Biomedical subjects

M J Holmes

Publications and source records attributed to M J Holmes.

At least 19 recordsLinked to original sources

PubMed2006

Approach to stochastic modelling of consumer exposure for any substance from canned foods using simulant migration data.

A two-dimensional probabilistic model was constructed to estimate the short-term dietary exposure of UK consumers to any generalized migrant from coated light metal food packaging. Using three UK National Dietary and Nutrition Surveys (NDNS) comprising 4-7-day dietary surveys for different age and gender groups, actual body weights and survey years, a sample representative of the dietary consumption of the UK population was obtained comprising around 4,200 food items. Interrogation of the raw data showed that the per capita consumption of food and beverage for an adult was 2.9 kg per person day(-1), which is comparable with the US FDA value of 3.0 kg. The packaging type of each food item was assigned from the survey descriptions or by sampling from distributions based upon market share information and expert judgement. Each food item was assigned to the relevant food simulant: A (aqueous), B (acidic) or D (fatty), so that simulant migration data could be used. The exposure model was used to evaluate exposure for a given level of migration and, conversely, the level of migration that could be tolerated whilst keeping within a target threshold exposure level. As examples, migration at 10 microg dm(-2) into fatty foods only resulted in an exposure ranging from 0.06 to 0.22 microg kg(-1) body (actual) weight day(-1) depending on the scenario. The model revealed that if migration from metal coatings was only into fatty foods, migration in the range 1.83-4.95 microg dm(2) (97.5th percentile, depending on the scenario) would give an exposure of less than 1.5 microg per person day(-1). This is a toxicological threshold limit used in the USA. If migration into simulants A and B is also considered to be at the same level as that for simulant D, then the level of migration for the threshold to be reached is, not surprisingly, lower (0.64-0.87 microg dm(-2)) than that if migration were only into fatty foods. In this case, clearly the main contributors to the exposure were foodstuffs represented by simulants A and B because of their importance in the diet. These estimates are based on 4- or 7-day food diaries and chronic exposure over the long-term would be expected to be lower.

Adolescent↗

PubMed2005

Dietary exposure to chemical migrants from food contact materials: a probabilistic approach.

A two-dimensional probabilistic model has been developed to estimate the short-term dietary exposure of UK consumers to migrants from food packaging materials. The current EU approach uses a default scenario of assuming that all individuals are 60 kg weight and consume 1 kg of food packaged in the material of interest per day. Using four UK National Dietary and Nutrition Surveys comprising 4-7 day dietary records for different age groups and survey years, a sample representative of the UK population has been obtained consuming around 4200 different food items. Each survey provides records for around 2000 individuals and supplies detailed information on the consumption of food and data on sex, height and socio-economic status which may be used to analyse the exposure of selected groups within the community. As a result we are able to address the variation in consumption of food amongst individuals, and account for actual body weights providing a more accurate representation of the 'true' exposure. The migrants bisphenol A diglycidyl ether (BADGE), di-2-ethylhexyl adipate (DEHA) and styrene were considered as specimen compounds although the methodology employed has the flexibility to adapt to other migrants and packaging types and indeed other food contaminants. Exposure for each individual is estimated by calculating and summing the individual exposure from each item in their diet, and is repeated for all individuals in each survey to produce a distribution of exposures for the population. The packaging type of each food item is assigned by utilizing known packaging types from the database or, by sampling from a distribution based upon market share information. The parameters contributing towards the exposure from a packaged dietary item are migrant concentration and item weight. Distributions are used to represent the inherent variation and uncertainty affecting these parameters. Where data on concentrations for a particular type of food are lacking, expert judgement is used to extrapolate from available data for other food types. The model can also be run using only migration data for food simulants. In this case, concentrations expected for each of the food items are assigned based on the data for the relevant food simulant. The primary outputs of the model are distributions of estimated daily intakes for the selected population. Each distribution gives the variation across the population subject to the uncertain parameters sampled in that iteration of the model. Analysing the ensemble of distributions allows us to obtain the confidence limits around estimates for percentiles due to the uncertainties. The probabilistic approach allows sensitivity analysis to evaluate the relative importance of the input parameters and places confidence bounds on the outputs to show the effect of the uncertainties and the contribution of each food type toward the overall exposure.

