Cost-effectiveness of onabotulinumtoxinA for the treatment of wrist and hand disability due to upper-limb post-stroke spasticity in Scotland.

BACKGROUND AND PURPOSE: The objective was to evaluate the cost-effectiveness of treating upper-limb post-stroke spasticity (ULPSS) with usual care (UC) plus onabotulinumtoxinA versus UC alone in Scotland. METHODS: We developed a model to simulate costs and quality-adjusted life years (QALYs) gained from treating ULPSS. Efficacy data and health utilities were taken from clinical trials. Unit costs were taken from published Scottish sources. We compared UC plus onabotulinumtoxinA and UC alone in three scenarios: (i) a scenario from the National Health Service perspective, which included differences in onabotulinumtoxinA use, specialist visits and day-hospital visits; (ii) a scenario that only included differences in onabotulinumtoxinA use and specialist visits; and (iii) a scenario from a societal perspective that included differences in onabotulinumtoxinA use, specialist visits and caregiver burden. RESULTS: In the first scenario, the model predicted that UC plus onabotulinumtoxinA produced 0.107 QALYs at an additional cost of £1099 compared with UC alone over 5 years, resulting in an incremental cost-effectiveness ratio (ICER) of £10,271/QALY. In the second scenario, the ICER increased to £27,134/QALY. In the third scenario (societal perspective), UC plus onabotulinumtoxinA produced lower total cost and higher QALYs, and therefore was superior to UC alone. CONCLUSIONS: Based on a model, UC plus onabotulinumtoxinA improved disability, which translated into greater QALYs but also increased direct medical costs compared with UC alone; however, the resulting ICER can be considered cost-effective. Moreover, UC plus onabotulinumtoxinA can be cost-saving if reduction in caregiver burden was included. OnabotulinumtoxinA offers value for money in the management of ULPSS in Scotland.

Cost of healthcare for patients with migraine in five European countries: results from the International Burden of Migraine Study (IBMS).

Migraine is a disabling neurological disease that affects 14.7 % of Europeans. Studies evaluating the economic impact of migraine are complex to conduct adequately and with time become outdated as healthcare systems evolve. This study sought to quantify and compare direct medical costs of chronic migraine (CM) and episodic migraine (EM) in five European countries. Cross-sectional data collected via a web-based survey were screened for migraine and classified as CM (≥15 headache days/month) or EM (<15 headache days/month), and included sociodemographics, resource use data and medication use. Unit cost data, gathered using publicly available sources, were analyzed for each type of service, stratified by migraine status. Univariate and multivariate log-normal regression models were used to examine the relationship between various factors and their impact on total healthcare costs. This economic analysis included data from respondents with migraine in the UK, France, Germany, Italy, and Spain. CM participants had higher level of disability and more prevalent psychiatric disorders compared to EM. CM participants had more provider visits, emergency department/hospital visits, and diagnostic tests; the medical costs were three times higher for CM than EM. Per patient annual costs were highest in the UK and Spain and lower in France and Germany. CM was associated with higher medical resource use and total costs compared to EM in all study countries, suggesting that treatments that reduce headache frequency could decrease the clinical and economic burden of migraine in Europe. Comparing patterns of care and outcomes among countries may facilitate the development of more cost-effective care, and bring greater recognition to patients affected by migraine.

OnabotulinumtoxinA improves quality of life and reduces impact of chronic migraine.

