Tuberculosis: a clinical problem of international importance.
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Biomedical subjects
Publications and source records attributed to J Cornwall.
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Between January 1983 and December 1990 in Auckland, New Zealand, 87 patients (28 paucibacillary disease (PBD) and 59 multibacillary disease (MBD)) commenced WHO multidrug therapy (MDT). All were immigrants from the Pacific Islands (65) or Asia (22). A total of 57 patients had already received non-WHO regimens, some continuously, but often intermittently, for many years; 30 patients received WHO MDT only. By December 1990, 50 had completed treatment, with 1 relapse and 1 late reaction, both in patients with PBD treated with WHO MDT only. There have been no relapses in those treated with WHO MDT after prior leprosy treatment. In those with MBD, type II leprosy reactions were less common (16%) in those treated only with WHO MDT than in those treated continuously before 1983 with older regimens (64%). Type I leprosy reactions occurred in about 20% of both these groups. The bacterial index fell faster in those who had had a prolonged prior treatment beginning WHO MDT than in those starting WHO MDT as their initial leprosy chemotherapy. Overall we found WHO MDT was well accepted and the compliance good, but 13 patients (15%) left Auckland before treatment was completed and 6 (7%) during follow up.
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Afferent pathways to the rostral reticular thalamic nucleus (Rt) in the rat were studied using anterograde and retrograde lectin tracing techniques, with sensitive immunocytochemical methods. The analysis was carried out to further investigate previously described subregions of the reticular thalamic nucleus, which are related to subdivisions of the dorsal thalamus, in the paraventricular and midline nuclei and three segments of the mediodorsal thalamic nucleus. Cortical inputs to the rostral reticular nucleus were found from lamina VI of cingulate, orbital and infralimbic cortex. These projected with a clear topography to lateral, intermediate and medial reticular nucleus respectively. Thalamic inputs were found from lateral and central segments of the mediodorsal nucleus to the lateral and intermediate rostral reticular nucleus respectively and heavy paraventricular thalamic inputs were found to the medial reticular nucleus. In the basal forebrain, afferents were found from the vertical and horizontal limbs of the diagonal band, substantia innominata, ventral pallidum and medial globus pallidus. Brainstem projections were identified from ventrolateral periaqueductal grey and adjacent sites in the mesencephalic reticular formation, laterodorsal tegmental nucleus, pedunculopontine nucleus, medial pretectum and ventral tegmental area. The results suggest a general similarity in the organisation of some brainstem Rt afferents in rat and cat, but also show previously unsuspected inputs. Furthermore, there appear to be at least two functional subdivisions of rostral Rt which is reflected by their connections with cortex and thalamus. The studies also extend recent findings that the ventral striatum, via inputs from the paraventricular thalamic nucleus, is included in the circuitry of the rostral Rt, providing further evidence that basal ganglia may function in concert with Rt. Evidence is also outlined with regard to the possibility that rostral Rt plays a significant role in visuomotor functions.
The connections of the laterodorsal tegmental nucleus (LDTg) have been investigated using anterograde and retrograde lectin tracers with immunocytochemical detection. Inputs to LDTg were found from frontal cortex, diagonal band, preoptic areas, lateral hypothalamus, lateral mamillary nucleus, lateral habenula; the interpeduncular nucleus, ventral tegmental area, substantia nigra and retrorubral fields; the medial terminal nucleus, interstitial nucleus, supraoculomotor central grey, medial pretectum, nucleus of the posterior commissure, paramedian pontine reticular formation, paraabducens and paratrochlear region; the parabrachial nuclei and nucleus of the tractus solitarius. Terminal labelling from PHA-L injections of LDTg was found in infralimbic, cingulate and hippocampal cortex, lateral septum, septofimbrial and triangular nuclei, horizontal limb of diagonal band and preoptic areas; in the anterior, mediodorsal, reuniens, centrolateral, parafascicular, paraventricular and laterodorsal thalamic nuclei, rostral reticular thalamic nucleus, and zona incerta; the lateral habenula and the lateral hypothalamus. A number of brainstem structures apparently associated with visual functions were also innervated, mainly the superior colliculus, medial pretectum, medial terminal nucleus, paramedian pontine reticular formation, inferior olive, supraoculomotor, paraabducens and supragenual regions, prepositus hypoglossi and nucleus of the posterior commissure. Also innervated were substantia nigra compacta, ventral tegmental area, interfascicular nucleus, interpeduncular nucleus, dorsal and medial raphe, pedunculopontine tegmental region, parabrachial nuclei, and nucleus of the tractus solitarius. These findings suggest the LDTg to be a highly differentiated part of the ascending "reticular activating" system, concerned not only with specific cortical and thalamic regions, especially those associated with the limbic system, but also with the basal ganglia, and visual (particularly oculomotor) mechanisms. Additional links with the habenula-interpeduncular system are discussed in this context.