Adipates↗

PubMed2003

Plastic changes in processing of graviceptive signals during spaceflight potentially contribute to postflight orthostatic intolerance.

Immediately following spaceflight, many astronauts are unable to maintain adequate perfusion of the brain after assuming an upright posture; this condition is called post-spaceflight orthostatic intolerance (PSOI). Considerable evidence shows that inputs from otolith organs and other graviceptors play an important role in regulating blood pressure during changes in posture in a 1-g environment. However, reflexes elicited by graviceptors, presumably including those affecting the cardiovascular system, are attenuated during spaceflight. Thus, PSOI could be related to effects of microgravity on the processing of inputs from otolith organs and other graviceptors by the central vestibular system. It is likely that successful countermeasures for PSOI must address the plastic changes induced in the nervous system by changes in the patterns of graviceptive inputs that occur during spaceflight.

Animals↗

PubMed2002

Effects of lesions of the caudal cerebellar vermis on cardiovascular regulation in awake cats.

The vestibular system is known to participate in cardiovascular regulation during movement and postural alterations. The present study considered whether lesions of two regions of the posterior cerebellar vermis (the nodulus and uvula) that provide inputs to vestibular nucleus regions that affect control of blood pressure would alter cardiovascular responses during changes in posture. Blood pressure and heart rate were monitored in awake cats during nose-up tilts up to 60 degrees in amplitude before and following aspiration lesions of the nodulus or uvula; in most animals, cardiovascular responses were also recorded following the subsequent removal of vestibular inputs. Lesions of the nodulus or uvula did not affect baseline blood pressure or heart rate, although cardiovascular responses during nose-up tilts were altered. Increases in heart rate that typically occurred during 60 degrees nose-up tilt were attenuated in all three animals with lesions affecting both dorsal and ventral portions of the uvula; in contrast, the heart rate responses were augmented in the two animals with lesions mainly confined to the nodulus. Furthermore, following subsequent removal of vestibular inputs, uvulectomized animals, but not those with nodulus lesions, experienced more severe orthostatic hypotension than has previously been reported in cerebellum-intact animals with bilateral labyrinthectomies. These data suggest that the cerebellar nodulus and uvula modulate vestibulo-cardiovascular responses, although the two regions play different roles in cardiovascular regulation.

Animals↗

PubMed2001

Role of the medial medullary reticular formation in relaying vestibular signals to the diaphragm and abdominal muscles.

Changes in posture can affect the resting length of respiratory muscles, requiring alterations in the activity of these muscles if ventilation is to be unaffected. Recent studies have shown that the vestibular system contributes to altering respiratory muscle activity during movement and changes in posture. Furthermore, anatomical studies have demonstrated that many bulbospinal neurons in the medial medullary reticular formation (MRF) provide inputs to phrenic and abdominal motoneurons; because this region of the reticular formation receives substantial vestibular and other movement-related input, it seems likely that medial medullary reticulospinal neurons could adjust the activity of respiratory motoneurons during postural alterations. The objective of the present study was to determine whether functional lesions of the MRF affect inspiratory and expiratory muscle responses to activation of the vestibular system. Lidocaine or muscimol injections into the MRF produced a large increase in diaphragm and abdominal muscle responses to vestibular stimulation. These vestibulo-respiratory responses were eliminated following subsequent chemical blockade of descending pathways in the lateral medulla. However, inactivation of pathways coursing through the lateral medulla eliminated excitatory, but not inhibitory, components of vestibulo-respiratory responses. The simplest explanation for these data is that MRF neurons that receive input from the vestibular nuclei make inhibitory connections with diaphragm and abdominal motoneurons, whereas a pathway that courses laterally in the caudal medulla provides excitatory vestibular inputs to these motoneurons.