OBJECTIVE: To assess the effects of treatment with onabotulinumtoxinA (Botox, Allergan, Inc., Irvine, CA) on health-related quality of life (HRQoL) and headache impact in adults with chronic migraine (CM). METHODS: The Phase III Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) clinical program (PREEMPT 1 and 2) included a 24-week, double-blind phase (2 12-week cycles) followed by a 32-week, open-label phase (3 cycles). Thirty-one injections of 5U each (155 U of onabotulinumtoxinA or placebo) were administered to fixed sites. An additional 40 U could be administered "following the pain." Prespecified analysis of headache impact (Headache Impact Test [HIT]-6) and HRQoL (Migraine-Specific Quality of Life Questionnaire v2.1 [MSQ]) assessments were performed. Because the studies were similar in design and did not notably differ in outcome, pooled results are presented here. RESULTS: A total of 1,384 subjects were included in the pooled analyses (onabotulinumtoxinA, n = 688; placebo, n = 696). Baseline mean total HIT-6 and MSQ v2.1 scores were comparable between groups; 93.1% were severely impacted based on HIT-6 scores ≥60. At 24 weeks, in comparison with placebo, onabotulinumtoxinA treatment significantly reduced HIT-6 scores and the proportion of patients with HIT-6 scores in the severe range at all timepoints including week 24 (p < 0.001). OnabotulinumtoxinA treatment significantly improved all domains of the MSQ v2.1 at 24 weeks (p < 0.001). CONCLUSIONS: Treatment of CM with onabotulinumtoxinA is associated with significant and clinically meaningful reductions in headache impact and improvements in HRQoL. CLASSIFICATION OF EVIDENCE: This study provides Class 1A evidence that onabotulinumtoxinA treatment reduces headache impact and improves HRQoL.

Disability, HRQoL and resource use among chronic and episodic migraineurs: results from the International Burden of Migraine Study (IBMS).

BACKGROUND: Migraine imposes significant burden on patients, their families and health care systems. In this study, we compared episodic to chronic migraine sufferers to determine if migraine status predicted headache-related disability, health-related quality of life (HRQoL) and health care resource utilization. METHODS: A Web-based survey was administered to panelists from nine countries. Participants were classified as having chronic migraine (CM), episodic migraine (EM) or neither using a validated questionnaire. Data collected and then analyzed included sociodemographics, clinical characteristics, Migraine Disability Assessment, Migraine-Specific Quality of Life v2.1, Patient Health Questionnaire and health care resource utilization. FINDINGS: Of the respondents, 5.7% had CM and 94.3% had EM, with CM patients reporting significantly more severe disability, lower HRQoL, higher levels of anxiety and depression and greater health care resource utilization compared to those with EM. INTERPRETATION: These results provide evidence that will enhance our understanding of the factors driving health care costs and will contribute to development of cost-effective health care strategies.

Preference and satisfaction with a 6-month subcutaneous injection versus a weekly tablet for treatment of low bone mass.

UNLABELLED: The Preference and Satisfaction Questionnaire (PSQ) compares patient preference and satisfaction between a 6-month subcutaneous injection and weekly oral tablet for treatment of bone loss. Patients preferred and were more satisfied with a treatment that was administered less frequently, suggesting the acceptability of the 6-month injection for treatment of bone loss. INTRODUCTION: The PSQ compares patient preference and satisfaction between a 6-month subcutaneous injection and a weekly oral tablet for treatment of bone loss. METHODS: Postmenopausal women with low bone mass who enrolled in two separate randomized phase 3 double-blind, double-dummy studies received a 6-month subcutaneous denosumab injection (60 mg) plus a weekly oral placebo or a weekly alendronate tablet (70 mg) plus a 6-month subcutaneous placebo injection. After 12 months, patients completed the PSQ to rate their preference, satisfaction, and degree of bother with each regimen. RESULTS: Most enrolled patients (1,583 out of 1,693; 93.5%) answered >or=1 item of the PSQ. Significantly more patients preferred and were more satisfied with the 6-month injection versus the weekly tablet (P < 0.001). More patients reported no bother with the 6-month injection (90%) than the weekly tablet (62%). CONCLUSION: Patients preferred, were more satisfied, and less bothered with a 6-month injection regimen for osteoporosis.

Design of the POSSIBLE UStrade mark Study: postmenopausal women's compliance and persistence with osteoporosis medications.

