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Biomedical subjects

R Howard

Publications and source records attributed to R Howard.

At least 91 records · Page 5Linked to original sources
PubMed1997

A cognitive neuropsychological approach to the study of delusions in late-onset schizophrenia.

OBJECTIVE: Hypotheses to explain delusion formation include distorted perceptual processing of meaningful stimuli (e.g. faces), abnormal reasoning, or a combination of both. The study investigated these hypotheses using standardized neuropsychological tests. DESIGN: A three-patient case-study, compared with a small group (n = 8) of age-matched normal control subjects. SETTING: Hospital in- and outpatients. Age-matched normal controls were from local residential homes. PATIENTS: Three subjects with late-onset schizophrenia, two currently deluded and one in remission. Both deluded subjects had persecutory beliefs. One had a delusion of misidentification. INTERVENTIONS: All subjects were administered standardized neuropsychological tests of facial processing and tests of verbal reasoning. MAIN OUTCOME MEASURES: The test scores of the three patients were compared with published normal values and the age-matched control data. RESULTS: The tests demonstrated impaired matching of unfamiliar faces in deluded subjects, particularly in the subject with delusional misidentification. Increasing the emotional content of logical reasoning problems had a significant effect on the deluded subjects' reasoning but not that of the normal controls. CONCLUSION: The findings suggest impaired visual processing plus abnormal reasoning in deluded subjects. However, these impairments are relatively subtle given the severity of psychiatric disorder in the patients studied.

Age of Onset↗
PubMed1997

Reduced airway resistance and work of breathing during mechanical ventilation with an ultra-thin, two-stage polyurethane endotracheal tube (the Kolobow tube).

OBJECTIVES: To compare dynamic pulmonary function studies using the ultrathin walled Kolobow endotracheal tube, with conventional endotracheal tubes of similar external diameter on rabbits during mechanical ventilation. To test the hypothesis that the increased internal diameter of the Kolobow tube will result in decreased airway resistance and work of breathing. DESIGN: Controlled animal study. SETTING: Institutional animal research facility. SUBJECTS: Adult female Dutch Belted rabbits (n = 6), weighing 1.4 to 1.6 kg. INTERVENTIONS: The animals were initially intubated with a conventional endotracheal tube (2.5-mm internal diameter; 3.6-mm outer diameter); they were paralyzed and placed on a mechanical ventilator. Ventilatory settings were adjusted to obtain standard arterial blood gases: pH of 7.35 to 7.45; PaCO2 of 35 to 40 torr (4.7 to 5.3 kPa), and PaO2 of 90 to 100 torr (12.0 to 13.3 kPa). After the stabilization period, pulmonary function tests (PFTs) were measured (period 1), the conventional endotracheal tube was replaced with a Kolobow tube, and PFTs were measured again and recorded (period 2). While continuously monitoring tidal volume, the peak inspiratory pressure was decreased to match the tidal volume measured during ventilation with the conventional endotracheal tube. Once the desired tidal volume was reached, PFTs were recorded (period 3). Flows were unchanged during the experiment and the length of the endotracheal tubes was the same for both the conventional and the Kolobow tube. MEASUREMENTS AND MAIN RESULTS: Mean values of the airway resistance and work of breathing from periods 1 and 3 were compared using the Student's t-test. There was a 59% decrease in total airway resistance (p = .001) and 45% decrease in the work of breathing (p = .0006). CONCLUSIONS: The use of the ultrathin walled Kolobow endotracheal tube resulted in significant decreases in airway resistance and work of breathing, which has the potential for improving the ventilatory mechanics in very small premature newborns.

Airway Resistance↗
PubMed1997

An ICAM-1 antisense oligonucleotide prevents and reverses dextran sulfate sodium-induced colitis in mice.

