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Biomedical subjects

R S Howard

Publications and source records attributed to R S Howard.

At least 19 recordsLinked to original sources
PubMed2006

Nerve excitability changes in critical illness polyneuropathy.

Patients in intensive care units frequently suffer muscle weakness and atrophy due to critical illness polyneuropathy (CIP), an axonal neuropathy associated with systemic inflammatory response syndrome and multiple organ failure. CIP is a frequent and serious complication of intensive care that delays weaning from mechanical ventilation and increases mortality. The pathogenesis of CIP is not well understood and no specific therapy is available. The aim of this project was to use nerve excitability testing to investigate the changes in axonal membrane properties occurring in CIP. Ten patients (aged 37-76 years; 7 males, 3 females) were studied with electrophysiologically proven CIP. The median nerve was stimulated at the wrist and compound action potentials were recorded from abductor pollicis brevis muscle. Strength-duration time constant, threshold electrotonus, current-threshold relationship and recovery cycle (refractoriness, superexcitability and late subexcitability) were recorded using a recently described protocol. In eight patients a follow-up investigation was performed. All patients underwent clinical examination and laboratory investigations. Compared with age-matched normal controls (20 subjects; aged 38-79 years; 7 males, 13 females), CIP patients exhibited reduced superexcitability at 7 ms, from -22.3 +/- 1.6% to -7.6 +/- 3.1% (mean +/- SE, P approximately 0.0001) and increased accommodation to depolarizing (P < 0.01) and hyperpolarizing currents (P < 0.01), indicating membrane depolarization. Superexcitability was reduced both in patients with renal failure and without renal failure. In the former, superexcitability correlated with serum potassium (R = 0.88), and late subexcitability was also reduced (as also occurs owing to hyperkalaemia in patients with chronic renal failure). In patients without renal failure, late subexcitability was normal, and the signs of membrane depolarization correlated with raised serum bicarbonate and base excess, indicating compensated respiratory acidosis. It is inferred that motor axons in these CIP patients are depolarized, in part because of raised extracellular potassium, and in part because of hypoperfusion. The chronic membrane depolarization may contribute to the development of neuropathy.

Acidosis, Respiratory↗
PubMed2006

Infection-associated encephalopathies: their investigation, diagnosis, and treatment.

Reduced level of consciousness is a common clinical finding in acutely sick patients. In the majority of cases a cause for the encephalopathy is readily identifiable,whilst in a minority the aetiology is more difficult to ascertain. Frequently the onset of encephalopathy is associated with, or follows, infection. The mechanisms through which infection leads to encephalopathy are diverse. They range from direct microbial invasion of the brain or its supporting structures, to remote, infection-triggered mechanisms such as acute disseminated encephalomyelitis. Most common however, is the encephalopathy caused through a remote effect of systemic sepsis-septic encephalopathy. This article discusses the clinical presentation and underlying pathogeneses of the acute encephalopathies associated with infection, aiming to aid both their recognition and treatment.

Brain↗
PubMed2006

Probabilistic diffusion tractography: a potential tool to assess the rate of disease progression in amyotrophic lateral sclerosis.

The goal of probabilistic tractography is to obtain a connectivity index along a white matter pathway that reflects fibre organization and is sensitive to pathological abnormalities contributing to disability. Here, we present the development of voxel-based connectivity measures along the tractography-derived corticospinal tract (CST). We investigated whether these connectivity measures are different in patients with amyotrophic lateral sclerosis (ALS) and correlate with the rate of disease progression. We also investigated whether fractional anisotropy (FA), which reflects directional coherence of fibre tracts, is reduced in the CST of ALS patients and relates to disease progression rate. Thirteen patients with probable or definite ALS and 19 healthy subjects were studied. The probabilistic tractography algorithm segmented the bilateral CST, along which FA and connectivity values were obtained. To take into account the asymmetric distribution of connectivity values, two summary statistic measures that focused on voxels with higher connectivity values were selected and then used in the analysis, together with the mean connectivity and the mean FA. To complete the analysis, the same summary measures for FA were included. Differences in all these indices between patients with moderate or rapid disease progression rate and controls were investigated using linear regression, adjusted for age and white matter fraction. The association between FA or connectivity in the CST and the disease progression rate was assessed using linear regression. Patients with a rapid disease progression rate had significantly lower summary connectivity measures than controls in the left CST, but there was only a borderline statistical difference in mean connectivity. Patients with rapid progression had a significantly lower mean FA, and any other FA measure, in both CSTs than controls. When only patients were considered, strong associations between the rate of disease progression and all the connectivity measures in the left CST were found (P-values between P < 0.001 and P = 0.002, partial correlation coefficients between -0.90 and -0.82). However, there was no evidence of an association between disease progression rate and any of the FA measures in the bilateral CST. Our findings suggest that FA and connectivity provide complementary information, since FA is sensitive to the detection of all the group differences, whereas the summary connectivity measures correlate with disease progression rate. The development of such connectivity measures raises their potential as markers of disease progression in ALS, and provides guidance for their use in other neurological diseases.

