Spongiform neuropathy induced in dogs by prolonged, low-level administration of 6-aminonicotinamide (6-ANA)

The objective of this study was to demonstrate the effects of prolonged exposure to 6-ANA at low dose-levels in dogs. A male and a female Beagle dog received daily oral repetitive doses of 1 mg/kg or less for 20 weeks. Both dogs showed lacrimation, conjunctivitis, reduced motility and anemia since the second week of treatment. The female dog was more affected than the male and at the end of treatment period it had tremor, hanging lower jaw, stepping gait of the hind limbs, hunched posture, and general debilitation. Post-mortem examination of the female dog revealed prominent brain edema with pressure atrophy of the dorsal cranial bones. Microscopic examination of the nervous system revealed spongiform neuropathy in both animals mainly affecting the telencephalic cortex and hippocampal fascia dentata, the substantia gelatinosa in the spinal cord and the dorsal root and autonomic ganglia. The changes were produced by vacuolation of astrocytes in the central nervous system and perineuronal satellite cells in the ganglia. Examination of the other organs revealed thymic atrophy and high hematopoietic activity of the bone marrow in both dogs. The male had severe interstitial edema and vacuolar degeneration of the testicular seminiferous tubules and the female had marked chronic pyelonephritis. This chemically induced spongiform neuropathy in dogs obviously represents a subchronic form of the "energy deprivation syndrome" induced by impaired glucose utilization. Vacuolar degeneration of the testicular seminiferous epithelium may have the same pathogenesis.     

Time and frequency domain estimates of spontaneous baroreflex sensitivity provide early detection of autonomic dysfunction in diabetes mellitus

Diabetic autonomic dysfunction is associated with a high risk of mortality which makes its early identification clinically important. The aim of our study was to compare the detection of autonomic dysfunction provided by classical laboratory autonomic function tests with that obtained through computer assessment of the spontaneous sensitivity of the baroreceptor-heart rate reflex (BRS) by time domain and frequency domain techniques. In 20 normotensive diabetic patients (mean age +/- SD 41.9 +/- 8.1 years) with no evidence of autonomic dysfunction on laboratory autonomic testing (D0) blood pressure (BP) and ECG were continuously monitored over 15 min in the supine position. BRS was assessed as the slope of the regression line between spontaneous increases or reductions in systolic BP and linearly related lengthening or shortening in RR interval over sequences of at least 4 consecutive beats (sequence method), or as the squared ratio between RR interval and systolic BP spectral powers around 0.1 Hz. We compared the results with those of 32 age-matched normotensive diabetic patients with abnormal autonomic function tests (D1) and with those of 24 healthy age-matched control subjects with normal autonomic function tests (C). Compared to C, BRS was markedly less in D1 when assessed by both the slope of the two types of sequences (data pooled) and by the spectral method (-71.3% and -60.2% respectively, both p < 0.01). However, BRS was consistently although somewhat less markedly reduced in D0, the reduction being clearly evident for all the estimates (-57.0% and -43.5%, both p < 0.01). The effects were more evident than those obtained by the simple quantification of the RR interval variability. These data suggest that time and frequency domain estimates of spontaneous BRS allow earlier detection of diabetic autonomic dysfunction than classical laboratory autonomic tests. The estimates can be obtained by short non-invasive recording of the BP and RR interval signals in the supine patient, i.e. under conditions suitable for routine outpatient evaluation.     