UNLABELLED: Failure to take prescribed medication is common. The POSSIBLE US study is evaluating the impact of physician and patient characteristics on patient-reported compliance and persistence with osteoporosis medications. We report our study design and the baseline characteristics of 4,994 postmenopausal women recruited from primary care physician offices in 33 states. INTRODUCTION: The Prospective Observational Scientific Study Investigating Bone Loss Experience (POSSIBLE US) is a longitudinal cohort study of osteoporosis therapy in primary care. METHODS: Between 2004 and 2007, 134 physicians (in 33 states) enrolled postmenopausal women initiating, changing, or continuing osteoporosis medications. After completing a baseline questionnaire, participants will provide data semi-annually for up to 3 years through 2008. Physicians provide patient data at baseline and routine follow-up visits. Participants from 23 sites also signed a release regarding administrative claims data for economic analyses and validation of self-reported data. BASELINE RESULTS: Four thousand nine hundred and ninety-four evaluable women were recruited from internal medicine (n = 1,784), family practice (n = 1,556), obstetrics/gynecology (n = 1,556), and from one rheumatology practice (n = 98). Mean participant age was 64.3 years (SD = 9.97); 89% were Caucasian; 59% had some college education. Sixty-three percent used a single osteoporosis agent, usually a bisphosphonate. For monotherapy patients, concordance between clinic- and patient-reported medication use was lowest for patients prescribed estrogen therapy (70%) or calcium/vitamin D (72%). Obstetrician/gynecologists enrolled younger women, who were more likely to use estrogen therapy than patients enrolled by other physicians. The 934 women (19%) prescribed only calcium/vitamin D were younger than women prescribed pharmacologic therapy. CONCLUSIONS: POSSIBLE US provides a unique foundation for evaluating longitudinal use of osteoporosis medications and related outcomes.

Aislamiento e identificación micológica de Paraccocidioides brasiliensis de una lesión bucal: reporte de un caso / Mycological isolation and identification of Paracoccidioides brasiliensis in an oral lesion: report of a case

El Paracoccidioides brasiliensis es el agente causal de una micosis profunda, la Paracoccidioidomicosis endémica en centro y sudamérica, que produce manifestaciones bucales y, en ocasiones, éstas son el primer y principal signo-síntoma de infección. El diagnóstico de esta micosis está basado en el aislamiento e identificación de los elementos fúngicos en las muestras clínicas. Acude al Servicio de Clínica Estomatológica de la Facultad de Odontología de la UCV unpaciente de sexo masculino de 59 años, referido por presentar lesión granulomatosa a nivel de la mucosa alveolar anteroinferior, con un diagnóstico provisional de carcinoma espinocelular. Por las características clínicas de la lesión y el antecedente del paciente de trabajar en fumigación de suelos, se decide realizar el aislamiento e identificación del Paraccocidioides brasiliensis por estudio micológico e histopatológico, confirmándose el diagnóstico de Paracoccidioidomicosis

Relationship between maternal church attendance and adolescent mental health and social functioning.

OBJECTIVE: This study compared maternal attendance at religious services with standard demographic characteristics such as race, type of religion, and mother's education in terms of their relative association with the behavioral and social functioning of young adolescents. METHODS: The Child Health and Illness Profile--Adolescent Edition and the Children's Depression Inventory were used to screen 445 youths age 11 through 13 who were randomly selected from two public middle schools in Baltimore. Based on the findings, the investigators selected a sample of 143 youths in which approximately two-thirds were at risk of having a psychiatric disorder and the remaining third were unlikely to have a psychiatric disorder. The youths and their mothers were interviewed at home to determine the mothers' frequency of participation in religious services and the youths' self-reported health and mental health status and social role functioning. RESULTS: Youths whose mothers attended religious services at least once a week had greater overall satisfaction with their lives, more involvement with their families, and better skills in solving health-related problems and felt greater support from friends compared with youths whose mothers had lower levels of participation in religious services. Maternal attendance at religious services had a strong association with the youths' outcome in overall satisfaction with health and perceived social support from friends, although family income was the strongest predictor of five other aspects of functioning, including academic performance. CONCLUSIONS: Frequent maternal participation in religious services was associated with healthy functioning and well-being in this sample of young adolescents. This association is as important as or more important than associations involving other traditional demographic variables, with the exception of family income.

Differentiation of rat hypothalamic dopaminergic neurons is stimulated in vitro by target cells: the melanotrophs.

