Central Nervous System Sites Research Articles

Functional Role of Kallikrein 6 in Regulating Immune Cell Survival

BackgroundKallikrein 6 (KLK6) is a newly identified member of the kallikrein family of secreted serine proteases that prior studies indicate is elevated at sites of central nervous system (CNS) inflammation and which shows regulated expression with T cell activation. Notably, KLK6 is also elevated in the serum of multiple sclerosis (MS) patients however its potential roles in immune function are unknown. Herein we specifically examine whether KLK6 alters immune cell survival and the possible mechanism by which this may occur.Methodology/Principal FindingsUsing murine whole splenocyte preparations and the human Jurkat T cell line we demonstrate that KLK6 robustly supports cell survival across a range of cell death paradigms. Recombinant KLK6 was shown to significantly reduce cell death under resting conditions and in response to camptothecin, dexamethasone, staurosporine and Fas-ligand. Moreover, KLK6-over expression in Jurkat T cells was shown to generate parallel pro-survival effects. In mixed splenocyte populations the vigorous immune cell survival promoting effects of KLK6 were shown to include both T and B lymphocytes, to occur with as little as 5 minutes of treatment, and to involve up regulation of the pro-survival protein B-cell lymphoma-extra large (Bcl-XL), and inhibition of the pro-apoptotic protein Bcl-2-interacting mediator of cell death (Bim). The ability of KLK6 to promote survival of splenic T cells was also shown to be absent in cell preparations derived from PAR1 deficient mice.Conclusion/SignificanceKLK6 promotes lymphocyte survival by a mechanism that depends in part on activation of PAR1. These findings point to a novel molecular mechanism regulating lymphocyte survival that is likely to have relevance to a range of immunological responses that depend on apoptosis for immune clearance and maintenance of homeostasis.

Central nervous system sites of the sleep promoting effects of eszopiclone in rats

We examined the effects of eszopiclone (ESZ), a GABA-A receptor agonist in current clinical use as a hypnotic medication, on the activity of subcortical wake- and sleep-active neuronal populations in the rat brain. Sleep-wake states were quantified after i.p. injections of ESZ (3 and 10 mg/kg) or vehicle administered early in the dark phase, when rats are spontaneously awake. Rats were euthanized 2 h post-injection and brain tissue was processed for c-Fos protein immunoreactivity (IR) and for neurotransmitter markers. ESZ at 3 and 10 mg/kg increased time spent in non-rapid-eye-movement (nonREM) sleep, but had no significant effect on Fos-IR in GABAergic neurons in the preoptic hypothalamus that normally express c-Fos during sleep. Among wake-active cell types examined, Fos-IR in hypocretin (HCRT) neurons in the perifornical lateral hypothalamus (LH) was reduced following 3 and 10 mg/kg ESZ. At 10 mg/kg, ESZ suppressed Fos-IR in cholinergic and noncholinergic neurons in the basal forebrain and in serotonergic and nonserotonegic neurons in the dorsal raphe. Having determined that HCRT neurons were responsive to the low dose of systemic ESZ, we unilaterally perfused ESZ directly into the LH of awake rats, using reverse microdialysis. Perfusion of ESZ at 50 μM into the LH for 2 h suppressed waking-related Fos-IR in HCRT neurons, but not in nonHCRT neurons ipsilateral to the dialysis probe. Bilateral LH perfusion of ESZ at 50 μM for 2 h early in the dark phase significantly increased sleep. These findings demonstrate that sleep induction by ESZ does not require activation of GABAergic sleep-regulatory neurons in the preoptic hypothalamus, and identify suppression of HCRT neurons in the LH and suppression of basal forebrain and dorsal raphe neurons as potential mechanisms underlying the sleep-promoting effects of ESZ.

