 occupation categories based on 1.4 million male and 1.36 million female cancer cases for 1961-2005 in the five Nordic countries provide the basis for an ecological study of the role of solar UVB in the risk of many types of cancer at high latitudes. Lip cancer SIRs less lung cancer SIRs for men was the best index of solar UVB dose, which was weakly inversely correlated with both melanoma and nonmelanoma skin cancer (NMSC) SIRs. Lung cancer SIRs were used as the index of the effects of smoking. For men, the UVB index was significantly inversely correlated with 14 types of internal cancer-bladder, breast, colon, gallbladder, kidney, laryngeal, liver, lung, oral, pancreatic, pharyngeal, prostate, rectal and small intestine cancer. For women, the same UVB index was inversely correlated with bladder, breast and colon cancer. These results generally agree with findings from other studies. These results provide more support for the UVB-vitamin D-cancer hypothesis and suggest that widespread fear of chronic solar ultraviolet (UV) irradiance may be misplaced.

Evidence continues to mount that vitamin D reduces the risk and mortality rates of many types of disease. However, evidence from prospective cohort studies is sometimes weaker than that from case-control and ecological studies. A suggested reason for this discrepancy is that, because serum levels of 25-hydroxyvitamin D [25(OH)D] change over time, a single 25(OH)D concentration measurement taken at study enrollment does not reliably indicate 25(OH)D concentration related to the health outcome. To evaluate this suggestion further, this paper plots results from 12 prospective cohort studies of all-cause mortality rate vs. follow-up time. The regression fit to the hazard ratio per 20-nmol/l increase in serum 25(OH)D concentration vs. time increased from 0.82 (95% CI, 0.67-1.02) for 6 y to 0.96 (95% CI, 0.90-1.01) for 14 y. The value extrapolated for zero follow-up time was 0.72 (95% CI, 0.50-1.03), giving a hazard ratio reduction 3.5 times higher than the standard result from the meta-analysis [0.92 (95% CI, 0.89-0.95)]. Using the example of the Vitamin D Pooling Project of Rarer Cancers, this paper also discusses follow-up time's effect in interpreting prospective cohort studies of cancer outcome. This paper recommends that meta-analyses of prospective cohort studies account for follow-up time and, if possible, that studies measure serum 25(OH)D concentration every 2-4 y.

Considerable disparities in cancer survival rates exist between African Americans (AAs) and white Americans (WAs). Various factors such as differences in socioeconomic status (SES), cancer stage at time of diagnosis, and treatment-which this analysis considers primary explanatory factors-have accounted for many of these differences. An additional factor not usually considered is vitamin D. Previous studies have inversely correlated higher solar ultraviolet-B (UVB) doses and serum 25-hydroxyvitamin D (25(OH)D) concentrations with incidence and/or mortality rates for about 20 types of cancer and improved survival rates for eight types of cancer. Because of darker skin pigmentation, AAs have 40% lower serum 25(OH)D concentrations than WAs. This study reviews the literature on disparities in cancer survival between AAs and WAs. The journal literature indicates that there are disparities for 13 types of cancer after consideration of SES, stage at diagnosis and treatment: bladder, breast, colon, endometrial, lung, ovarian, pancreatic, prostate, rectal, testicular, and vaginal cancer; Hodgkin lymphoma and melanoma. Solar UVB doses and/or serum 25(OH)D concentrations have been reported inversely correlated with incidence and/or mortality rates for all of these cancers. This finding suggests that future studies should consider serum 25(OH)D concentrations in addressing cancer survival disparities through both measurements of serum 25(OH)D concentrations and increasing serum 25(OH)D concentrations of those diagnosed with cancer, leading to improved survival rates and reduced disparities.

Evidence that vitamin D reduces the risk of many types of disease is increasing exponentially. In 2011, 3,100 publications with "vitamin D" in the title or abstract were published, up from 2,606 in 2010, 1,303 in 2005, and 796 in 2000. A committee operating under the auspices of the Institute of Medicine (IOM) of the US National Academies reviewed the evidence for beneficial effects of vitamin D. Their report, issued at the end of 2010,(1) found what they considered to be strong evidence for only one health outcome: skeletal health. They considered beneficial evidence only from published randomized controlled trials (RCTs) focused mainly on skeletal health. In contrast, to justify concern about higher vitamin D intake and serum 25(OH)D concentrations, they used data from nested case-control studies reporting U-shaped outcomes of prediagnostic serum 25-hydroxyvitamin D [25(OH)D] for cancer and all-cause mortality rates. They set the daily recommended intake of vitamin D at 600-800 IU for most children and adults and defined vitamin D sufficiency as a serum 25(OH)D level above 20 ng/ml (50 nmol/l). They also set a daily upper intake of 4,000 IU of vitamin D(3) and called for more RCTs to determine nonskeletal health effects. As of this writing, more than 130 journal publications have criticized the IOM report as being too conservative. One summarized the problems succinctly: "The IOM recommendations for vitamin D fail in a major way on logic, on science, and on effective public health guidance. Moreover, by failing to use a physiological referent, the IOM approach constitutes precisely the wrong model for development of nutritional policy."(2).

