Is Vitamin D the Fountain of Youth?

ObjectiveTo review the role of vitamin D deficiency for both classic and “nonclassic” effects and raise the caution that association does not prove causation.MethodsThe pertinent literature regarding vitamin D and its effects on bone, muscle function, immune function, glucose tolerance, cancer risk, and development of cardiovascular disease and other conditions is reviewed. In addition, the limitations of observational studies are discussed.ResultsVitamin D inadequacy is common worldwide and classically causes osteomalacia and rickets. More recently, the contribution of low vitamin D status to increased falls and fracture risk has become appreciated. Additionally, nonclassic effects of vitamin D inadequacy are being recognized, and low vitamin D status is being potentially associated with a multitude of conditions (including Alzheimer disease, osteoarthritis, multiple sclerosis, and hypertension) and higher overall mortality. It is important to recognize that associations in observational studies can be due to chance, bias, or confounders or may be indicative of causality.ConclusionBecause vitamin D deficiency has been established to have adverse musculoskeletal consequences, optimization of vitamin D status, for both the individual patient and the overall population, is indicated. (Endocr Pract. 2009;15:590-596)     

Is Zinc Concentration in Toxic Phase Plasma Related to Dengue Severity and Level of Transaminases?

Objective

To determine the relationship between plasma zinc values and the severity of dengue viral infection (DVI) and DVI-caused hepatitis.

Methods

A prospective cohort study was conducted during 2008–2010 in hospitalized children aged <15 years confirmed with DVI. Complete blood count, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and zinc values (mcg/dL) were determined twice: first during the toxic phase (Zn1) and secondly two weeks after recovery (Zn2).

Results

39 patients were enrolled with a mean age of 9.7±3.7 years, and 15/39 diagnosed with dengue shock syndrome (DSS). Zn1 values were lower than Zn2 values [median (IQR): 46.0 (37.0, 58.0) vs 65.0 (58.0, 81.0) mcg/dL, respectively, p <0.01]. Zn1 but not Zn2 values had a negative correlation with AST and ALT (r_s = −0.33, p = 0.04 and r_s = −0.31, p = 0.05, respectively). Patients with DSS had lower Zn1 but not Zn2 values compared with non-DSS patients [median (IQR) Zn1, 38.0 (30.0, 48.0) vs 52.5 (41.2, 58.7), p = 0.02; Zn2, 61.0 (56.0, 88.0) vs 65.0 (59.5, 77.5), respectively, p = 0.76]. Zn1 values showed a decreasing trend across increasing dengue severity groups (p = 0.02). Age <5 years and DVI-associated diarrhea were associated with low Zn1.

Conclusion

Children who had a higher grade of dengue disease severity and liver cell injury had lower Zn1 values. Low Zn1 values were probably caused by loss from diarrhea and from zinc translocating to liver cells.     

From Skin Cells to Ovarian Follicles?

Generating oocytes from cells derived from skin in vitro may provide a valuable modelfor identifying factors involved in germ cell formation and oocyte differentiation. In addition, the“oocytes” produced could potentially be useful for therapeutic cloning, and thus offer newpossibilities for tissue therapy. We recently reported the differentiation of cells derived fromporcine fetal skin into cells resembling germ cells and oocytes. A subpopulation of these cellsexpressed germ cell markers and formed aggregate like oocyte-cumulus complexes that secretedovarian steroid hormones and responded to gonadotropin stimulation. Some of these aggregatesextruded large oocyte-like cells that expressed markers appropriate to oocytes. We now showfurther evidence of germ cell marker expression during differentiation. We have also comparedthe oocyte-like cells with natural oocytes for their expression levels of Oct4, growthdifferentiation factor-9b (GDF9b), the deleted in azoospermia -like (DAZL) gene, vasa, zonapellucida (ZP), and the meiosis marker synaptonemal complex protein 3 (SCP3), and haverevealed interesting similarities and differences.     

Will the 'Good Fairies' Please Prove to us that Vitamin E Lessens Human Degenerative Disease?

