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Objectives The aim was to assess the incidence of sink contamination by multidrug-resistant (MDR) Pseudomonas aeruginosa and Enterobacteriaceae, risk factors for sink contamination and splashing, and their association with clinical infections in the intensive care setting. Methods A prospective French multicentre study (1 January to 30 May 2020) including in each intensive care unit (ICU) a point-prevalence study of sink contamination, a questionnaire of risk factors for sink contamination (sink use, disinfection procedure) and splashing (visible plashes, distance and barrier between sink and bed), and a 3-month prospective infection survey. Results Seventy-three ICUs participated in the study. In total, 50.9% (606/1191) of the sinks were contaminated by MDR bacteria: 41.0% (110/268) of the sinks used only for handwashing, 55.3% (510/923) of those used for waste disposal, 23.0% (62/269) of sinks daily bleached, 59.1% (126/213) of those daily exposed to quaternary ammonium compounds (QACs) and 62.0% (285/460) of those untreated; 459 sinks (38.5%) showed visible splashes and 30.5% (363/1191) were close to the bed ( Discussion Our data showed frequent and multifactorial infectious risks associated with contaminated sinks in ICUs.

In the present study, we investigated whether high-pressure hypotonic saline solution (Hphss) affects the basal level of Nerve Growth Factor (NGF) and expression of receptors in the cochlea, bark earing, retina, and visual cortex.For this study, we used three weeks old female Sprague Dawley (SD) rats (n = 12). Rats were housed in polypropylene cages and were kept under standard conditions (12 h light:12 h dark cycle) with free access to water and food (Purina chow food). A specific dispenser was employed to deliver sterile hypotonic saline at high pressure (pressing emission level (PEL): 7 g/s; emission time (ET): 0.5 s). Rats were divided into two groups: untreated (n = 6) and treated with Hphss (n = 6), three times per day, for 10 consecutive days. Treatment was performed in both nostrils with 50 µl of Hphss using a microsyringe equipped with a plastic tip.We observed a significant enhancement in the level of NGF in the cochlea and bark earing, but not in the retina and visual cortex. This is likely because the nasolacrimal duct pathway does not appear to have an effect on the retina, and the visual cortex appears to be too far from the cribriform plate to be reached by nasal NGF.This treatment can significantly protect and/or delay degeneration of cochlear auditory NGF-target cells. It is free from side effects and can be used in chronic diseases for as long as needed. It remains to be investigated whether the effects of short-term therapy are long-lasting, or if the treatment must be repeated.

Nerve Growth Factor (NGF) is a neurotrophic factor known to play a critical role in growth, survival, differentiation and neuroprotection of peripheral sensory and sympathetic neurons, as well as brain neurons. We have recently reported that nasal administration of high-pressure isotonic physiological saline solution (HPpSIS) enhances the level of NGF and the expression of NGF receptors in neurons of the olfactory bulbs and forebrain cholinergic neurons of laboratory animals. In the present study, we sought to determine whether the same treatment affects the levels of NGF within the brain tumor tissue.This study was conducted on eight adult patients, 4 males and 4 females with malignant anterior cranial fossa tumor. Before surgery, four subjects, two males and two females received nasal administration of HPpSIS for ten consecutive days.The levels of NGF in surgical removed peripheral tumor brain samples of patients treated with nasal HPpSIS administration are more elevated compared to the levels of NGF in peripheral brain tissues of HPpSIS untreated patients.We observed that nasal administration of HPpSIS enhances not only the basal brain NGF levels and the expression of NGF receptors but also the tumor suppressor protein p73. The possible functional significance of these observations will be described and discussed.

Aim: To evaluate the expression of neurotrophic factors (nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF)) and their association with the clinical-radiological characteristics and outcome of children with viral and bacterial meningoencephalitis (ME). Methods: Prospective observational clinical study performed on 13 children with ME and 12 controls with non-inflammatory obstructive hydrocephalus. Neurotrophic factor levels in the cerebro-spinal fluid (CSF) and plasma were measured using an immunoenzymatic assay. Results: High levels of NGF and BDNF were demonstrated in all patients, while GDNF levels did not undergo significant variations. NGF expression in the CSF was higher in viral ME than in bacterial ME and was correlated with CSF cellularity (particularly mononuclear cells). BDNF expression in the CSF was higher in bacterial ME than in viral ME and was correlated with CSF cellularity and blood platelet count. No relationships were noted between CSF protein or serum C-reactive protein levels and the expression of neurotrophic factors. Regarding clinical and radiological features, elevated NGF/BDNF levels in the CSF correlated with higher incidence of seizures and prolonged comatose state and with specific radiological lesions. No correlation was found between NGF/BDNF levels and final outcome. Conclusions: The variations in neurotrophic factor levels may reflect an endogenous attempt at neuroprotection against biochemical and molecular changes during both viral and bacterial ME. The expression of these factors is likely to play a neuro-immunomodulatory or neurosurvival role in ME infections.

