Cardiovascular fitness in late adolescent males and later risk of serious non-affective mental disorders: a prospective, population-based study.

BACKGROUND: Cardiovascular fitness in late adolescence is associated with future risk of depression. Relationships with other mental disorders need elucidation. This study investigated whether fitness in late adolescence is associated with future risk of serious non-affective mental disorders. Further, we examined how having an affected brother might impact the relationship. METHOD: Prospective, population-based cohort study of 1 109 786 Swedish male conscripts with no history of mental illness, who underwent conscription examinations at age 18 between 1968 and 2005. Cardiovascular fitness was objectively measured at conscription using a bicycle ergometer test. During the follow-up (3-42 years), incident cases of serious non-affective mental disorders (schizophrenia and schizophrenia-like disorders, other psychotic disorders and neurotic, stress-related and somatoform disorders) were identified through the Swedish National Hospital Discharge Register. Cox proportional hazards models were used to assess the influence of cardiovascular fitness at conscription and risk of serious non-affective mental disorders later in life. RESULTS: Low fitness was associated with increased risk for schizophrenia and schizophrenia-like disorders [hazard ratio (HR) 1.44, 95% confidence interval (CI) 1.29-1.61], other psychotic disorders (HR 1.41, 95% CI 1.27-1.56), and neurotic or stress-related and somatoform disorders (HR 1.45, 95% CI 1.37-1.54). Relationships persisted in models that included illness in brothers. CONCLUSIONS: Lower fitness in late adolescent males is associated with increased risk of serious non-affective mental disorders in adulthood.

Cardiovascular fitness in early adulthood and future suicidal behaviour in men followed for up to 42 years.

BACKGROUND: Cardiovascular fitness influences many aspects of brain function. However, the relationship between cardiovascular fitness and suicidal behaviour is unknown. Therefore, we aimed to determine whether cardiovascular fitness at age 18 years is associated with future risk of suicide attempt/death. METHOD: We performed a population-based Swedish longitudinal cohort study of male conscripts with no previous or ongoing mental illness (n = 1,136,527). The conscription examination, which took place during 1968-2005, included the cycle ergonometric test and tests of cognitive performance. Future risk of suicide attempt/death over a 5- to 42-year follow-up period was calculated with Cox proportional hazards models controlling for several confounders including familial factors. RESULTS: At least one suicide attempt was recorded for 12,563 men. Death by suicide without a prior attempt was recorded in 4814 additional individuals. In fully adjusted models low cardiovascular fitness was associated with increased risk for future attempt/death by suicide [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.64-1.94]. The HR changed only marginally after exclusion of persons who received in-patient care for depression (HR 1.76, 95% CI 1.61-1.94). Poor performance on both the cardiovascular fitness and cognitive tests was associated with a fivefold increased risk of suicide attempt or suicide death (HR 5.46, 95% CI 4.78-6.24). CONCLUSIONS: Lower cardiovascular fitness at age 18 years was, after adjustment for a number of potential confounders, associated with an increased risk of attempt/death by suicide in adulthood. It remains to be clarified whether interventions designed to improve fitness in teens can influence the risk of suicidal behaviour later in life.

Grafting of neural stem and progenitor cells to the hippocampus of young, irradiated mice causes gliosis and disrupts the granule cell layer.

Ionizing radiation persistently reduces the pool of neural stem and progenitor cells (NSPCs) in the dentate gyrus (DG) of the hippocampus, which may explain some of the learning deficits observed in patients treated with radiotherapy, particularly pediatric patients. A single dose of 8 Gy irradiation (IR) was administered to the brains of postnatal day 14 (P14) C57BL/6 mice and 1.0 × 10(5) bromodeoxyuridine-labeled, syngeneic NSPCs were injected into the hippocampus 1 day, 1 week or 6 weeks after IR. Cell survival and phenotype were evaluated 5 weeks after grafting. When grafted 1 day post-IR, survival and neuronal differentiation of the transplanted NSPCs were lower in irradiated brains, whereas the survival and cell fate of grafted cells were not significantly different between irradiated and control brains when transplantation was performed 1 or 6 weeks after IR. A young recipient brain favored neuronal development of grafted cells, whereas the older recipient brains displayed an increasing number of cells developing into astrocytes or unidentified cells. Injection of NSPCs, but not vehicle, induced astrogliosis and reduced thickness of the dorsal blade of the GCL after 5 months. In summary, we demonstrate that age and interval between IR and grafting can affect survival and differentiation of grafted NSPCs. The observed long-term gliosis and degeneration warrant caution in the context of NSPC grafting for therapeutical purposes.