Mice treated p.o. with 5% dextran sodium sulfate develop a mild to moderate colitis characterized by focal areas of inflammation and crypt abscesses. Immunohistological analysis of colons from dextran sodium sulfate-treated mice revealed an increased expression of intercellular adhesion molecule 1 (ICAM-1) and infiltration of lymphocyte function antigen 1-positive cells. A murine-specific antisense oligonucleotide, ISIS 3082, was used to determine the role of ICAM-1 expression in the development of colitis. Prophylactic treatment of dextran sodium sulfate-treated mice with ISIS 3082 reduced the clinical signs of colitis in a dose-dependent manner, with maximal effects occurring at a dose of 1 mg/kg/day. Reductions in ICAM-1 immunostaining and infiltrating leukocytes were observed in colons of animals treated with 1 mg/kg ISIS 3082. Scrambled control oligonucleotides failed to modify the course of the disease. The ICAM-1 oligonucleotide also diminished the clinical severity of colitis in mice with established colitis. The toxicity of ISIS 3082 was assessed in normal CD-1 mice by administering the oligonucleotide intravenously every other day for 2 weeks. At pharmacologically relevant doses of ISIS 3082 (1 and 10 mg/kg), there were no signs of toxicity with respect to body and organ weights, clinical chemistry or hematology. At a dose of oligonucleotide 20- to 100-fold greater than maximal pharmacological doses, the oligonucleotide produced an increase in liver and spleen weights; a mild chronic inflammation in liver, lung and lymph nodes; monocytosis and an elevation of serum liver transaminases. These data suggest that an antisense oligonucleotide that reduces ICAM-1 expression could be effective in the therapy of inflammatory bowel disease in humans and that such an oligonucleotide would be safe at pharmacologically relevant doses.

Animals↗
PubMed1997

Optimization of the MGH repair using an algorithm for tenorrhaphy evaluation.

Previous investigations have demonstrated the superior strength and toughness of the MGH four-strand tendon repair technique and shown that it neither weakens during maximum tendon softening nor interferes with healing in an in vivo rabbit model. In the current study, the biomechanical performance of the modified Becker (MGH) and the modified Kessler repairs were compared in situ using a dynamic human cadaveric model to evaluate strength, toughness, glide efficiency, and operator variability. Three different surgeons performed a total of 42 zone II flexor digitorum profundus repairs in 14 fresh human cadaver hands. The modified Becker (MGH) repairs were stronger (79 +/- 3 versus 64 +/- 4 N; p < 0.01) and tougher (0.092 +/- 0.002 versus 0.078 +/- 0.003 J; p < 0.01) than the Kessler repairs while allowing equally efficient glide (32 +/- 6 versus 33 +/- 4 percent; p > 0.9). Strength was operator-dependent only for the modified Kessler repair (p < 0.005). We then established the optimal configuration of the MGH tenorrhaphy (number of preloaded crosses on either side of the tendon transection) by examining gap resistance ex vivo. Fifty-one MGH flexor tendon repairs were performed on explanted fresh human cadaver tendons. The experimental groups were randomly assigned to receive 0, 1, 2, 3, or 4 crosses on each side of the tenorrhaphy. Strength and toughness to gap formation and to ultimate failure were assessed tensiometrically. The MGH two-cross configuration was most resistant to gap formation (peak load 39 +/- 3 N; p < 0.05), establishing this configuration as the optimal design of this four-strand crisscrossing repair technique. The augmented Becker (MGH) repair is significantly stronger and tougher than the modified Kessler repair and demonstrates no operator dependence. It is a superior technique for zone II tenorrhaphy in the human hand. An algorithm is presented as a systematic approach that includes the important elements necessary for the rigorous biomechanical evaluation of any tendon repair technique.

Algorithms↗
PubMed1997

Schizophrenia with onset at the extremes of adult life.

OBJECTIVE: To define the epidemiology, phenomenology, premorbid and risk factors in patients with the first manifestation of a schizophrenia-like illness after the age of 60 years, and compare them with patients with an onset before the age of 25 years. DESIGN/SETTING/SUBJECTS: All contacts for a non-affective psychotic illness across all ages of onset were ascertained through a psychiatric case register; patients were rediagnosed according to operationalized criteria for psychotic illness, and those with a very early and very late onset compared. MAIN OUTCOMES MEASURES: Phenomenological, premorbid and aetiological parameters were compared in the two groups, using risk ratios and 95% confidence intervals. RESULTS: Very late onset patients (N = 72) were, compared to their very early onset counterparts (N = 192), more likely to be female, have good premorbid functioning and development history, and to exhibit persecutory delusions and hallucinations; they were less likely to have negative schizophrenic symptoms, to have a positive family history of schizophrenia, or have suffered pregnancy or birth complications. CONCLUSIONS: The results highlight premorbid, aetiological and phenomenological differences between patients with the onset of a schizophrenia-like illness at the extremes of adult life, and suggest it is premature to consider the two groups to be merely different manifestations of the same illness.