Adult↗
PubMed2006

Serine proteases purified from sera of patients with amyotrophic lateral sclerosis (ALS) induce contrasting cytopathology in murine motoneurones to IgG.

Affinity purified IgG from sera of patients with amyotrophic lateral sclerosis (ALS) is claimed to enhance transmitter release, induce apoptotic death of cultured motoneurones, and elicit a distinctive cytopathology with raised Ca(2+) in mouse motoneurones. An alternative hypothesis attributes these events to serine proteases in ALS sera. To test this, motoneurones in BALB/c mice injected intraperitoneally with plasminogen affinity purified from sera of ALS patients and healthy controls were analysed using immunochemical and ultrastructural morphometric methods. The responses were validated in motoneurones of mice injected with commercially purified plasminogen, tissue plasminogen activator (tPA), or plasmin. Motoneurones in non-injected mice had normal morphology and ultrastructure without evidence of electron-dense degeneration. Purified plasminogen from both ALS patients and healthy controls, evoked electron-dense motoneurone degeneration, as did commercially purified plasminogen and tPA. The common cytopathology comprised disruption and distension of Nissl body rough endoplasmic reticulum, cytoplasmic polyribosomal proliferation, and significant Ca(2+) enhancement in mitochondria. By contrast, using affinity purified serum immunoglobulins, ALS-IgG but not IgG from healthy or disease controls, elicited necrosis, with 30% of ALS-IgGs tested evoking electron-dense degeneration in 40% of motoneurones. The primary cytopathology was extensive swelling of Golgi endoplasmic reticulum and mitochondria, with enhancement of Ca(2+) in Golgi endoplasmic reticulum and presynaptic boutons. We conclude that serine proteases purified from sera of ALS patients elicits a distinctive cytopathology and pattern of Ca(2+) enhancement in motoneurones different from that found on passive transfer of affinity purified ALS-IgG.

Adult↗
PubMed2005

Analysis of an adult Duchenne muscular dystrophy population.

BACKGROUND: Advances in management have led to increasing numbers of patients with Duchenne muscular dystrophy (DMD) reaching adulthood. Older patients with DMD are necessarily severely disabled, and their management presents particular practical issues. AIM: To review the management of a late adolescent and adult DMD population, and to identify areas in which the present service provisions may be inadequate to their needs. DESIGN: Retrospective review. METHODS: We studied 25 patients with DMD referred to an adult neuromuscular clinic over a 7-year period. Clinical details were obtained retrospectively, from case notes or direct observations. RESULTS: There were 24 males and one symptomatic female carrier. Nine patients died during the observation period. There was no significant correlation between age of wheelchair confinement and age of death. Sixteen patients received non-invasive positive pressure support. Twelve attended mainstream schools and 12, residential special schools. All the patients lived at home for some or all of the time, when their main carers were either one or both of the parents. The most striking difficulties were with the provision of practical aids, including appropriate hoists and belts, feeding and toileting aids, and the conversion of accommodation. Patients rarely wished to discuss the later stages of their disease, and death was often more precipitate than expected. Death usually occurred outside hospital and the final cause was often difficult to establish. DISCUSSION: Adult patients with DMD develop progressive impairment, due to respiratory, orthopaedic and general medical factors. However, the particular areas of difficulty in this study often reflected inadequate and poorly directed social and medical support, illustrating the need for improvements in the structure, co-ordination and breadth of rehabilitation services for adult patients with DMD.