Expression of ezrin radixin moesin proteins in the adult subventricular zone and the rostral migratory stream.

Continuous proliferation occurs in the adult subventricular zone (SVZ) of the lateral ventricles throughout life. In the SVZ, progenitor cells differentiate into neuroblasts, which migrate tangentially along the rostral migratory stream (RMS) to reach their final destination in the olfactory bulb. These progenitor cells mature and integrate into the existing neural network of the olfactory bulb. Long distance migration of neuroblasts in the RMS requires a highly dynamic cytoskeleton with the ability to respond to surrounding stimuli. Radixin is a member of the ERM (Ezrin, Radixin, Moesin) family, which connect the actin cytoskeleton to the extracellular matrix through transmembrane proteins. The membrane-cytoskeleton linker proteins of the ERM family may regulate cellular events with a high demand on cytoskeleton plasticity, such as cell motility. Recently, specific expression of the ERM protein ezrin was shown in the RMS. Radixin however has not been characterized in this region. Here we used immunohistochemistry and confocal microscopy to examine the expression of radixin in the different cell types of the adult subventricular zone niche and in the RMS. Our findings indicate that radixin is strongly expressed in neuroblasts of the adult RMS and subventricular zone, and also in Olig2-positive cells. We also demonstrate the presence of radixin in the cerebral cortex, striatum, cerebellum, thalamus, hippocampus as well as the granular and periglomerular layers of the olfactory bulb. Our studies also reveal the localization of radixin in neurosphere culture studies and we reveal the specificity of our labeling using Western blotting. The expression pattern demonstrated here suggests a role for radixin in neuronal migration and differentiation in the adult RMS. Understanding how adult neuronal migration is regulated is of importance for the development of new therapeutic interventions using endogenous repair for neurodegenerative diseases.

Apoptosis-inducing factor deficiency decreases the proliferation rate and protects the subventricular zone against ionizing radiation.

Cranial radiotherapy in children often leads to progressive cognitive decline. We have established a rodent model of irradiation-induced injury to the young brain. A single dose of 8 Gy was administered to the left hemisphere of postnatal day 10 (P10) mice. Harlequin (Hq) mice, carrying the hypomorphic apoptosis-inducing factor AIF(Hq) mutation, express 60% less AIF at P10 and displayed significantly fewer dying cells in the subventricular zone (SVZ) 6 h after IR, compared with wild type (Wt) littermates. Irradiated cyclophilin A-deficient (CypA(-/-)) mice confirmed that CypA has an essential role in AIF-induced apoptosis after IR. Hq mice displayed no reduction in SVZ size 7 days after IR, whereas 48% of the SVZ was lost in Wt mice. The proliferation rate was lower in the SVZ of Hq mice. Cultured neural precursor cells from the SVZ of Hq mice displayed a slower proliferation rate and were more resistant to IR. IR preferentially kills proliferating cells, and the slower proliferation rate in the SVZ of Hq mice may, at least partly, explain the protective effect of the Hq mutation. Together, these results indicate that targeting AIF may provide a fruitful strategy for protection of normal brain tissue against the detrimental side effects of IR.

Preweaning enrichment has no lasting effects on adult hippocampal neurogenesis in four-month-old mice.