Effect of ketamine on endogenous pain modulation in healthy volunteers

Inhibitory and facilitatory descending pathways, originating at higher central nervous system sites, modulate activity of dorsal horn nociceptive neurons, and thereby influence pain perception. Dysfunction of inhibitory pain pathways or a shift in the balance between pain facilitation and pain inhibition has been associated with the development of chronic pain. The N-methyl-d-aspartate receptor antagonist ketamine has a prolonged analgesic effect in chronic pain patients. This effect is due to desensitization of sensitized N-methyl-d-aspartate receptors. Additionally, ketamine may modulate or enhance endogenous inhibitory control of pain perception. Diffuse noxious inhibitory control (DNIC) and offset analgesia (OA) are 2 mechanisms involved in descending inhibition. The present study investigates the effect of a ketamine infusion on subsequent DNIC and OA responses to determine whether ketamine has an influence on descending pain control. Ten healthy subjects (4 men/6 women) received a 1-hour placebo or S(+)-ketamine (40mg per 70kg) infusion on 2 separate occasions in random order. Upon the termination of the infusion, DNIC and OA responses were obtained. After placebo treatment, significant descending inhibition of pain responses was present for DNIC and OA. In contrast, after ketamine infusion, no DNIC was observed, but rather a significant facilitatory pain response (P<0.01); the OA response remained unchanged. These findings suggest that the balance between pain inhibition and pain facilitation was shifted by ketamine towards pain facilitation. The absence of an effect of ketamine on OA indicates differences in the mechanisms and neurotransmitter influences between OA and DNIC.Diffuse noxious inhibitory control responses following a 1-hour low-dose ketamine treatment displayed facilitation of pain in response to experimental noxious thermal stimulation.

Combination Therapy for Testicular Lymphoma Gives Reassuring Results

Primary testicular diffuse large B-cell lymphoma (DLBCL) is rare and usually presents with stage IE or IIE disease but with a high propensity for relapse in the central nervous system (CNS) and other extranodal sites, including the contralateral testis. Now, researchers have conducted a multicenter phase II trial to investigate the effect of a combination treatment on progression-free survival (PFS) in patients with untreated stage I or II primary …

Should Clinical Services Provided by Pharmacists be Compensated

This review gives an overview of our recent findings and developments in research on brain mechanisms of morphine reward from studies using the place preference conditioning paradigm. Intracranial place conditioning methodology has become a valuable and firmly established and very widely used tool in behavioural pharmacology and drug reward mechanisms. Several studies have established that morphine induces a conditioned preference for the place in which it has been administered in rats. Transmitter systems that have been investigated with respect to their involvement in morphine reward mechanisms include dopamine, GABA, acetylcholine, adrenalin and nitric oxide, the motivational significance of which has been examined either directly, by using respective agonist or antagonist drugs. Although, considerable evidence suggested that the mesocorticolimbic DA system, which originates in the VTA and projects to the Nac, various limbic and cortical areas is a major neural substrate of the rewarding effects produced by morphine, but the role of other brain sites such as hippocampus and amygdala also exist. Overall, our intracranial place conditioning studies showed that there are a number of receptors, neuronal pathways and discrete central nervous system sites involved in the morphine reward mechanisms.

CHO cell expression, long‐term stability, and primate pharmacokinetics and brain uptake of an IgG–paroxonase‐1 fusion protein

Paraoxonase (PON)-1 is the most potent human organophosphatase known, but recombinant forms of human PON1 have been difficult to produce owing to poor secretion by host cells. In the present investigation, human PON1 is re-engineered as an IgG-PON1 fusion protein. The 355 amino acid human PON1 is fused to the carboxyl terminus of the heavy chain of a chimeric monoclonal antibody (MAb) against the human insulin receptor (HIR), and this fusion protein is designated HIRMAb-PON1. The HIRMAb part of the fusion protein enables brain penetration of the PON1, which was considered important, because organophosphate toxicity causes death via a central nervous system site of action. A high producing line of stably transfected Chinese hamster ovary (CHO) cells secreting the HIRMAb-PON1 fusion protein in the absence of serum or lipid acceptors was cloned. The bioreactor generated fusion protein was purified to homogeneity with low impurities by protein A affinity chromatography and anion exchange chromatography. The HIRMAb-PON1 fusion protein was stable as a sterile liquid formulation stored at 4°C for at least 1 year. The plasma pharmacokinetics (PK) of the HIRMAb-PON1 fusion protein was evaluated in Rhesus monkeys, which is the first PK evaluation of a recombinant PON1 protein. The fusion protein was rapidly removed from blood, primarily by the liver. The blood-brain barrier permeation of the HIRMAb-PON1 fusion protein was high and comparable to other HIRMAb fusion proteins. Re-engineering human PON1 as the HIRMAb fusion protein allows for production of a stable, field-deployable formulation of the enzyme that is brain-penetrating.