We have investigated in vitro the influence of pituitary intermediate lobe melanotrophs on the differentiation of their afferent hypothalamic dopaminergic neurons. The presence of melanotrophs in primary cultures of foetal hypothalamic neurons induces an increase of the number of dopaminergic neurons (while the total neuronal population remains unchanged) and induces a stimulation of their neuritic outgrowth. These effects are mediated by diffusible factors since they are reproduced by application of conditioned medium issued from co-cultures with intermediate lobe cells from newborn rats. Moreover, by immunoneutralization of alpha-melanocyte-stimulating hormone (alphaMSH) in the co-culture or conditioned medium, or by application of the peptide itself, we demonstrate that the neuritotrophic effect on dopaminergic neurons is mediated by alphaMSH, the main secretory product of melanotrophs, whereas the inductive effect on the number of dopaminergic neurons is attributable to another diffusible neurotrophic factor(s) present in foetal, but not adult, adenohypophysis. Similar effects are observed on cultures of newborn hypothalamic neurons. However, at this stage of neuronal development, alphaMSH also increases the number of dopaminergic neurons, which could be due to a change of neuronal receptivity. We show that the neuritotrophic influence of alphaMSH is restricted to the dopaminergic neurons connected to the melanotrophs, and that in addition, these neurons systematically co-express the tyrosine hydroxylase and glutamate decarboxylase as the neurons innervating the melanotrophs in situ. These findings indicate that the differentiation of dopaminergic hypothalamic neurons is influenced by the target cells, melanotrophs, and that this trophic influence implicates alphaMSH.

Diet-induced insulin resistance precedes other aspects of the metabolic syndrome.

This study was designed to examine the effects of a high-fat refined-sugar (HFS) or a low-fat complex-carbohydrate (LFCC) diet on insulin-stimulated skeletal muscle glucose transport, plasma insulin, blood pressure, plasma triglycerides, plasma glycerol, body weight, and body fat in female Fischer rats. Insulin-stimulated glucose transport was significantly reduced in the HFS group at 2 wk, 2 mo, and 2 yr, whereas serum insulin was significantly elevated at all time points. Blood pressure was not significantly elevated in the HFS group until 12 mo, and all HFS animals were hypertensive by 18 mo. Glycerol, triglycerides, and abdominal fat cell size were not significantly different at 2 wk but were significantly elevated in the HFS rats at 2 and 6 mo. Body weight was similar in both groups until 20 wk on the diet, when the HFS rats started to gain more weight. These results demonstrate that insulin resistance and hyperinsulinemia occur before the other manifestations of the metabolic syndrome and that diet, not obesity, is the underlying cause.

Partial cortical devascularization results in elevations of cortical nerve growth factor and increases nerve growth factor protein within basal forebrain cholinergic neurons.

Previous studies have demonstrated that partial cortical devascularization results in increased levels of nerve growth factor protein within the tissue immediately surrounding the infarcted region. In the present study, we have used this lesion model to further characterize the nerve growth factor increase by investigating: (i) the time course for this phenomenon; (ii) the impact of the devascularizing lesion on cortical regions not directly impinged upon by the lesion; and (iii) the response of nerve growth factor-sensitive nucleus basalis neurons providing afferent cortical innervation to the increased availability of nerve growth factor within their target territory. Our results indicate that, within the infarcted cortex, nerve growth factor levels increase rapidly following the lesion (up 51% by one day post lesion), reach a maximum of 136% above controls by three days and undergo a slow decline back to baseline levels by 23 days. Within the frontal and cingulate cortices, which are not devascularized by the lesion and show no signs of pathological damage, nerve growth factor levels increase over a similar time course, and with a similar magnitude, to those in the lesioned cortex. Nerve growth factor-sensitive nucleus basalis neurons on the side ipsilateral to the lesion respond to increased cortical nerve growth factor levels with an increased accumulation of nerve growth factor within their cell bodies (revealed by nerve growth factor immunohistochemistry and quantitative enzyme-linked immunosorbent assay) which was apparent at three days following the lesion, but no longer discernible at seven or 14 days or later. The present study investigated a model of cortical devascularization for its ability to alter nerve growth factor levels within the cortex. Nerve growth factor levels were rapidly increased within the infarcted cortical tissue beneath the lesion but were also elevated to a similar extent, and with a similar time course, in cortical regions not directly impinged upon by the lesion. The retrograde impact of elevated cortical nerve growth factor levels was demonstrated by an increased accumulation of nerve growth factor within the cell bodies of nucleus basalis neurons providing innervation to the cortex. This lesion model should provide a potential avenue for investigating the functional role(s) of nerve growth factor in the intact and lesioned adult central nervous system, as well as the internal mechanisms for regulating its synthesis, release, uptake, and degradation.