Adult↗
PubMed1997

Methylmalonic acidemia, cobalamin C type, presenting with cutaneous manifestations.

BACKGROUND: Erosive dermatitis resembling the skin lesions of acrodermatitis enteropathica has been described in a number of aminoacidopathies and organic acidemias. In some, the dermatitis is a manifestation of untreated disease, while in others, including methylmalonic acidemia, skin lesions have been ascribed to nutritional deficiency due to therapeutic amino acid restrictions. OBSERVATIONS: We report 2 cases of methylmalonic acidemia presenting with cutaneous manifestations in the perinatal period before restrictive nutritional interventions. The cutaneous involvement consisted of cheilitis and diffuse erythema with erosions and desquamation. Methylmalonic acidemia, cobalamin C type, was subsequently diagnosed in both cases. CONCLUSIONS: An erosive, desquamating dermatitis with histopathologic characteristics resembling acrodermatitis enteropathica may be a presenting sign in cobalamin C methylmalonic acidemia, even in the absence of long-standing nutritional restrictions or deficiency.

Acrodermatitis↗
PubMed1996

Inhibition of growth of human tumor cell lines in nude mice by an antisense of oligonucleotide inhibitor of protein kinase C-alpha expression.

A 20-mer phosphorothioate oligodeoxynucleotide (ISIS 3521) designed to hybridize sequences in the 3'-untranslated region of human protein kinase C-alpha (PKC-alpha) mRNA has been shown to inhibit the expression of PKC-alpha in multiple human cell lines. In human bladder carcinoma (T-24) cells, inhibition of PKC-alpha was both concentration dependent and oligonucleotide sequence specific. ISIS 3521 had a IC50 of 50-100 nM for PKC-alpha mRNA reduction and was without effect on the expression of other members of the PKC family of genes (PKC-eta and zeta). Toxicity studies in mice revealed that the oligodeoxynucleotide was well tolerated at repeat doses of 100 mg/kg i.v. for up to 14 days, with no acute toxicity apparent. The oligodeoxynucleotide was found to also inhibit the growth of three different human tumor cell lines, the T-24 bladder, human lung carcinoma (A549), and Colo 205 colon carcinoma grown in nude mice. The inhibition was dose dependent with ID50 values for the growth inhibition between 0.06 and 0.6 mg/kg daily when given i.v., depending on the cell line examined. Three control phosphorothioate oligodeoxynucleotides not targeting human PKC-alpha were without effect on the growth of the tumors at doses as high as 6 mg/kg. Recovery of ISIS 3521 from tumor tissue and resolution by capillary gel electrophoresis revealed that 24 It after the final dose of oligodeoxynucleotide, intact, full-length 20-mer material was present as well as some apparent exonuclease degradation products (e.g., n-1 and n-2 mers). These studies demonstrate the in vivo antitumor effects of an antisense oligodeoxynucleotide targeting PKC-alpha and suggest that this compound may be of value as a chemotherapeutic agent in the treatment of human cancers.

Animals↗
PubMed1996

Studies of renal injury. II. Activation of the glucose transporter 1 (GLUT1) gene and glycolysis in LLC-PK1 cells under Ca2+ stress.

Injury to the renal proximal tubule is common and may be followed by either recovery or cell death. The survival of injured cells is supported by a transient change in cellular metabolism that maintains life even when oxygen tension is reduced. This adaptive process involves the activation of the gene encoding the glucose transporter GLUT1, which is essential to maintain the high rates of glucose influx demanded by glycolysis. We hypothesized that after cell injury increases of cell Ca2+ (Ca2+i) initiate the flow of information that culminates with the upregulation of the stress response gene GLUT1. We found that elevations of Ca2+i caused by the calcium ionophore A23187 activated the expression of the GLUT1 gene in LLC-PK1 cells. The stimulatory effect of Ca2+i on GLUT1 gene expression was, at least in part, transcriptional and resulted in higher levels of GLUT1 mRNA, cognate protein, cellular hexose transport activity, glucose consumption, and lactate production. This response was vital to the renal cells, as its interruption severely increased Ca2+-induced cytotoxicity and cell mortality. We propose that increases of Ca2+i initiate stress responses, represented in part by activation of the GLUT1 gene, and that disruption to the flow of information originating from Ca2+-induced stress, or to the coordinated expression of the stress response, prevents cell recovery after injury and may be an important cause of permanent renal cell injury and cell death.