Abdominal Muscles↗

PubMed2001

Immune-mediated parasite clearance in mice infected with Plasmodium berghei following treatment with manzamine A.

Manzamine A, a sponge-derived alkaloid, was recently shown to possess in vivo antimalarial activity against the blood stages of the rodent malaria parasite Plasmodium berghei. A single intraperitoneal dose of 100 micromol/kg of manzamine A suppressed parasite growth but was followed by parasite recrudescence. Forty percent of mice with recrudescing parasites were able to recover and clear the fulminating parasitaemia. Examination of sera from these mice revealed that infected mice treated with manzamine A had a suppressed IFN-gamma production but an increase in their IL-10 and IgG production. The prolonged survival of infected mice treated with manzamine A and the eventual clearance of recrudescing parasites in some of these mice involve a down-regulation of Thl responses and a switch to antibody dependent-Th2 responses.

Animals↗

PubMed2000

Adaptive plasticity in vestibular influences on cardiovascular control.

Data collected in both human subjects and animal models indicate that the vestibular system influences the control of blood pressure. In animals, peripheral vestibular lesions diminish the capacity to rapidly and accurately make cardiovascular adjustments to changes in posture. Thus, one role of vestibulo-cardiovascular influences is to elicit changes in blood distribution in the body so that stable blood pressure is maintained during movement. However, deficits in correcting blood pressure following vestibular lesions diminish over time, and are less severe when non-labyrinthine sensory cues regarding body position in space are provided. These observations show that pathways that mediate vestibulo-sympathetic reflexes can be subject to plastic changes. This review considers the adaptive plasticity in cardiovascular responses elicited by the central vestibular system. Recent data indicate that the posterior cerebellar vermis may play an important role in adaptation of these responses, such that ablation of the posterior vermis impairs recovery of orthostatic tolerance following subsequent vestibular lesions. Furthermore, recent experiments suggest that non-labyrinthine inputs to the central vestibular system may be important in controlling blood pressure during movement, particularly following vestibular dysfunction. A number of sensory inputs appear to be integrated to produce cardiovascular adjustments during changes in posture. Although loss of any one of these inputs does not induce lability in blood pressure, it is likely that maximal blood pressure stability is achieved by the integration of a variety of sensory cues signaling body position in space.

Afferent Pathways↗

PubMed2000

A mathematical model of tumour angiogenesis incorporating cellular traction and viscoelastic effects.

Angiogenesis is defined as the outgrowth and formation of new vessels from a pre-existing vascular network (Rakusan, In: Cardiac Growth and Regeneration. Annals of the New York Academy of Sciences, 1995), and is of fundamental importance in understanding the processes by which a tumour achieves vascularization. Diffusible substances, collectively called tumour angiogenesis factors are released from the tumour to elicit a variety of responses from the surrounding tissues, most importantly the migration of endothelial cells (lining neighbouring vessels) towards the tumour. To facilitate locomotion, the cells exert appreciable traction forces upon the interstitial extracellular matrix which, in turn, influences the resulting direction of their migration. In this paper, we examine the role played by cellular traction during cell migration and the corresponding viscoelastic effects of the extracellular matrix.

Cell Movement↗

PubMed2000

LC and LC-MS-MS analyses of undeclared codeine in antiasthmatic Chinese proprietary medicine.

This paper describes an accurate and sensitive reversed phase high-performance liquid chromatographic (RP-HPLC) method for the detection and quantification of undeclared codeine in a Chinese Proprietary Medicine (CPM) for asthma. A rapid and specific liquid chromatography-mass spectrometry-mass spectrometry (LC-MS-MS) method was applied to confirm the presence of codeine by selected reaction monitoring (SRM). Codeine was extracted from the capsules by dissolving in sodium dihydrogen phosphate buffer (10 mM, pH = 2.2) and ethanol, then made alkaline (pH = 9) and extracted using chloroform. The amount of codeine in AsthmaWan was found to be 61.8 microg/capsule (R.S.D. = 7.9%, n = 9). Excellent resolution was obtained despite the complexity of the product which claimed to contain at least nine herbal ingredients, none of which will give rise to codeine. As a further confirmation method, LC-MS-MS is accurate and specific. The LC method has been validated for linearity, limit of detection, limit of quantification, accuracy and specificity. Greater awareness of and control over undeclared drugs in complementary medicine are necessary to ensure patients' safety.