Diagnosing community health by factorial analysis]

The electrophysiologic evaluation of patients with erectile dysfunction presents an important diagnostic challenge. The bulbocavernosus reflex (BCR) latency has been commonly used to evaluate these disorders. However, it is a measure of somatic penile innervation, whereas erection is primarily dependent on autonomic function. We evaluated 195 men with erectile dysfunction over a 3 year period. Each had electrophysiologic studies, nerve conduction studies and a BCR. BCR studies were abnormal in only 7%, of which most had diabetes or pelvic trauma. The BCR was the sole electrophysiologic abnormality in only 2%. Autonomic testing (AT) was additionally performed in 19 diabetic and 23 non-diabetic patients. This included sympathetic skin responses and measurement of the Valsalva ratio and heart rate variability with 6/min breathing. In the diabetic group, AT was positive in 63%, and most often was the sole abnormality. The bulbocavernosus reflex is relatively insensitive in the diagnosis of erectile dysfunction. Brief autonomic testing may provide valuable additional data, particularly in diabetics.     

An automatic device for the assessment of cardiovascular autonomic function

Autonomic neuropathy is a common complication of diabetes mellitus and is associated with significant morbidity and possibly an increase in mortality. Despite this, however, autonomic dysfunction is not usually sought in the routine assessment of diabetic patients. We report the development and testing of a small, portable and reliable device that allows the routine testing of cardiac autonomic function in the outpatient setting with minimal inconvenience to the patient. This should facilitate the accurate assessment both of patients with symptoms suggestive of autonomic dysfunction and of autonomic function in research.     

Chymotrypsin inhibitory conformation of dipeptides constructed by side chain-side chain hydrophobic interactions

We prospectively evaluated autonomic function in 50 patients with clinical and manometric features of a neuropathic form of chronic intestinal pseudo-obstruction (CIP). In 26 patients, there were underlying disease processes that may have affected extrinsic neural control to viscera: diabetes mellitus (n = 16), previous gastric surgery (n = 5), and other neurologic disorders (n = 5). Our aim was to characterize autonomic function in these patients, and those 24 with CIP unassociated with a known underlying neurologic disorder (idiopathic group). We assessed vagal function and sympathetic cholinergic and adrenergic function by means of standardized autonomic tests and quantitated postprandial antral pressure activity. We also measured postprandial levels of pancreatic polypeptide and neurotensin as indicators of vagal function and of the delivery of nutrients to the distal small bowel. Among the idiopathic group (n = 24), two had evidence of a generalized sympathetic neuropathy and five abdominal vagal dysfunction (one had both). Among diabetic patients, three had sympathetic adrenergic failure, six had orthostasis with normal plasma noradrenaline, ten had signs of generalized sympathetic neuropathy and eight had abdominal vagal dysfunction. Vagal dysfunction was identified in all three patients who underwent vagotomy as part of their previous gastric surgery. In the other neurologic syndromes, vagal function was abnormal in three of the five patients. Thus, autonomic and, particularly, vagal dysfunction are confirmed in a majority of patients with CIP associated with known diabetes or neurologic disorders; however, a previously unrecognized autonomic (chiefly vagal) neuropathy of undetermined cause has been identified in five of the 24 'idiopathic' CIP patients.     

Cardiovascular and sweating dysfunction in patients with Holmes-Adie syndrome

A cross-sectional study is reported in which 53 patients with Holmes-Adie syndrome have been subjected to a battery of tests of autonomic nervous function referable to the cardiovascular system, to two objective tests of sweating function, and to subjective assessment of sweating by application of quinizarin powder followed by body heating. The majority of patients were consecutive referrals; none was selected because of clinical indications of autonomic dysfunction. Eighty three per cent of these patients had at least one, 57% at least two, and 40% at least three objective test abnormalities, as defined by values lying outside 95 percentiles of healthy subjects who were matched for age and subjected to the same tests. In the context of multiple testing, the probability of finding outside values was such that a minimum of 3 was required to define abnormality. On this basis 40% of patients were found to have significant evidence of autonomic dysfunction. The most frequent abnormalities were impaired digital vasoconstriction to cold (23%), a reduced heart rate response to the Valsalva manoeuvre (17%), and excessive variability in sweating between test sites (in one of the tests, 43%) which is consistent with patchy loss. Abnormal quinizarin test appearances were seen in 10 patients and in a further five patients the appearances were thought to be suggestive of abnormality. Though assessment of the results of this test are subjective, the observations are consistent with the findings obtained from the objective tests which were applied. Cardiovascular and sweating abnormality did not concur significantly and only the former was found to increase progressively with known duration of the pupillotonia. It is concluded that Holmes-Adie syndrome is commonly accompanied by progressive mild but widespread autonomic involvement but rarely is this symptomatic. If symptoms suggestive of autonomic neuropathy are found in a patient with tonic pupils, a careful search for some other generalised disorder is recommended.     