Since both living in an enriched environment and physical activity stimulate hippocampal neurogenesis in adult mice, we endeavored to examine whether pre-weaning enrichment, a sensory enrichment paradigm with very limited physical activity, had similar effects on neurogenesis later in life. Mice were removed from the dams for periods of increasing length from post-natal day 7 to 21, and exposed to a variety of sensory stimuli. At the age of 4 months, significant differences could be found between previously enriched and nonenriched animals when spontaneous activity was monitored. Enriched mice moved longer distances, and spent more time in a defined center zone of the open field. Adult neurogenesis was examined by labeling proliferating cells in the dentate gyrus with bromodeoxyuridine (BrdU). Cell proliferation, survival of the newborn cells, and net neurogenesis were similar in both groups. Volumetric measurements and stereological assessment of total granule cell counts revealed no difference in size of the dentate gyrus between both groups. Thus, in contrast to postweaning enrichment, preweaning enrichment had no lasting measurable effect on adult neurogenesis. One of the parameters responsible for this effect might be the lack of physical activity in preweaning enrichment. As physical activity is an integral part of postweaning enrichment, it might be a necessary factor to elicit a neurogenic response to environmental stimuli. The result could also imply that baseline adult hippocampal neurogenesis is independent of the changes induced by preweaning enrichment and might not contribute to the sustained types of plasticity seen in enriched animals.

Adult neurogenesis: a compensatory mechanism for neuronal damage.

It is now evident that the adult vertebrate brain including the human brain is efficiently and continuously generating new neurons. In the first part we describe the current view of how neurons are generated in the adult brain and the possible compensatory reactions to pathological situations in which neuronal damage might stimulate neural stem cell activity. In the second part, we discuss the current knowledge on the signals and cells involved in the process of neurogenesis. This knowledge is important because any neuronal replacement strategy depends on our ability to induce or modulate each step on the way to a new neuron: stem cell proliferation, cell fate determination, progenitor migration, and differentiation into specific neuronal phenotypes. Identification of the molecular signals that control these events are essential for the application of neural stem cell biology to develop repair strategies for neurodegenerative disorders.

Analysis of neurogenesis and programmed cell death reveals a self-renewing capacity in the adult rat brain.

The adult central nervous system was thought to be very limited in its regenerative potential; however, the discovery that stem cell populations produce neurons in the adult brain highlights the dynamics of a previously assumed 'static' organ. The continuous generation of new neurons in the adult brain, nevertheless, leads to the question of whether neurogenesis is counterbalanced by an accompanying cell death in the same regions. The objective of this study was to stereologically analyze neurogenesis and programmed cell death in adult brain regions with known neurogenic activity. Using bromodeoxyuridine (BrdU) to identify newborn cells we find that within a few days of BrdU-labeling the adult dentate gyrus and olfactory bulb generate high numbers of newborn neurons. More importantly, dUTP-nick end labeling (TUNEL) reveals that areas of adult neurogenesis also contain high numbers of apoptotic cells. We conclude that programmed cell death may have an important regulatory function by eliminating supernumerous cells from neurogenic regions and may thus contribute to a self-renewal mechanism in the adult mammalian brain.

Proliferation and differentiation of progenitor cells throughout the intact adult rat spinal cord.

The existence of multipotent progenitor populations in the adult forebrain has been widely studied. To extend this knowledge to the adult spinal cord we have examined the proliferation, distribution, and phenotypic fate of dividing cells in the adult rat spinal cord. Bromodeoxyuridine (BrdU) was used to label dividing cells in 13- to 14-week-old, intact Fischer rats. Single daily injections of BrdU were administered over a 12 d period. Animals were killed either 1 d or 4 weeks after the last injection of BrdU. We observed frequent cell division throughout the adult rodent spinal cord, particularly in white matter tracts (5-7% of all nuclei). The majority of BrdU-labeled cells colocalized with markers of immature glial cells. At 4 weeks, 10% of dividing cells expressed mature astrocyte and oligodendroglial markers. These data predict that 0.75% of all astrocytes and 0.82% of all oligodendrocytes are derived from a dividing population over a 4 week period. To determine the migratory nature of dividing cells, a single BrdU injection was given to animals that were killed 1 hr after the injection. In these tissues, the distribution and incidence of BrdU labeling matched those of the 4 week post injection (pi) groups, suggesting that proliferating cells divide in situ rather than migrate from the ependymal zone. These data suggest a higher level of cellular plasticity for the intact spinal cord than has previously been observed and that glial progenitors exist in the outer circumference of the spinal cord that can give rise to both astrocytes and oligodendrocytes.