Anti-Asthmatic Agents↗

PubMed2000

In vivo antimalarial activity of the beta-carboline alkaloid manzamine A.

Manzamine A, a beta-carboline alkaloid present in several marine sponge species, inhibits the growth of the rodent malaria parasite Plasmodium berghei in vivo. More than 90% of the asexual erythrocytic stages of P. berghei were inhibited after a single intraperitoneal injection of manzamine A into infected mice. A remarkable aspect of manzamine A treatment is its ability to prolong the survival of highly parasitemic mice, with 40% recovery 60 days after a single injection. Oral administration of an oil suspension of manzamine A also produced significant reductions in parasitemia. The plasma manzamine A concentration peaked 4 h after injection and remained high even at 48 h. Morphological changes of P. berghei were observed 1 h after treatment of infected mice. (-)-8-Hydroxymanzamine A also displayed antimalarial activity, whereas manzamine F, a ketone analog of manzamine A, did not. Our results suggest that manzamine A and (-)-8-hydroxymanzamine A are promising new antimalarial agents.

Animals↗

PubMed1999

Detection of diarrhetic shellfish poisoning toxins from tropical shellfish using liquid chromatography-selected reaction monitoring mass spectrometry.

A negative mode liquid chromatography-selected reaction monitoring mass spectrometry (LC-SRM MS) method was developed to detect low concentrations of the diarrhetic shellfish poisoning (DSP) toxins okadaic acid and dinophysistoxin-1 (DTX-1). Detection relies upon monitoring the transition of negative precursor ions [M - H]- to a common fragment ion of m/z 255. Our limit of detection for okadaic acid with this method is 0.5 pg on column. LC-SRM MS has allowed us to detect persistent, low concentrations of DSP toxins from Singapore shellfish.

Animals↗

PubMed1999

Spontaneous regeneration of severed optic axons restores mapped visual responses to the adult rat superior colliculus.

To test whether a spontaneous and functional regeneration of severed axons could occur within the adult mammalian central nervous system, a long-term recovery of microelectrode-mapped visual response was sought in the superior colliculus (SC) after its total or near-total abolition by a precise guillotine cut of the retinocollicular pathway. Recoveries were found 3 weeks or later in 15 of the 36 animals studied; in 10 of these recoveries, half or more of the width of the SC was involved. The recovered responses were often activated from within a normally small area of the visual field. Appropriate retinotopic maps were restored. Intraocular horseradish peroxidase tracing revealed a variety of novel optic trajectories, passing around lesions even of totally cut pathways, which eventually terminated in normally retinorecipient layers of those recovered SCs. Such detours could not be explained by a mechanical reorientation of brain structures. When exactly comparable lesions were examined within a few days, there were no detours: severed optic axons faced the cuts. In long-term animals where responsiveness remained absent, optic axonal reorientations were observed near lesions but the SC was not innervated. Extensive long-term recoveries were in marked contrast to the occasional rapid ones, found within a few days postlesion, which involved only an outermost silenced border of SC. These were attributed to a rapid reversal of conduction failure in spared, bordering, axons of this topographically organized pathway. The findings support the conclusion that, after they are cut, numbers of optic axons can regenerate to the SC and restore appropriate circuitry therein.

Animals↗

PubMed1998

Knee pain and the infrapatellar branch of the saphenous nerve.

Pain over the front of the knee is common after surgery or trauma but often a definite diagnosis is difficult to make. Over the past year we have seen five cases in which the pain could be ascribed to damage to a branch of the infrapatellar branch of the saphenous nerve. Two were subsequent to trauma and three to surgical procedures. In all five cases surgical exploration gave symptomatic relief. Eight cadaveric knees were prosected to explore further the anatomy of this nerve in relation to the injuries. Injury to one of these branches should be considered in cases of persistent anterior, anteromedial or anterolateral knee pain or neurological symptoms following surgery or trauma.

