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.

Protein kinase regulates tumor necrosis factor mRNA stability in virus-stimulated astrocytes.

Infection of astrocytes with Newcastle disease virus stimulated the production of 1,2-diacylglycerol, and resulted in the kinase-dependent expression of mRNAs encoding tumor necrosis factor (TNF), interferon alpha and beta, and interleukin 6. The half-life of TNF mRNA was significantly decreased in the presence of protein kinase inhibitors H-7 and staurosporine, but not in the presence of HA1004. In contrast to the decay of TNF mRNA, the half-lives of other cytokine mRNAs were only minimally affected by the kinase inhibitors. These data indicated that the stability of TNF mRNA was regulated through a novel, kinase-dependent pathway.

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.

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.

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.

Selective accumulation of T cells according to T-cell receptor V beta gene usage in skin cancer.

To investigate whether specific T-cell populations are overrepresented in tumor-infiltrating lymphocytes (TIL) in skin cancer, we determined the T-cell receptor (TCR) diversity in biopsy specimens of basal cell carcinoma and squamous cell carcinoma. Immunostaining of tissue sections indicated that the majority of T cells expressed alpha beta TCRs. To assess diversity of the TCR beta chain, RNA was isolated directly from the tumor specimens and peripheral blood mononuclear cells (PBMC) from the same patient, cDNA was synthesized, and variable (V) beta chain gene usage was determined by the polymerase chain reaction (PCR). In each basal cell (n = 11) and squamous cell (n = 7) carcinoma studied, several V beta families were overrepresented in TIL versus PBMC, in that they accounted for greater than 5% of the repertoire in TIL and were at least 2% higher in TIL than in PBMC. The predominant V beta gene segments overrepresented in TIL generally differed from individual to individual. Simultaneous comparison of the V beta repertoire of TIL to that of uninvolved skin and PBMC from the same individual revealed preferential expression of V beta families within the TIL in three of five basal cell and four of four squamous cell carcinomas. Again, the predominant V beta s differed from individual to individual. Comparison of the TCR repertoire in uninvolved skin versus PBMC did indicate that some V beta families were overexpressed in the resident T-cell compartment in skin, although the overrepresented families were not constant from individual to individual. These data indicate the selective concentration of T cells bearing specific alpha beta TCRs in the local immune response to basal cell and squamous cell carcinomas.

Sarcoma arising in oligodendroglioma of the brain.

A case is reported of a tumor composed of both oligodendrogliomatous and sarcomatous elements. The interpretation is offered that the sarcoma arose secondarily by neoplastic transformation of the hyperplastic blood vessels formed in response to the presence of the oligodendroglioma. This tumor may be considered analogous to the astrocytoma-sarcoma, which is much more common, and to the metastatic carcinoma with secondary sarcoma, of which one case has been reported.

Case of the month: April 1997--a 32 year old man with mental status changes and a severe occipital headache.

A 32 year old man with symptoms of an upper respiratory infection one week prior presented with mental status changes, diffuse hyperreflexia, and bilateral extensor plantar responses. An MRI scan showed multifocal areas of high signal intensity predominantly in the parietal and occipital white matter, unassociated with mass affect. Despite aggressive treatment, the patient's symptoms rapidly progressed and he was declared brain dead. Post-mortem examination revealed acute hemorrhagic leukoencephalopathy. The clinical and pathologic features of this disorder are reviewed.

Pergolide mesylate: a potent day-long inhibitor of prolactin in rhesus monkeys and patients with Parkinson's disease.

The effect of a new synthetic ergot alkaloid, pergolide mesylate, on the inhibition of PRL during 24-h periods was evaluated in four rhesus monkeys and three patients with Parkinson's disease. In the monkeys, the mean PRL level during the 24-h period fell to 24% of control in response to 50 micrograms. With 1000 micrograms pergolide daily and to 6.6% of control with 200 micrograms pergolide daily, PRL was unmeasurable in the great majority of samples over 24 h. In addition, the marked episodic fluctuation in PRL occurring in controls was not observed in treated animals. In three patients with Parkinson's disease, treatment with pergolide also resulted in uniform 24-h suppression of PRL. In one patient on pergolide (100 micrograms/day), the mean 24-h PRL level fell to 18% of control, and in two other patients on 200 and 600 micrograms pergolide, respectively, whose mean PRL levels were 4.1 and 7.4 ng/ml, respectively, before treatment, no PRL was detected in any of the blood samples obtained during the 24-h periods. These data provide evidence that pergolide is a potent inhibitor of PRL in rhesus monkeys and in patients with Parkinson's disease; the effect is iniform over 24-h periods.

