Knowing the rate of addition of new granule cells to the adult dentate gyrus is critical to understanding the function of adult neurogenesis. Despite the large number of studies of neurogenesis in the adult dentate gyrus, basic questions about the magnitude of this phenomenon have never been addressed. The S-phase marker bromodeoxyuridine (BrdU) has been extensively used in recent studies of adult neurogenesis, but it has been carefully tested only in the embryonic brain. Here, we show that a high dose of BrdU (300 mg/kg) is a specific, quantitative, and nontoxic marker of dividing cells in the adult rat dentate gyrus, whereas lower doses label only a fraction of the S-phase cells. By using this high dose of BrdU along with a second S-phase marker, [(3)H]thymidine, we found that young adult rats have 9,400 dividing cells proliferating with a cell cycle time of 25 hours, which would generate 9,000 new cells each day, or more than 250,000 per month. Within 5-12 days of BrdU injection, a substantial pool of immature granule neurons, 50% of all BrdU-labeled cells in the dentate gyrus, could be identified with neuron-specific antibodies TuJ1 and TUC-4. This number of new granule neurons generated each month is 6% of the total size of the granule cell population and 30-60% of the size of the afferent and efferent populations (West et al. [1991] Anat Rec 231:482-497; Mulders et al. [1997] J Comp Neurol 385:83-94). The large number of the adult-generated granule cells supports the idea that these new neurons play an important role in hippocampal function.

/pdf/adult-neurogenesis-produces-a-large-pool-of-new-granule-35brap9zt4.pdf

Adult neurogenesis produces a large pool of new granule cells in the dentate gyrus.

Biodegradable metals are breaking the current paradigm in biomaterial science to develop only corrosion resistant metals. In particular, metals which consist of trace elements existing in the human body are promising candidates for temporary implant materials. These implants would be temporarily needed to provide mechanical support during the healing process of the injured or pathological tissue. Magnesium and its alloys have been investigated recently by many authors as a suitable biodegradable biomaterial. In this investigative review we would like to summarize the latest achievements and comment on the selection and use, test methods and the approaches to develop and produce magnesium alloys that are intended to perform clinically with an appropriate host response.

/pdf/degradable-biomaterials-based-on-magnesium-corrosion-4sw919tlb2.pdf

Degradable biomaterials based on magnesium corrosion

Cadmium (Cd) is a toxic non-essential transition metal that poses a health risk for both humans and animals. It is naturally occurring in the environment as a pollutant that is derived from agricultural and industrial sources. Exposure to cadmium primarily occurs through the ingestion of contaminated food and water and, to a significant extent, through inhalation and cigarette smoking. Cadmium accumulates in plants and animals with a long half-life of about 25–30 years. Epidemiological data suggest that occupational and environmental cadmium exposure may be related to various types of cancer, including breast, lung, prostate, nasopharynx, pancreas, and kidney cancers. It has been also demonstrated that environmental cadmium may be a risk factor for osteoporosis. The liver and kidneys are extremely sensitive to cadmium’s toxic effects. This may be due to the ability of these tissues to synthesize metallothioneins (MT), which are Cd-inducible proteins that protect the cell by tightly binding the toxic cadmium ions. The oxidative stress induced by this xenobiotic may be one of the mechanisms responsible for several liver and kidney diseases. Mitochondria damage is highly plausible given that these organelles play a crucial role in the formation of ROS (reactive oxygen species) and are known to be among the key intracellular targets for cadmium. When mitochondria become dysfunctional after exposure to Cd, they produce less energy (ATP) and more ROS. Recent studies show that cadmium induces various epigenetic changes in mammalian cells, both in vivo and in vitro, causing pathogenic risks and the development of various types of cancers. The epigenetics present themselves as chemical modifications of DNA and histones that alter the chromatin without changing the sequence of the DNA nucleotide. DNA methyltransferase, histone acetyltransferase, histone deacetylase and histone methyltransferase, and micro RNA are involved in the epigenetic changes. Recently, investigations of the capability of sunflower (Helianthus annuus L.), Indian mustard (Brassica juncea), and river red gum (Eucalyptus camaldulensis) to remove cadmium from polluted soil and water have been carried out. Moreover, nanoparticles of TiO2 and Al2O3 have been used to efficiently remove cadmium from wastewater and soil. Finally, microbial fermentation has been studied as a promising method for removing cadmium from food. This review provides an update on the effects of Cd exposure on human health, focusing on the cellular and molecular alterations involved.

https://www.mdpi.com/1660-4601/17/11/3782/pdf

The Effects of Cadmium Toxicity

目的 探讨CD25单抗在无血缘关系造血干细胞移植（UHSCT）中对干细胞植入和移植物抗宿主病（GVHD）的作用。方法 27例UHCST中，移植后1、4d给予CD25单抗1mg/kg。结果 27例中，除1例早期死亡外，26例患者造血全部重建。17例发生急性GVHD，其中Ⅱ度以上急性GVHD6例（23％）。复发3例，严重感染3例。26例可评价患者中，19例无病生存（73％）。结论 CD25单抗在UHSCT中对保证干细胞植入和预防GVHD有肯定的作用，白血病复发并不增加。此研究为UHCST和HLA不合的造血干细胞移植提供一个可选择的途径。