Exploring neurogenesis outside the niche: atypical locations of mammalian neural stem/progenitor cells.

ing new nerve and glial cells throughout life, is a phylogenetically highly conserved feature that challenges the dogma of the nervous system as a static, non-renewable tissue (Gage, 2000). Yet, unlike invertebrates and non-mammalian vertebrates, in which neurogenesis persists in wide regions of the central nervous system (CNS), in adult mammals it is mainly restricted to two specific brain sites: the forebrain subventricular zone and the hippocampal dentate gyrus (Gage, 2000; Kriegstein and AlvarezBuylla, 2009). It is now clear that the persistence of neurogenesis in these zones depends on stem cells which reside in niches as vestigial remnants of embryonic germinal layers (Kriegstein and AlvarezBuylla, 2009). This fact leaves the remainder of the CNS as a non-renewable tissue substantially incapable to repair damage coming from neurodegenerative diseases, ischemic/traumatic lesions. In the last few years, the persistence of neurogenesis has been observed also in other CNS sites and in sensory organs, in addition to the neurogenic zones quoted above. The most striking example, known for many years, is that of olfactory receptor neurons which are continuously renewed in the olfactory mucosa (see article by Mackay-Sim, in this issue). Other examples have subsequently emerged and this special issue deals specifically with these less studied stem/progenitor cells responsible for adult neurogenesis in niches outside the forebrain and hippocampus. The review by Locker et al. summarizes a decade of research on quiescent stem cells in the mammalian retina, also taking into account the advances made in animal models of stem cell-mediated retinal regeneration. The article by Metzger gives an overview of the development, structure and function of the enteric nervous system, focusing on the persistence of neural stem cells in the gut. Pardal et al. report on stem cells existing in the carotid body, a chemoreceptor organ of the peripheral nervous system that supports neurogenesis in response to hypoxemia. Finally, Miura and Barlow address the issue of the continuous renewal of taste receptor cells, a type of electrochemically excitable cells which are epithelial in origin but capable of releasing neurotransmitter onto afferent nerve fibers. Proliferating/quiescent progenitor cells have been demonstrated to occur even in diverse regions of the adult CNS out of the forebrain and hippocampus (Nishiyama et al., 2009; Ohira et al., 2009). These additional neurogenic sites also raise the issue of comparative studies in mammalian species and in other animal groups. The occurrence of neurogenesis within the mature brain parenchyma, not related with persistent germinal layers, can be frequently found in non-vertebrate species which harbour disperse, highly active niche-like neurogenic sites in widespread CNS regions (Kaslin et al., 2008) accounting for remarkable regenerative capacity (Zupanc, 2009). By contrast, most local Exploring neurogenesis outside the niche: atypical locations of mammalian neural stem/progenitor cells

Anaplastic ependymoma with sclerotic bone metastases

Ependymomas are glial central nervous system (CNS) tumors that arise from the ependymal layer of brain and spinal cord. These are heterogeneous group of tumors with varied histopathological features and prognosis. They frequently relapse at the primary site and may disseminate to other CNS sites. Extraneural metastases are, however, extremely rare. We present a case of ependymoma in a child with widespread metastasis to her bones, a previously unreported event.