Experience with selegiline and levodopa in advanced Parkinson's disease.

We compared the results of treatment with selegiline (deprenyl, Eldepryl) in 17 patients with advanced Stage 4 Parkinson Disease (PD) who were on levodopa (as Sinemet) with 65 Stage 2 or 3 patients with early PD who were also on levodopa. The first group consisted of 17 patients with advanced Stage 4 PD without response fluctuations ("wearing off" or "on off" phenomena). Their mean age was 72.1 +/- 7.5 years, their mean duration of PD was 7.4 +/- 3.2 years. The second group consisted of 65 patients with Stage 2 or 3 PD who had recently been started on levodopa. Their mean age was 63 +/- 12.1 years, their mean duration of PD was 7.4 +/- 3.2 years. The mean dose of selegiline was 10.0 +/- 1.8 mg per day (range 5-20 mg). The mean duration of treatment was 1.5 +/- 0.8 years. During the four years of observation 55.3 +/- 8.0% of the Stage 2 or 3 patients improved while only 14.3 +/- 13.5% of the Stage 4 patients improved. This difference was significant (p less than 0.05). During this time 22.0 +/- 6.7% of the Stage 2 or 3 patients worsened and 60.7 +/- of the Stage 4 patients worsened. This degree of worsening was significant (p less than 0.05). Adverse effects were minor and reversible. Our observations suggest that selegiline is more effective (higher percent of patients improving, lower percent of patients worsening) when it is added earlier with patients on levodopa than when it is added later.

Adrenal medullary transplants as a treatment for advanced Parkinson's disease.

Open autologous adrenal medullary to caudate nucleus transplantation was performed in 12 patients with advanced Parkinson's disease (PD). Ten of these patients had diurnal response fluctuations including "wearing off" and "on/off" phenomena. All of the patients were no longer satisfactorily responding to levodopa/carbidopa and dopamine agonists. The mean age of the patients was 55.1 years (range 37-65 yrs); mean duration of PD was 11.7 years (range 4-40 yrs); mean stage "on" was 3.3 (range 2-4); mean stage "off" was 4.8 (range 4-5). Mean duration of follow up from surgery was 10.4 months (range 2-17 months). Three patients improved dramatically with major changes in their lifestyle. The course of improvement in these 3 patients was different in each, implying that different mechanisms were responsible for the improvement. One of the patients died unexpectedly. In this patient, there were no surviving adrenal cells. Three patients improved moderately. Patients reported that they were "on" longer and had to take medication less often and were less dependent on individual doses of levodopa/carbidopa. The improvement has been sustained in two patients. However, in one of these patients there had to be frequent changes in scheduling to maintain the improvement. Two patients after technically successful implants did not improve. One of these patients subsequently died. In this patient there were a few surviving adrenal medullary cells. Four patients suffered major complications. One patient had a cerebral infarction and two had cerebral hemorrhages. One of these patients has shown a good recovery. One patient with autonomic insufficiency had a cardiac arrest with cerebral anoxia one week after surgery. This patient has shown a partial recovery.(ABSTRACT TRUNCATED AT 250 WORDS)

Cloning and genomic organization of the mouse gene slc23a1 encoding a vitamin C transporter.

Vitamin C is known to exist in particularly high concentrations in brain tissue, and its free radical scavenging function is thought to represent a major antioxidative defense system. We have cloned, sequenced and analyzed the genomic structure of a mouse sodium-dependent vitamin C transporter gene, Slc23a1 (also known as Svct2). The mouse Slc23a1 cDNA is 6.4 kb long and was cloned directly from a mouse brain RNA preparation. Hybridization screening of a mouse genomic BAC library identified BAC 53L21 which contains at least the entire coding sequence of the mouse Slc23a1 gene. Determination of the exon-intron structure of the gene revealed 17 exons ranging from 58 bp to 4407 bp extending over 50 kb of the mouse genome, with the translation start codon located in exon 3. Its 1944 nucleotide open reading frame encodes a polypeptide of 647 aa, which is highly similar to rat and human orthologs. The mouse gene was assigned to chromosome 2qG2 by fluorescence in situ hybridization analysis. Expression of this gene was demonstrated in a wide range of tissues, with especially high levels in brain. Neurodegenerative diseases with an established role for oxidative stress in the cytoplasm may therefore be conditions of SLC23A1 dysfunction. Key words: gene structure; Vitamin C; transporter; oxidative stress

The use of pergolide, a potent dopamine agonist, in Parkinson's disease.