Nerve growth factor (NGF) is a neurotrophin which promotes and regulates the survival of neurons in the peripheral nervous system. The aim of this study was to investigate the effect of high-pressure administration of sterile physiological saline isotonic solution (HpPSIS) into nasal cavity of laboratory animals on NGF levels and NGF-receptor expression in the olfactory bulbs and brain.For this study we used three weeks old female Sprague Dawley SD rats (n=48). Rats were divided into two groups, the first one treated delivering physiological saline solution with a normal syringe modified at the extremity to fit the rats' nostril (5 ml) (n=24) and the second one treated spray with HpPSIS (n=24 rats). Rats were treated three times a day either for 5 consecutive days (shorth term treatment) or 10 consecutive days (longer treatment) in both nostrils of HpPSIS delivered at high pressure (pression emission level: PEL: 7 g/sec for emission time ET: 0.5 sec) with a specific forced spray erogator. Untreated rats received a similar manipulation three times a day through a syringe in the nostrils, but no HpPSIS administration.The results of these studies highlight the possibility that endogenous enhancement of NGF by stimulation of NGF-producing cells within the nasal cavities and also in the CNS represent a novel experimental approach to enhance the brain NGF levels with a new therapy. HpPSIS treatment further enhances the presence of NGF in the four brains examined. Indeed, a significant increase of NGF was first observed after 5 days of HpPSIS treatment, compared to HpPSIS untreated rats. The increase was over 25% in the OB, ST, HI and in CX, while 10 days after HpPSIS treatments the levels of NGF were even higher. These differences were statistically significant, p0.05.It was found that forced administration of HpPSIS enhances the presence of these neurotrophic signals, not only in the olfactory bulbs, but also in forebrain cholinergic neurons, which are known to degenerate as result of memory loss and brain aging, including Alzheimer Disease. These findings for the first time in the literature demonstrate the possibility of enhancing the endogenous NGF to protect NGF-damaged neurons. Since the enhanced expression of NGF was first observed after 5 days of treatment and higher after 10 days of treatment, a reasonable hypothesis is that longer HpPSIS treatment might further enhance the level of NGF in brain and olfactory bulbs.

Nerve Growth Factor (NGF) has a prominent action on immature crest-derived nerve cells and on differentiation and survival of neurons in central and peripheral nervous system. NGF is produced by a variety of neuronal and non-neuronal cells, including neoplastic cells. Its role in tumor cells is largely unknown and controversial. The aim of the present study was to investigate the effect of NGF on brain neoplastic cells using primary cultures from ependymoblastoma (EP) tissue. Human EP tissues were cultured to obtain in vitro cells and their structural, biochemical, and molecular responses to NGF were investigated. The results showed that under basal conditions, human EP cells are characterized by low presence of high-affinity NGF-receptors. Time-course and dose-response studies revealed that EP cells undergo differentiation after exposure to NGF. Our findings showed that in human EP cells, NGF exerts a marked action on differentiation rather than proliferation.

The aging brain is characterized by selective neurochemical changes involving several neural populations. A deficit in the cholinergic system of the basal forebrain is thought to contribute to the development of cognitive symptoms of dementia. Attempts to prevent age-associated cholinergic vulnerability and deterioration therefore represent a crucial point for pharmacotherapy in the elderly. In this paper we provide evidence for the protective effect of nicergoline (Sermion) on the degeneration of cholinergic neurons induced by nerve growth factor deprivation. Nerve growth factor deprivation was induced by colchicine administration in rats 13 and 18 months old. Colchicine induces a rapid and substantial down-regulation of choline acetyltransferase messenger RNA level in the basal forebrain in untreated adult, middle-aged and old rats. Colchicine failed to cause these effects in old rats treated for 120 days with nicergoline 10 mg/kg/day, orally. Moreover, a concomitant increase of both nerve growth factor and brain-derived neurotrophic factor content was measured in the basal forebrain of old, nicergoline-treated rats. Additionally, the level of messenger RNA for the brain isoform of nitric oxide synthase in neurons of the basal forebrain was also increased in these animals. Based on the present findings, nicergoline proved to be an effective drug for preventing neuronal vulnerability due to experimentally induced nerve growth factor deprivation.

Numerous studies published in the last two decades provide evidence that nerve growth factor (NGF), a polypeptide originally discovered because of its neurotrophic activity, acts on a variety of cells of the immune system, including mast cells, eosinophils, and B and T lymphocytes. NGF has been shown to increase during inflammatory responses, autoimmune disorders, parasitic infections, and allergic diseases. Moreover, stress, which is characterized also by activation of a variety of immune cells, causes a significant increase in basal plasma NGF levels. Recently published studies reveal that hematopoietic progenitor cells seem to be able to produce and/or respond to NGF. We report these data and discuss the hypothesis of the possible implication of NGF on the functional activities of immune cells. Microsc. Res. Tech. 45:285–291, 1999. © 1999 Wiley-Liss, Inc.

Our acute awareness of the cosmetic, psychosocial and sexual importance of subcutaneous adipose tissue contrasts dramatically with how poorly we have understood the biology of this massive, enigmatic, often ignored and much‐abused skin compartment. Therefore, it is timely to recall the exciting, steadily growing, yet underappreciated body of evidence that subcutaneous adipocytes are so much more than just ‘fat guys’, hanging around passively to conspire, at most, against your desperate attempts to maintain ideal weight. Although the subcutis, quantitatively, tends to represent the dominant architectural component of human skin, conventional wisdom confines its biological key functions to those of energy storage, physical buffer, thermoregulation and thermoinsulation. However, already the distribution of human superficial adipose tissue, by itself, questions how justified the popular belief is that ‘skin fat’ (which actually may be more diverse than often assumed) serves primarily thermoinsulatory purposes. And although the metabolic complications of obesity are well appreciated, our understanding of how exactly subcutaneous adipocytes contribute to extracutaneous disease – and even influence important immune and brain functions! – is far from complete. The increasing insights recently won into subcutaneous adipose tissue as a cytokine depot that regulates innate immunity and cell growth exemplarily serve to illustrate the vast open research expanses that remain to be fully explored in the subcutis. The following public debate carries you from the evolutionary origins and the key functional purposes of adipose tissue, via adipose‐derived stem cells and adipokines straight to the neuroendocrine, immunomodulatory and central nervous effects of signals that originate in the subcutis – perhaps, the most underestimated tissue of the human body. The editors are confident that, at the end, you shall agree: No basic scientist and no doctor with a serious interest in skin, and hardly anyone else in the life sciences, can afford to ignore the subcutaneous adipocyte – beyond its ample impact on beauty, benessence and body mass.