Origins, functions, and potential of adult neural stem cells.

In recent years, the existence of neural stem cells (NSCs) in the adult mammalian brain has been confirmed. The generation of new neurons from these cells is regulated by growth factors, hormones, and environmental cues; however, the function of newly generated neurons in the adult brain remains elusive. Two recent articles emphasize the impact of motor activity and learning on in situ hippocampal neurogenesis,((1,2)) suggesting a close link to hippocampal function. Adult NSCs can be isolated and expanded in vitro. It was presumed that the origins of the NSCs were within subependyma of the lateral ventricle; however, new evidence suggests that the "real" stem cells may reside in the ependymal lining.((3)) In a related study, these same cells were transplanted into irradiated mice and were able to integrate into the bone marrow and produce various blood cell types,((4)) challenging the limits of neural cell fate determination.

[New nerve cells for the adult brain. Adult neurogenesis and stem cell concepts in neurologic research]. / Neue Nervenzellen für das erwachsene Gehirn. Adulte Neurogenese und Stammzellkonzepte in der neurologischen Forschung.

A growing branch of neuroscience is investigating conditions that permit neurogenesis in the adult brain. Partially, this aims at using the neuroectodermal stem or precursor cells that persist in the adult brain to induce neuroregenerative processes in the treatment for neurologic disorders. In ex vivo approaches, isolated precursor cells are implanted into the host brain, while in vivo concepts favor a stimulation of precursor cells in situ.

Experience-induced neurogenesis in the senescent dentate gyrus.

We demonstrate here that under physiological conditions neurogenesis continues to occur in the dentate gyrus of senescent mice and can be stimulated by living in an enriched environment. Neurogenesis was investigated by confocal microscopy of three-channel immunofluorescent staining for the proliferation marker bromodeoxyuridine (BrdU) and neuronal and glial markers. Quantification was performed with unbiased stereological counting techniques. Neurogenesis decreased with increasing age. Stimulation of adult and aged mice by switching from standard housing to an enriched environment with opportunities for social interaction, exploration, and physical activity for 68 d resulted in an increased survival of labeled cells. Phenotypic analysis revealed that, in enriched living animals, relatively more cells differentiated into neurons, resulting in a threefold net increase of BrdU-labeled neurons in 20-month-old mice (105 vs 32 cells) and a more than twofold increase in 8-month-old mice (684 vs 285 cells) compared with littermates living under standard laboratory conditions. Corresponding absolute numbers of BrdU-positive astrocytes and BrdU-positive cells that did not show colabeling for neuronal or glial markers were not influenced. The effect on the relative distribution of phenotypes can be interpreted as a survival-promoting effect that is selective for neurons. Proliferation of progenitor cells appeared unaffected by environmental stimulation.

Genetic influence on neurogenesis in the dentate gyrus of adult mice.

To address genetic influences on hippocampal neurogenesis in adult mice, we compared C57BL/6, BALB/c, CD1(ICR), and 129Sv/J mice to examine proliferation, survival, and differentiation of newborn cells in the dentate gyrus. Proliferation was highest in C57BL/6; the survival rate of newborn cells was highest in CD1. In all strains approximately 60% of surviving newborn cells had a neuronal phenotype, but 129/SvJ produced more astrocytes. Over 6 days C57BL/6 produced 0.36% of their total granule cell number of 239,000 as new neurons, BALB/c 0.30% of 242,000, CD1 (ICR) 0.32% of 351,000, and 129/SvJ 0.16% of 280,000. These results show that different aspects of adult hippocampal neurogenesis are differentially influenced by the genetic background.