Silencing Nox4 in the Paraventricular Nucleus Improves Myocardial Infarction–Induced Cardiac Dysfunction by Attenuating Sympathoexcitation and Periinfarct Apoptosis

Myocardial infarction (MI)-induced heart failure is characterized by central nervous system-driven sympathoexcitation and deteriorating cardiac function. The paraventricular nucleus (PVN) of the hypothalamus is a key regulator of sympathetic nerve activity and is implicated in heart failure. Redox signaling in the PVN and other central nervous system sites is a primary mechanism of neuro-cardiovascular regulation, and excessive oxidant production by activation of NADPH oxidases (Noxs) is implicated in some neuro-cardiovascular diseases. We tested the hypothesis that Nox-mediated redox signaling in the PVN contributes to MI-induced sympathoexcitation and cardiac dysfunction in mice. Real-time PCR revealed that Nox4 was the most abundantly expressed Nox in PVN under basal conditions. Coronary arterial ligation (MI) caused a selective upregulation of this homolog compared to Nox1 and Nox2. Adenoviral gene transfer of Nox4 (AdsiNox4) to PVN (bilateral) attenuated MI-induced superoxide formation in this brain region (day 14) to the same level as that produced by PVN-targeted gene transfer of cytoplasmic superoxide dismutase (AdCu/ZnSOD). MI mice treated with AdsiNox4 or AdCu/ZnSOD in the PVN showed marked improvement in cardiac function as assessed by echocardiography and left ventricular hemodynamic analysis. This was accompanied by significantly diminished sympathetic outflow and apoptosis in the periinfarct region of the heart. These results suggest that MI causes dysregulation of Nox4-mediated redox signaling in the PVN, which leads to sympathetic overactivation and a decline in cardiac function. Targeted inhibition of oxidant signaling in the PVN could provide a novel treatment for MI-induced heart failure.

Cryosurgery: an easy and cheap therapy for facial angiofibromas in tuberous sclerosis

Auteur(s) : Carmelo Schepis, Maddalena Siragusa Oasi Institute (IRCCS), Unit of Dermatology, Via Conte Ruggero, 73, 94018 Troina, Italy Tuberous Sclerosis Complex (TCS) is a neurocutaneous syndromic disorder which affects skin, the central nervous system, the heart, kidney, lung and other sites of the human body. It is an autosomal dominant genetic condition related to two tumour suppressor genes located on chromosome 9 or chromosome 16 [1]. Cutaneous manifestations of TSC are considered [...]

A fresh look at NASH pathogenesis. Part 1: The metabolic movers

The strong relationship between over-nutrition, central obesity, insulin resistance/metabolic syndrome and non-alcoholic fatty liver disease (NAFLD) suggest pathogenic interactions, but key questions remain. NAFLD starts with over-nutrition, imbalance between energy input and output for which the roles of genetic predisposition and environmental factors (diet, physical activity) are being redefined. Regulation of energy balance operates at both central nervous system and peripheral sites, including adipose and liver. For example, the endocannabinoid system could potentially be modulated to provide effective pharmacotherapy of NAFLD. The more profound the metabolic abnormalities complicating over-nutrition (glucose intolerance, hypoadiponectinemia, metabolic syndrome), the more likely is NAFLD to take on its progressive guise of non-alcoholic steatohepatitis (NASH). Interactions between steatosis and insulin resistance, visceral adipose expansion and subcutaneous adipose failure (with insulin resistance, inflammation and hypoadiponectinemia) trigger amplifying mechanisms for liver disease. Thus, transition from simple steatosis to NASH could be explained by unmitigated hepatic lipid partitioning with failure of local adaptive mechanisms leading to lipotoxicity. In part one of this review, we discuss newer concepts of appetite and metabolic regulation, bodily lipid distribution, hepatic lipid turnover, insulin resistance and adipose failure affecting adiponectin secretion. We review evidence that NASH only occurs when over-nutrition is complicated by insulin resistance and a highly disordered metabolic milieu, the same 'metabolic movers' that promote type 2 diabetes and atheromatous cardiovascular disease. The net effect is accumulation of lipid molecules in the liver. Which lipids and how they cause injury, inflammation and fibrosis will be discussed in part two.