Adolescent↗
PubMed2005

Factors influencing PCR detection of viruses in cerebrospinal fluid of patients with suspected CNS infections.

BACKGROUND: Polymerase chain reaction (PCR) is used to detect viruses in the cerebrospinal fluid (CSF) of patients with neurological disease. However, data to assist its use or interpretation are limited. OBJECTIVE: We investigated factors possibly influencing viral detection in CSF by PCR, which will also help clinicians interpret positive and negative results. METHODS: CSF from patients with was tested for human herpesviruses types 1-6, JC virus, enteroviruses, and Toxoplasma gondii. The likelihood of central nervous system (CNS) infection was classified as likely, possible, or unlikely. PCR findings in these categories were compared using single variable and logistic regression analysis. RESULTS: Of 787 samples tested, 97 (12%) were PCR positive for one or more viruses. Of episodes likely to be CNS viral infections, 30% were PCR positive compared to 5% categorised as unlikely. The most frequent positive findings were Epstein Barr virus (EBV), enteroviruses, and herpes simplex virus (HSV). Enteroviruses and HSV were found predominantly in the likely CNS viral infection group, whereas EBV was found mainly in the unlikely group. Positive PCR results were more likely when there were 3-14 days between symptom onset and lumbar puncture, and when CSF white cell count was abnormal, although a normal CSF did not exclude a viral infection. CONCLUSIONS: The diagnostic yield of PCR can be maximised by using sensitive assays to detect a range of pathogens in appropriately timed CSF samples. PCR results, in particular EBV, should be interpreted cautiously when symptoms cannot readily be attributed to the virus detected.

Adolescent↗
PubMed2004

Frontotemporal lobar degeneration with ubiquitin-only-immunoreactive neuronal changes: broadening the clinical picture to include progressive supranuclear palsy.

The frontotemporal lobar degenerations (FTLDs) are a group of disorders in which the clinical picture is not necessarily predictive of the underlying neuropathology. The FTLD with ubiquitin-only-immunoreactive neuronal changes (FTLD-U) subtype is pathologically characterized by ubiquitin-positive, tau and alpha-synuclein-negative neuronal cytoplasmic inclusions in the frontotemporal cortex and hippocampal dentate fascia. When similar pathological changes are accompanied by histological features of motor neuron disease (MND), the term FTLD-MND is used. The latter pathological changes may be found in patients with or without clinical evidence of MND. We retrospectively reviewed the clinical details of three patients with a rapidly progressive, levodopa-unresponsive bradykinetic-rigid syndrome and frontal cognitive impairment. A diagnosis of progressive supranuclear palsy (PSP) had been considered in all three cases at initial presentation. Two of the cases fulfilled clinical diagnostic criteria for PSP, which was the final clinical diagnosis during life. Pathological analysis showed typical histological appearances of FTLD-MND in two cases and of FTLD-U in one case. Semi-quantitative analysis of pathological load seemed to correlate with the clinical phenotype. FTLD-U or FTLD-MND should be considered in the differential diagnosis of progressive frontal dementia with an akinetic rigid syndrome and supranuclear gaze palsy or Steele-Richardson-Olszewski disease.

Aged↗
PubMed2004

Herpes simplex encephalitis: an audit of the use of laboratory diagnostic tests.

BACKGROUND: The combination of both PCR and intrathecal antibody studies is recommended to confirm or refute the diagnosis of herpes simplex encephalitis (HSE). AIM: To investigate the pattern of use of laboratory tests in the diagnosis of suspected cases of HSE, and to determine the final diagnosis in cases proven not to be HSE. DESIGN: Structured audit. METHODS: We reviewed the case-notes of all patients who, over a five-year time period, presented with suspected encephalitis; and/or were prescribed aciclovir. Clinical and laboratory criteria were used to categorize the likelihood of HSE. RESULTS: We identified 222 patients: 10 (5%) had definite HSE, 24 (10%) possible HSE, and 144 (65%) a definite alternative diagnosis. In 44 (20%), no final diagnosis was made, but the diagnosis of HSE was excluded. PCR was performed in 68 (31%), intrathecal antibody studies in 24 (11%), and brain biopsy in 17 (8%). A wide range of diseases mimicked HSE, but most common were inflammatory diseases and other infections of the central nervous system. DISCUSSION: Laboratory tests, particularly intrathecal antibody assays, are under-used in the diagnosis of HSE. Although early empirical treatment of suspected HSE is essential, confirmation or exclusion of the diagnosis is equally important to avoid overlooking alternative diagnoses. Identification of the aetiology of encephalitis is of particular importance, given the current concerns of emerging infections and bioterrorism.