A cumulative labelling protocol using 5-bromo-2′-deoxyuridine (BUdR) was followed to determine: (1) the growth fraction (i.e., the proportion of cells that comprise the proliferating population), (2) the length of the cell cycle, and (3) the length of the DNA-synthetic phase (S-phase) for proliferative cells in the dentate gyrus of the mouse. On postnatal day 20 (P20), C57BL/6J mice were injected with BUdR at two hour intervals for a total period of 12 hours. Animals were sacrificed at selected intervals, and the brains were processed for immunohistochemistry using a monoclonal antibody directed against single-stranded DNA containing BUdR. The numbers of BUdR-labelled and unlabelled cells in sections through the hilus of the dentate gyrus were counted. The number of BUdR-labelled cells increased linearly from an initial value of about 12% of the total number of cells to a maximum value of just over 24% of the total. These findings indicate that, at P20, a maximum of 24.2 ± 1.2% of the cells in the dentate hilus are part of the proliferating population. The calculated length of the cell cycle of the cells comprising the intrahilar proliferative zone was estimated to be 16.1 ± 0.8h. The length of the S-phase was estimated at 8.0 ± 0.4 h. In addition, mathematical analysis, using one and two population models, indicates that over 90% of the proliferating cells in the dentate hilus at this age comprise a single population at least in terms of the lengths of the cell cycle and the S-phase. This protocol provides a convenient method for thein situ analysis of the cell cycle for anatomically defined proliferative populations.

Bromodeoxyuridine immunohistochemical determination of the lengths of the cell cycle and the DNA-synthetic phase for an anatomically defined population

Cadmium : Toxic effects on the reproductive system and the embryo

A review is presented on the effects of lithium in therapeutic doses on the outcome of human pregnancy. The results of various studies including cohort, prospective, retrospective and small number case reports indicate that lithium is a "weak" teratogen in humans. The main effects attributable to lithium are, cardiac malformations and babies with increased birth weight. There is a possibility that, in particular, lithium may be associated with the Ebstein anomaly but present evidence cannot definitely affirm or deny this association. Animal studies with lithium using doses comparable to human therapeutic serum levels have not reported any abnormalities. However, higher doses have produced exencephaly, skeletal and craniofacial defects and abnormalities of blood vessel development. Experiments with other vertebrates have shown that lithium affects dorsoventral specification and inhibition of vasculogenesis. Both these effects can be prevented by pretreatment with myo-inositol indicating that lithium interferes with the phosphatidyl inositol cycle. More recent findings have shown that the effects of lithium on invertebrates may be mediated through inhibition of GSK-3beta in the Wnt-GSK-3 pathway.

Teratogenic and developmental effects of lithium.

Stereology of the placenta in type 1 and type 2 diabetes

The objective of this study was to see what, if any, cellular changes occurred in the mouse embryo following a single injection of ethanol, a known teratogen in humans and animals, on day 9 of gestation. No changes were seen until 6 hours after injection, when many degenerating cells and necrotic fragments were seen in the neuroepithelium of the neural groove and of the neural tube. In addition, large clear vacuoles were seen in the cytoplasm of many cells and the pseudopodia at the luminal side of the neural groove appeared swollen. The cytoplasm of the latter also contained vacuoles. When tritiated thymidine was injected 5 hours after ethanol and 1 hour before sacrifice, many degenerating cells were labelled. In addition, many cells with labelled nuclei had abnormal vacuoles in the cytoplasm. Hence, it is likely that the toxicity of ethanol is exerted primarily on some component of the cytoplasm and not on DNA synthesis. Twelve hours after ethanol, the cytoplasmic vacuoles and swollen pseudopodia had disappeared, but dying cells were still evident. By 24 hours, the necrotic debris had been completely phagocytosed by healthy neuroepithelial cells. By 50 hours, the neuroepithelium had been cleared of cell debris, although many ethanol-treated embryos had open defects of the cranial neural tube. Treatment of pregnant mice with single doses of acetaldehyde, also an established teratogen in animals, did not produce any cellular changes. However, a single dose of acetaldehyde is rapidly metabolized by the mother, and would not be comparable to the small but continuous blood levels that a dose of ethanol would produce. Hence, we could not conclude with certainty that the cytotoxic effects of ethanol were exerted directly.

John Bannigan

Papers

Cadmium : Toxic effects on the reproductive system and the embryo

Teratogenic and developmental effects of lithium.

Stereology of the placenta in type 1 and type 2 diabetes

Ethanol teratogenicity in mice: A light microscopic study

Effects of cadmium on cell death and cell proliferation in chick embryos.