Numerous studies published in the last 10-15 years have shown that nerve growth factor (NGF), a polypeptide originally discovered in connection with its neurotrophic activity, also acts on cells of the immune system. NGF has been found in various immune organs including the spleen, lymph nodes, and thymus, and cells such as mast cells, eosinophils, and B and T cells. The circulating levels of NGF increase in inflammatory responses, in various autoimmune diseases, in parasitic infections, and in allergic diseases. Stress-related events both in animal models and in man also result in an increase of NGF, suggesting that this molecule is involved in neuroendocrine functions. The rapid release of NGF is part of an alerting signal in response to either psychologically stressful or anxiogenic conditions in response to homeostatic alteration. Thus, the inflammation and stress-induced increase in NGF might alone or in association with other biologic mediators induce the activation of immune cells during immunologic insults. A clearer understanding of the role of NGF in these events may be useful to identify the mechanisms implicated in certain neuroimmune and immune dysfunctions.

We have studied the neuropathological characteristics of the brain of rats receiving daily intracerebroventricular administration of freshly dissolved human immunodeficiency virus type 1 recombinant protein gp120 (100 ng per rat per day) given for up to 14 days. Histological examination of serial brain sections revealed no apparent gross damage to the cortex or hippocampus, nor did cell counting yield significant neuronal cell loss. However, the viral protein caused after 7 and 14 days of treatment DNA fragmentation in 10% of brain cortical neurons. Interestingly, reduced neuronal nitric oxide synthase (NOS) expression along with significant increases in nerve growth factor (NGF) were observed in the hippocampus, where gp120 did not cause neuronal damage. No changes in NGF and NOS expression were seen in the cortex, where cell death is likely to be of the apoptotic type. The present data demonstrate that gp120-induced cortical cell death is associated with the lack of increase of NGF in the cerebral cortex and suggest that the latter may be important for the expression of neuropathology in the rat brain. By contrast, enhanced levels of NGF may prevent or delay neuronal death in the hippocampus, where reduced NOS expression may be a reflection of a subcellular insult inflicted by the viral protein.

BACKGROUND: Acupuncture has been used as treatment for infertility for hundreds of years, and recently it has been studied in male and female infertility and in assisted reproductive technologies, although its role in reproductive medicine is still debated. AIM: To review studies on acupuncture in reproductive medicine, in experimental and clinical settings. METHODS: Papers were retrieved on PubMed and Google Scholar and were included in the review if at least the abstract was in English. RESULTS: There is evidence of benefit mainly when acupuncture is performed on the day of embryo transfer (ET) in the live birth rate. Benefit is also evident when acupuncture is performed for female infertility due to polycystic ovary syndrome (PCOS). There is some evidence of sperm quality improvement when acupuncture is performed on males affected by idiopathic infertility. Experimental studies suggest that acupuncture effects are mediated by changes in activity of the autonomic nervous system and stimulation of neuropeptides/neurotransmitters which may be involved in the pathogenesis of infertility. CONCLUSIONS: Acupuncture seems to have beneficial effects on live birth rate when performed on the day of ET, and to be useful also in PCOS as well as in male idiopathic infertility, with very low incidence of side effects. However, further studies are necessary to confirm the clinical results and to expand our knowledge of the mechanisms involved.

Purpose To evaluate tear level of nerve growth factor (NGF) in normal dogs. Methods In the present study we investigated the presence and the level of NGF in the tear of 12 normal dogs (24 eyes) with different sex (5 males and 7 females) and age (ranging from 2 to 12 years old). Tears were collected by washing the eye surface 150 microliter of physiological salt after clinical examinations. Tear samples were stored at -20°C until tested for presence of NGF performed with a commercially available immunoenzymatic assay and expressed as pg/ml of sample. Results All samples examined showed presence of NGF, suggesting that this growth factor is a constitutive biological mediator of the ocular surface. It was also found that the level of NGF in the right eye is different from the left eye. Thus, the average concentration in the tear of the right was 7,97 (ranging from 5.0 to 38.3 pg/ml), whereas the average in the left eyes was 15,79 (ranging from 5.0 to 67.5 pg/ml). Conclusion Tear fluid is a secretion of lacrimal gland that lubrificates the eye surface and plays a critical role in response to eye irritation, by improving optical performance and the deficit induced by keratoconjuntivitis sicca. The observation that NGF is present in tear of dogs in a physiological relevant amount suggests that this molecule may be involved in the regulation of corneal homeostasis. Moreover, as NGF is known to play a role in emotional and anxiety-like behaviour, and tear secretion is a widespread phenomena among vertebrates, the possibility exists that NGF might be also involved in these behaviour responses. Because cats rarely suffer from emotional behavioural and keratoconjuntivitis sicca further studies may help to understand the role of NGF in tear secretion.