The lost domain of pain

Pain is a warning that something is wrong. But for those who suffer from persistent, intense pain it loses any positive purpose and means only suffering and disability. Chronic pain becomes threatening and aversive, restricting mobility and shrinking the social world. A system that apparently evolved to warn and protect, to aid healing and ultimately to preserve life, can become a pathology, ‘have a life of its own’ (Daudet, 2002) and create an enormous human and economic burden (http://www.efic.org/costs-of-chronic-pain.php). The challenge to provide relief from pain runs through all branches of medicine and yet many physicians are surprisingly unaware or even uninterested in the complexity of pain. As a society we have turned to neuroscience, especially cellular and molecular neuroscience, which together with strong backing from the pharmaceutical industry promise the development of new analgesics targeted towards specific peripheral and central mechanisms of pain. While this has resulted in a huge escalation of knowledge in the neurobiology of pain, the practical application of this knowledge to the relief of pain has been disappointing—a fact that has led to considerable soul searching about the potential for translation of experimental laboratory-based pain research into clinical pain management (Mao, 2009; Mogil, 2009). In our enthusiasm for probing the biology of nocioception in laboratory models, we may have lost sight of the fundamental problem: pain intensity is not simply determined by how much noxious information arises from injured areas of the body—pain is the outcome of neural processing at multiple central nervous system sites in the spinal cord and brainstem, limbic system, hypothalamus and cortex (Kehlet et al. , 2006). The sensory component which makes it so clearly distinguishable from other sensations is only part of the pain experience. Reflex movements, autonomic reactions, altered attention, cessation of behaviour, a sense of unpleasantness …

Ghrelin: Central Nervous System Sites of Action in Regulation of Energy Balance

Ghrelin, a peptide hormone secreted by the stomach, has been shown to regulate energy homeostasis by modulating electrical activity of neurons in the central nervous system (CNS). Like many circulating satiety signals, ghrelin is a peptide hormone and is unable to cross the blood-brain barrier without a transport mechanism. In this review, we address the notion that the arcuate nucleus of the hypothalamus is the only site in the CNS that detects circulating ghrelin to trigger orexigenic responses. We consider the roles of a specialized group of CNS structures called the sensory circumventricular organs (CVOs), which are not protected by the blood-brain barrier. These areas include the subfornical organ and the area postrema and are already well known to be key areas for detection of other circulating hormones such as angiotensin II, cholecystokinin, and amylin. A growing body of evidence indicates a key role for the sensory CVOs in the regulation of energy homeostasis.

Emerging & Rare Fungal Infections in Solid Organ Transplant Recipients

Emerging & Rare Fungal Infections in Solid Organ Transplant Recipients

Cannabinoid-1 receptor inverse agonists: current understanding of mechanism of action and unanswered questions

Rimonabant and taranabant are two extensively studied cannabinoid-1 receptor (CB1R) inverse agonists. Their effects on in vivo peripheral tissue metabolism are generally well replicated. The central nervous system site of action of taranabant or rimonabant is firmly established based on brain receptor occupancy studies. At the whole-body level, the mechanism of action of CB1R inverse agonists includes a reduction in food intake and an increase in energy expenditure. At the tissue level, fat mass reduction, liver lipid reduction and improved insulin sensitivity have been shown. These effects on tissue metabolism are readily explained by CB1R inverse agonist acting on brain CB1R and indirectly influencing the tissue metabolism through the autonomic nervous system. It has also been hypothesized that rimonabant acts directly on adipocytes, hepatocytes, pancreatic islets or skeletal muscle in addition to acting on brain CB1R, although strong support for the contribution of peripherally located CB1R to in vivo efficacy is still lacking. This review will carefully examine the published literature and provide a perspective on what new tools and studies are required to address the peripheral site of action hypothesis.

