Developing palliative care practice in the community

The inadequacy of some areas of palliative care provision was acknowledged in the NHS Cancer Plan (DoH 2000). Many patients would prefer to die at home, but only one quarter are able to do so because of the lack of community or specialist palliative care teams in some parts of the country. The Lancashire and South Cumbria Cancer Services Network developed an initiative to meet the educational and training needs of practitioners delivering palliative care in the community.     

A4T mutation in the SOD1 gene causing familial amyotrophic lateral sclerosis

We report the clinical and laboratory findings in the largest kindred so far recorded with familial amyotrophic lateral sclerosis due to an A4T mutation in the SOD1 gene. The age of onset ranged from 32 to 60 years, with a mean of 46 years. Weakness in the legs was the most frequent early symptom and there was a predominance of lower motor neuron signs. The mean time from onset of symptoms to death was 14 months. One man with onset at the age of 37 has shown a slowly developing form and is currently alive 76 months after diagnosis (October 2002), although severely affected. The A4T mutation, with one exception, was of similar severity to the A4V mutation.     

Role of proteolysis in polyglutamine disorders

To date, nine polyglutamine disorders have been characterised, including Huntington's disease (HD), spinobulbar muscular atrophy (SBMA), dentatorubral-pallidoluysian atrophy (DRPLA), and spinocerebellar ataxias 1, 2, 3, 6, 7 and 17 (SCAs). Although knockout and transgenic mouse experiments suggest that a toxic gain of function is central to neuronal death in these diseases (with the probable exception of SCA6), the exact mechanisms of neurotoxicity remain contentious. A further conundrum is the characteristic distribution of neuronal damage in each disease, despite ubiquitous expression of the abnormal proteins. One mechanism that could possibly underlie the specific distribution of neuronal toxicity is proteolytic cleavage of the full-length expanded polyglutamine tract-containing proteins. There is evidence found in vitro or in vivo (or both) of proteolytic cleavage in HD, SBMA, DRPLA, and SCAs 2, 3, and 7. In HD, cleavage has been demonstrated to be regionally specific, occurring as a result of caspase activation. These diseases are also characterised by development of intraneuronal aggregates of the abnormal protein that co-localise with components of the ubiquitin-proteasome pathway. It remains unclear whether these aggregates are pathogenic or merely disease markers; however, at least in the case of ataxin-3, cleavage promotes aggregation. Inhibition of specific proteases constitutes a potential therapeutic approach in these diseases.     

Near-total absence of the cerebellum.

We report five cases of near-total absence of the cerebellum with accompanying pontine hypoplasia. The cerebellar remnant in each case comprised only antero-superior masses, the posterior fossa being otherwise fluid filled. Three of these patients, two teenagers and an infant, presented a fairly consistent clinical and neuroradiological phenotype, and a few similar cases are recorded in the literature. The cerebellar remnant was irregular and asymmetrical, and no ventral pontine prominence was discernible. In at least the older two, cerebellar motor functions were not greatly compromised, and intellectual handicap was of a mild degree. We propose that these cases represent a distinct entity of "near-total absence of the cerebellum with flat ventral pons, and relatively mild clinical affection". All cases have been sporadic, implying that the risk of recurrence within a family may be low. Quite different clinical pictures, of considerably greater severity, are demonstrated in the remaining two cases. One had pontocerebellar hypoplasia type 2, while the other had a complex cerebellar and cerebral malformation.     

Molecular ontogeny of major neurotransmitter receptor systems in the mammalian central nervous system: norepinephrine, dopamine, serotonin, acetylcholine, and glycine

Neurotransmitter receptors are critical elements in intercellular signaling within the central nervous system and are divided into two major types based on their molecular structure and biophysical properties. The first are ionotropic receptors--ligand-gated ion channels that directly affect the membrane potential via passage of permeant ions (such as sodium and calcium) and mediate fast synaptic transmission. The second type are slower metabotropic receptors that are also ligand gated but depend on an interaction with guanine nucleotide-binding proteins and mediate signal transduction by activating second-messenger systems within the cell. In the past two decades, a wealth of information has emerged regarding the molecular biology and pharmacology of classic neurotransmitter receptors (including adrenergic, dopaminergic, serotonergic, cholinergic, glycine, gamma-aminobutyric acid [GABA(A)], and glutamate receptors). Further, the distribution of subunits comprising these receptors has been extensively studied. This review focuses on the molecular ontogeny of several of the major neurotransmitter receptor systems in the mammalian central nervous system, highlighting the role that some of these may play during brain development and in certain pathologic states.     

A comparison of five clock scoring methods using ROC (receiver operating characteristic) curve analysis

OBJECTIVE: To compare the accuracy of five clock scoring methods for detecting dementia in English-speaking patients. DESIGN: A prospective cohort study. SETTING: A general geriatric outpatient clinic in southwest Sydney, Australia. PARTICIPANTS: A total of 127 consecutive new referrals to the clinic, of mean age 78.2 years. MEASUREMENTS: The clock drawing test was conducted at the beginning of each clinic appointment by a blinded observer. Each patient was then assessed by a geriatrician, who collected demographic data, administered the modified Barthel index, the geriatric depression scale, and the Folstein Mini-Mental State Examination, and categorised each patient as demented or not demented, according to DSM-4 criteria. Each clock was scored according to the methods of Mendez, Shulman, Sunderland, Watson and Wolf-Klein, and evaluated for reliability, and predictive accuracy, using receiver operating characteristic (ROC) curve analysis. RESULTS: The area under the ROC curve was largest for the Shulman (0.79, 95% CI 0.70-0.85) and Mendez (0.78, 95% CI 0.70-0.85) methods. Both predicted dementia more accurately than the Sunderland (area = 0.71) and Watson (area = 0.65) methods (p < 0.05). The inter-rater (0.81-0.93) and intra-rater (0.87-0.96) correlation coefficients were high for all five methods. CONCLUSIONS: While substantial differences among the clock scoring methods were evident in our sample, the accuracy of each was modest at best. Unless further studies in relevant settings suggest otherwise, we caution on the use of clock drawing alone to screen for dementia.