Specialist and Patient Perspectives on Strategies to Improve Cardiovascular Disease Prevention Among Persons Living with Psoriatic Disease.

Background: Psoriasis is an immune-mediated disease associated with excess risk for cardiovascular disease (CVD). Guidelines recognize psoriasis as a CVD risk enhancer; however, psoriasis patients often do not have CVD risk factors identified nor managed. Objective: This study examines strategies to improve CVD prevention care from the perspective of dermatologists and patients with psoriasis. Methods: Qualitative interviews were conducted using the Consolidated Framework for Implementation Research to examine the perspectives of physicians (N = 16) and patients with psoriatic disease (N = 16) on barriers/facilitators to CVD prevention. Interviews were transcribed and coded using an integrated approach designed to enhance reliability and validity using NVivo software. Results: We found three major themes suggesting areas to target for the future: (1) Appropriateness: perceptions of whether CVD care should be deployed in this setting by both clinicians and patients, (2) Feasibility: whether CVD prevention care could be integrated into the current structure of specialist practice, and (3) Care Coordination: an interest by all parties to better integrate a team approach in CVD preventative care to reduce duplicative efforts, work practically in an already existing system rather than reinventing the wheel, and progress with the patients' best interests in mind. Conclusions: These findings will inform the design of a clinical trial comparing the effectiveness of specialist clinician implementation of CVD guideline-based prevention care in patients with psoriasis. Ultimately, this study aims to increase the lifespan and health of patients living with psoriatic disease by decreasing barriers to their receiving appropriate CVD prevention care.

H3K9 methyltransferases and demethylases control lung tumor-propagating cells and lung cancer progression.

Epigenetic regulators are attractive anticancer targets, but the promise of therapeutic strategies inhibiting some of these factors has not been proven in vivo or taken into account tumor cell heterogeneity. Here we show that the histone methyltransferase G9a, reported to be a therapeutic target in many cancers, is a suppressor of aggressive lung tumor-propagating cells (TPCs). Inhibition of G9a drives lung adenocarcinoma cells towards the TPC phenotype by de-repressing genes which regulate the extracellular matrix. Depletion of G9a during tumorigenesis enriches tumors in TPCs and accelerates disease progression metastasis. Depleting histone demethylases represses G9a-regulated genes and TPC phenotypes. Demethylase inhibition impairs lung adenocarcinoma progression in vivo. Therefore, inhibition of G9a is dangerous in certain cancer contexts, and targeting the histone demethylases is a more suitable approach for lung cancer treatment. Understanding cellular context and specific tumor populations is critical when targeting epigenetic regulators in cancer for future therapeutic development.

Microglial responses around intrinsic CNS neurons are correlated with axonal regeneration.

BACKGROUND: Microglia/macrophages and lymphocytes (T-cells) accumulate around motor and primary sensory neurons that are regenerating axons but there is little or no microglial activation or T-cell accumulation around axotomised intrinsic CNS neurons, which do not normally regenerate axons. We aimed to establish whether there was an inflammatory response around the perikarya of CNS neurons that were induced to regenerate axons through a peripheral nerve graft. RESULTS: When neurons of the thalamic reticular nucleus (TRN) and red nucleus were induced to regenerate axons along peripheral nerve grafts, a marked microglial response was found around their cell bodies, including the partial enwrapping of some regenerating neurons. T-cells were found amongst regenerating TRN neurons but not rubrospinal neurons. Axotomy alone or insertion of freeze-killed nerve grafts did not induce a similar perineuronal inflammation. Nerve grafts in the corticospinal tracts did not induce axonal regeneration or a microglial or T-cell response in the motor cortex. CONCLUSIONS: These results strengthen the evidence that perineuronal microglial accumulation (but not T-cell accumulation) is involved in axonal regeneration by intrinsic CNS and other neurons.

Vaginal wet mounts on asymptomatic adolescent females; are they beneficial?