Purpose To investigate if topical Nerve Growth Factor (NGF) affects the ocular flora and to study corneal conjunctival cytology in dogs with different eye surface disease. Methods The present study has been conducted on 9 dogs (18 eyes) affected by different ocular surface disease. The dogs were various ages (from 2 to 10 years old) and different sexes (5 males - 4 females). 6 dogs were affected by dry eye, 1 had a superficial keratitis and 2 dogs had a cornea ulcer. All dogs underwent the following examinations: cornea evaluation by slit lamp, fluorescent staining, Schirmer tear test I (STT I), corneal and conjunctival cytology. All samples made with ocular swabs were placed in a sterile blood agar. 6 dogs showed no bacteria, 3 dogs displayed Staphylococcus spp. Cytology pointed out many inflammatory cells. The dogs were topically treated with purified murine NGF diluted in paraffin oil (200 microg/ml) for 4 weeks (50 microg every 12 h). Results The result revealed that all swabs were sterile, while the cytology analysis showed a significant reduction in the number of corneal inflammatory cells. This latter observation is related to a decrease of the corneal inflammatory reduction. Conclusion This report demonstrated that NGF exerts an antibacterial and anti inflammatory activity that confirmed and extended previous evidences on NGF research. Moreover, our results suggest a potential therapeutic use of NGF in dogs with different ocular inflammatory surface. However, further clinical studies need to be done to assess the consistency of this clinic approach.

Purpose: To study the effect of Nerve Growth Factor (NGF) on spontaneous keratoconjunctivitis sicca (KCS) in dogs and to evaluate the potential therapeutic action of this molecule. Methods: The present study has been conducted on a sample of randomized dogs affected by spontaneous KCS. It consists of 6 cases (12 eyes), various ages (from 2 to 10 years old), different sexes (4 males- 2 females). All dogs showed: different stages of muco purulent filaments and redness; they were negative to fluorescein; Schirmer tear test I (STT I) on right eye was 5,8 ± 2,0 mm/1 min on left one was 6,0 ± 1,4 mm/1 min; cytology showed many inflammatory cells. The dogs were topically treated with purified murine NGF diluted in paraffin oil (value: 50 microgram/ml) for 4 weeks (2 drops every 12 hours). Results: The result of these studies showed a significant improvement as evaluated by STT I. Thus, the right eye was 13,1 ± 2,4 mm/1 min (p < 0,05), left eye was 14,0 ± 2,4 mm/1 min (p < 0,05). Moreover, dogs treated with NGF displayed decreased purulent corneal secretion and redness and improvement of corneal transparency. Cytology analysis indicated a significant reduction in the number of corneal inflammatory cells. Conclusions: This report demonstrated that NGF is involved in the regulation of tears production, most probably by acting on tear-producing cells. NGF caused also a marked anti-inflammatory action of the dog’s cornea. This result confirmed and extended previous evidences on human dry eye and previous findings suggesting a potential therapeutic utility of NGF in spontaneous KCS affecting dogs. Neverthless, further clinical studies are necessary to assess the consistency of this clinic approach.

Type 1 diabetes mellitus (DM), a "classical" result of a pancreatic-beta cell damage, is associated with various metabolic, neuronal, endocrine and immune alterations at cellular, tissue and organ levels. Nerve growth factor (NGF) is one of the most extensively studied neurotrophic factors, which is produced and released by numerous cells including the pancreatic beta cells. NGF plays an important role during brain development and may be able to delay or even reverse damaged forebrain cholinergic neurons that undergo degeneration in aged animals and in Alzheimer's disease (AD). Recent reports indicate that experimentally induced DM in rodents can cause brain biochemical and molecular alterations similar to those observed in sporadic AD. Given the importance of NGF in the pathophysiology of brain cholinergic neurons, we looked for NGF changes in the pancreas and brain of diabetic rats. The aim of this study was, therefore, to investigate the effect of streptozotocin-induced DM on NGF and NGF receptor expression in pancreas and brain. The results showed that DM is associated with altered NGF, NGF-receptor expression in both pancreas and brain.

The aim of our study was to investigate the role of nerve growth factor (NGF) on the expression of the p73 protein in human ependymoblastoma (EP) and medulloblastoma (MB) cells. It was found that NGF exposure on MB cells blocks proliferation, as well as on EP cells and induces overexpression of p73. NGF reduces the number of cells and promotes the expression of TrkA of these neoplastic cells. Moreover, NGF plus cisplatin treatment reduces the cytotoxic effect of cisplatin. These observations indicate that NGF by interfering with mechanisms associated with cells proliferation and survival might induce the differentiation event through TrkA pathways.

