Biomedical subjects
Publications and source records attributed to D H Miller.
The chloride secretory response to bradykinin in T84 cells is regulated. The efflux rate of 125I from these cells can be used to measure this response, and to demonstrate that the sensitivity to bradykinin varies with time in culture. The response in NuT84 cells is greater than that in T84, and can be blocked by the B2 receptor antagonist HOE-140.
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In 31 patients with definite or suspected multiple sclerosis (MS) presenting with a cervical cord syndrome, somatosensory evoked potentials (SEPs) were recorded to median and posterior tibial nerve stimulation, using cephalic and noncephalic reference electrodes. Magnetic resonance imaging (MRI) of the brain and cervical spinal cord was performed, the latter in sagittal and axial views. SEPs were abnormal in 67.7% of patients, whereas MRI showed cervical cord lesions in 74.2% and intracranial lesions possibly involving the somatosensory pathways in 64.5% of cases. A significant correlation was found between abnormalities of cervical (N13) and cortical (N20) potentials following median nerve stimulation with Fz reference and MRI abnormalities involving the ipsilateral or posterior half of the cervical cord, but not the contralateral or anterior half. The N13 potential, recorded from the low cervical region to a supraglottal reference, was most frequently abnormal in patients with MRI lesions at C6 or C7, whereas P14, recorded from the scalp to a clavicle reference, was most often affected by lesions at Cl or the cervicomedullary junction. Abnormalities of the cortical P40 to tibial nerve stimulation were less significantly correlated with cervical MRI lesions. The latency of N20 measured from N9 at the clavicle and the absolute latency of P40 were significantly correlated with the length of MRI abnormalities in the ipsilateral cervical cord. No significant correlation was observed between SEP abnormalities and brain MRI lesions, which it was considered might possibly involve the intracranial somatosensory pathways. It was concluded that (1) the morphological lesions seen in MRI of the cervical cord usually give rise to appropriate electrophysiological deficits, but the occasional finding of a widespread MRI lesion with normal SEP suggests that myelin damage is not the only or the major factor responsible for abnormal MRI signal; and (2) 'clinically silent' lesions apparently involving the radiations and other sensory structures of the brain appear not to give rise to detectable SEP abnormalities, using the methods of the present study.
Eighteen patients with acute optic neuritis underwent optic nerve magnetic resonance imaging (MRI) before and after injection of gadolinium-diethylene triamine pentacetic acid (Gd-DTPA). Ten were re-examined 4 weeks later. Leakage of Gd-DTPA across the blood-optic nerve barrier was a consistent finding in the acute lesion, and its presence was associated with abnormal visual acuity and colour vision, retro-ocular pain on eye movement, and afferent pupillary defect, and a reduced amplitude of the P100 component of the visual evoked potential. Gd-DTPA leakage had ceased in 9/11 nerves when restudied 4 wks later, and this evolution was associated with improved visual acuity and an increased P100 amplitude. Leakage is likely to reflect inflammation, and we conclude that the latter plays an important part in the production of conduction block and clinical deficit, and that its resolution is an important step in clinical remission from acute episodes of demyelination.
Serial gadolinium enhanced MRI of the brain detects much clinically silent disease activity in early relapsing-remitting and secondary progressive multiple sclerosis (MS), and thus has an important role in monitoring the effects of therapy. Based on the proceedings of a recent Commission of the European Communities (CEC) workshop and a review of the literature, guidelines are presented for using MRI to monitor treatment trials in MS. The guidelines consider: A) MRI system and techniques; B) patient selection; C) trial design; D) analysis of results. Priorities for future research are also indicated.
The production of tissue kallikrein and the short-circuit current (SCC) response in the human colonic epithelial cell line T84 to bradykinin have been studied. These cells produce true tissue kallikrein and secrete it into the growth medium, and addition of bradykinin results in a small increase in SCC. After growth of T84 cells as a xenograft in athymic (nude) mice (NuT84), however, the cellular concentration of the enzyme increases 38-fold, and the maximal change in SCC (delta SCC) induced by bradykinin increases 35-fold. The SCC response to prostaglandin E1 is not changed, and the response to forskolin increases eightfold. The bradykinin-induced delta SCC was inhibited by piretanide, suggesting that a secretory movement of chloride was responsible for the change, and the effect was attenuated by an antagonist to kinin receptors. We conclude that both the production of true tissue kallikrein and the chloride secretory response to bradykinin can be regulated in T84 cells by changes in the cell environment.