Acute Kidney Injury↗
PubMed1996

"Mirror, mirror on the wall, who...?": towards a model of visual self-recognition.

Self-recognition and self-awareness are processes fundamental to human development. This report describes the case of an 80-year-old woman who demonstrated the ''mirror sign'', an inability to recognise the reflection of oneself in a mirror. An attempt has been made to provide a cognitive neuropsychological explanation for this profound impairment in visual self-recognition, incorporating current cognitive theories of delusion formation and, specifically, delusions involving distorted appreciation of the self or others. We speculate that the impairment in visual self-recognition arises from deficits in visual and personal semantic memory related to bilateral hippocampal lesions, and that the greater extent of impairment in visual self-recognition compared with that for other familiar persons is possible evidence for a specific self-recognition process, represented as a separate ''self-identity node'' in the current face-processing model of Bruce and Young (1986).

Journal Article↗
PubMed1996

Auditory hallucinations inhibit exogenous activation of auditory association cortex.

Percepts unaccompanied by a veridical stimulus, such as hallucinations, provide an opportunity for mapping the neural correlates of conscious perception. Functional magnetic resonance imaging (fMRI) can reveal localized changes in blood oxygenation in response to actual as well as imagined sensory stimulation. The safe repeatability of fMRI enabled us to study a patient with schizophrenia while he was experiencing auditory hallucinations and when hallucination-free (with supporting data from a second case). Cortical activation was measured in response to periodic exogenous auditory and visual stimulations using time series regression analysis. Functional brain images were obtained in each hallucination condition both while the patient was on and off antipsychotic drugs. The response of the temporal cortex to exogenous auditory stimulation (speech) was markedly reduced when the patient was experiencing hallucinating voices addressing him, regardless of medication. Visual cortical activation (to flashing lights) remained normal over four scans. From the results of this study and previous work on visual hallucinations we conclude that hallucinations coincide with maximal activation of the sensory and association cortex, specific to the modality of the experience.

Acoustic Stimulation↗
PubMed1996

Mucins in airway secretions from healthy and chronic bronchitic subjects.

Little is known about whether the properties of respiratory mucins are altered as a result of airway irritation, but histochemical studies of respiratory tract secretory cells show a more 'acidic' staining pattern after exposure to tobacco smoke. Furthermore it has been suggested that proteoglycans are the major glycoconjugates in 'normal' respiratory secretions, whereas mucins predominate in sputum. To investigate these observations further, mucins from secretions collected from the tracheal surface of healthy non-smoking 'normal' subjects and sputum from patients with chronic bronchitis were compared. All samples contained one major mucin population after density-gradient centrifugation, and a small amount of 'denser' mucin was present in some chronic bronchitic and one of the 'normal' samples. Proteoglycans were not a major component of 'normal' secretions. The major mucin population from chronic bronchitic samples had molecular masses between 10 and 30 MDa and behaved as random coils in solution. Whole mucins from 'normal' individuals and chronic bronchitic patients were excluded from Sepharose CL-2B, whereas reduced subunits were included. Proteolysis of subunits yielded two populations of high-molecular-mass glycopeptides differing in size, suggesting the presence of two different tandem repeat regions in the mucins. Finally, mucins from patients with chronic bronchitis are less, rather than more, acidic than those from 'normal' individuals. Mucins from bronchitic sputum and 'normal' secretions are thus similar in their macromolecular properties, but differ slightly in charge density.

Adolescent↗
PubMed1996

Statistical methods of estimation and inference for functional MR image analysis.