An increasing number of researchers of the metabolic syndrome assume that many mechanisms are involved in its complex pathophysiology such as an increased sympathetic activity, disorders of the hypothalamo-pituitary-adrenal axis, the action of chronic subclinical infections, proinflammatory cytokines, and the effect of adipocytokines or psychoemotional stress. An increasing body of scientific research in this field confirms the role of the neurotrophins and mastocytes in the pathogenesis of inflammatory and immune diseases. Recently it has been proved that neurotrophins and mastocytes have metabotrophic effects and take part in the carbohydrate and lipid metabolism. In the early stage of the metabolic syndrome we established a statistically significant increase in the plasma levels of the nerve growth factor. In the generalized stage the plasma levels of the neutrophines were statistically decreased in comparison to those in the healthy controls. We consider that the neurotrophin deficit is likely to play a significant pathogenic role in the development of the metabolic anthropometric and vascular manifestations of the generalized stage of MetSyn. We suggest a hypothesis for the etiopathogenesis of the metabolic syndrome based on the neuro-immuno-endocrine interactions. The specific pathogenic pathways of MetSyn development include: (1) increased tissue and plasma levels of proinflammatory cytokines Interleukin-1(IL-1), Interleukin-6 (IL-6 ) and tumor necrosis factor - alpha (TNF-alpha) caused by inflammatory and/or emotional distress; (2) increased plasma levels of neurotrophin - nerve growth factor (NGF) caused by the high IL-1, IL-6 and TNFalpha levels; (3) high plasma levels of NGF which enhance activation of: the autonomous nerve system--vegetodystonia (disbalance of neurotransmitters); Neuropeptide Y (NPY)--enhanced feeding, obesity and increased leptin plasma levels; hypothalamo-pituitary-adrenal axis--increased corticotropin-releasing hormone (CRH) and cortisol (hormonal disbalance); immune cells--increased number and degranulation of mastocytes (MC)--immunological disbalance; (4) as a result of 1-3 insulin resistance is exhibited leading to diabetes mellitus. The hypothesis is confirmed by results obtained after 6-month nonsteroid anti-inflammatory treatment of patients with MetSyn. These results are reported in a separate publication.

BACKGROUND: Nerve growth factor (NGF) and nerve growth factor receptor (NGFR) expressions have been found to be increased in sub-conjunctival scarring. OBJECTIVE: The aim of this study was to investigate the in vitro effects of NGF on some pro-fibrogenic properties of human conjunctival fibroblasts. METHODS: Expression of NGF, trkA(NGFR) and p75NTR on human fibroblasts grown from conjunctival biopsies and incubated for 2 or 6 days with NGF were evaluated by immunofluorescence, RT-PCR, flow cytometry and ELISA. The fibrogenic effect of NGF on conjunctival fibroblasts was investigated by evaluating their migration (wound model), proliferation ([3H]-thymidine incorporation), collagen production (3H]-proline incorporation), expression of alpha-smooth muscle actin (alpha-SMA) (cell surface ELISA) and contraction of 3D collagen gels. RESULTS: NGF induced the expression of p75NTR in the fibroblasts that constitutively expressed only trkA(NGF) and increased the migration of wounded fibroblasts, but not their proliferation and collagen production. NGF induced the conversion of fibroblasts into myofibroblasts expressing alpha-SMA, and enhanced their contraction of a collagen matrix. Interestingly, chronic NGF treatment induced transforming growth factor-beta1 (TGF-beta1) production by fibroblasts, and following specific TGF-beta neutralization, all the NGF-induced effects were completely abrogated. CONCLUSION: Our findings indicate that NGF, via TGF-beta induction, is likely to be involved in the healing or fibrotic processes occurring in conjunctiva during some pathological conditions.

Rett syndrome is a severe neurological developmental disorder. In this syndrome, the high incidence of sudden death is correlated with an alteration of ventricular repolarization. The purpose of this study was to evaluate plasmatic levels of nerve growth factor (NGF) in Rett patients with prolonged corrected QT (QTc) interval in comparison with those of Rett patients with normal QTc. We observed 23 female Rett patients (9.9 ± 4.7 years). NGF plasma levels and QTc interval were measured in all patients. Student t-test was performed for statistical analysis. NGF plasma levels were significantly lower in Rett patients with QTc interval prolongation (QTc > 0.44 sec) in comparison with Rett patients with a normal QTc interval (4.5 ± 4.5 vs 11 ± 8.3 pg/ml, p = 0.02). The alteration of NGF levels, observed in Rett patients with a long QTc interval, may explain the presence of an altered ventricular repolarization associated with a higher risk of cardiac arrhythmias.

Cholecystokinin-8 (CCK-8), the small peptide initially described as a gastric factor involved in the regulation of feeding behavior, is today recognized as one of the most abundant neurotransmitters/ neuropeptides in brain and is an important signal factor for the peripheral and central nervous systems. In the past twenty years, many studies have focused on possible clinical applications of this peptide and its receptor ligands in psychiatric diseases and gastrointestinal pathologies. Recently it has been suggested that CCK-8 may also have a neuroprotective role, thus opening a new field of interest around the physiology and the pharmacology of this neuropeptide and its receptors. It has been demonstrated that CCK-8 counteracts neuronal deficit following chemical or surgical lesions in both the central and peripheral nervous systems and that Nerve Growth factor (NGF) is involved in the CCK-induced recovery process. By using selective CCK receptor antagonists it has been demonstrated that CCK-8, when injected intraperitoneally, has the ability to stimulate NGF synthesis in brain and peripheral organs by a mechanism that involves the activation of CCK receptors. As has been widely reported, NGF is an essential survival and differentiative factor for selective neuronal populations of the PNS and CNS and plays a role in the events of degeneration and repair of the nervous system in diseases with different etiologies, e.g. neurodegenerative and autoimmune diseases as well as diabetes-associated pathologies. The possibility of using NGF in therapy has been evaluated and systemic and intracerebral NGF treatment have been tested in patients and animal models. Although the results of these studies are encouraging, the difficulty to predict and/or eliminate the side effects of NGF/NGF antibody treatment has made it difficult to fully evaluate the potential of the beneficial effects. In this context recent results obtained in our laboratories may offer a new prospective for the pharmacological approaches to the diseases associated with altered NGF production and functions. The data of our recent observations on NGF and CCK-8 is covered in this review.