Pergolide, a semisynthetic ergoline and a potent long-acting adenylcyclase-linked dopamine agonist, was given to 40 patients with advanced Parkinson's disease whose response to levodopa had diminished considerably. The group included 31 patients with marked diurnal oscillations in performance ("wearing off" and/or "on-off" phenomena). Pergolide alone (7 patients) or combined with levodopa (33 patients), resulted in a reduction in disability (P less than or equal to 0.01) as assessed in both the patients' "on" and "off" periods. Pergolide also resulted in an increase (P less than or equal to 0.001) in the number of hours in which patients were on from 3.8 (+/-0.4) to 11.9 (+/-0.9). The mean daily dose of pergolide was 2.4 mg (range 0.1 to 10.0). The mean duration of the study was 12 mo (range 1 to 24). Pergolide is effective in Parkinson's disease and will change the management of patients whose response to levodopa has diminished.

Cardiac effects of pergolide.

We examined the effect of pergolide, a semisynthetic ergot alkaloid, alone or combined with carbidopa and levodopa (Sinemet), on the cardiac rhythm of 12 patients with Parkinson's disease. The patients were selected on the basis of severe Parkinson's disease and stable cardiac rhythm as determined by 1 to 5 days of Holter monitoring. Monitoring was then carried out for an additional period of between 2 and 10 wk while the patients were on pergolide. Seven of the 12 patients had repetitive ventricular rhythms (RVRs). These were isolated, infrequent, and not associated with increases in premature ventricular contractions. The dose at which the RVRs occurred may be a function of the presence or absence of heart disease, but the significance of RVRs remains to be determined.

Ultrastructural organisation of the projection from the superior colliculus to the ventral lateral geniculate nucleus of the rat.

Retinorecipient regions of the ventral lateral geniculate nucleus of the thalamus and the superior colliculus of the midbrain are linked by reciprocal axonal projections. In this study we have investigated the ultrastructural characteristics, the distribution, and the postsynaptic targets of the terminals of axons projecting to the ventral lateral geniculate nucleus from the superior colliculus. Horseradish peroxidase was injected into the superior colliculi of adult albino rats, and the Hanker-Yates method was used to visualize anterogradely and retrogradely transported peroxidase in the ventral lateral geniculate nuclei 24 hours following the injection. Labelled terminals were found in the lateral and ventrolateral parts of the external division of the ipsilateral ventral lateral geniculate nucleus. The labelled terminals were confined to areas of simple, nonglomerular neuropil. They were 0.45-1.5 micron in diameter; contained small, dark mitochondria and spherical synaptic vesicles; and established Gray type I (asymmetrical) synaptic contacts with the dendritic shafts, dendritic spines, and occasionally cell bodies of cells with the ultrastructural characteristics of projection cells. A few labelled terminals established synaptic contact with retrogradely labelled cells. Thus, in the rat, the projection from the superior colliculus gives rise to a uniform population of axon terminals in the nonglomerular neuropil of the lateral portion of the ventral lateral geniculate nucleus, which synapse with, and are probably excitatory to, geniculocollicular and other projection cells.

Neurons in layer I of the developing occipital cortex of the rat.

This paper describes the neurons in layer I of the rat occipital cortex, and traces postnatal changes in the numbers and morphology of the different cell types therein. Golgi-Cox and Nissl material from adults and from 0.5,2,4,6,8,10,11,12,13,14,15,16,18,20,24,28 and 35 day-old rats, was utilized. Horizontal, vertical and classical non-pyramidal cells without axons were recognized. Horizontal cells included foetal horizontal cells (Retzius-Cajal cells) and persisting horizontal cells. The former were fully differentiated and numerous at birth and were bipolar, with dendrite and axon extending from opposite poles, and fine ascending (vertical) branches. Some such cells possessed two axons. Almost all degenerated and disappeared over the first two to three postnatal weeks. An analogy with Rohon-Beard cells is drawn and it is suggested that these cells receive an early input which is subsequently withdrawn and/or concentrated on cells in deeper layers. There is no evidence of transformation of foetal to persisting horizontal cells, which are not numerous and most commonly give rise to two dendrites from opposite perikaryal poles. Vertical cells, with spinous dendrites and descending axons, differentiate and reach adult numbers by the end of the first postnatal week. Classical non-pyramidal cells include spinous and spine-free varieties, resemble those in deeper layers, and are mature by the end of the third postnatal week. In the upper stratum of layer I are small numbers of cells without axons.