Alcohol abuse exaggerates autonomic dysfunction in chronic liver disease

BACKGROUND: Advanced chronic liver disease is characterized by peripheral arterial vasodilation and increased plasma catecholamine concentrations. These haemodynamic alterations may reflect impaired vascular responsiveness due to autonomic nerve dysfunction. METHODS: Three established non-invasive tests based on the heart reactions to deep breathing (expiratory/inspiratory (E/I) ratio) and to tilt (acceleration and brake indices) were used to evaluate age-related autonomic nerve function in 27 patients with chronic alcoholic and non-alcoholic liver disease. Liver function was estimated by demethylating capacity. The results were compared with a control group consisting of 56 healthy individuals. RESULTS: Overall, 12 patients (52%) had autonomic neuropathy (10 of 13 (77%) patients with alcoholic and 2 of 14 (14%) with non-alcoholic liver disease). Variance analysis showed that the age-corrected E/I ratio, but not the acceleration and brake indices, was significantly decreased compared with controls both in patients with alcoholic and non-alcoholic liver disease, indicating vagal nerve dysfunction (P < 0.0001 and 0.0133, respectively). The decrease in E/I ratio was also significantly more pronounced (-1.77 (0.62) (median (interquartile range)) versus 0.76 (0.70); P = 0.049) in patients with alcoholic compared with non-alcoholic liver disease. Furthermore, in contrast to non-alcoholics, patients with alcoholic liver disease were unable to increase their diastolic blood pressure after return to upright from a tilted position, indicating additional sympathetic neuropathy. CONCLUSIONS: Autonomic, mainly vagal, nerve dysfunction is common in patients with liver diseases and is further exaggerated by alcohol abuse. Autonomic neuropathy may contribute to altered vascular responsiveness in patients with chronic liver diseases.     

Noninvasive assessment of cardiac diabetic neuropathy by carbon-11 hydroxyephedrine and positron emission tomography

OBJECTIVES: The purpose of this investigation was to evaluate the sympathetic nervous system of the heart by positron emission tomographic (PET) imaging in patients with diabetes mellitus with and without diabetic autonomic neuropathy. BACKGROUND: The clinical assessment of cardiac involvement in diabetic autonomic neuropathy has been limited to cardiovascular reflex testing. With the recent introduction of radiolabeled catecholamines such as carbon (C)-11 hydroxyephedrine, the sympathetic innervation of the heart can be specifically visualized with PET imaging. METHODS: Positron emission tomographic imaging was performed with C-11 hydroxyephedrine and rest myocardial blood flow imaging with nitrogen-13 ammonia. Three patient groups were studied, including healthy volunteers as control subjects, diabetic patients with normal autonomic function testing and diabetic patients with varying severity of autonomic neuropathy. Homogeneity of cardiac tracer retention as well as absolute tracer retention was determined by relating myocardial tracer retention to an arterial C-11 activity input function. RESULTS: Abnormal regional C-11 hydroxyephedrine retention was seen in seven of eight patients with autonomic neuropathy. Relative tracer retention was significantly reduced in apical, inferior and lateral segments. The extent of the abnormality correlated with the severity of conventional markers of autonomic dysfunction. Absolute myocardial tracer retention index measurements showed a 45 +/- 21% decrease in distal compared with proximal myocardial segments in autonomic neuropathy (0.069 +/- 0.037 min-1 vs. 0.13 +/- 0.052 min-1, p = 0.02). CONCLUSIONS: This study demonstrates a heterogeneous pattern of neuronal abnormalities in patients with diabetic cardiac neuropathy. The extent of this abnormality correlated with the severity of neuropathy assessed by conventional tests. Future studies in larger groups of patients are required to define the relative sensitivity of this imaging approach in detecting cardiac neuropathy and to determine the clinical significance of these scintigraphic findings in comparison with conventional markers of autonomic innervation.     