Ramelteon: a review of its therapeutic potential in sleep disorders

Ramelteon is a tricyclic synthetic analog of melatonin that acts specifically on MT(1) and MT(2) melatonin receptors. Ramelteon's half-life is longer than that of melatonin, being metabolized in the body to four main metabolites, M-I, M-II, M-III, and M-IV. M-II has an affinity to MT(1) and MT(2) of about one-tenth of the parent compound, but its concentration in the circulation exceeds that of ramelteon by more than an order of magnitude. Ramelteon is effective in decreasing latency to persistent sleep and increasing total sleep time in freely moving monkeys. A number of clinical studies have been undertaken to study the efficacy of ramelteon in subjects with chronic insomnia. In almost all of these studies, ramelteon, in various doses of 4, 8, or 16 mg most commonly, significantly reduced sleep latency and increased sleep duration. Its primary action in sleep promotion is not a generalized gamma-aminobutyric (GABA)-ergic central nervous system depression, but rather it acts as a melatonergic agonist in the suprachiasmatic nucleus (and at other central nervous system sites), from where downstream processes, including GABA-ergic effects, are controlled via the hypothalamic sleep switch. Unlike other commonly prescribed hypnotic drugs, ramelteon is not associated with next morning hangover effects or reductions in alertness, nor has it been shown to cause withdrawal symptoms. The adverse symptoms reported with ramelteon are mild. All long-term investigations that have been carried out support the conclusion that ramelteon is a well tolerated and effective drug for the treatment of insomnia.

Opioid receptor mechanisms at the hypoglossal motor pool and effects on tongue muscle activity in vivo

Opioids can modulate breathing and predispose to respiratory depression by actions at various central nervous system sites, but the mechanisms operating at respiratory motor nuclei have not been studied. This study tests the hypotheses that (i) local delivery of the mu-opioid receptor agonist fentanyl into the hypoglossal motor nucleus (HMN) will suppress genioglossus activity in vivo, (ii) a component of this suppression is mediated by opioid-induced acetylcholine release acting at muscarinic receptors, and (iii) delta- and kappa-opioid receptors also modulate genioglossus activity. Seventy-two isoflurane-anaesthetised, tracheotomised, spontaneously breathing rats were studied during microdialysis perfusion into the HMN of (i) fentanyl and naloxone (mu-opioid receptor antagonist), (ii) fentanyl with and without co-application of muscarinic receptor antagonists, and (iii) delta- and kappa-opioid receptor agonists and antagonists. The results showed (i) that fentanyl at the HMN caused a suppression of genioglossus activity (P < 0.001) that reversed with naloxone (P < 0.001), (ii) that neither atropine nor scopolamine affected the fentanyl-induced suppression of genioglossus activity, and (iii) that delta-, but not kappa-, opioid receptor stimulation also suppressed genioglossus activity (P = 0.036 and P = 0.402 respectively). We conclude that mu-opioid receptor stimulation suppresses motor output from a central respiratory motoneuronal pool that activates genioglossus muscle, and this suppression does not involve muscarinic receptor-mediated inhibition. This mu-opioid receptor-induced suppression of tongue muscle activity by effects at the hypoglossal motor pool may underlie the clinical concern regarding adverse upper airway function with mu-opioid analgesics. The inhibitory effects of mu- and delta-opioid receptors at the HMN also indicate an influence of endogenous enkephalins and endorphins in respiratory motor control.