Acyclovir↗
PubMed2003

Mutation accumulation in growing asexual lineages.

The stochastic loss of entire classes of individuals bearing the fewest number of mutations-a process known as Muller's ratchet-is studied in asexual populations growing unconstrained from a single founder. In the neutral regime, where mutations have zero effect on fitness, we derive a recursion equation for the probability distribution of the minimum number of mutations carried by individuals in the least-loaded class, and obtain an explicit condition for the halting of the ratchet. Next, we consider the case of deleterious mutations, and show that weak selection can actually accelerate the ratchet beyond that achieved for the neutral regime. This effect is transitory, however, as our results suggest that even weak purifying selection will eventually lead to the complete cessation of the ratchet. These results may have important implications for problems in biology and the medical sciences.

Models, Genetic↗
PubMed2003

Passive transfer of purified IgG from patients with amyotrophic lateral sclerosis to mice results in degeneration of motor neurons accompanied by Ca2+ enhancement.

It has been reported that immunoglobulins (IgG) in sera of patients with amyotrophic lateral sclerosis (ALS) kill cultured motoneurones (MN), but whether they also cause MN degeneration in vivo is unclear. To test this, protein-A affinity purified and dialysed IgGs were prepared from sera of 44 ALS patients without paraproteinemias, 20 healthy controls and 15 disease controls. Control and ALS-IgGs were injected intraperitoneally into groups of mice for 5 consecutive days and examined at day 8. IgG was localised immunocytochemically and spinal MN were characterised histologically and ultrastructurally and by comparative counts of Ca(2+) containing organelles revealed with oxylate-pyroantimonate histochemistry. ELISA revealed no differences in IgG concentration between ALS patients and control subjects. Immunocytochemistry showed IgG was present in MN of mice injected with control or ALS-IgG, but densitometry showed immunostaining in MN was stronger in mice injected with ALS-IgG. Compared to MN of non-injected mice, control-IgG-treated mice showed near normal MN morphology and numbers of Ca(2+)-containing organelles. Disease control IgGs evoked negligible or minor morphological changes according to disease, but normal numbers of Ca(2+) containing organelles. Ultrastructurally, about 70% of ALS-derived IgGs induced a population of MN with electron lucent cytoplasm, distended Golgi, disrupted Nissl and mitochondria (i.e., necrosis). However 30% of ALS-IgGs additionally induced electron-dense degeneration in 40% of the MN. These MN exhibited shrinkage, condensed nuclear chromatin and ill-defined nuclear membranes and resembled preliminary stages of apoptosis. We conclude that passive transfer of ALS-derived, but not control IgGs, does result in MN degeneration in the recipient mice. This appears to be associated with abnormal calcium homeostasis, but the exact target of ALS-IgG remains conjectural, and the possibilities are discussed.

Adult↗
PubMed2003

Opposites attract? Mate choice for parasite evasion and the evolutionary stability of sex.

If sex is naturally selected as a way to combat parasites, then sexual selection for disease resistance might increase the overall strength of selection for outcrossing. In the present study, we compared how two forms of mate choice affect the evolutionary stability of outcrossing in simultaneous hermaphrodites. In the first form, individuals preferred to mate with uninfected individuals (condition-dependent choice). In the second form, individuals preferred to mate with individuals that shared the least number of alleles in common at disease-resistance loci. The comparisons were made using individual-based computer simulations in which we varied parasite virulence, parasite transmission rate, and the rate of deleterious mutation at 500 viability loci. We found that alleles controlling both forms of mate choice spread when rare, but their effects on the evolutionary stability of sex were markedly different. Surprisingly, condition-dependent choice for uninfected mates had little effect on the evolutionary stability of sexual reproduction. In contrast, active choice for mates having different alleles at disease-resistance loci had a pronounced positive effect, especially under low rates of deleterious mutation. Based on these results, we suggest that mate choice that increases the genetic diversity of offspring can spread when rare in a randomly mating population, and, as an indirect consequence, increase the range of conditions under which sexual reproduction is evolutionarily stable.