Background: Nerve growth factor (NGF), discovered because of its action on cells in the peripheral and the central nervous system, is now known to act also on immune cells in developing and adult subjects. Whether peripheral lymphocytes of aged subjects are responsive to this molecule is less clear. Objective: Aim of our study was to investigate whether or not plasma NGF undergoes any significant changes during aging and whether or not NGF receptors on peripheral lymphocytes are affected in old subjects. Methods: To address these questions, we used RT-PCR, immunohistochemistry, and immunoenzymatic analysis to evaluate the expression of NGF receptors in human peripheral lymphocytes and NGF-like immunoreactivity. Results: These results revealed a low amount of NGF in the plasma of old subjects associated with a reduced expression of mRNA for NGF receptor trkA in peripheral lymphocytes. They also showed elevated levels of circulating interleukin-1beta (IL-1β), and interleukin-6 (IL-6) in the bloodstream of adult and aged subjects. Conclusion: Our data indicate that peripheral lymphocytes are targets for circulating NGF and suggest that changes in NGF-receptor expression on lymphocytes might be potential marker for aging lymphocytes.

The biological effects of Nerve Growth Factor (NGF) are primarily mediated via its high affinity receptor-TrkA. In the present study, we examined the effect of experimental autoimmune encephalomyelitis (EAE) upon the expression of TrkA in neuronal and non-neuronal cells of the spinal cord of Lewis rats during the acute (14 days postimmunization) and chronic (12 months postimmunization) phases of the disease. In the normal spinal cord, both of mature and aged rats, we found TrkA immunoreaction (TrkA-IR) in the motoneurons of the Rexed lamina IX and in both oligo- and astroglia cells. In the acute phase of the disease, we found a reduction of TrkA immunoreactivity in motoneurons and its up-regulation in oligodendroglia, mainly in the white matter. We also confirmed our previous findings concerning the up-regulation of TrkA-IR in astroglia. Both neuronal and non-neuronal changes of TrkA immunoreactivity had a transient character: they were not seen in the chronic phase of the disease. Our results suggest that both neuronal and glial TrkA expression changes depend on inflammation. Moreover, our data indicate that, during the acute phase of EAE, the glial cells become more receptive to NGF, pointing to glia as an important target for pharmacological manipulations, particularly for exogenously administered NGF.

Rett syndrome (RS) is a progressive neurodevelopmental disorder predominant in females, characterised by mental deficiency, stereotyped hand-washing and apraxia. Notwithstanding the recent identification of the MECP2 gene likely involved in the pathogenesis of SR, the neurobiological bases of this syndrome are still largely unknown. Converging evidence shows that the brain levels of nerve growth factor (NGF), a neurotrophin regulating the development and functioning of central cholinergic neurons, are decreased in RS girls. In this study, the serum levels of NGF were measured in classic RS, in the preserved speech variant (PSV) and in normal controls. Overall analysis failed to evidence significant differences among the three groups. However, whereas NGF levels increased significantly with age in controls, the opposite profile was observed in classic RS, with a progressive age-dependent decrease of NGF. In PSV subjects NGF levels remained constant with age. These findings strengthen the hypothesis of NGF involvement in the pathogenesis of RS.

Stress is elicited by environmental, social or pathological conditions occurring during the life of animals and humans that determine changes in the nervous, endocrine and immune systems. In the present review, we present data supporting the hypothesis that stress-related events both in animal models and humans are characterized by modifications of endogenous nerve growth factor (NGF) synthesis and/or utilization. Stress inducing alteration in NGF synthesis and/or utilization appears to be more severe during neurogenesis and in early postnatal life. However, NGF endogenously released during stress may promote remodeling of damaged tissues following acute and/or chronic stressful events.

Nerve growth factor (NGF) is the first described neurotrophin that stimulates the growth and differentiation of nerve cells and promotes skin and peripheral tissue regeneration. Recent studies suggest that NGF influences endothelial cell proliferation and angiogenic activity. In view of these proposed regenerative effects, we evaluated the efficacy of subcutaneous administration of highly purified murine NGF in a child with severe crush syndrome of the lower left limb. NGF 10 micro g was administered subcutaneously every eight hours for seven days to the extensive ischaemic skin lesion of the calcaneal area. After treatment we observed gradual improvement of the ischaemic area; no side effects were noted. The child was discharged in good clinical condition to await a limited calcaneal escharotomy.

Despite extensive research on the pathogenesis of polycystic ovary syndrome (PCOS), there is still disagreement on the underlying mechanisms. The rat model for experimentally induced polycystic ovaries (PCO)-produced by a single injection of estradiol valerate-has similarities with human PCOS, and both are associated with hyperactivity in the sympathetic nervous system. Nerve growth factor (NGF) is known to serve as a neurotrophin for both the sympathetic and the sensory nervous systems and to enhance the activity of catecholaminergic and possibly other neuron types. Electro-acupuncture (EA) is known to reduce hyperactivity in the sympathetic nervous system. For these reasons, the model was used in the present study to investigate the effects of EA (12 treatments, approximately 25 min each, over 30 days) by analyzing NGF in the central nervous system and the endocrine organs, including the ovaries. The main findings in the present study were first, that significantly higher concentrations of NGF were found in the ovaries and the adrenal glands in the rats in the PCO model than in the control rats that were only injected with the vehicle (oil or NaCl). Second, that repeated EA treatments in PCO rats resulted in concentrations of NGF in the ovaries that were significantly lower than those in non-EA-treated PCO rats but were within a normal range that did not differ from those in the untreated oil and NaCl control groups. The results in the present study provide support for the theory that EA inhibits hyperactivity in the sympathetic nervous system.