The postnatal development of neurons in the dorsal lateral geniculate nucleus of the rat: a Golgi study.

The postnatal differentiation of neurons in the dorsal lateral geniculate nucleus of the albino rat was studied using the Golgi-Cox technique. At least four animals were used at postnatal ages 12 hours, 2, 4, 6, 8, 10, 11, 12, 13, 14, 15, 16, 18, 20, 24, 28, 35 days and adult. Presumptive thalamo-cortical projection cells (Class A cells of Grossman et al., '73) and non-projection, intrinsic neurons (Class B cells) are distinguishable at 12 hours after birth. At this stage both types of neuron are immature, with prominent growth cones at their dendritic extremities. Dendritic growth and differentiation appear to be complete by 18 days. Relay cells display two apparent "growth spurts" characterized by noticeable enlargement of the perikaryon and a marked increase in dendritic length and complexity. One occurs between days 4 and 6 and coincides with a period of enhanced synaptogenesis and gliogenesis: the second occurs between days 14 and 15, around the time of eye opening (day 14) and may be related to a further phase of increased synaptogenesis and gliogenesis (Karlsson, '67; Biesold et al., '76). Class B cells appear to "lag" behind class A cells in their initial postnatal differentiation, but also reach their mature condition by day 18.

Are there connections between the thalamic reticular nucleus and the brainstem reticular formation?

Increasing awareness that the thalamic reticular nucleus (TRN) plays an important role in controlling the output of cortically projecting cells in nuclei of the dorsal thalamus has focused attention on the question of whether there exist ascending projections to the TRN from the mesencephalic or other parts of the brainstem reticular formation (BRF). We have examined this and the related question of whether the neurons of TRN project to the BRF, by anterograde and retrograde tracing experiments with horseradish peroxidase (HRP) and HRP conjugated to wheat germ agglutinin. Injections of tracer were placed stereotaxically in the BRF at various depths and rostrocaudal and mediolateral coordinates, and the TRN and adjacent nuclei were examined in serial coronal sections, using tetramethylbenzidine as the principal chromogen. Retrogradely labelled cell bodies were consistently seen in hypothalamus and zona incerta but never in TRN, suggesting that, in the rat, TRN neurons do not project caudal to the thalamus. After 54 out of 60 injections, no terminal label was detected in any part of the TRN although such label was present in other parts of the thalamus, including the intralaminar nuclei, in the same sections. We therefore conclude that direct projections from the BRF to the TRN must be extremely sparse, and that those effects of BRF stimulation upon thalamocortical transmission that are mediated by the TRN (rather than by direct projections to dorsal thalamic nuclei) probably depend chiefly on indirect polysynaptic pathways.

The cell recognition molecule CHL1 is strongly upregulated by injured and regenerating thalamic neurons.

Close homologue of L1 (CHL1) is a cell recognition molecule known to promote axonal growth in vitro. We have investigated the expression of CHL1 mRNA by regenerating central nervous system (CNS) neurons, by using in situ hybridisation 3 days to 10 weeks following the implantation of living and freeze-killed peripheral nerve autografts into the thalamus of adult rats. At all survival times after implantation of living grafts, neurons of the thalamic reticular nucleus (TRN), close to the graft tip and up to 1 mm away from it, displayed strong signal for CHL1 mRNA, even though TRN neurons show very low levels of CHL1 mRNA expression in unoperated animals. When the cell bodies of regenerating neurons were identified by retrograde labelling from the distal portion of the grafts, 4-6 weeks after operation, most of the labelled cells were found in the TRN and could be shown to haveupregulated CHL1 mRNA. In addition, some neurons in dorsal thalamic nuclei near the graft tip transiently upregulated CHL1 mRNA during the first 3 weeks after graft implantation, and glial cells showing CHL1 mRNA expression were present at the brain/graft interface 3 days to 2 weeks after operation. Freeze-killed grafts, into which axons do not regenerate, caused a transient upregulation of CHL1 in very few TRN neurons near the graft tip and in glial cells at the brain/graft interface but did not produce prolonged CHL1 mRNA expression. CHL1 can therefore be added to the list of molecules (including GAP-43, L1, and c-jun) strongly expressed by CNS neurons that regenerate their axons into nerve grafts, but not by those neurons that fail to regenerate their axons.