Adult↗

PubMed1997

Epidemic neuromyasthenia and chronic fatigue syndrome in west Otago, New Zealand. A 10-year follow-up.

BACKGROUND: In 1984, an outbreak of an illness characterized by prolonged unexplained fatigue was reported in West Otago, New Zealand. This outbreak resembled other reported outbreaks of epidemic neuromyasthenia in that affected individuals presented with a spectrum of complaints ranging from transient diarrhea and upper respiratory disorders to chronic fatigue syndrome (CFS). OBJECTIVE: To obtain a perspective on the natural history of CFS not possible in clinic-based studies. METHODS: Twenty-three of the 28 patients in the original report were contacted and asked to complete written questionnaires. Interviews were obtained in person or via telephone. RESULTS: Ten (48%) of the 21 patients with satisfactory interviews appeared to meet the current Centers for Disease Control and Prevention (CDC) case definition of CFS, and 11 were classified as having prolonged or idiopathic fatigue. A return to premorbid activity was seen in most (n = 16) patients, although some reported the need to modify their lifestyle to prevent relapses. A female predominance was noted in those meeting the CDC case definition for CFS, whereas males predominated in patients diagnosed as having prolonged or idiopathic fatigue. CONCLUSIONS: The high proportion of patients recovering from CFS in the West Otago cluster suggests that epidemic-associated CFS has a better prognosis than sporadic cases. Female sex was confirmed as an important risk factor for CFS.

Adolescent↗

PubMed1995

Cooliatoxin, the first toxin from Coolia monotis (Dinophyceae).

Coolia monotis is a benthic dinoflagellate previously thought to be non-toxic. We describe a new toxin, named cooliatoxin, purified from cultures of a strain of C. monotis isolated from Australia. Cooliatoxin is likely a mono-sulphated, polyether toxin (M = 1,062; i.p. LD50 = 1 mg/kg in mice) that induces hypothermia and respiratory failure in mice after a pronounced delay period during which there are no obvious signs of intoxication. These signs in mice are similar to those reported for the shellfish toxin named yessotoxin and the molecular weight of cooliatoxin corresponds to the mono-sulphated form of yessotoxin, suggesting that cooliatoxin may be an analogue of yessotoxin. Cooliatoxin has no effect on the mouse phrenic nerve or diaphragm musculature in vitro but causes initial stimulation and subsequent block of unmylenated nerves in vitro. In isolated guinea pig left atria, cooliatoxin (above 20 nm) induced a slow developing concentration dependent sustained inotropic response. Propranolol or tetrodotoxin reversed the positive inotropic effects, indicating that the majority of the cooliatoxin induced response was mediated by stimulation of nerves associated with the atrial musculature, resulting in the release of noradrenaline. Cooliatoxin induced transient contractions in isolated guinea pig vas deferens preparations. Atria and vas deferens preparations were tachyphylactic to a second equivalent dose of cooliatoxin applied after the effects of the first dose had diminished. The observed in vitro effects of cooliatoxin on peripheral nerves are unlikely to account for the lethal effects in mice and a central action of this toxin is suspected.

Adrenergic beta-Antagonists↗

PubMed1994

Ionspray mass spectrometry of ciguatoxin-1, maitotoxin-2 and -3, and related marine polyether toxins.