BACKGROUND: Wet mounts are commonly performed at the time of pelvic exam in some settings; however, there is a paucity of data on their usefulness in asymptomatic teen patients. OBJECTIVE: To determine if wet mounts in asymptomatic teen women are useful in detecting gonorrhea or chlamydia, when compared with DNA amplification testing. DESIGN AND METHODS: 93 consecutive charts for asymptomatic adolescent female patients seen for a routine visit were retrospectively reviewed. Data was collected for vaginal pH, presence or absence of discharge on physical exam, appearance of cervix, wet mount results, and cervical testing results. Outcome measures were wet mount findings and result of DNA amplification test on cervical sample for gonorrhea and chlamydia RESULTS: Wet mounts were abnormal in 29 (31.2%) patients. There was no significant relationship between abnormal wet mount and positive Neisseria gonorrhoeae and Chlamydia trachomatis cultures (P = 0.083). After excluding abnormal wet mounts due to Trichomonas vaginalis, BV or Candida, all remaining patients with positive N gonorrhoeae and C trachomatis had normal wet mounts. For N gonorrhoeae, the wet mount had a sensitivity of 0% and specificity of 92.6%. For C trachomatis, the wet mount had a sensitivity of 0% and specificity of 92.1%. CONCLUSION: Wet mounts were not useful to detect N gonorrhoeae and C trachomatis in asymptomatic teen patients. The finding of T vaginalis and BV in these asymptomatic patients may justify continuing wet mount evaluation but this practice needs further study to determine if treatment in this population will result in clinically significant effects.

Soluble receptor for advanced glycation end products in multiple sclerosis: a potential marker of disease severity.

OBJECTIVES: To compare serum levels of the receptor for advanced glycation end products (sRAGE) between multiple sclerosis (MS) patients and healthy control subjects, and to investigate whether serum sRAGE levels correlate with MS disease severity as indicated by the Kurtzke Expanded Disability Status Scale (EDSS). METHOD: 37 patients with clinical diagnosis of MS and 22 healthy control subjects were investigated in a cross-sectional study using enzyme-linked immunosorbent assays (ELISA). RESULTS: Serum levels of sRAGE were found to be significantly lower in MS patients compared to levels in healthy controls (p = 0.005). A trend toward lower levels of serum sRAGE was observed in female MS patients compared to their male counterparts (p = 0.05). A relationship between sRAGE and EDSS, and sRAGE and rate of clinical relapse was observed (p = 0.012). CONCLUSION: The significant reduction of sRAGE in MS patients relative to healthy controls supports the potential role for RAGE axis in MS clinical pathology. Lower levels of sRAGE may be associated with enhanced inflammatory responses. Based on these observations, further investigations into the role of sRAGE in MS clinical pathology is warranted.

Reassignment of the murine 3'TRDD1 recombination signal sequence.

T cell receptor genes are assembled in developing T lymphocytes from discrete V, D, and J genes by a site-specific somatic rearrangement mechanism. A flanking recombination signal, composed of a conserved heptamer and a semiconserved nonamer separated by 12 or 23 variable nucleotides, targets the activity of the rearrangement machinery to the adjoining V, D, and J genes. Following the rearrangement of V, D, or J genes, their respective recombination signals are ligated together. Although these signal joints are allegedly invariant, created by the head-to-head abuttal of the heptamers, some do exhibit junctional diversity. Recombination signals were initially identified by comparison and alignment of germ-line sequences with the sequence of rearranged genes. However, their overall low level of sequence conservation makes their characterization solely from sequence data difficult. Recently, computational analysis unraveled correlations between nucleotides at several positions scattered within the spacer and recombination activity, so that it is now possible to identify putative recombination signals and determine and predict their recombination efficiency. In this paper, we analyzed the variability introduced in signal joints generated after rearrangement of the TRDD1 and TRDD2 genes in murine thymocytes. The recurrent presence of identical nucleotides inserted in these signal joints led us to reconsider the location and sequence of the TRDD1 recombination signal. By combining molecular characterization and computational analysis, we show that the functional TRDD1 recombination signal is shifted inside the putative coding sequence of the TRDD1 gene and, consequently, that this gene is shorter than indicated in the databases.

Distribution and expression of tissue inhibitors of metalloproteinase in dorsal root entry zone and dorsal column after dorsal root injury.