Aims: Some low-grade malignant tumours arising in the abdomen tend to remain loco-regionally confined to peritoneal surfaces, without systemic dissemination. In these cases complete surgical tumour cytoreduction followed by intra- or post-operative regional chemotherapy has curative potential. The aim of this study was to evaluate the outcome for patients treated in this way. Methods: Peritonectomy was performed, involving the complete removal of all the visceral and parietal peritoneum involved by disease. After peritonectomy, hyperthermic antiblastic perfusion was carried out throughout the abdomino-pelvic cavity for 90 min, at a temperature of 41.5–42.5°C, with mitomycin C (3.3 mg/m 2 /l) and cisplatin (25 mg/m 2 /l) (for appendicular or colorectal primaries), or cisplatin alone (for ovarian primaries). Alternatively, the immediate post-operative regional chemotherapy was performed with 5-fluorouracil (13.5 mg/kg) and Lederfolin (125 mg/m 2 ) (for colonic or appendicular tumours) or cisplatin (25 mg/m 2 ) (for ovarian tumours), each day for 5 days. Results: Thirty-five patients affected by extensive peritoneal carcinomatosis were submitted to peritonectomy, with no residual macroscopic disease in all cases except three. Twenty-six patients were able to undergo the combined treatment involving loco-regional chemotherapy. Complications were observed in 54% of the patients and led to death in four of them. At a mean follow-up of 17 months overall 2-year survival was 55.2%, with a median survival of 26 months. Conclusions: After a learning curve of 18 months the feasibility of the integrated treatment increased to more than 90%, while mortality decreased dramatically. The curative potential of the combined therapeutic approach seems high in selected patients with peritoneal carcinomatosis not responding to systemic chemotherapy. Careful selection of patients can minimize the surgical risk, but the treatment should currently be reserved for clinical trials.

Background: Nerve growth factor (NGF), a neurotrophic factor that indirectly induces fibroblast proliferation and collagen production, has been found to be increased in the affected dermis of patients with systemic sclerosis (SSc). To investigate the possibility of a relationship between cutaneous NGF production and pulmonary damage in SSc, we studied seven non-smoking scleroderma patients. Methods: Abnormalities in lung structure were assessed by radiological lung examination, and pulmonary epithelial permeability (PEP) was determined by ventilation lung scintigraphy. All patients underwent skin punch biopsy with NGF immunohistological staining. Results: A statistically significant correlation was found between the PEP values and the cutaneous NGF staining scores, which were markedly increased in all of the patients examined, irrespective of the age, disease duration, or radiologically defined lung abnormalities. Conclusion: These results support the hypothesis that functional and anatomical changes in SSc target organs may be determined by a local tissue hyperproduction of NGF.

We have previously reported that administration of Thymosin alpha 1 (T-alpha1) can enhance the level of the Nerve Growth Factor and the distribution of its receptor in the developing Central Nervous System (CNS) of rat. To further explore the role of T-alpha1 and verify its presence in cells of rat CNS, we carried out an immunohistochemical study using a polyclonal antibody against T-alpha1. T-alpha1 immunoreactivity was found mainly in neurons of the hippocampus and spinal cord and in several small cells, resembling glial cells, of specific regions of the brain. Moreover, to study whether cerebral cells were receptive to T-alpha1, we injected iodinated T-alpha1 (125I-T-alpha1) i.c.v.. 125I-T-alpha1 labelled neurons were observed in the hypothalamus and septal nuclei. Our results indicate that specific neuronal populations in the rat CNS are able to express and respond to T-alpha1.

It has been reported that maternal ethanol consumption leads to deficits in the limbic areas involved in cognitive functions and interferes with synthesis and utilization of neurotrophins. In the present study, it was hypothesized that prenatal alcohol intake might induce neuroanatomical alterations in the entorhinal cortex (EC). We also investigated the possible EC involvement of brain nerve growth factor (NGF), the first neurotrophin to be isolated, during such pathological events. To test this hypothesis, we used pregnant mice exposed to ethanol during EC neurogenesis (starting about gestational day 8). Our data show that prenatal alcohol intake in male mice alters the EC neuronal growth and differentiation. These morphological alterations are accompanied by an altered NGF level in the EC of prenatal alcohol-treated mice. We also found a decrease in choline acetyltransferase- and neuropeptide Y-immunopositive neurons in the EC of alcohol-exposed mice. However, the relationship between neuronal damage induced in the EC by ethanol, low presence of NGF, and the possible functional and behavioral consequences remains to be elucidated.