Animals↗
PubMed2003

Hypocretin (orexin) deficiency in narcolepsy and primary hypersomnia.

The discovery that hypocretins are involved in narcolepsy, a disorder associated with excessive daytime sleepiness, cataplexy, and unusually rapid transitions to rapid eye movement sleep, opens a new field of investigation in the area of disorders of sleep and activation. Hypocretin-1 (hcrt-1) and hypocretin-2 (hcrt-2) (also called orexin-A and orexin-B) are newly discovered neuropeptides processed from a common precursor. Hypocretin containing cells are located exclusively in the lateral hypothalamus, with widespread projections within the central nervous system. The role of the hypocretin system in other disorders causing excessive daytime sleepiness is more uncertain. This study reports the findings of a prospective study measuring cerebrospinal fluid concentrations of hypocretin-1 and hypocretin-2 in HLA DQB1*0602 positive narcolepsy with cataplexy, monosymptomatic narcolepsy, and primary hypersomnia. The results confirmed the previous observations, that hcrt-1 is deficient in narcolepsy and for the first time report very low levels of hcrt-1 in primary hypersomnia. It is also reported for the first time that there is a generalised defect in hcrt-2 transmission in all three of these clinical entities compared with controls.

Adult↗
PubMed2003

Diffusion tensor imaging detects corticospinal tract involvement at multiple levels in amyotrophic lateral sclerosis.

BACKGROUND: Histopathological studies of amyotrophic lateral sclerosis (ALS) are of end stage disease. Diffusion tensor imaging (DTI) provides the opportunity to investigate indirectly corticospinal tract pathology of ALS in vivo. METHODS: DTI was used to study the water diffusion characteristics of the corticospinal tracts in 21 patients with ALS and 14 normal controls. The authors measured the fractional anisotropy (FA) and mean diffusivity (MD) along the pyramidal tracts from the internal capsules down to the pyramids. A mixed model regression analysis was used to compare FA and MD between the ALS and control groups. RESULTS: FA showed a downward linear trend from the cerebral peduncles to the pyramids and was lower in the ALS group than controls at multiple levels of the corticospinal tract. At the internal capsules, FA was higher on the right. MD showed an upward trend, progressing caudally from the internal capsules to the pyramids. MD was higher at the level of the internal capsule in the ALS group, but caudally this difference was not maintained. No correlations were found between clinical markers of disability and water diffusion indices. CONCLUSIONS: These findings provide insights into the pathological processes of ALS. Differences in diffusion characteristics at different anatomical levels may relate to underlying tract architecture or the distribution of pathological damage in ALS. Further development may permit monitoring of progression and treatment of disease.

Adult↗
PubMed2003

Brain stem encephalitis caused by primary herpes simplex 2 infection in a young woman.

A 27 year old woman developed a vesicular genital rash and cerebellar dysfunction with progressive neurological deterioration suggesting brain stem encephalitis. Respiratory support was required. Magnetic resonance imaging (MRI) of the brain on day 7 showed signal hyperintensity in the central medulla and ventral pons, typical of acute inflammation. The course was severe and relapse occurred. MRI on day 33 showed a haemorrhagic area in the medulla. Treatment with aciclovir/valaciclovir eventually led to gradual recovery. Herpes simplex virus 2 (HSV-2) DNA was detected in CSF on days 11 and 14. HSV-2 was also detected in vesicle fluid from the genital rash. Serum was initially negative for HSV-1 and HSV-2 antibodies, but convalescent samples showed seroconversion to HSV-2, indicating primary infection. Intrathecal synthesis of oligoclonal IgG bands specific for HSV was identified in the CSF. It is important to differentiate HSV-2 from HSV-1, and primary from initial or reactivated infection, so that prolonged aciclovir treatment followed by prophylaxis is instituted to prevent the high likelihood of symptomatic relapse in primary HSV-2 infection.

Acyclovir↗