Recent research about the role of free radical derivatives of oxygen and nitrogen in biological systems has highlighted the possibility that antioxidants, such as vitamin E, that prevent these processes in vitro may be capable of carrying out a similar function in living organisms in vivo. There is increasing evidence that free radical reactions are involved in the early stages, or sometimes later on, in the development of human diseases, and it is therefore of particular interest to inquire whether vitamin E and other antioxidants, which are found in the human diets, may be capable of lowering the incidence of these diseases. Put simply, the proposition is that by improving human diets by increasing the quantity in them of antioxidants, it might be possible to reduce the incidence of a number of degenerative diseases. Of particular significance to these considerations is the likely role of the primary fat-soluble dietary antioxidant vitamin E in the prevention of degenerative diseases such as arteriosclerosis, which is frequently the cause of consequent heart attacks or stroke, and prevention of certain forms of cancer, as well as several other diseases. Substantial evidence for this proposition now exists, and this review is an attempt to give a brief account of the present position. Two kinds of evidence exist; on the one hand there is very substantial basic science evidence which indicates an involvement of free radical events, and a preventive role for vitamin E, in the development of human disease processes. On the other hand, there is also a large body of human epidemiological evidence which suggests that incidence of these diseases is lowered in populations having a high level of antioxidants, such as vitamin E, in their diet, or who have taken steps to enhance their level of intake of the vitamin by taking dietary supplements. There is also some evidence which suggests that intervention with dietary supplements of vitamin E can result in a lowered risk of disease, in particular of cardiovascular disease, which is a major killer disease among the developed nations of the world. The intense interest in this subject recently has as its objective the possibility that, by making some simple alterations to dietary lifestyle, or by enhancing the intake of vitamin E by fortification of foods, or by dietary supplements, it may be possible to reduce substantially the risk of a large amount of common, highly disabling human disease. By this simple means, therefore it may be possible to improve substantially the quality of human life, in particular for people of advancing years.     

Will the 'Good Fairies' Please Prove to us that Vitamin E Lessens Human Degenerative Disease?

Recent research about the role of free radical derivatives of oxygen and nitrogen in biological systems has highlighted the possibility that antioxidants, such as vitamin E, that prevent these processes in vitro may be capable of carrying out a similar function in living organisms in vivo. There is increasing evidence that free radical reactions are involved in the early stages, or sometimes later on, in the development of human diseases, and it is therefore of particular interest to inquire whether vitamin E and other antioxidants, which are found in the human diets, may be capable of lowering the incidence of these diseases. Put simply, the proposition is that by improving human diets by increasing the quantity in them of antioxidants, it might be possible to reduce the incidence of a number of degenerative diseases. Of particular significance to these considerations is the likely role of the primary fat-soluble dietary antioxidant vitamin E in the prevention of degenerative diseases such as arteriosclerosis, which is frequently the cause of consequent heart attacks or stroke, and prevention of certain forms of cancer, as well as several other diseases. Substantial evidence for this proposition now exists, and this review is an attempt to give a brief account of the present position. Two kinds of evidence exist; on the one hand there is very substantial basic science evidence which indicates an involvement of free radical events, and a preventive role for vitamin E, in the development of human disease processes. On the other hand, there is also a large body of human epidemiological evidence which suggests that incidence of these diseases is lowered in populations having a high level of antioxidants, such as vitamin E, in their diet, or who have taken steps to enhance their level of intake of the vitamin by taking dietary supplements. There is also some evidence which suggests that intervention with dietary supplements of vitamin E can result in a lowered risk of disease, in particular of cardiovascular disease, which is a major killer disease among the developed nations of the world. The intense interest in this subject recently has as its objective the possibility that, by making some simple alterations to dietary lifestyle, or by enhancing the intake of vitamin E by fortification of foods, or by dietary supplements, it may be possible to reduce substantially the risk of a large amount of common, highly disabling human disease. By this simple means, therefore it may be possible to improve substantially the quality of human life, in particular for people of advancing years.     

Is Vitamin D Binding Protein a Novel Predictor of Labour?

Vitamin D binding protein (VDBP) has previously been identified in the amniotic fluid and cervicovaginal fluid (CVF) of pregnant women. The biological functions of VDBP include acting as a carrier protein for vitamin D metabolites, the clearance of actin that is released during tissue injury and the augmentation of the pro-inflammatory response. This longitudinal observational study was conducted on 221 healthy pregnant women who spontaneously laboured and delivered either at term or preterm. Serial CVF samples were collected and VDBP was measured by ELISA. Binary logistic regression analysis was performed to assess the utility of VDBP as a predictor of labour. VDBP in the CVF did not change between 20 and 35 weeks'' gestation. VDBP measured in-labour was significantly increased 4.2 to 7.4-fold compared to 4–7, 8–14 and 15–28 days before labour (P<0.05). VDBP concentration was 4.3-fold significantly higher at 0–3 days compared to 15–28 days pre-labour (P<0.05). The efficacy of VDBP to predict spontaneous labour onset within 3 days provided a positive and negative predictive value of 82.8% and 95.3% respectively (area under receiver operator characteristic curve  = 0.974). This longitudinal study of pregnant women suggests that VDBP in the CVF may be a useful predictor of labour.     