Unlabelled: , Purpose: This paper addresses whether nonmelanoma skin cancer (NMSC) mortality rates can serve as a useful index of population ultraviolet-B (UVB) irradiance and vitamin D production in a manner that affects the risk of internal cancers , Methods: This analysis uses the ecological study approach with cancer mortality rate data from 19 state economic areas in California. This paper uses age-adjusted data for those aged 40 y or older. Two additional indices for solar UVB doses were also used: latitude and surface UVB doses for July 1992 from the total ozone mapping spectrometer. Lung cancer mortality rates served as the index of the health effects of smoking, Results: Significant inverse correlations with NMSC mortality rate in multiple linear regression analyses were found during the period 1950-64 for eight types of cancer for males: bladder, brain, colon, gastric, prostate, and rectal cancer; multiple myeloma; and non-Hodgkin lymphoma. No similar results emerged for females with respect to all three UVB indices. Their NMSC mortality rates averaged 60% lower than those for males. Lung cancer mortality rates were directly correlated with three types of cancer for males: laryngeal, oral, and renal. No significant correlations with NMSC mortality rates appeared for later periods, Conclusions: NMSC mortality rates were found inversely correlated with internal cancers for males in the period 1950-64. After that period, no further such correlations were found. The reasons may hypothetically include reduced NMSC mortality rates, high immigration rates, movement from rural to urban locations and reduced solar UVB irradiance.

Large geographical variations in dental health and tooth loss among US adolescents and young adults have been reported since the mid-1800s. Studies in the 1920s and 1930s noted that vitamin D and ultraviolet-B (UVB) irradiance reduced caries formation, the proposed mechanism being improved calcium absorption and metabolism. This paper reviews the history of studies of dental caries with respect to vitamin D, geographical location and available solar UVB doses. In addition, data on mean dental health rank by state for US servicemen from three periods, 1918, 1934 and 1943, were used in regression analyses with respect to summertime solar UVB doses and an index for mottled enamel, a proxy for natural fluoridation of drinking water, for 1935. There was a significant inverse correlation for dental health rank with respect to solar UVB from doses of 4.0 to 6.5 kJ/m(2) with little change thereafter. Adding data for mottled enamel rates for the states with UvB doses <6.6 kJ/m(2) improved the adjusted R(2) from 0.45 to 0.52. The mechanism whereby UVB reduces risk of dental caries is likely through production of vitamin D, followed by induction of cathelicidin and defensins, which have antimicrobial properties. Serum 25-hydroxyvitamin D concentrations at or above 30-40 ng/ml should significantly reduce the formation of dental caries. It is unfortunate that the UVB and vitamin D findings were not given more consideration in the 1950s as a way to reduce the risk of dental caries when water fluoridation was being proposed.

Ecological studies have reported strong inverse correlations between indices of solar ultraviolet-B (UVB) doses and incidence and/or mortality rates for many types of cancer. Case-control studies (CCS) generally find inverse correlations between serum 25-hydroxyvitamin D [25(OH)D] concentration measured at time of diagnosis for cancer incidence, whereas nested case-control studies (NCCS), which involve a several-year follow-up time after serum sampling, generally do not. This paper examines the relation between follow-up interval and relative risk (RR) for breast, colorectal, and prostate cancer. I plot the RR versus serum 25(OH)D data as a function of follow-up time from the literature for each type of cancer. For breast cancer, RRs were significantly reduced only for follow-up periods less than 3 years. For colorectal cancer, RRs were generally significantly reduced for follow-up periods up to 12 years. For prostate cancer, RRs were not statistically significant from 4 years to 28 years. This study included no CCS. Follow-up periods after serum sampling should not be too long for breast cancer because once a tumor reaches a diameter of 1-3 mm, it requires angiogenesis to continue growing, and vitamin D reduces angiogenesis around tumors. Breast cancer diagnoses are more common in spring and fall than in summer or winter, indicating that they can grow rapidly if circulating 25(OH)D drops in the fall or melatonin levels drop in spring. Serum sampling should be conducted during the study, perhaps every 2 years, to overcome the problem of change of 25(OH)D concentration during cohort studies.

