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G D Borasio

Publications and source records attributed to G D Borasio.

At least 37 records · Page 2Linked to original sources
PubMed2001

Palliative care in ALS: searching for the evidence base.

The poor prognosis of amyotrophic lateral sclerosis (ALS) makes palliative care a challenge for the neurologist. Most of the disabilities from progressive disease can be effectively relieved by symptomatic treatment. Prognosis and treatment options should be openly discussed with patient and relatives. Adequate assistance and palliative treatment in the terminal phase are of paramount importance. Unfortunately, training in communication skills for young doctors and evidence-based recommendations for palliative care are insufficient at present. In addition, new data from a randomized study question the concept of "health-related quality of life" and favor an individualized approach to the definition of quality of life in ALS.

Amyotrophic Lateral Sclerosis↗
PubMed2000

Axotomy of the sciatic nerve differentially affects expression of metabotropic glutamate receptor mRNA in adult rat motoneurons.

Previous studies indicated that axotomy exposes motoneurons to glutamatergic excitotoxic stress and protection from glutamatergic overactivation might be crucial for survival. Depending on the experimental model and the subtype involved, activation of metabotropic glutamate receptors (mGluRs) may either enhance excitotoxicity or exert protective effects. To investigate a possible involvement of mGluRs in neuronal rescue mechanisms after axotomy we have monitored the distribution of mGluR mRNA with in situ hybridization in adult rat motoneurons 1, 2, 3, and 4 weeks after sciatic nerve transection. Motoneurons in sham-operated control animals expressed mGluR 1, 4, and 7 mRNA. The mGluR1 mRNA signal was reduced to 49.6+/-6.9% as compared to the contralateral side 2 weeks after axotomy and 31.2+/-8.3% after 4 weeks. The mGluR4 signal declined to 22.1+/-5.1% after 1 week and 10.2+/-1.6% after 2 weeks, remaining stable thereafter. During the entire observation period the mRNA for mGluR7 was not significantly altered. Axotomy did not change the overall number of motoneurons on the ipsi- or contralateral side. The differential regulation of mGluR subtypes may be part of an adaptive cell program that helps to rescue adult motoneurons from excitotoxic cell death during the stress induced by peripheral denervation.

Animals↗
PubMed1999

Differential expression of group I metabotropic glutamate receptors in rat spinal cord somatic and autonomic motoneurons: possible implications for the pathogenesis of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the progressive loss of somatic, but not autonomic, motoneurons. The reason for this selective vulnerability is unknown. The pathogenesis of ALS is thought to involve glutamatergic excitotoxic mechanisms. While overactivation of ionotropic glutamate receptors may trigger excitotoxicity, we have previously shown that stimulation of group I metabotropic glutamate receptors (mGluRs) can exert neuroprotective effects on cultured motoneurons. Using in situ hybridization, we found a differential expression of group I mGluRs (mGluR1 and 5) in rat spinal cord. Autonomic motoneurons from the sacral parasympathetic Onuf's nucleus and thoracic sympathetic neurons, which are spared in ALS, express high levels of mGluR5, while somatic motoneurons do not. In addition, mGluR1 mRNA is found only in smaller somatic motoneurons, which seem to be less vulnerable in ALS. Thus, differential mGluR expression might provide a possible clue to the selective vulnerability of different motoneuronal subpopulations in ALS.

Amyotrophic Lateral Sclerosis↗
PubMed1999

Honesty and hope: announcement of diagnosis in ALS.

Informing patients and their families about a diagnosis such as amyotrophic lateral sclerosis (ALS) is a daunting task for any physician. The way the diagnosis is communicated will have a major impact on the physician-patient relationship and the attitude of the patient toward the disease and toward symptomatic treatment measures. Breaking the news can be truly defined as the starting point of palliative care in ALS. It is an ongoing information process which, by its nature, escapes narrow definitions or standardization attempts. Nevertheless, a number of techniques exist to facilitate the process and ease the burden for physicians, patients, and families. We believe that the terminal phase should be discussed at the latest when first respiratory symptoms appear, to prevent unwarranted fears of "choking to death."

Amyotrophic Lateral Sclerosis↗
PubMed1998

Activation of metabotropic glutamate receptors delays apoptosis of chick embryonic motor neurons in vitro.

Glutamatergic excitotoxicity has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). However, activation of metabotropic glutamate receptors (mGluRs) is neuroprotective in several paradigms. We therefore tested the effect of selective mGluR agonists on cultured chick embryonic motor neurons. Activation of group I mGluRs with (s)-3,5-dihydroxyphenylglycine (DHPG) and group III mGluRs with L-2-amino-4-phosphono-butanoate (L-AP4) promoted a modest but significant, dose-dependent delay of apoptosis, which could be blocked by specific mGluR antagonists. Group II or selective mGluR5 stimulations were ineffective. Correspondingly, in situ hybridization experiments showed only expression of mGluR1 (group I) and mGluR4 and 7 (group III) in human motor neurons. Dissection of the pathways involved in this survival effect may help to elucidate the pathogenesis of ALS.