The effect of subchronic intracerebroventricular injection of the human immunodeficiency virus type 1 (HIV-1) recombinant protein gp120 (100 ng, given daily for up to seven consecutive days) on interleukin-1beta expression was studied by immunohistochemistry in the brain of adult rats. In comparison to control, bovine serum albumin (300 ng, given intracerebroventricularly for up to seven days) -treated animals (n=6), interleukin-1beta immunoreactivity increased in the brain cortex and hippocampus of rats (n=6) receiving a single injection of the viral protein 24 h before analysis with more substantial increases being observed in these regions of the brain (n=6) after seven days treatment. Double-labelling immunofluorescence experiments support a neuronal and, possibly, a microglial cell origin for gp120-enhanced interleukin-1beta expression. Transmission electron microscopy analysis of brain tissue sections revealed that combination treatments (given intracerebroventricularly daily for seven days) with gp120 (100 ng) and interleukin-1 receptor antagonist (80 ng) or with the interleukin converting enzyme inhibitor II (100 pmol), but not with leupeptin (100 pmol), prevented apoptotic death of rat (n=6/group) brain cortical cells typically elicited by the viral protein. These data demonstrate that gp120 enhances interleukin-1beta expression in the brain and this may be involved in the mechanism underlying apoptosis induced by gp120 in the brain cortex of rat. Further support to this hypothesis comes from the evidence that intracerebroventricular injection of murine recombinant interleukin-1beta (200 U, given daily for seven consecutive days) produces DNA fragmentation in the brain cortex of rat (n=6). Interestingly, the latter treatment enhanced nerve growth factor level in the hippocampus but not in the cerebral cortex and this coincides with a similar effect recently reported in identical brain areas of rats treated likewise with gp120. In conclusion, the present data demonstrate that treatment with gp120 enhances interleukin-1beta expression and this participates in the mechanism of apoptotic cell death in the brain cortex of rat. By contrast, in the hippocampus, gp120-enhanced interleukin-1beta expression elevates nerve growth factor that may prevent or delay apoptosis in this plastic region of the rat brain.

Background: Several studies provide evidence that nerve growth factor (NGF) has an expanding role in neuroimmune interactions. Methods: We review our data on circulation levels of NGF in allergic diseases as well as on the relationships between this neurotrophin and primary and secondary effector cells of allergic inflammation. Results: In vernal keratoconjunctivitis, a close relationship exists between the increased NGF plasma values and the number of mast cells infiltrating the conjunctiva. NGF serum values are also increased in other allergic diseases and asthma, and are related to the severity of the inflammatory process and disease. Human CD4+ T cell clones (preferentially of activated Th2 type) produce and release NGF, and express high–affinity NGF receptors. NGF is preformed in and can act on human peripheral blood eosinophils to preferentially release inflammatory mediators. Immunoreactivity for high affinity NGF receptors is present both in basal epithelial cells and in the inflamed stroma of the allergic conjunctiva. Topical administration of NGF results in a complete healing of neurotophic corneal ulcers in man, thus suggesting a profound effect of NGF on human fibroblasts and extracellular matrix. Conclusion: Data presented suggest that NGF is an important molecule in allergic inflammation and tissue remodelling occurring in allergic diseases.

We have previously shown that the level of nerve growth factor (NGF) undergoes significant changes in the cerebrospinal fluid of patients with Multiple Sclerosis and in the brain of rats affected by Experimental Allergic Encephalomyelitis (EAE). The functional significance of the endogenous disregulation of NGF is not known, though recent studies seem to suggest that NGF might be associated with the ability of oligodendrocytes (OLs) to produce and/or utilise NGF. The aim of the present study was therefore to investigate whether NGF is involved in the development and differentiation of cells of the subventricular zone (SVz) which arbors undifferentiated cells that can give rise to OLs. The results show that NGF injected into the brain of developing rats and of rats affected by EAE is retrogradely transported from the SVz to the brain parenchyma. These findings suggest that during the early phase of brain development and during EAE, NGF, along with other growth factors, is implicated in growth and/or differentiation of OLs and in protecting neuronal injury. The possible functional role of NGF in these events has been discussed.

Fas is a receptor of the tumor necrosis factor (TNF)/ nerve growth factor (NGF) receptor superfamily that mediates apoptosis and some inflammatory changes. As the central administration of TNF is known to activate the hypothalamus-pituitary-adrenal axis (HPAA) and to induce peripheral responses including induction of serum interleukin (IL)-6 and serum amyloid A (SAA), we investigated the effects of intracerebroventricular (i.c.v.) administration of agonist anti-Fas monoclonal antibody Jo2. Centrally administered anti-Fas (1 microg/mouse, i.c.v.) induced elevated levels of corticosterone, IL-6, and SAA comparable to those observed after i.c.v. administration of recombinant murine TNF. On the other hand, administration of murine NGF did not elevate serum corticosterone or IL-6, but induced SAA. Thus, Fas can trigger a centrally mediated anti-inflammatory response (HPAA activation) and induce a peripheral acute-phase response comparable to that induced with TNF, whereas NGF induces only acute-phase proteins.

Nerve growth factor (NGF) is the first discovered and best known neurotrophic factor and is required for the survival and differentiation of a variety of neuronal cell types in both the peripheral and central nervous system. Recent studies indicate that NGF is synthesized by cells of immune system lineage and that its level increases during inflammatory responses, while cytokines such as interleukin-1 beta and tumor necrosis factor-alpha are potent inducers of NGF secretion. The role played by NGF on cells of the immune system was strengthened by recent evidence demonstrating that cells normally present in inflammatory tissues, such as mast cells and lymphocytes, express NGF receptors and are receptive to the action of NGF. Studies carried out in our and other laboratories showed that NGF is expressed in the synovial fluid of patients with rheumatoid arthritis and other forms of chronic arthritis, as well as in the synovium of pharmacologically-induced arthritis in animal models. Moreover, arthritic transgenic mice which carry and express the human tumor necrosis factor-gene also showed elevated levels of NGF. Significant increases in NGF levels have been found in the sera of patients with systemic lupus erythematosus and in the dermis of patients affected by systemic sclerosis. In this paper the hypothesis that NGF is involved in the pathophysiology of autoimmune rheumatic arthritis is discussed.