The Cohort Consortium Vitamin D Polling Project of Rarer Cancers (VDPP ) study failed to find a beneficial role of prediagnostic serum 25-hydroxyvitamin D [25(OH)D] levels on risk of seven types of rarer cancer: endometrial, esophageal, gastric, kidney, ovarian and pancreatic cancer and non-Hodgkin's lymphoma (NHL). However, ecological studies and studies of oral vitamin D intake have generally found solar ultraviolet B (UVB) and oral vitamin D inversely correlated with incidence and/or mortality rates of these cancers. To explore the discrepancy, I conducted an ecological study of cancer mortality rates for white Americans in the United States for 1950-1994 with data for 503 state economic areas in multiple linear regression analyses with respect to UVB for July, lung cancer, alcohol consumption and urban/rural residence. UVB was significantly inversely correlated with six types of cancer (not pancreatic cancer) in both periods. However, the adjusted R(2) values were much lower for cancers with lower mortality rates than those in an earlier ecological study that used state-averaged data. This finding suggests that the VDPP study may have had too few cases. Thus, the VDPP study should not be considered as providing strong evidence against the solar UVB-vitamin D-cancer hypothesis.

Frank Caldwell Garland, Ph.D., died August 17, 2010 after a year-long battle with cancer. He will be remembered for his seminal work with his brother Cedric F. Garland in proposing the ultraviolet-B (UVB)-vitamin D-cancer hypothesis to explain the geographical variation of colon cancer mortality rates in the United States in 1980. This hypothesis has been extended to about 20 types of cancer using the ecological approach, and supported strongly by observational studies of prediagnostic serum 25-hydroxyvitamin D [25(OH) D] for incidence of breast, colorectal and ovarian cancer, and a randomized controlled trial that used sufficient vitamin D (1,150 IU/day) to and found a strongly beneficial effect on cancer incidence. The UVB-vitamin D-cancer hypothesis is also supported by studies that used as the index of solar UVB irradiance the amount of sunlight exposure in childhood or incidence of non-melanoma skin cancer. Survival after diagnosis was increased for individuals with higher serum 25(OH)D levels at the time of cancer diagnosis for six types of cancer: breast, colorectal, lung and prostate cancer; melanoma and non-Hodgkin's lymphoma. The ecological study approach is ideally suited to studying cancer risk-modifying factors since the lag between cancer initiation and detection or death can be 20-40 years or more, making ordinary observational studies difficult. The impact on vitamin D research by both Frank Garland and Cedric Garland has been immense. Health policy leaders will realize this in the near future, providing a rich legacy for humanity.

France has unexplained large latitudinal variations in cancer incidence and mortality rates. Studies of cancer rate variations in several other countries, as well as in multicountry studies, have explained such variations primarily in terms of gradients in solar ultraviolet-B (UVB) doses and vitamin D production. To investigate this possibility in France, I obtained data on cancer incidence and mortality rates for 21 continental regions and used this information in regression analyses with respect to latitude. This study also used dietary data. Significant positive correlations with latitude emerged for breast, colorectal, esophageal (males), lung (males), prostate, both uterine cervix and uterine corpus, all and all less lung cancer. Although correlations with latitude were similar for males and females, the regression variance for all and all less lung cancer was about twice as high for males than for females. Lung cancer incidence and mortality rates for females had little latitudinal gradient, indicating that smoking may have also contributed to the latitudinal gradients for males. On the basis of the available dietary factor, micro- and macronutrient data, dietary differences do not significantly affect geographical variation in cancer rates. These results are consistent with solar UVB's reducing the risk of cancer through production of vitamin D. In the context of serum 25-hydroxyvitamin D level-cancer incidence relations, cancer rates could be reduced significantly in France if everyone obtained an additional 1,000 IU/day of vitamin D. Many other benefits of vitamin D exist as well.

The International Agency for Research on Cancer (IARC) reported meta-analyses of the association of cutaneous malignant melanoma (CMM), finding significant correlations with ever use of sunbeds and first use of sunbeds prior to age 35 years; it did not claim that the associations showed causal links. However, some observational studies in the meta-analysis included individuals in the UK with skin phenotype at increased genetic risk of CMM without adjustment for skin phenotype. Treating the five UK studies separately from the other 14 corrected this oversight. In the original study, the summary relative risk (RR ) of CMM with respect to sunbed use was 1.15 (95% confidence interval [CI], 1.00-1.31). In this study, the similar RR was 1.20 (95% CI, 1.03-1.38). The RR for the five UK studies was 2.09 (95% CI, 1.14-3.84), whereas the RR for the other 14 studies was 1.09 (95% CI, 0.96-1.24). For first use of sunbeds prior to age 35 years, the IARC found a summary RR of 1.75 (95% CI, 1.35-2.36). This study plotted the RRs versus latitude of each study population, with a linear regression analysis carried out for all but the one UK study. The RR increased at 0.077 per degree of latitude and the regression explained 67% of the variance. It is also argued that factors other than sunbed use explain the increasing worldwide trends in CMM. Because solar-UV-simulating sunbeds induce production of vitamin D, the health benefits of their use greatly outweigh any possible risks.