Two questions arising in the analysis of functional magnetic resonance imaging (fMRI) data acquired during periodic sensory stimulation are: i) how to measure the experimentally determined effect in fMRI time series; and ii) how to decide whether an apparent effect is significant. Our approach is first to fit a time series regression model, including sine and cosine terms at the (fundamental) frequency of experimental stimulation, by pseudogeneralized least squares (PGLS) at each pixel of an image. Sinusoidal modeling takes account of locally variable hemodynamic delay and dispersion, and PGLS fitting corrects for residual or endogenous autocorrelation in fMRI time series, to yield best unbiased estimates of the amplitudes of the sine and cosine terms at fundamental frequency; from these parameters the authors derive estimates of experimentally determined power and its standard error. Randomization testing is then used to create inferential brain activation maps (BAMs) of pixels significantly activated by the experimental stimulus. The methods are illustrated by application to data acquired from normal human subjects during periodic visual and auditory stimulation.

Acoustic Stimulation↗
PubMed1996

Movement-related effects in fMRI time-series.

This paper concerns the spatial and intensity transformations that are required to adjust for the confounding effects of subject movement during functional MRI (fMRI) activation studies. An approach is presented that models, and removes, movement-related artifacts from fMRI time-series. This approach is predicated on the observation that movement-related effects are extant even after perfect realignment. Movement-related effects can be divided into those that are a function of position of the object in the frame of reference of the scanner and those that are due to movement in previous scans. This second component depends on the history of excitation experienced by spins in a small volume and consequent differences in local saturation. The spin excitation history thus will itself be a function of previous positions, suggesting an autoregression-moving average model for the effects of previous displacements on the current signal. A model is described as well as the adjustments for movement-related components that ensue. The empirical analyses suggest that (in extreme situations) over 90% of fMRI signal can be attributed to movement, and that this artifactual component can be successfully removed.

Artifacts↗
PubMed1996

Drug treatment of schizophrenia and delusional disorder in late life.

As people live longer, an increasing proportion of patients with schizophrenia and delusional disorder will be elderly. Little has been published on treatment response, effective treatment strategies, or the use of atypical neuroleptics in this group. This review of the literature explores documented response rate, route and dose of neuroleptic, indicators of poor response, and the use of novel drugs. Despite great variation in the neuroleptic dose ranges employed, patients with late-onset disease often continue to experience psychotic symptoms. Compliance with treatment is the most important determinant of outcome. Atypical neuroleptics are specifically indicated for patients with visual hallucinations or extrapyramidal symptoms. Elderly psychotic patients should be treated as vigorously and with as wide a range of neuroleptics as their younger counterparts. Physicians should not restrict drug doses to modest levels in all cases as long as patients are monitored frequently for the emergence of side effects.

Aged↗
PubMed1996

Brefeldin A effects in plant and fungal cells: something new about vesicle trafficking?

Whilst the function and organization of the secretory machinery in eukaryotic cells exhibit basic similarities, the compartmentation of the endomembrane system can show significant differences between the fungal, plant and animal kingdoms. The use of the antibiotic brefeldin A (BFA) as an inhibitor of secretion in both animal and yeast cells has resulted in a remarkable advance in our understanding of the modes of action of vesicle shuttles between the endoplasmic reticulum and Golgi apparatus and within the Golgi apparatus itself. It is now apparent that application of the drug to filamentous fungi and plants will also help unravel the workings of the secretory system in these organisms. In this paper we review recent progress in our laboratories on elucidating the effects of BFA on the morphology of the Golgi apparatus and compare these with recently published data on fungal and plant cells. Variation in the response to BFA are reported, which may not all be attributed to differences in drug concentration and time of treatment. These may reflect differences in cellular sensitivity or multiple sites of action of the drug, and the existence of a specific molecular target for BFA is questioned.

Biological Transport↗
PubMed1996

Comparison of caudal bupivacaine and diamorphine with caudal bupivacaine alone for repair of hypospadias.

Forty-five boys undergoing repair of hypospadias were allocated randomly to one of two groups. After induction of anaesthesia, 22 patients received 0.25% caudal bupivacaine 0.5 ml kg-1 and diamorphine 30 micrograms kg-1 and the remaining 23 patients received 0.25% caudal bupivacaine 0.5 ml kg-1 alone. Pain scores (Children's Hospital of Eastern Ontario Pain Scale), sedation scores, ventilatory frequency, analgesic requirements and associated side effects were recorded for the first 24 h after operation. The two groups were indistinguishable in age, weight and duration of surgery. There was a statistically significant reduction in early pain scores. There was also a statistically significant increase in the time to first passage of urine in those boys in the diamorphine group who were not catheterized during operation.

Analgesics, Opioid↗