A range of marine polyether toxins from dinoflagellates were analysed by ionspray mass spectrometry. Ciguatoxin-1 ([M+H]+ m/z = 1,111.8) purified from several fish species yielded singly charged ions corresponding to the parent ion, sodium and H2O adducts and ions for the loss of up to five H2O molecules. Ciguatoxin-1 was detected to 1 ng; however, interference from fish lipids precluded direct detection of ciguatoxin-1 in crude extracts from fish flesh spiked with ciguatoxin-1 at a level equivalent to 1.5 ng ciguatoxin-1/g of extracted flesh. Maitotoxin-2 yielded doubly and triply charged ions for sodium and potassium salts and likely possessed only one sulphate ester (M(r) = 3,298 for the mono-sodium salt). Maitotoxin-3, a recently isolated small maitotoxin, yielded singly charged ions including ions for the loss of one sulphate and up to four H2O molecules. Maitotoxin-3 is proposed to be a polyether compound possessing two sulphate esters (M(r) = 1,060.5 for the disodium salt). Brevetoxin-A ([M+H]+ m/z = 867.5) and brevetoxin-B ([M+H]+ m/z = 895.5) yielded singly charged ions corresponding to the parent ion, Na+ adducts and the loss of up to four H2O molecules. Okadaic acid ([M+H]+ m/z = 805.5) yielded singly charged ions corresponding to the parent ion and ions for the loss of up to three H2O molecules. A signal for M + 18 Da species that may represent [M+NH4]+ was observed for ciguatoxin-1, brevetoxin-A and -B, and okadaic acid. For all polyethers examined, the orifice potential influenced the relative intensity of the ions detected in a predictable manner.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Purification and characterisation of large and small maitotoxins from cultured Gambierdiscus toxicus.

Three strains of cultured Gambierdiscus toxicus yielded distinct maitotoxins (maitotoxin-1, -2, and -3) which were purified to homogeneity by high pressure liquid chromatography. Maitotoxins-1 and -2 are large toxins (molecular weights for the sodium salts = 3,422 and 3,298, respectively), whereas maitotoxin-3 is relatively small (molecular weight = 1,060 for the sodium salt). The contractile actions on isolated guinea-pig left atria, vas deferens and ilea of maitotoxins-1 and -2 were compared with those of the small maitotoxin, maitotoxin-3. Maitotoxin-1, -2 and -3 each produced quantitatively similar, concentration-dependent patterns of positive and negative inotropy in atria when compared on a mouse unit/ml basis (one mouse unit is the intraperitoneal LD50 dose for a 20 g mouse; the LD50 for maitotoxin-2 = 0.08 microgram/kg). Concentrations of maitotoxin-2 greater than 5 x 10(-13) M caused positive inotropy. The three maitotoxins produced patterns of contractions in vas deferens and ilea that were qualitatively similar, including a period of prominent spike activity in vas deferens. On a mouse unit/ml basis, the order of potency on smooth muscle was maitotoxin-1 > maitotoxin-3 > maitotoxin-2. The contractile responses of smooth muscle to the maitotoxins were followed by an inhibitory phase where control agonist responses could not be elicited. The maitotoxin-induced contractile responses of vas deferens were inhibited by nicardipine but not phentolamine, indicating that in this tissue, each maitotoxin has mainly a direct contractile effect that requires calcium influx through voltage-sensitive calcium channels.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Origin and transfer of toxins involved in ciguatera.

1. Ciguatera is a disease caused by sodium channel activator toxins and results from the consumption of warm water fish contaminated by the ciguatoxin class of polyether toxins. 2. Other toxins, including okadaic acid and maitotoxin, have no proven role in causing human illness associated with ciguatera. 3. Ciguatera often affects only a discrete region of a reef, with flare-ups of ciguatera being both temporally and spatially unpredictable. 4. The ciguatoxins likely arise through the biotransformation and acid-catalysed spiroisomerisation of gambiertoxin-4A produced by Gambierdiscus toxicus and it is unlikely that other toxic benthic dinoflagellates are involved. 5. Events leading to a ciguatera outbreak are initiated by environmental and genetic factors that favour the proliferation of gambiertoxins, with an apparent role for anthropomorphic effects; however, the precise factors involved are yet to be determined. 6. The gambiertoxins and/or ciguatoxins are transferred from the benthos to herbivorous species (fish, invertebrates etc) and then to carnivorous fish via marine food chains. 7. Factors influencing the concentration of ciguatoxins that accumulate in fish include the rate of dietary intake, the efficiency of assimilation, the degree and nature of any toxin biotransformation, the rate of depuration, and the rate of growth of fish.

Animals↗