Human induced pluripotent stem-derived retinal pigment epithelium (RPE) cells exhibit ion transport, membrane potential, polarized vascular endothelial growth factor secretion, and gene expression pattern similar to native RPE

Age-related macular degeneration (AMD) is one of the major causes of blindness in aging population that progresses with death of retinal pigment epithelium (RPE) and photoreceptor degeneration inducing impairment of central vision. Discovery of human induced pluripotent stem (hiPS) cells has opened new avenues for the treatment of degenerative diseases using patient-specific stem cells to generate tissues and cells for autologous cell-based therapy. Recently, RPE cells were generated from hiPS cells. However, there is no evidence that those hiPS-derived RPE possess specific RPE functions that fully distinguish them from other types of cells. Here, we show for the first time that RPE generated from hiPS cells under defined conditions exhibit ion transport, membrane potential, polarized vascular endothelial growth factor secretion, and gene expression profile similar to those of native RPE. The hiPS-RPE could therefore be a very good candidate for RPE replacement therapy in AMD. However, these cells show rapid telomere shortening, DNA chromosomal damage, and increased p21 expression that cause cell growth arrest. This rapid senescence might affect the survival of the transplanted cells in vivo and therefore, only the very early passages should be used for regeneration therapies. Future research needs to focus on the generation of "safe" as well as viable hiPS-derived somatic cells.     

Mechanism for Quinolinic Acid Cytotoxicity in Human Astrocytes and Neurons

There is growing evidence implicating the kynurenine pathway (KP) and particularly one of its metabolites, quinolinic acid (QUIN), as important contributors to neuroinflammation in several brain diseases. While QUIN has been shown to induce neuronal and astrocytic apoptosis, the exact mechanisms leading to cell death remain unclear. To determine the mechanism of QUIN-mediated excitotoxicity in human brain cells, we measured intracellular levels of nicotinamide adenine dinucleotide (NAD⁺) and poly(ADP-ribose) polymerase (PARP) and extracellular lactate dehydrogenase (LDH) activities in primary cultures of human neurons and astrocytes treated with QUIN. We found that QUIN acts as a substrate for NAD⁺ synthesis at very low concentrations (<50 nM) in both neurons and astrocytes, but is cytotoxic at sub-physiological concentrations (>150 nM) in both the cell types. We have shown that the NMDA ion channel blockers, MK801 and memantine, and the nitric oxide synthase (NOS) inhibitor, L-NAME, significantly attenuate QUIN-mediated PARP activation, NAD⁺ depletion, and LDH release in both neurons and astrocytes. An increased mRNA and protein expression of the inducible (iNOS) and neuronal (nNOS) forms of nitric oxide synthase was also observed following exposure of both cell types to QUIN. Taken together these results suggests that QUIN-induced cytotoxic effects on neurons and astrocytes are likely to be mediated by an over activation of an NMDA-like receptor with subsequent induction of NOS and excessive nitric oxide (NO^?)-mediated free radical damage. These results contribute significantly to our understanding of the pathophysiological mechanisms involved in QUIN neuro- and gliotoxicity and are relevant for the development of therapies for neuroinflammatory diseases.     

Protective role of IL‐22 against Schistosoma mansoni soluble egg antigen‐induced granuloma in Vitro

The role of T helper‐17 (Th17) lymphocytes in the regulation of Schistosoma mansoni soluble egg antigen (SEA)‐induced granuloma is unknown. This study examined the effect of Th17 cytokines (IL‐17 and IL‐22) on granulocyte recruitment and functions during SEA‐induced granuloma formation in vitro in Schistosoma‐infected and noninfected individuals. Granulocytes were isolated from 27 Schistosoma‐infected patients and 13 controls and were used for granuloma induction using SEA‐conjugated polyacrylamide beads in the presence of Th17 cytokines. Granuloma index was assessed, and granulocyte mediators such as tumour necrosis factor (TNF‐α), hydrogen peroxide (H₂O₂) and nitric oxide (NO) were measured in the culture supernatant at the 7th day using enzyme‐linked immunosorbent assay (ELISA). Schistosoma‐infected patients had significant larger SEA‐induced granuloma than controls. IL‐17 (125 pg/mL) induced the optimum size for granuloma within 3‐7 days. However, IL‐22 at different concentrations up to 300 pg/mL had no effect on granuloma formation. Using both cytokines simultaneously, IL‐22 suppressed the effect of IL‐17 and prevented granuloma formation. IL‐17 significantly decreased TNF‐α, H₂O₂ and NO levels in Schistosoma‐infected individuals. In contrast, IL‐22 increased TNF‐α and H₂O₂ levels. In conclusion, IL‐17 accelerates SEA‐induced granuloma formation and inhibits granulocytes functions in Schistosoma‐infected patients, while IL‐22 inhibited the granuloma formation, but enhanced granulocyte functions.     

Genetic and environmental factors in vascular dementia: an update of blood brain barrier dysfunction

Vascular dementia (VaD) describes a combination of both cognitive and behavioural manifestations associated with variable brain lesions of vascular origin. While vascular risk factors have been implicated in VaD, the relationship is most evident when the factors are considered together and not individually. This review will examine the significance of the integrity of blood brain barrier (BBB) tight junction (TJ) proteins – occludin and claudins in the pathophysiology of VaD. Specifically, some of the genetic contributors to VaD, namely those responsible for the integrity of the BBB, will be reviewed in detail. Moreover, environmental factors will be considered in conjunction with these genes to examine how the interaction of environmental and genetic factors contributes to one's susceptibility to VaD.     

Schizophrenia and substance abuse: prevalence issues.

A review of studies of the prevalence of substance abuse among schizophrenics suggest that both demographic and environmental factors are strong determinants of the extent of substance abuse in this population as well as the type of substances used. In a mid-sized Canadian city, a sample of schizophrenic patients referred to a dual diagnoses clinic were administered the Addiction Severity Index. With age and gender included as a factor, no significant differences were found in the choice or length of use of most drugs between diagnostic groups, contrary to some other reports from large urban centres. Compared with a population of a similar age, there were fewer regular and more former drinkers among the schizophrenic patients. The choice of other substances by the sample reflected the pattern of use in the population at large. This approach to prevalence provides a more balanced perspective of the substance abuse by schizophrenics. The major targets for prevention remain the alcohol, caffeine and tobacco consumption.     

The optimal psychiatrist-to-population ratio: a Canadian perspective

A systematic effort is underway to rationalize the planning of physician supply. This paper summarizes the current methodologies available and focuses on the attempts to determine the optimal psychiatrist-to-population ratio in Canada. The impact of several variables influencing this ratio is discussed. An outline of the correlation between target physician supply and requirements of future trainees is presented. While the relevant methodology is rapidly evolving, an improved process of data collection is urgently required. A number of challenges for our profession lay ahead, such as the need for sensitive and reliable measures of the adequacy of psychiatrist and subspecialist supply and public issues arising from the poor geographic distribution of psychiatric manpower.     

Using measures of readiness to change in individuals with schizophrenia

The literature suggests that substance abuse treatment for schizophrenia patients should consider both the patients' readiness for active treatment and matching phases of intervention with phases of the patient's acceptance of his or her dual problems. This study assessed the suitability of existing measures of "readiness to change" for use with individuals with schizophrenia. Outpatients (n = 39) with a diagnosis of schizophrenia and alcohol and/or drug dependency or abuse were given three measures to assess the stage of readiness to change. Results suggested that there was no agreement between stages defined by the interviewer and stages defined by self-report. This has implications for assessing readiness to change in terms of substance use in a population with schizophrenia.