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Rat colonic mucosae fixed in situ in Ussing chambers provided a model of the extrusion of absorptive enterocytes and less commonly of goblet and enteroendocrine cells. The cells were lost at extrusion zones midway between crypt mouths. Even in mucosae in which the number of extruding cells was large, epithelial continuity was maintained as evaluated morphologically and electrophysiologically. Beneath points of remaining contact between desquamating cells and the epithelial sheet, microfilaments of the terminal web formed band-like structures linking adjacent junctional complexes. Freeze-fracture replicas disclosed extensive macular regions of tight junction strands in the plasma membranes of desquamating cells. Tight junctions between newly neighboring cells were often irregular and often occurred beneath the terminal web region. Dithiothreitol enhanced cell loss and increased basal epithelial conductance, but histological continuity was maintained and the mucosae continued to respond typically to bradykinin. These observations suggest that during the loss of senescent enterocytes, tight junctions are maintained; old junctional elements are lost, and tight junctions are formed between remaining adjacent cells. This model offers a means to study the synthesis and turnover of tight junctions and the maintenance of the colonic epithelial barrier.
The pathophysiology and optimal therapy of patients who develop unstable angina in spite of long-term aspirin intake ("aspirin failure") have not been well defined. As part of a prospective study of thrombolytic therapy, 19 consecutive patients were identified who were admitted with unstable angina despite long-term aspirin therapy, and they were compared with 12 patients with unstable angina without previous aspirin use. Both groups received urokinase (3.0 million units over 30 minutes intravenously), maximal antianginal therapy, and intravenous heparin. Fibrinolytic system effects were characterized with serial measurements of fibrinogen, d-dimer, and fibrinogen degradation products (FDPs) at baseline and over the 24 hours following therapy. In comparison with those without previous aspirin use, the aspirin failure patients demonstrated greater d-dimer production after treatment at all points, the values becoming highly significant at 24 hours (1337 +/- 671 versus 709 +/- 620 ng/dl, p less than 0.02), as well as significantly greater FDPs at all points in the first 24 hours after treatment. Post-treatment arteriography (at 24 to 72 hours) indicated more extensive coronary artery disease in the aspirin failure patients (2.56 +/- 8.3 versus 1.63 +/- 1.06 vessels with greater than 50% stenosis, p less than 0.01) and more severe stenoses of the culprit artery (92.7 +/- 22.9% versus 77.3 +/- 36.9% diameter reduction, p = 0.09). By 7 days, both groups had equally low rates of new ischemic events or infarction (3 of 12 for no aspirin versus 4 of 19 for aspirin failure patients). Despite more extensive underlying coronary disease, unstable angina after long-term aspirin therapy appears to respond equally well to thrombolytic therapy.(ABSTRACT TRUNCATED AT 250 WORDS)
Results of recent clinical trials have unequivocally established the value of intravenous thrombolytic therapy in enhancing survival after acute myocardial infarction. However, the optimum long-term antithrombolytic strategy for prevention of recurrent cardiac complications after thrombolysis is unknown at the current time. To determine whether aspirin or warfarin best prevents postdischarge recurrent cardiac events (unstable angina, reinfarction, pulmonary edema, or/and death), we analyzed the long-term course of 203 patients at our institution who received intravenous thrombolytic therapy (streptokinase, tissue plasminogen activator, or urokinase) for acute myocardial infarction. Of these, 129 (64%) survived to hospital discharge without revascularization--92 patients (71%) received aspirin (325 mg/day). whereas 37 (29%) received warfarin. The choice of drug was made by the treating physician. By a mean of 2.5 years of follow-up, 34 of 92 patients receiving aspirin (37%) versus 6 or 37 receiving warfarin (16%) (p less than or equal to 0.02) had unstable angina, reinfarction, pulmonary edema, and/or death. No life-threatening hemorrhage occurred in either group. Warfarin appears to be superior to aspirin long term in patients with postlysis myocardial infarction for the prevention of recurrent cardiac complications.