To understand whether tissue inhibitors of metalloproteinase (TIMPs) contribute to the failure of regenerating sensory axons to enter the spinal cord, we used in situ hybridization and immunocytochemistry to examine the expression of TIMP1, TIMP2, and TIMP3 in the dorsal root, dorsal root entry zone (DREZ), and dorsal column after dorsal root injury in adult rats. We found that the three TIMPs and their mRNAs were up-regulated in a time-, region-, and cell-type-specific manner. Strong up-regulation of all three TIMPs was seen in the injured dorsal roots. TIMP2 was also significantly up-regulated in the DREZ and degenerating dorsal column, where TIMP1 and TIMP3 showed only moderate up-regulation. Most cells up-regulating the TIMPs in the DREZ and degenerating dorsal column were reactive astrocytes, but TIMP2 was also up-regulated by microglia/macrophages, especially at long postoperative survival times. These results suggest that TIMPs may be involved in controlling tissue remodelling following dorsal root injury and that manipulation of the expression of TIMPs may provide a means of promoting axonal regeneration into and within the injured spinal cord.

Patterns of expression of brain-derived neurotrophic factor and tyrosine kinase B mRNAs and distribution and ultrastructural localization of their proteins in the visual pathway of the adult rat.

We have examined the cellular and subcellular distribution and the patterns of expression of brain-derived neurotrophic factor (BDNF), and of its high affinity receptor, tyrosine kinase B (TrkB), in retinorecipient regions of the brain, including the superior colliculus, the lateral geniculate nucleus and the olivary pretectal nucleus. In the retinorecipient layers of the superior colliculus, BDNF protein and mRNA were present in the cell bodies of a subpopulation of neurons, and BDNF protein was present in the neuropil as punctate or fiber-like structures. In the lateral geniculate nucleus, however, BDNF mRNA was not detected, and BDNF protein was restricted to punctate and fiber-like structures in the neuropil, especially in the most superficial part of the dorsal lateral geniculate nucleus, just below the optic tract. At the ultrastructural level, BDNF protein was localized predominantly to axon terminals containing round synaptic vesicles and pale mitochondria with irregular cristae, which made asymmetric (Gray type I) synaptic specializations (R-boutons). Enucleation of one eye was followed by loss of BDNF immunoreactivity and disappearance of BDNF-positive R-boutons in the contralateral visual centers, confirming the retinal origin of at least most of these terminals. TrkB was present in postsynaptic densities apposed to immunoreactive R-boutons in the superior colliculus and lateral geniculate nucleus, and was also associated with axonal and dendritic microtubules. These findings suggest that BDNF is synthesized by a subpopulation of retinal ganglion cells and axonally transported to visual centers where this neurotrophin is assumed to play important roles in visual system maintenance and/or in modulating the excitatory retinal input to neurons in these centers.

Effects of lipopolysaccharide-induced inflammation on expression of growth-associated genes by corticospinal neurons.

BACKGROUND: Inflammation around cell bodies of primary sensory neurons and retinal ganglion cells enhances expression of neuronal growth-associated genes and stimulates axonal regeneration. We have asked if inflammation would have similar effects on corticospinal neurons, which normally show little response to spinal cord injury. Lipopolysaccharide (LPS) was applied onto the pial surface of the motor cortex of adult rats with or without concomitant injury of the corticospinal tract at C4. Inflammation around corticospinal tract cell bodies in the motor cortex was assessed by immunohistochemistry for OX42 (a microglia and macrophage marker). Expression of growth-associated genes c-jun, ATF3, SCG10 and GAP-43 was investigated by immunohistochemistry or in situ hybridisation. RESULTS: Application of LPS induced a gradient of inflammation through the full depth of the motor cortex and promoted c-Jun and SCG10 expression for up to 2 weeks, and GAP-43 upregulation for 3 days by many corticospinal neurons, but had very limited effects on neuronal ATF3 expression. However, many glial cells in the subcortical white matter upregulated ATF3. LPS did not promote sprouting of anterogradely labelled corticospinal axons, which did not grow into or beyond a cervical lesion site. CONCLUSION: Inflammation produced by topical application of LPS promoted increased expression of some growth-associated genes in the cell bodies of corticospinal neurons, but was insufficient to promote regeneration of the corticospinal tract.

Depression in Parkinson's disease -- a review.