Primary central nervous system lymphoma: tumor-related clones exist in the blood and bone marrow with evidence for separate development

AbstractPrimary central nervous system (CNS) lymphoma is an aggressive B-cell tumor that is defined clinically by the absence of systemic disease. We have used immunoglobulin variable (V)–gene analysis to identify tumor cells at the CNS site in 12 cases and to probe the involvement of peripheral tissues in 3 patients. Clonal tracking revealed tumor cells in the bone marrow and/or blood for 3 of 3 cases, with evidence for increased V-gene mutational activity at peripheral sites. In 2 of 3 cases, intraclonal variant analysis revealed identity with the brain biopsy but detected additional variants unique to extracerebral sites. These findings suggest that peripheral tumor cells can undergo separate development locally with no reentry into the brain. Primary CNS lymphoma appears to have both CNS-specific and systemic components with limited interchange. The more malignant behavior of tumor cells in the CNS suggests either a local environmental influence or a less malignant phenotype of the peripheral clone.

Primary breast non‐Hodgkin's lymphoma: A large single center study of initial characteristics, natural history, and prognostic factors

The aims of this study were to define the initial pathological and clinical characteristics, and prognostic factors of patients with primary breast malignant lymphoma (PBL). All patients treated at the Institut Curie for lymphoma with breast involvement were reviewed. A pathological review of all cases was performed. Forty-five cases were selected in whom 38 cases were of diffuse large B-cell lymphoma. A complete analysis was then performed on these 38 patients. Twenty out of 28 cases (71%) of cases were Bcl-2 positive and four out of 28 (14%) had a CD10 positive staining. Peculiar initial characteristics showed nodal involvement in 58% of the cases and two or more extra-nodal sites in 31% of the cases. Among the 37 patients for whom all data were available, and according to the International Prognostic Index, 19 patients (51%) were classified in the low-risk group, 5 cases (14%) in the low- to intermediate-risk group, 6 patients (16%) in the intermediate- to high-risk group, and 7 (19%) case in the high-risk group. At the end of initial therapy, 34 patients (89%) achieved CR. With a median follow-up of 96 months, 18 patients (47%) relapsed of whom 3 had a relapse in central nervous system site. The 5-year disease-free (DFS) and overall survivals (OS) were 54% and 61%, respectively. In multivariate analysis, the presence of 2 or more extranodal sites was prognostic for lower DFS (P = 0.0008) and OS (P = 0.09), and a performance status > or = 1 was prognostic for lower OS (P = 0.005). Finally, when our series was compared with a historical series of 111 patients with aggressive nodal lymphomas, we observed significant lower survival rates in localized PBL (P < 0.03). Initial breast localization has a pejorative impact on the outcome of patients with Non-Hodgkin's Lymphoma (NHL), with an impressive adverse influence of additional extranodal sites. These results suggest a specific management of NHL with breast involvement.

Nitric oxide synthase activity and expression are decreased in the paraventricular nucleus of pregnant rats

Pregnancy is characterized by elevated heart rate and decreased total peripheral resistance and arterial blood pressure. Plasma volume is expanded and plasma osmolality is decreased, yet vasopressin secretion in pregnant animals, including humans, is no different than levels in the nonpregnant state. Although reflex compensatory sympathoexcitation is suppressed, baseline sympathetic nerve activity to the heart and vasculature is well maintained or slightly elevated in pregnancy. Clearly there are central nervous system (CNS) adaptations in systems for regulation of cardiovascular and body fluid homeostasis in pregnant animals. The paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus are important CNS sites for control of sympathetic nerve activity and vasopressin secretion. Nitric oxide (NO), an important neuromodulator in these hypothalamic nuclei, contributes to tonic inhibition of neurosecretory and pre-autonomic neurons. Alterations in NO within the PVN and SON could contribute to changes in regulation of vasopressin and sympathetic nerve activity in pregnancy. In the present study, nitric oxide synthase (NOS) activity (NADPH-diaphorase staining), neuronal NOS (nNOS) protein, and nNOS mRNA were assessed in nonpregnant estrus stage and near-term pregnant rats. nNOS mRNA, protein, and activity were greater in the PVN than in the SON. In the PVN only, pregnancy was associated with significant decreases in all three measurements for assessment of nNOS. Thus decreased NO production and relative disinhibition of the PVN may contribute to maintenance of baseline vasopressin secretion and baseline sympathetic nerve activity in the pregnant state.