Epidermal growth factor and fibroblast growth factor-2 have different effects on neural progenitors in the adult rat brain.

Neurons and glia are generated throughout adulthood from proliferating cells in two regions of the rat brain, the subventricular zone (SVZ) and the hippocampus. This study shows that exogenous basic fibroblast growth factor (FGF-2) and epidermal growth factor (EGF) have differential and site-specific effects on progenitor cells in vivo. Both growth factors expanded the SVZ progenitor population after 2 weeks of intracerebroventricular administration, but only FGF-2 induced an increase in the number of newborn cells, most prominently neurons, in the olfactory bulb, the normal destination for neuronal progenitors migrating from the SVZ. EGF, on the other hand, reduced the total number of newborn neurons reaching the olfactory bulb and substantially enhanced the generation of astrocytes in the olfactory bulb. Moreover, EGF increased the number of newborn cells in the striatum either by migration of SVZ cells or by stimulation of local progenitor cells. No evidence of neuronal differentiation of newborn striatal cells was found by three-dimensional confocal analysis, although many of these newborn cells were associated closely with striatal neurons. The proliferation of hippocampal progenitors was not affected by either growth factor. However, EGF increased the number of newborn glia and reduced the number of newborn neurons, similar to the effects seen in the olfactory bulb. These findings may be useful for elucidating the in vivo role of growth factors in neurogenesis in the adult CNS and may aid development of neuronal replacement strategies after brain damage.

More hippocampal neurons in adult mice living in an enriched environment.

Neurogenesis occurs in the dentate gyrus of the hippocampus throughout the life of a rodent, but the function of these new neurons and the mechanisms that regulate their birth are unknown. Here we show that significantly more new neurons exist in the dentate gyrus of mice exposed to an enriched environment compared with littermates housed in standard cages. We also show, using unbiased stereology, that the enriched mice have a larger hippocampal granule cell layer and 15 per cent more granule cell neurons in the dentate gyrus.

Reversible Schwann cell hyperplasia and sprouting of sensory and sympathetic neurites after intraventricular administration of nerve growth factor.

Substantial dysfunction and loss of cholinergic neurons occur in Alzheimer's disease (AD). Nerve growth factor (NGF) is a potent neurotrophic factor for cholinergic basal forebrain neurons, and the use of NGF to stimulate residual dysfunctional cells in AD is being considered. To define the effects of NGF on other cell populations in the brain, NGF was continuously infused into the lateral ventricle of rats for 7 weeks. At the end of treatment, Schwann cell hyperplasia and abundant sensory and sympathetic neurite sprouting were observed in the subpial region of the medulla oblongata and the spinal cord. Following withdrawal of NGF, the Schwann cell hyperplasia and sprouting of sensory and sympathetic neurites disappeared completely. These findings suggest that better temporal and spatial delivery systems for NGF must be explored to limit potential undesirable side effects while maintaining the survival and function of diseased basal forebrain cholinergic neurons.

Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation.

The hippocampus is one of the few areas of the rodent brain that continues to produce neurons postnatally. Neurogenesis reportedly persists in rats up to 11 months of age. Using bromodeoxyuridine (BrdU) labeling, the present study confirms that in the adult rat brain, neuronal progenitor cells divide at the border between the hilus and the granule cell layer (GCL). In adult rats, the progeny of these cells migrate into the GCL and express the neuronal markers NeuN and calbindin-D28k. However, neurogenesis was drastically reduced in aged rats. Six-to 27-month-old Fischer rats were injected intraperitoneally with BrdU to detect newborn cells in vivo and to follow their fate in the dentate gyrus. When killed 4-6 weeks after BrdU labeling, 12- to 27-month-old rats exhibited a significant decline in the density of BrdU-positive cells in the granule cell layer compared with 6-month-old controls. Decreased neurogenesis in aging rats was accompanied by reduced immunoreactivity for poly-sialylated neural cell adhesion molecule, a molecule that is involved in migration and process elongation of developing neurons. When animals were killed immediately (12 hr) after BrdU injection, significantly fewer labeled cells were observed in the GCL and adjacent subgranular zone of aged rats, indicative of a decrease in mitotic activity of neuronal precursor cells. The reduced proliferation was not attributable to a general aged-related metabolic impairment, because the density of BrdU-positive cells was not altered in other brain regions with known mitotic activity (e.g., hilus and lateral ventricle wall). The decline in neurogenesis that occurs throughout the lifespan of an animal can thus be related to a decreasing proliferation of granule cell precursors.