Animals↗
PubMed1998

Inhibitors of p38 mitogen-activated protein kinase promote neuronal survival in vitro.

Mammalian mitogen-activated protein kinases include the extracellular signal-regulated protein kinase, the c-Jun amino-terminal kinase, and the p38 subgroups. Sustained activation of Jun kinase and p38 have been shown to precede apoptosis of PC12 pheochromocytoma cells induced by withdrawal of trophic factors. To investigate the possible role of p38 in neuronal apoptosis, we tested the effect of two selective p38 inhibitors, the pyridinyl imidazole compounds SB203580 and SB202190, on different populations of chick embryonic neurons in vitro. Both substances promoted the in vitro survival of sensory, sympathetic, ciliary and motor neurons in a dose-dependent fashion. When assayed in nerve growth factor-stimulated PC12 cells, SB203580 pretreatment inhibited the activation of both ribosomal S6 kinases-1 and -2 with the same IC50 (approximately 30 microM) that inhibited apoptosis in primary neurons. Thus, p38 inhibitor-sensitive pathways may be involved in apoptosis of neurotrophic factor-deprived primary neurons, and in activation of ribosomal S6 kinases.

Animals↗
PubMed1998

CEP-1347/KT7515, a JNK pathway inhibitor, supports the in vitro survival of chick embryonic neurons.

Developing neurons depend on target-derived trophic factors for survival in vivo and in vitro, which also decrease the activity of c-Jun N-terminal kinase (JNK). We have recently described a survival-promoting effect of inhibitors of cyclin-dependent kinases and JNK on chick peripheral embryonic neurons. Here, we report that the small trophic molecule CEP-1347/KT7515, which has been shown to inhibit the JNK signalling pathway, can promote long term-survival of cultured chick embryonic dorsal root ganglion, sympathetic, ciliary and motor neurons. Because of their pharmacological properties, small trophic molecules such as CEP-1347/KT7515 might be of interest for the treatment of neurodegenerative disorders.

Animals↗
PubMed1998

[Noninvasive intermittent self-ventilation as a palliative measure in amyotrophic lateral sclerosis].

Almost all patients with amyotrophic lateral sclerosis (ALS) experience symptoms of nocturnal hypoventilation during the course of the illness. These symptoms can develop years before death and may severely affect quality of life. Non-invasive intermittent home mechanical ventilation (HMV) via mask is a possible palliative measure for these symptoms, which is not often used in Germany. We report on our experience with HMV in 24 patients with ALS. Our data show a good palliative effect in 17 of 24 treated patients. Severe complications did not occur. The mean ventilation time at present is 14 months. Available options and their consequences need to be discussed in detail with patients and relatives before HMV is initiated.

Adult↗
PubMed1998

Discontinuation of mechanical ventilation in patients with amyotrophic lateral sclerosis.

Mechanical ventilation, both invasive and non-invasive, may be an effective means of improving the quality of life and prolonging the survival of patients suffering from amyotrophic lateral sclerosis (ALS). However, the attitude towards this palliative measure varies greatly between different centres and countries. One of the arguments cited against this procedure is the fear that a patient might request the physician to discontinue life support. We believe that the question of withdrawal of mechanical ventilation can only be meaningfully addressed in the general context of palliative care. Here, we review possible modes of action in response to a patient's request for life support withdrawal and their medical, legal and ethical implications. We propose that the following goals should be pursued: (1) prevention of unwanted ventilation by early, open discussion with patient and relatives, (2) delivery of optimal palliative care by the caring team, (3) recognition of the patient's right to withdraw his/her consent to an invasive medical procedure. If these goals have been met, it may be medically, legally and ethically justified for the physician to take all necessary steps to ensure a peaceful death after discontinuation of life support.

Amyotrophic Lateral Sclerosis↗
PubMed1998

Mechanical ventilation in amyotrophic lateral sclerosis: a cross-cultural perspective.

Mechanical ventilation is known to be an effective means of relieving symptoms of chronic hypoventilation and prolonging life in patients with amyotrophic lateral sclerosis (ALS). Various methods of mechanical ventilation are available to patients with ALS. However, attitudes towards mechanical ventilation in ALS vary widely across different cultures, and even within a given medical system. This article describes differences and similarities between a North American, a European and a Japanese approach, based on the respective medical and cultural traditions. The common goal is to provide optimal palliative care to patients with ALS.

Amyotrophic Lateral Sclerosis↗
PubMed1998

Breaking the news in amyotrophic lateral sclerosis.