Major depression is present, at any given time, in 20-40% of Parkinson's disease (PD) patients, several times the prevalence in the general population. In addition, depression may precede the diagnosis of PD. These observations and reports of depression during deep brain stimulation of regions contiguous to the substantia nigra, as well as reports of dopamine agonist improving depression, suggest depression, rather than being mainly a psychological reaction to a debilitating disease, is part of PD. It is postulated that mesolimbic and mesocortical dopaminergic pathways that mediate affect, behavior, and cognition, contribute to depression in PD.

Growth-associated protein GAP-43 and L1 act synergistically to promote regenerative growth of Purkinje cell axons in vivo.

Neuronal expression of growth-associated protein 43 (GAP-43) and the cell adhesion molecule L1 has been correlated with CNS axonal growth and regeneration, but it is not known whether expression of these molecules is necessary for axonal regeneration to occur. We have taken advantage of the fact that Purkinje cells do not express GAP-43 or L1 in adult mammals or regenerate axons into peripheral nerve grafts to test the importance of these molecules for axonal regeneration in vivo. Transgenic mice were generated in which Purkinje cells constitutively express L1 or both L1 and GAP-43 under the Purkinje cell-specific L7 promoter, and regeneration of Purkinje cell axons into peripheral nerve grafts implanted into the cerebellum was examined. Purkinje cells expressing GAP-43 or L1 showed minor enhancement of axonal sprouting. Purkinje cells expressing both GAP-43 and L1 showed more extensive axonal sprouting and axonal growth into the proximal portion of the graft. When a predegenerated nerve graft was implanted into double-transgenic mice, penetration of the graft by Purkinje cell axonal sprouts was strongly enhanced, and some axons grew along the entire intracerebral length of the graft (2.5-3.0 mm) and persisted for several months. The results demonstrate that GAP-43 and L1 coexpressed in Purkinje cells can act synergistically to switch these regeneration-incompetent CNS neurons into a regeneration-competent phenotype and show that coexpression of these molecules is a key regulator of the regenerative ability of intrinsic CNS neurons in vivo.

Can Alzheimer's type pathology influence the clinical phenotype of Parkinson's disease?

OBJECTIVES: Patients with clinical and pathological diagnosis of Parkinson's disease (PD) may, at death, also be found to have the pathological changes of Alzheimer's disease (AD). With this study we aim to determine the influence of AD pathology on the clinical phenotype of PD. METHODS: We studied 64 patients who donated their brains to the University of Miami Brain Endowment Bank(TM) and fulfilled the clinical and pathological criteria for PD. For the evaluation of AD pathology we used the CERAD criteria. Dementia was diagnosed, in life, also using standard criteria. Case histories were abstracted and reviewed by one investigator (SP) who then made comparisons between patients. RESULTS: Patients with AD pathology (PD-AD) were older both at the time of diagnosis and death. The presence of AD pathology did not seem to influence disease duration in our cohort of PD patients. As expected there was a clear relation between AD pathology and dementia but not all PD-AD patients were demented. Psychosis and depression were also found to be more prevalent in the PD-AD patients. In the comparison between demented and non-demented PD-AD patients dementia was more likely to appear in patients with PD and definite criteria for AD. CONCLUSION: Apart from dementia AD pathology seems to be associated with a number of other clinical characteristics of PD.

Dementia in Parkinson's disease: a post-mortem study in a population of brain donors.

OBJECTIVE: To identify factors associated with dementia in a cohort of Parkinson's disease (PD) brain donors and determine whether its presence may influence the clinical phenotype of the disease. METHODS: We included 67 consecutive patients with a clinical and pathological diagnosis of PD, who while alive, consented to donate their brains to the University of Miami Brain Endowment Bank(TM). Dementia and psychiatric complications of PD were diagnosed according to established criteria. Case histories were abstracted and reviewed and comparisons between PD patients with (PD-D, n = 34) and without (PD, n = 33) dementia were made. RESULTS: Age at death, age at disease onset and disease duration did not differ significantly between PD-D and PD patients. Other symptoms were similar in both groups. Visual hallucinations and bilateral symptoms at diagnosis were significantly higher in PD-D patients. No association between dementia and overall survival duration was found. Although the frequency of depression and psychosis was higher in the PD patients with dementia no statistical significance was reached. The overall lifetime prevalence of dementia in our group was 50.7%. CONCLUSIONS: Visual hallucinations and bilateral symptoms were associated with dementia in our cohort of PD brain donors. No association between dementia and survival duration was found. Understanding the influence of dementia on the clinical phenotype of the disease and predicting its development is essential for the successful management of PD.