Survival and differentiation of adult neuronal progenitor cells transplanted to the adult brain.

The dentate gyrus of the hippocampus is one of the few areas of the adult brain that undergoes neurogenesis. In the present study, cells capable of proliferation and neurogenesis were isolated and cultured from the adult rat hippocampus. In defined medium containing basic fibroblast growth factor (FGF-2), cells can survive, proliferate, and express neuronal and glial markers. Cells have been maintained in culture for 1 year through multiple passages. These cultured adult cells were labeled in vitro with bromodeoxyuridine and adenovirus expressing beta-galactosidase and were transplanted to the adult rat hippocampus. Surviving cells were evident through 3 months postimplantation with no evidence of tumor formation. Within 2 months postgrafting, labeled cells were found in the dentate gyrus, where they differentiated into neurons only in the intact region of the granule cell layer. Our results indicate that FGF-2 responsive progenitors can be isolated from the adult hippocampus and that these cells retain the capacity to generate mature neurons when grafted into the adult rat brain.

Differential expression of two mRNA species indicates a dual function of peripheral myelin protein PMP22 in cell growth and myelination.

Two peripheral myelin protein PMP22 transcripts, CD25 and SR13, have been identified by Northern blot and RNA-polymerase chain reaction (PCR) methods in rat. The CD25 and SR13 mRNA species (each approximately 1.8 kb in size) differ significantly in their 5'-untranslated region (5'-UTR) sequences but encode the same protein. While CD25 mRNA is largely confined to the peripheral nervous system, the SR13 transcript is more ubiquitously expressed in rat tissues. Both transcripts are differentially expressed during postnatal sciatic nerve development. While CD25 expression steadily increases from low levels in neonates up to a maximum at postnatal day 14, SR13 mRNA levels are elevated at birth but decrease throughout adulthood. CD25 and SR13 transcripts are expressed at very low constant levels in developing and adult brain. In degenerating and regenerating segments of injured peripheral nerve changes in CD25 mRNA levels clearly resemble the expression pattern of other myelin genes, whereas expression of SR13 is inversely correlated with the time course of Schwann cell proliferation. In cultured rat meningeal fibroblasts SR13 mRNA expression is strictly growth arrest-specific and independent of forskolin. On the other hand, regulation of CD25 mRNA levels in these cells is more complex with respect to interfering effects of serum and forskolin. In cultured Schwann cells neither CD25 nor SR13 expression is growth arrest-specific. However, both transcript levels are consistently enhanced by forskolin under all conditions of cell growth tested. Expression of CD25 (but not SR13) depends on high Schwann cell density. Our results substantiate the hypothesis that PMP22 serves two biological functions, one related to cell growth (SR13) and another to myelination (CD25).

[Ulcerative colitis or amebic colitis--a case report]. / Colitis ulcerosa oder Amöbenkolitis--ein kasuistischer Bericht.

The large intestine reacts relatively monomorphically to different stimuli. From this differential-diagnostic problems may result. The history of a patient is described which could be pursued retrospectively and prospectively over 14 years and during the course of which the correction of the diagnosis ulcerous colitis into chronic relapsing amoebic colitis was necessary. As a conclusion is emphasized that in every symptomatology of colitis primarily bacterial and parasitologic examinations of the faeces should be brought about and it must be also thought of spontaneous amoebic infections in our country.