The branching pattern of axons arising from cells in the basal forebrain and laterodorsal tegmental nucleus of the pontine grey, was examined using the double retrograde transport of rhodamine- and coumarin-labelled latex microspheres injected into the olfactory bulb and the mediodorsal thalamic nucleus. About 30-50% of basal forebrain neurones were double-labelled, and approximately 30-40% of laterodorsal tegmental neurones were double-labelled ipsilateral to the injections. No contralateral single or double label was observed in the basal forebrain, but approximately 30% of the contralateral laterodorsal tegmental projection was also double-labelled.
Quantitative analysis of the branching pattern of output projections from the prefrontal cortex and the laterodorsal tegmental nucleus of the brainstem, has been carried out using the newly developed method for double retrograde labelling of neurons with fluorescent labelled latex microspheres. At least 34% of cortical mediodorsal projection neurones in lamina VI send collateral axons to the reticular thalamic nucleus, and at least 40% of cortical reticular projection neurones and collateral axons to mediodorsal nucleus. In the brainstem, laterodorsal neurones are also highly collateralized; at least 44% of mediodorsal projection neurones also innervating nucleus reticularis, and at least 47% of reticularis projection neurones innervating the mediodorsal nucleus.
A method is described for the quantitative analysis of double retrograde labelled neuronal cell bodies following labelling of branched axonal projections. This exploits the known ability of retrograde translocator proteins to transport latex microspheres following their uptake at nerve terminals. Conditions necessary for uptake and transport include small bead diameter (0.05-micron) and carboxylation of the latex particle. Using coumarin- and rhodamine-labelled microspheres a reliable, sensitive, rapid method has been developed, which results in double retrograde cell labelling in branched axonal pathways from the frontal cortex, basal forebrain, and brainstem. The technique has several advantages over currently available double retrograde labelling methods and yields repeatable quantitative estimates of populations of neurones bearing branched axons.
The topography of afferent projections to the mediodorsal thalamic nucleus of the rat has been studied using the retrograde transport of unconjugated wheat germ agglutinin as identified by immunocytochemistry. Inputs were defined according to the lateral, central or medial segments of the nucleus injected, and controlled by additional injections into the habenula, central medial and paraventricular nuclei of the thalamus. Cortical afferents to the lateral segment arose from anterior cingulate and prelimbic areas on the medial surface of the hemisphere, those to the central segment arose mainly from ventral orbital area, whilst those to the medial segment arose from the infra-limbic and agranular insular areas. This strict cortical topography was matched by the organization of afferents from the reticular thalamic nucleus; i.e. lateral, intermediate and medial reticular neurons from the rostral nucleus projected to lateral, central and medial segments of the mediodorsal thalamus respectively. In the basal forebrain ventral pallidum projected only to the medial segment, whilst magnocellular preoptic region projected only to the central segment. Lateral preoptic area projected to lateral and central segments and the diagonal band mainly to central segment. Projections from substantia innominata were found regardless of the area of mediodorsal nucleus injected. The paraventricular nucleus of thalamus, lateral habenula and substantia nigra reticulata projected to the lateral segment only, whilst central gray projected only to the medial segment. Projections from amygdala (mainly basolateral and central nucleus) were found only following central and medial segment injections. All regions of the mediodorsal nucleus injected received input from the lateral hypothalamus, the ventral tegmental area and the dorsal tegmental gray. The results are discussed and particular emphasis is placed on the possible functions of the thalamocortical connections and the role of the reticular thalamic nucleus as a potential regulator of thalamocortical activity.
Afferent projections to the parafascicular nucleus of the rat have been mapped using the retrograde transport of unconjugated wheat germ agglutinin and immunohistochemistry using very short survival times. Retrogradely labelled neurones were found in laminae V and V1 of primary motor cortex, lamina V1 of primary somatosensory cortex, and deep laminae of gustatory cortex; in the reticular thalamic nucleus and zona incerta; and in the caudate-putamen, entopeduncular nucleus, mesencephalic reticular formation and pretectum. Additional label was found in the laterodorsal tegmental nucleus, nucleus tegmenti pedunculopontinus, dorsal and ventral parabrachial nuclei, vestibular nuclei and the lateral cervical, medial and interpositus nuclei of the cerebellum. These results are discussed in the context of the connections of parafascicular nucleus with the motor system, particularly the basal ganglia. Of particular interest are inputs from laterodorsal tegmental nucleus, nucleus reticularis of thalamus, mesencephalic reticular formation, nucleus tegmenti pedunculopontinus, primary motor cortex and deep cerebellar nuclei. These indicate that the parafascicular nucleus lies at an interface between the reticular activating system on the one hand, and the motor system on the other. This result thus enlarges on present concepts of the parafascicular nucleus. Comparison of afferent projections to a variety of non-specific thalamic nuclei, the parafascicular, paraventricular and mediodorsal thalamic nuclei, indicate a remarkable set of topographic parallels from cortical, reticular thalamic, hypothalamic and brainstem sites. These comparisons provide clues as to the organisational principles of these non-specific thalamic nuclei, particularly in the context of the reticular activating system.