Formation of Toxic Oligomeric α-Synuclein Species in Living Cells

Background

Misfolding, oligomerization, and fibrillization of α-synuclein are thought to be central events in the onset and progression of Parkinson''s disease (PD) and related disorders. Although fibrillar α-synuclein is a major component of Lewy bodies (LBs), recent data implicate prefibrillar, oligomeric intermediates as the toxic species. However, to date, oligomeric species have not been identified in living cells.

Methodology/Principal Findings

Here we used bimolecular fluorescence complementation (BiFC) to directly visualize α-synuclein oligomerization in living cells, allowing us to study the initial events leading to α-synuclein oligomerization, the precursor to aggregate formation. This novel assay provides us with a tool with which to investigate how manipulations affecting α-synuclein aggregation affect the process over time. Stabilization of α-synuclein oligomers via BiFC results in increased cytotoxicity, which can be rescued by Hsp70 in a process that reduces the formation of α-synuclein oligomers. Introduction of PD-associated mutations in α-synuclein did not affect oligomer formation but the biochemical properties of the mutant α-synuclein oligomers differ from those of wild type α-synuclein.

Conclusions/Significance

This novel application of the BiFC assay to the study of the molecular basis of neurodegenerative disorders enabled the direct visualization of α-synuclein oligomeric species in living cells and its modulation by Hsp70, constituting a novel important tool in the search for therapeutics for synucleinopathies.     

Is there a vitamin E paradox?

In addition to epidemiologic studies that suggest a benefit for high intakes of alpha-tocopherol, studies of supplementation in humans have clearly shown that alpha-tocopherol decreases lipid peroxidation, platelet aggregation, and functions as a potent anti-inflammatory agent. In the five large prospective clinical trials with alpha-tocopherol therapy, four have shown a beneficial effect on cardiovascular end-points (two studies on a primary end-point and two studies on other cardiovascular end-points). Thus, the totality of evidence based on the epidemiologic data, in-vitro studies and animal models, and the clinical trials appears to support a benefit for alpha-tocopherol supplementation in patients with pre-existing cardiovascular disease. However, definitive recommendations must await ongoing clinical trials.     

Is MutaMouse insensitive to clastogens?

Several studies suggest that MutaMouse is insensitive to clastogens, including the accompanying paper by Mahabir et al., which describes a study with bleomycin, camptothecin, m-AMSA (4'-(9-acridinylamino)-methanesulfon-m-anisidide) and its ortho-analogue, o-AMSA (4'-(9-acridinylamino)-methanesulfon-o-anisidide). Only camptothecin was clastogenic in MutaMouse and none of these four compounds induced mutations at the lacZ locus. However, to improve exposure, dose range-finding studies were performed in CD2F1 mice, the parental strain of MutaMouse. Male CD2F1 mice (n=3) were treated with bleomycin (25-100 mg/kg bw, p.o. and i.p.), camptothecin (1-10 mg/kg bw p.o.) and m-AMSA (10-50mg/kg bw p.o. and 1-5 mg/kg bw i.p.) for 5 days and blood was sampled on day 3 and/or day 6 for analysis by flow cytometry to determine % MN-RETs. Camptothecin (1 mg/kg bw, day 6) induced a 3.6-fold increase in % MN-RET (P<0.05) but was toxic at higher doses. All day-3 camptothecin samples were positive (P<0.05). Bleomycin was negative when administered p.o. but positive at all doses on both days when given i.p. (P<0.05) whereas m-AMSA was negative when given i.p. or orally. Based on these results, male MutaMouse mice (5 per group) were dosed daily with bleomycin (50 mg/kg bw) for 5 days or with camptothecin (5 mg/kg bw) for 2 days. Peripheral blood was sampled 24 h after the final dose in each group and tissues were sampled 37 days later. Both compounds induced significant increases in % MN-RET, but only bleomycin induced a significant increase in MF (6-fold in liver, 4.5-fold in kidney and 2-fold in lung) compared with the untreated control. These studies support the view that MutaMouse is insensitive to compounds where the genotoxic mechanism of action is predominantly clastogenesis, but demonstrates that the peripheral blood micronucleus test is a useful adjunct to the transgenic gene-mutation assay.     

Is height related to longevity?