Reversible sedimentation and masking of nerve growth factor (NGF) antigen by high molecular weight fractions from rat brain.

Nerve growth factor (NGF) was recently found to be largely associated with sedimentable fractions of adult rat brain and treatments of the fractions by alkaline pH increased the measurable amount of their NGF antigen as well as its solubilization [M.C. Hoener, E. Hewitt, J.M. Conner, J.W. Costello and S. Varon, Nerve growth factor (NGF) content in adult rat brain tissues is several-fold higher than generally reported and is largely associated with sedimentable fractions, Brain Res., 728 (1996) 47-56; M.C. Hoener and S. Varon, Effects of sodium chloride, Triton X-100, and alkaline pH on the measurable contents and sedimentability of the nerve growth factor (NGF) antigen in adult rat hippocampal tissue extracts, J. Neurosci. Res., in press (1997); C. Zettler, D.C.McL. Bridges, X.-F. Zhou and R.A. Rush, Detection of increased tissue concentrations of nerve growth factor with improved extraction procedure, J. Neurosci. Res., 46 (1996) 581-594]. We have further investigated the reversibility of these pH effects. Reversal of the pH of an adult rat hippocampal tissue extract from 10.5 to 7.4 led to an almost complete transfer of NGF back from nonsedimentable to sedimentable fractions and to a remasking of the previously unmasked portion of NGF antigen. Thus, molecules causing masking and sedimentation of NGF at pH 7.4 were likely to be present in the alkaline extract. A gel filtration column in PBS, pH 10.5 was used to separate such putative binding molecules from the NGF. All of the NGF antigen from rat hippocampal alkaline extract was found to elute with 19 kDa fractions. The same apparent molecular weight was found for mouse submaxillary beta-NGF and recombinant human beta-NGF. Masking and sedimentation no longer occurred when newly generated 19 kDa rat brain NGF was returned to pH 7.4. When high molecular weight fractions derived from the same gel filtration (in PBS, pH 10.5) were added back to the 19 kDa NGF pool at pH 7.4 and the mixture incubated and centrifuged, the measurability of 19 kDa rat brain NGF antigen was markedly reduced and half of the antigen was recovered in sedimentable fractions. Similar but less dramatic results were obtained when mixing the same high molecular weight fractions with 19 kDa mouse or human beta-NGF. These findings provide new opportunities to identify molecules to which NGF may be bound within intact brain tissues.

Effects of sodium chloride, Triton X-100, and alkaline pH on the measurable contents and sedimentability of the nerve growth factor (NGF) antigen in adult rat hippocampal tissue extracts.

Nerve growth factor (NGF) was found to be largely associated with sedimentable fractions of hippocampal and other neural tissues of the adult rat (Hoener et al.: Brain Res 728:47-56, 1996), verified by both bioassay and ELISA techniques. In the present study, the ELISA assay conditions were improved and simplified. Bovine serum albumin was needed in the phosphate buffered saline for maximal measurability of NGF antigen. Hippocampal tissue sonicates were separated into nonsedimentable supernatant and sedimentable pellet fractions. Individual or combined treatments with sodium chloride, Triton X-100, and pH were applied to the samples for possible effects on the i) measurable content of NGF antigen and ii) distribution of sedimentable and nonsedimentable forms. The amount of measurable NGF antigen was found to be increased in a dose dependent fashion by sodium chloride between 0.15 and 0.35 M, Triton X-100 between 0 and 0.5%, and pH between 8.5 and 10.5. The same treatment that led to maximal measurable NGF levels (0.7% Triton X-100 and pH 10.5) also caused the release of the NGF antigen from sedimentable to nonsedimentable fractions. Similar findings regarding maximal NGF antigen levels and release were seen for treatments applied to the sonicate before separation into a supernatant and pellet fraction.