Deaths during the 1918-1919 influenza pandemic have been linked to both the influenza virus and secondary bacterial lung infections. Case fatality rates and percentage of influenza cases complicated by pneumonia were available from survey data for twelve United States locations in the 1918-1919 pandemic. This study analyzes case fatality rates and cases complicated by pneumonia with respect to estimated summertime and wintertime solar ultraviolet-B (UVB) doses as indicators of population mean vitamin D status. Substantial correlations were found for associations of July UVB dose with case fatality rates (r = -0.72, p = 0.009) and rates of pneumonia as a complication of influenza (r = -0.77, p = 0.005). Similar results were found for wintertime UVB. Vitamin D upregulates production of human cathelicidin, LL-37, which has both antimicrobial and antiendotoxin activities. Vitamin D also reduces the production of proinflammatory cytokines, which could also explain some of the benefit of vitamin D since H1N1 infection gives rise to a cytokine storm. The potential role of vitamin D status in reducing secondary bacterial infections and loss of life in pandemic influence requires further evaluation.

Emerging scientific evidence strongly supports the beneficial role of vitamin D in reducing the risk of incidence and death from many chronic and infectious diseases. This study estimates increases in melanoma and nonmelanoma skin cancer mortality rates and decreases in chronic and infectious disease mortality rates in the US from the standpoint of approximately doubling population doses of solar UVB to increase mean serum 25-hydroxyvitamin D levels from 16 ng/mL for black Americans and 25 ng/mL for white Americans to 45 ng/mL. The primary benefits are expected to come from reductions in cancer and cardiovascular diseases. Although a few thousand excess deaths per year might occur from melanoma and skin cancer, the avoided premature death rate could be near 400,000/ year, with most of the avoided deaths coming late in life. While oral sources of vitamin D could be used instead of UVB or when UVB irradiance is not available, public health policies do not yet recommend the 3,000-4,000 IU/day required to raise serum 25-hydroxyvitamin D levels to the levels required for optimal health, which would be required before vitamin D fortification levels in food can be raised. Until then, moderate solar UVB irradiance remains an import source, and the health benefits greatly outweigh the risks.

This study examines whether maternal vitamin D deficiency is a risk factor for infantile autism disease (IAD). We used epidemiologic data seasonal variation of birth rates and prevalence of IAD for cohorts born before 1985. For seven studies reporting spring-to-summer excess birth rates for IAD, the season progressed from broad near 30 degrees N latitude, spring/summer in midlatitudes, to winter at the highest latitude. Also, using data from 10 studies, we found a strong effective latitudinal (related to wintertime solar ultraviolet B radiation) increase in IAD prevalence. These findings are consistent with maternal vitamin D deficiency's being a risk factor for IAD, possibly by affecting fetal brain development as well as possibly by affecting maternal immune system status during pregnancy. Further investigation of this hypothesis is warranted.

The primary features of the epidemiology of septicemia in the United States include highest rates in winter and the Northeast, lowest in fall and in the West; higher rates among African Americans than white Americans; a rapid increase in incidence with age; comorbidity with several chronic and infectious diseases; and a rapid increase in incidence rate starting in the early 1980s. This article reviews the literature on the epidemiology of septicemia in the United States, along with the roles of solar ultraviolet-B (UVB) and vitamin D3 related to the more important features. Solar UVB doses in summer are highest in the Southwest and lowest in the Northeast. Serum 25-hydroxyvitamin D [25(OH)D] levels are highest in summer, lowest in winter. African Americans have much lower 25(OH)D levels than those of white Americans. Serum 25(OH)D levels decline rapidly with advancing age. The risk of diseases comorbid with septicemia are generally inversely correlated with serum 25(OH)D levels. Sun-avoidance messages may have led to lower population levels of 25(OH)D, although prevalence of antibiotic-resistant bacteria may have increased. Previous reports have shown that 1,25-dihydroxyvitamin D upregulates human cathelicidin, LL-37, which has antimicrobial as well as antiendotoxin activity. The general agreement between the epidemiology of septicemia in the United States and the variations of solar UVB and the effects of vitamin D supports the hypothesis that both play important roles in reducing the risk of septicemia. Further study is warranted to evaluate this hypothesis.