Telling the diagnosis to patients with amyotrophic lateral sclerosis (ALS) is a daunting task for any neurologist. Obviously, breaking the news in ALS is not a standardizable procedure. However, proven techniques exist to reduce the trauma to the patient and ease the burden on the doctor, thus reducing the risk of burnout and the tendency to 'pull away' from the patient. Such communication skills are of fundamental importance to clinical practice and should be more prominent in medical teaching. The way the patient is told the diagnosis is now recognized to be the first and one of the most delicate steps in palliative care. Information is best offered in a stepwise fashion at the patient's pace with an emphasis on positive aspects, and in the presence of the patient's family. Reviewing available therapeutic options and current research efforts may foster hope for the future, while pointing out that almost all symptoms of ALS can be alleviated by palliative therapy may help to reduce fears. Encouraging patients to ask questions and disclose anxieties is important for their psychological wellbeing. Available options for mechanical ventilation should be reviewed early enough to allow for unhurried decision-making. We believe that the terminal phase of the disease should be discussed at the latest when dyspneic symptoms appear, in order to prevent unwarranted fears of 'choking to death'.

Amyotrophic Lateral Sclerosis↗
PubMed1998

Apoptosis of central and peripheral neurons can be prevented with cyclin-dependent kinase/mitogen-activated protein kinase inhibitors.

Previous studies have indicated that certain members of the cyclin-dependent kinase/mitogen-activated protein kinase superfamily are involved in apoptosis of neuronal cells. Here, we have examined programmed cell death induced by withdrawal of neurotrophic support from CNS (rat retinal) and PNS (chick sympathetic, sensory, and ciliary) neurons. All four neuron types were equally rescued by the purine analogues olomoucine and roscovitine. Olomoucine inhibits multiple cyclin-dependent and mitogen-activated protein kinases with similar potency. Roscovitine is a more selective cyclin-dependent kinase inhibitor; but, so is butyrolactone I, which did not prevent retinal ganglion cell death. The specific p38MAPK inhibitor SB-203580 did not prevent apoptosis in retinal ganglion cells. Death of these cells in the absence of neurotrophic factors was accompanied by morphological changes indicative of apoptosis, including nuclear condensation and fragmentation. Treatment with olomoucine or roscovitine not only prevented these apoptotic changes in retinal ganglion cells but also blocked neurite outgrowth. The survival-promoting activity of olomoucine correlated with its in vitro IC50 for c-Jun N-terminal kinase-1 and its potency to repress c-jun induction in live PC12 cells. Roscovitine was more potent in rescuing neurons than in inhibiting Jun kinase. Thus, the antiapoptotic action of roscovitine might be due to inhibition of additional kinases.

Animals↗
PubMed1998

Dopaminergic deficit in amyotrophic lateral sclerosis assessed with [I-123] IPT single photon emission computed tomography.

Dopamine transporter imaging was performed in 18 patients with sporadic amyotrophic lateral sclerosis (ALS) and 11 age matched controls with [I-123] IPT (N-(3-iodopropen-2-yl)-2beta-carbomethoxy-3beta(4-chlorophen yl)-tropane), a new cocaine analogue that selectively binds to the dopamine transporter located on dopaminergic nerve terminals. Image analysis showed that striatal IPT binding was moderately but significantly reduced in the ALS group compared with controls (p<0.01). The reduction of IPT binding was similar for patients with bulbar onset compared with those with limb onset. There was no correlation between values for uptake of striatal IPT and the age of the patients or the duration of the disease. These data indicate that nigrostriatal dopaminergic neurons are subclinically affected in a subset of patients with sporadic ALS.

Adult↗
PubMed1998

A placebo-controlled trial of insulin-like growth factor-I in amyotrophic lateral sclerosis. European ALS/IGF-I Study Group.

To test the safety and efficacy of recombinant human insulin-like growth factor-I (rhIGF-I) in ALS, 183 patients from eight European centers were randomized to receive double-blind placebo (n = 59) or rhIGF-I 0.1 mg/kg/day (n = 124) subcutaneously for 9 months. At study completion, the primary efficacy outcome measure (change in disease progression as assessed by the Appel ALS rating scale) showed no significant difference between treatment groups. RhIGF-I appeared to be safe and well-tolerated.

Adult↗
PubMed1997

Survival-promoting activity of inhibitors of cyclin-dependent kinases on primary neurons correlates with inhibition of c-Jun kinase-1.

Cyclin-dependent kinases and mitogen-activated protein kinases have been implicated in the regulation of cellular survival and apoptosis. We tested the effect of two mitogen-activated/cyclin-dependent kinase inhibitors, olomoucine and butyrolactone I, on the in vitro survival of chick embryonic neurons. Sensory, sympathetic, and ciliary neurons, when prepared at their respective time point of programmed cell death, could be rescued from apoptosis by both inhibitors in a dose-dependent fashion. In contrast, dividing sympathetic precursors underwent apoptosis when treated with olomoucine, but not butyrolactone I, at the same range of concentration. With similar potency, olomoucine and butyrolactone I inhibited immunocomplex c-Jun kinase activity. Both substances inhibited neurite outgrowth in a dose-dependent manner; developmentally younger neurons were more sensitive to this effect than older ones. These results suggest that certain mitogen-activated/cyclin-dependent kinases associated with cell division in neuronal precursors (i) may become essential components of the apoptotic machinery by the time neurons reach their phase of naturally occurring cell death and (ii) may be necessary for neurite outgrowth during development.

Animals↗