NGF and BDNF in the anterior pituitary lobe of adult rats.

Previous studies revealed that NGF-like immunoreactivity is present in cells from the adult rat anterior pituitary lobe, both in vivo and in vitro, and that in both situations NGF colocalizes with the thyroid-stimulating hormone (TSH). More recently, brain-derived neurotrophic factor (BDNF) was similarly found to occur in the anterior pituitary tissue, again with a general colocalization with TSH. In the present study, we have extended the use of adult rat anterior pituitary cultures to show their content of BDNF-immunoreactive cells and their main colocalization with TSH. We have also explored the question of whether neurotrophins nerve growth factor (NGF) and/or BDNF are actually produced within anterior pituitary cells. Use of the sensitive method reverse transcription-polymerase chain reaction (RT-PCR) has allowed us to confirm the presence of NGF and BDNF mRNAs in the cell suspension freshly derived from adult anterior pituitary. In situ hybridization techniques applied to the cell cultures from such a suspension, however, have revealed only a variable presence of NGF mRNA-positive cells but no recognizable BDNF mRNA. Thus, the question of whether the two neurotrophins are produced within the very cells whose immunoreactive content can be recognized remains an open one.

Developmental profile of NGF immunoreactivity in the rat brain: a possible role of NGF in the establishment of cholinergic terminal fields in the hippocampus and cortex.

In the current investigation, we have examined the developmental profile of nerve growth factor immunoreactivity (NGF-ir) in the postnatal rat. During the first 3 weeks after birth, NGF-ir was observed within the hippocampal mossy fiber region, where it persists throughout adulthood and appeared transiently within three additional zones-the dentate gyrus supragranular zone, the tenia tecta/intermediate lateral septum, and the cingulate/retrosplenial cortex. In all cases, the appearance of NGF-ir progressed in a rostrocaudal pattern over time. A strong correlation was seen between the pattern of NGF-ir and cholinergic innervation in the dentate gyrus supragranular zone, both spatially and temporally, suggesting that NGF may direct the innervation of cholinergic afferents to this region. A spatial correlation was also observed between NGF-ir and cholinergic innervation within the retrosplenial cortex and tenia tecta. With our current techniques, however, we were unable to determine at what point during development the adult-like pattern of cholinergic terminal innervation in these regions occurred and, thus, were not able establish a temporal correlation in these regions. Within the cingulate cortex, there was no evidence suggesting that the developmental appearance of NGF-ir in this region was associated with a specific enhancement of cholinergic innervation. Thus, the results of the current investigation clearly identify the presence of transiently occurring zones of NGF-ir during postnatal CNS development, although defining their exact functional role will require additional investigation.

Neurotrophin-4 (NT-4) and glial cell line-derived neurotrophic factor (GDNF) promote the survival of corticospinal motor neurons of neonatal rats in vitro.

We have used enriched dissociated, low density cultures of neonatal rat corticospinal motor neurons to evaluate the survival-promoting effect of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), and glial cell line-derived neurotrophic factor (GDNF) and the ciliary neurotrophic factor (CNTF). Our current findings demonstrated that CNTF promoted the survival of corticospinal motor neurons, in the same fashion and at an equivalent potency, as was previously described using a different assay system. Among the other factors tested, we also found that NT-4 and GDNF increased the number of surviving neurons in a dose-dependent manner, whereas NGF, BDNF and NT-3 showed no survival promoting effect on corticospinal motor neurons.

Distribution of brain-derived neurotrophic factor (BDNF) protein and mRNA in the normal adult rat CNS: evidence for anterograde axonal transport.