Afferent projections to midline thalamic cell groups which innervate nucleus accumbens, were identified by the retrograde transport of unconjugated wheat germ agglutinin followed by the identification of labelled cell groups with immunocytochemistry. Large numbers of neurones were labelled in a variety of hypothalamic nuclei; principally in the medial preoptic area, anterior hypothalamic area, ventromedial, periventricular, arcuate and posterior hypothalamic nuclei, and in the supramammillary and lateral hypothalamic areas. Following rostral thalamic injections labelled cells were also found in the lateral septum, bed nucleus of the stria terminalis, and zona incerta. Prominent and localised label was found in the nucleus reticularis of thalamus at its most rostral medial tip. Cortical label was found in the ventral subiculum following rostral injections, and in the perirhinal cortex following mid-thalamic injections. In the brainstem label was found in central grey, laterodorsal tegmental nucleus, raphe, dorsal and ventral parabranchial nuclei and nucleus of the tractus solitarius. The results are discussed in the context of striatal function, particularly the nucleus accumbens, which is a component of the ventral striatum. Thus, the midline thalamic nuclei may provide an interface where a variety of inputs from many limbic regions and hypothalamic nuclei can influence nucleus accumbens function. Comparison of afferents to several thalamic nuclei directly related to striatal function and the prefrontal cortex show, that forebrain thalamic afferents from pallidal and hypothalamic sites, are organised with a clear topography. Some afferents suggest specific routes which may allow the reticular activating system to participate in the regulation of basal ganglia function.
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We have investigated the role of the parafascicular-intralaminar thalamus in the regulation of dopaminergic function in the caudate-putamen by making unilateral injections of the excitotoxin, ibotenic acid, into the thalamus of the halothane-anaesthetized rat. Dopamine utilization was measured at 4 h, 18 h, and 7 days after operation in microdissected tissue from caudate-putamen, substantia nigra, and nucleus accumbens. High performance liquid chromatography with electrochemical detection was used to simultaneously determine dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid. Dopamine utilization was recorded as a ratio of metabolite to its parent amine. At 4 h following injection large bilateral increases in dopamine utilization were recorded in both medial and lateral sectors of caudate-putamen. The percentage increases found for homovanillic acid-based ratios were larger than those found for 3,4-dihydroxyphenylacetic acid-based ratios. These results probably reflect increased dopamine release resulting from the acute effects of ibotenic acid. These changes were independent of dopamine utilization ratios recorded in the substantia nigra, which showed no change either ipsilateral or contralateral to the injection. In contrast to these findings, at 7 days following injection, dopamine utilization ratios were reduced both ipsilateral and contralateral to the injection, although only the ipsilateral reductions were significant. Again, no change was found for this survival time in the substantia nigra. At 18 h survival an intermediate pattern between the 4 h and 7 day result was found. In the nucleus accumbens, ibotenic acid injection produced similar results to those found in caudate-putamen, i.e. a bilateral increase in dopamine utilization at early time intervals and a unilateral ipsilateral decrease at long intervals following injection. These results show that dopamine release in the caudate-putamen is sensitive to experimentally induced changes in neural activity and lesions of its thalamic input. Since the effect of presumed stimulation is markedly greater than lesion, it would appear that, under the conditions employed in these experiments, the thalamus is relatively silent; a suggestion consistent with other evidence. Furthermore, since the changes found occurred in the absence of changes in utilization ratios in the substantia nigra, the mechanisms whereby thalamus regulates dopamine release may be exerted via a local circuit and/or a presynaptic mechanism in the region of dopamine terminals. The anatomical routes responsible for these effects are discussed.(ABSTRACT TRUNCATED AT 400 WORDS)
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The organization of collateral axons projecting from neurones in the pontine laterodorsal tegmental nucleus (LDTg) has been examined using combinations of retrograde neuronal tracers with immunocytochemical markers for the acetylcholine-synthesizing enzyme choline acetyltransferase (CHAT), focussing on projections to the midline, mediodorsal and parafascicular thalamic nuclei and the ventral tegmental area. 25-59% of LDTg neurones projecting to the mediodorsal nucleus provided collaterals to the midline nuclei. Virtually all (87-96%) of these double retrogradely labelled neurones appeared cholinergic. 9-18% of LDTg neurones projecting to the parafascicular nuclei also provided a collateral to the midline nuclei and 50-78% of these double retrogradely labelled neurones stained for CHAT. 26-29% of the single LDTg neurones which projected collaterals to both the mediodorsal and midline nuclei, were found to project a third collateral to the ventral tegmental area. These anatomical findings, taken together with functional evidence, suggest that cholinergic terminals arising from LDTg are involved in coordinating thalamic mechanisms of brain state control; and in regulating dopaminergic pathways, both directly and via the thalamus.