Over the last 100 years, studies have provided mixed results on the mortality and health of tall and short people. However, during the last 30 years, several researchers have found a negative correlation between greater height and longevity based on relatively homogeneous deceased population samples. Findings based on millions of deaths suggest that shorter, smaller bodies have lower death rates and fewer diet-related chronic diseases, especially past middle age. Shorter people also appear to have longer average lifespans. The authors suggest that the differences in longevity between the sexes is due to their height differences because men average about 8.0% taller than women and have a 7.9% lower life expectancy at birth. Animal experiments also show that smaller animals within the same species generally live longer. The relation between height and health has become more important in recent years because rapid developments in genetic engineering will offer parents the opportunity to increase the heights of their children in the near future. The authors contend that we should not be swept along into a new world of increasingly taller generations without careful consideration of the impact of a worldwide population of taller and heavier people.     

Is iNOS beginning to smoke?

Inducible nitric oxide synthase (iNOS) helps drive numerous inflammatory disorders, but its inhibition has not had therapeutic success. Now Seimetz et?al. (2011) make a case for inhibiting iNOS in an effort to treat one of the world's leading causes of death-chronic obstructive pulmonary disease.     

Is There A Pre-RC Checkpoint That Cancer Cells Lack?

Critical for genomic integrity, accurate DNA replication is tightly regulated by the convergence of prereplication protein complexes (pre-RCs) to “license” replicating origins on DNA in G1 and is activated by S-phase promoting kinases that selectively target and trigger origin firing in S-phase. To present, a checkpoint mechanism monitoring pre-RC complex formation and activation has yet to be elucidated. However, perturbation of these protein complexes has yielded divergent phenotypes in recent reports: normal cells arrest in the cell cycle, whereas cancerous cells arrest and die. These data implicate a mechanism by which normal cells sense pre-RC deficiency and then signal for cell cycle arrest. The potential for therapeutic exploits of this disparity between normal and cancer cells is apparent. Here, we explore recent data supporting the existence of a pre-RC checkpoint that ensures faithful pre-RC formation, a cell cycle mechanism that is intriguingly compromised in cancer cells.     

Cadmium Toxicity in Plants: Is There any Analogy to its Carcinogenic Effect in Mammalian Cells?

Cadmium is a heavy metal, which is classified as a human carcinogen and is known to be toxic to plants. However, plants do not respond to this metal by massive cell proliferation. In this review the various aspects of cadmium toxicity in plants are compared to related processes in mammalian cells. The following issues are discussed: cellular uptake of Cd ions, their intracellular transport, the effects on cellular signaling, nucleic acids and proteins, modification of gene expression, cell cycle control and apoptosis. Reviewed data suggest that such features as: ability to remove the oxidized proteins, slightly different regulation of cell cycle genes, specific pattern of apoptosis, makes plants resistant to Cd²⁺-induced uncontrolled cell proliferation.     

Do Cells Contribute to Tendon and Ligament Biomechanics?

Introduction

Acellular scaffolds are increasingly used for the surgical repair of tendon injury and ligament tears. Despite this increased use, very little data exist directly comparing acellular scaffolds and their native counterparts. Such a comparison would help establish the effectiveness of the acellularization procedure of human tissues. Furthermore, such a comparison would help estimate the influence of cells in ligament and tendon stability and give insight into the effects of acellularization on collagen.

Material and Methods

Eighteen human iliotibial tract samples were obtained from nine body donors. Nine samples were acellularized with sodium dodecyl sulphate (SDS), while nine counterparts from the same donors remained in the native condition. The ends of all samples were plastinated to minimize material slippage. Their water content was adjusted to 69%, using the osmotic stress technique to exclude water content-related alterations of the mechanical properties. Uniaxial tensile testing was performed to obtain the elastic modulus, ultimate stress and maximum strain. The effectiveness of the acellularization procedure was histologically verified by means of a DNA assay.

Results

The histology samples showed a complete removal of the cells, an extensive, yet incomplete removal of the DNA content and alterations to the extracellular collagen. Tensile properties of the tract samples such as elastic modulus and ultimate stress were unaffected by acellularization with the exception of maximum strain.

Discussion

The data indicate that cells influence the mechanical properties of ligaments and tendons in vitro to a negligible extent. Moreover, acellularization with SDS alters material properties to a minor extent, indicating that this method provides a biomechanical match in ligament and tendon reconstruction. However, the given protocol insufficiently removes DNA. This may increase the potential for transplant rejection when acellular tract scaffolds are used in soft tissue repair. Further research will help optimize the SDS-protocol for clinical application.