The effects of endogenous and exogenous glucocorticoids on renal active and prokallikrein levels (ng/mg protein) and in vivo kallikrein synthesis rate were studied in the conscious rat. Within two hours after low dose methylprednisolone (MP, 0.0125 to 0.05 mg/100 g body wt), active kallikrein and prokallikrein fell (29.1 +/- 2.3 and 35.1 +/- 2.7 ng/mg protein, respectively, compared to 38.4 +/- 3.7 and 42.7 +/- 3.4 in vehicle-treated rats, P less than 0.05 or less). These changes were accompanied by a significant fall in prokallikrein synthesis rate relative to total protein synthesis. The reductions in active and prokallikrein levels were transient, dissipating by six hours. With increasing MP doses, there was further dose-dependent reduction in active kallikrein. However, prokallikrein levels increased to normal as the MP dose was increased despite continued suppression of synthesis, suggesting that prokallikrein activation was inhibited. Renal kallikrein levels were also examined in relation to changes in endogenous glucocorticoid levels. In intact rats, three hours after plasma corticosterone peaked (10 p.m.), active and prokallikrein levels were 30.2 +/- 2.9 and 27.0 +/- 1.6 ng/mg protein, respectively, compared to 36.9 +/- 2.3 and 37.2 +/- 2.6 (P less than 0.005) three hours after the corticosterone nadir (11 a.m.). Furthermore, adrenalectomy increased active and prokallikrein (47.3 +/- 4.8 and 87.3 +/- 6.0 ng/mg protein, respectively), compared to levels in intact or shamoperated rats (intact: 32.9 +/- 2.9 and 54.9 +/- 5.3 ng/mg protein, P less than 0.01 or less). Adrenalectomy also eliminated the diurnal changes in kallikrein levels seen in intact rats. These data suggest that renal prokallikrein synthesis and activation are physiologically regulated by glucocorticoids.
Brain MRI was performed on 12 patients with acute disseminated encephalomyelitis (ADEM). Multifocal white matter lesions indistinguishable from those seen in multiple sclerosis (MS) were found in 10. In 5 there were rather extensive symmetric abnormalities in the cerebral (2) or cerebellar white matter (2), or basal ganglia (1). Follow-up MRI after intervals of 2 wks to 18 months demonstrated partial resolution of the abnormalities, but some persisting lesions. New MRI lesions were found at follow-up in only 1 case after an interval of 2 wks. Serial MRI makes a useful contribution to the distinction between MS and ADEM.
Magnetic resonance imaging (MRI) was performed on 36 children and two adults (with clinical presentation during childhood) with white-matter disease of the central nervous system. Abnormalities were readily demonstrated in patients with multiple sclerosis, acute disseminated encephalomyelitis, leucodystrophies and subacute sclerosing panencephalitis: MRI demonstrated the extent and distribution of abnormalities more clearly than computed tomography for all these disorders. The abnormalities tended to be asymmetrical and multifocal in multiple sclerosis and acute disseminated encephalomyelitis, and more confluent and symmetrical in the leucodystrophies. Children with clinically isolated optic neuritis had a significantly lower frequency of MRI brain-lesions than adults with the same disorder. MRI should be regarded as the radiological investigation of choice when white-matter disease is suspected in children.
The prevalence of multiple sclerosis (MS) has been recently reported from nine regions of Australia and New Zealand. There is a marked variation of prevalence with latitude. MS is seven times more common in southern New Zealand than in tropical Queensland. On current evidence, it is suggested that in both countries this variation is predominantly due to environmental rather than genetic factors.
This note traces the history of the "right-to-die" damage action. These are cases in which health care providers have been sued for providing unwanted life-sustaining treatment. After briefly describing the development of basic right-to-die law, the principle theories behind damage claims and the cases themselves are discussed, and the primary stumbling blocks are analyzed.
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A review was undertaken of all cases of tuberculous meningitis seen in Wellington since 1962. It showed, in conjunction with an earlier study, a steady decline in the incidence of the disease since 1940. There was a relatively high incidence in Maori and Pacific Island Polynesians. Good outcome was seen in 17/28 (61%). Poor recovery was associated with delayed treatment, confusion or stupor at presentation, and male sex. The diagnosis is not excluded by a normal peripheral white count, ESR, chest x-ray or cerebrospinal fluid.