A sensitive immunohistochemical technique was used, along with highly specific affinity-purified antibodies to brain-derived neurotrophic factor (BDNF), to generate a detailed mapping of BDNF immunoreactivity (BDNF-ir) throughout the adult rat CNS. A parallel analysis of sites of BDNF synthesis was performed with in situ hybridization techniques using a cRNA probe to the exon encoding mature rat BDNF protein. These combined data revealed (1) groups of cell bodies containing diffuse BDNF-ir throughout the CNS that were strongly correlated with fields of cells containing BDNF mRNA; (2) varying degrees of BDNF-ir outside of cell bodies, in what appeared to be fibers and/or terminals; and (3) many regions containing extremely heavy BDNF-immunoreactive fiber/terminal labeling that lacked BDNF mRNA (e.g., medial habenula, central nucleus of the amygdala, bed nucleus of stria terminalis, lateral septum, and spinal cord). The latter observation suggested that in these regions BDNF was derived from anterograde axonal transport by afferent systems. In the two cases in which this hypothesis was tested by the elimination of select afferents, BDNF immunostaining was completely eliminated. These data, along with the observation that BDNF-ir was rarely found within dendrites or fibers en passage, suggest that BDNF protein produced in adult CNS neurons is polarized primarily along axonal processes and is preferentially stored in terminals within the innervation target.

Synthetic NGF peptide derivatives prevent neuronal death via a p75 receptor-dependent mechanism.

Cyclized peptides corresponding to beta-loop regions of NGF were purified by HPLC and assayed for neurotrophic activity using DRG neurons. Peptides with the highest activity corresponded to loop region 29-35, a domain likely to interact with the p75 receptor. Unexpectedly, activity was confined to late-eluting HPLC fractions containing peptide multimers and primarily promoted neuronal survival without neurite outgrowth. Directed synthesis of dimer and monomer cyclized peptides demonstrated that dimers acted as partial NGF agonists in that they had both survival-promoting and NGF-inhibiting activity while monomer and linear peptides were inactive. Dimer activity was not affected by the Trk inhibitor K252a but was blocked by p75 receptor antibody and absent using p75 null mutant neurons. These studies suggest that region 29-35 peptide derivatives inhibit neuronal death via a structure- and p75-dependent mechanism.

Dopaminergic regulation of BDNF content in the pituitary intermediate lobe.

Previous studies in adult rats have demonstrated that the neurotrophin, brain-derived neurotrophic factor (BDNF), is present in virtually all cells of the pituitary intermediate lobe. In the present study, we demonstrate that cells cultured from adult intermediate lobe pituitary (ILP) rapidly lose their BDNF immunoreactivity (IR). Furthermore, a similar loss of immunostaining occurs in whole (undissociated) ILP within 30 min after removal from the rat. However, when the dopamine agonist apomorphine is present throughout the dissociation procedure and during cultivation, BDNF-IR is preserved. Supplying apomorphine only during either dissociation or cultivation did not prevent the loss of BDNF-IR in the 24 h cultures. These results suggest that a tonic dopaminergic stimulus is required to maintain BDNF-IR in ILP cells.

The role of NGF and afferent denervation in the process of sympathetic fiber ingrowth into the hippocampal formation.

Nerve growth factor (NGF) has been postulated to play an important role in the process of sympathetic sprouting into the septally deafferented hippocampal formation. In the current investigation we have used transplants of NGF-dependent neonatal superior cervical ganglion (SCG) neurons to investigate the influence of NGF and septal denervation (either alone or in combination with one another) upon neuronal survival and intrahippocampal sprouting. In the current model, SCG transplants were placed onto the dorsal surface of the CA1 hippocampal subfield and a continuous infusion device was used to deliver either NGF or vehicle into the hippocampal parenchyma. Following 15 days of vehicle infusion, little or no sympathetic neuronal survival was observed and no hippocampal fiber outgrowth was detected. NGF infusions, however, promoted both neuronal survival and intrahippocampal fiber outgrowth directed mainly toward the location of the infusion cannula. Septal denervation, achieved by either a septal ablation or fimbria-fornix transection, had no discernible impact upon SCG neuronal survival or fiber outgrowth, with or without NGF infusions. Similar results were also obtained when SCG were transplanted directly within the cortex, with or without an intracortical infusion. It appears, therefore, that NGF may be a sufficient, as well as necessary, component for eliciting and guiding the invasion of a tissue by NGF-sensitive fibers.