Upregulation of activating transcription factor 3 (ATF3) by intrinsic CNS neurons regenerating axons into peripheral nerve grafts.

The expression of the transcription factor ATF3 in the brain was examined by immunohistochemistry during axonal regeneration induced by the implantation of pieces of peripheral nerve into the thalamus of adult rats. After 3 days, ATF3 immunoreactivity was present in many cells within approximately 500 mum of the graft. In addition, ATF3-positive cell nuclei were found in the thalamic reticular nucleus (TRN) and medial geniculate nuclear complex (MGN), from which most regenerating axons originate. CNS cells with ATF3-positive nuclei were predominantly neurons and did not show signs of apoptosis. The number of ATF3-positive cells had declined by 7 days and further by 1 month after grafting when most ATF3-positive cells were found in the TRN and MGN. 14 days or more after grafting, some ATF3-positive nuclei were distorted and may have been apoptotic. In some experiments of 1 month duration, neurons which had regenerated axons to the distal ends of grafts were retrogradely labeled with DiAsp. ATF3-positive neurons in these animals were located in regions of the TRN and MGN containing retrogradely labeled neurons and the great majority were also labeled with DiAsp. SCG10 and c-Jun were found in neurons in the same regions as retrogradely labeled and ATF3-positive cells. Thus, ATF3 is transiently upregulated by injured CNS neurons, but prolonged expression is part of the pattern of gene expression associated with axonal regeneration. The co-expression of ATF3 with c-jun suggests that interactions between these transcription factors may be important for controlling the program of gene expression necessary for regeneration.

Massive symptomatic subependymoma of the lateral ventricles: case report and review of the literature.

Subependymomas are benign intraventricular tumors with an indolent growth pattern, which are usually asymptomatic, and most commonly occur in the fourth and lateral ventricles. When symptomatic, subependymomas often obstruct critical portions of the cerebrospinal fluid (CSF) pathway, causing hydrocephalus, and range from 3 cm to 5 cm in size. We report a case of an unusually massive subependymoma of the lateral ventricles treated with subtotal resection, ventriculoperitoneal shunt, and post-surgical radiation. The clinical course, radiographic and pathologic characteristics of this massive intraventricular subependymoma are discussed, as well as the differential diagnosis of lateral ventricular masses and a review of the literature concerning subependymomas.

[Endoscopic management of chronic frontal sinusitis in the Negev population, Israel].

BACKGROUND: Chronic frontal sinusitis is a relatively common condition, yet one with potential for complications. The treatment of chronic frontal sinusitis has always been a challenge for the otolaryngologist, and it remains so even in the age of endoscopic sinus surgery. Successful treatment is evaluated by both subjective (patient history) and objective (radiologic and endoscopic) criteria. PURPOSE: This article aims to present our experience in endoscopic surgery for chronic frontal sinusitis, with particular focus on the importance of the wide opening of the naso-frontal outflow tract, with maximal preservation of the mucosa in this area. METHODS: During the period 1999 to 2001, 72 patients at the Soroka University Medical Center underwent endoscopic surgery for chronic frontal sinusitis. We reviewed the cases of fifty four patients of this group with a minimum six months follow-up. Patients who did not return for routine post-operative visits were excluded from this study. We evaluated and quantified subjective measurements including facial pain, nasal respiratory obstruction and hyposmia, and objective measurements, based on radiographic studies and endoscopic examination. RESULTS: Most patients experienced improvement in all of the subjective categories, and particularly in the categories of facial pain/headache and nasal respiratory obstruction. Most patients who experienced this improvement had suffered from chronic pansinusitis. CONCLUSIONS: The endoscopic management of chronic frontal sinus disease is an effective treatment, when principles of wide sinus drainage with maximal mucosal preservation are observed. Most patients undergoing this type of procedure experience significant clinical and radiologic improvement in their condition.

Novel insertional presenilin 1 mutation causing Alzheimer disease with spastic paraparesis.

A four-generation pedigree exhibiting early-onset autosomal dominant Alzheimer disease (AD) with spastic paraplegia, dystonia, and dysarthria due to a novel 6-nucleotide insertional mutation in exon 3 of the presenilin 1 gene (PS1) is described. Serial examinations, PET scans, and autopsy revealed that the mutation in this highly conserved portion of PS1 causes an aggressive dementia that maintains the usual regional hierarchy of disease pathology while extending abnormalities into more widespread brain areas than typically seen in AD.

ATF3 upregulation in glia during Wallerian degeneration: differential expression in peripheral nerves and CNS white matter.

BACKGROUND: Many changes in gene expression occur in distal stumps of injured nerves but the transcriptional control of these events is poorly understood. We have examined the expression of the transcription factors ATF3 and c-Jun by non-neuronal cells during Wallerian degeneration following injury to sciatic nerves, dorsal roots and optic nerves of rats and mice, using immunohistochemistry and in situ hybridization. RESULTS: Following sciatic nerve injury--transection or transection and reanastomosis--ATF3 was strongly upregulated by endoneurial, but not perineurial cells, of the distal stumps of the nerves by 1 day post operation (dpo) and remained strongly expressed in the endoneurium at 30 dpo when axonal regeneration was prevented. Most ATF3+ cells were immunoreactive for the Schwann cell marker, S100. When the nerve was transected and reanastomosed, allowing regeneration of axons, most ATF3 expression had been downregulated by 30 dpo. ATF3 expression was weaker in the proximal stumps of the injured nerves than in the distal stumps and present in fewer cells at all times after injury. ATF3 was upregulated by endoneurial cells in the distal stumps of injured neonatal rat sciatic nerves, but more weakly than in adult animals. ATF3 expression in transected sciatic nerves of mice was similar to that in rats. Following dorsal root injury in adult rats, ATF3 was upregulated in the part of the root between the lesion and the spinal cord (containing Schwann cells), beginning at 1 dpo, but not in the dorsal root entry zone or in the degenerating dorsal column of the spinal cord. Following optic nerve crush in adult rats, ATF3 was found in some cells at the injury site and small numbers of cells within the optic nerve displayed weak immunoreactivity. The pattern of expression of c-Jun in all types of nerve injury was similar to that of ATF3. CONCLUSION: These findings raise the possibility that ATF3/c-Jun heterodimers may play a role in regulating changes in gene expression necessary for preparing the distal segments of injured peripheral nerves for axonal regeneration. The absence of the ATF3 and c-Jun from CNS glia during Wallerian degeneration may limit their ability to support regeneration.

NG2 proteoglycan expression in the peripheral nervous system: upregulation following injury and comparison with CNS lesions.

The chondroitin sulphate proteoglycan NG2 blocks neurite outgrowth in vitro and thus may be able to inhibit axonal regeneration in the CNS. We have used immunohistochemistry to compare the expression of NG2 in the PNS, where axons regenerate, and the spinal cord, where regeneration fails. NG2 is expressed by satellite cells in dorsal root ganglia (DRG) and in the perineurium and endoneurium of intact sciatic nerves of adult rats. Endoneurial NG2-positive cells were S100-negative. Injury to dorsal roots, ventral rami or sciatic nerves had no effect on NG2 expression in DRG but sciatic nerve section or crush caused an upregulation of NG2 in the damaged nerve. Strongly NG2-positive cells in damaged nerves were S100-negative. The proximal stump of severed nerves was capped by dense NG2, which surrounded bundles of regenerating axons. The distal stump, into which axons regenerated, also contained many NG2-positive/S100-negative cells. Immunoelectron microscopy revealed that most NG2-positive cells in distal stumps had perineurial or fibroblast-like morphologies, with NG2 being concentrated at the poles of the cells in regions exhibiting microvillus-like protrusions or caveolae. Compression and partial transection injuries to the spinal cord also caused an upregulation of NG2, and NG2-positive cells and processes invaded the lesion sites. Transganglionically labelled ascending dorsal column fibres, stimulated to sprout by a conditioning sciatic nerve injury, ended in the borders of lesions among many NG2-positive processes. Thus, NG2 upregulation is a feature of the response to injury in peripheral nerves and in the spinal cord, but it does not appear to limit regeneration in the sciatic nerve.