Platelet dysfunction associated with immune-mediated thrombocytopenia in dogs

The effect of antiplatelet antibody on in vitro platelet function was investigated in 15 dogs with immune-mediated thrombocytopenia (ITP). Platelet aggregation was assessed after addition of serum from healthy dogs (n = 5) or dogs with ITP (n = 15) to platelet-rich plasma from a healthy donor dog. The aggregation responses to adenosine diphosphate, thrombin, and collagen/epinephrine were measured as the maximum aggregation observed after 2 minutes. In 13 of 15 dogs with ITP, maximal aggregation was significantly inhibited in response to ADP, thrombin, or collagen/epinephrine. The slope of the aggregation curve was decreased after addition of serum from 9 of 15 patients. A polyclonal rabbit anti-dog platelet antiserum induced inhibition of aggregation with all 3 agonists. Serum from control dogs neither inhibited nor activated platelet aggregation. Aggregation experiments were repeated with all 3 agonists after addition of patient immunoglobulin (Ig)G or IgG from a healthy dog to platelet-rich plasma. The IgG fraction from 9 of 10 dogs with ITP suppressed platelet aggregation. The IgG fraction from polyclonal rabbit anti-dog platelet antiserum inhibited platelet aggregation with all agonists. These results suggest that many canine ITP patients have circulating antibodies that, in addition to causing platelet destruction, may cause platelet dysfunction.     

Anatomy of medullary and peripheral autonomic neurons innervating the neonatal porcine heart

Gross and microscopic anatomical investigations were carried out in 14 piglets aged from 4 to 66 days. True Blue (7-50 microliters) and Diamidino Yellow (7-50 microliters) were injected individually into 2 different cardiac sites (the right atrial ganglionated plexus, the inferior vena cava, inferior atrial ganglionated plexus, the right atrium or the right ventricle). Gross anatomy: Globular superior cervical and nodose ganglia, elongated stellate ganglia, multiple small middle cervical ganglia and multiple small mediastinal ganglia along the course of cardiopulmonary nerves were identified. Microscopic anatomy: Neurons innervating specific cardiac regions or intrinsic cardiac ganglionated plexuses were distributed relatively evenly among stellate (primarily in their cranial poles) and middle cervical ganglia bilaterally, fewer labeled neurons being located in the superior cervical and mediastinal ganglia bilaterally. Parasympathetic efferent preganglionic neurons associated with either intrinsic cardiac ganglionated plexus studied were identified primarily throughout the ventrolateral region (the external formation) of the nucleus ambiguus bilaterally. Labeled neurons were also identified throughout the right and left nodose ganglia. Individual neurons did not project axons to different cardiac regions, as no double-labeled neurons were identified. No correlation between age and the numbers and locations of labeled neurons was apparent. Thus, porcine sympathetic efferent neurons which innervate individual cardiac regions, including intrinsic cardiac ganglionated plexuses, lie scattered primarily throughout the right and left mediastinal and middle cervical ganglia as well as the cranial poles of stellate ganglia at birth, apparently changing little during the first 2 months of age. Porcine cardiac parasympathetic efferent preganglionic neurons are located primarily in the external formation of the nucleus ambiguus bilaterally at birth. The numbers of afferent cardiac neurons distributed throughout the nodose ganglia bilaterally also change little during that time. It is concluded that most of the autonomic neurons which innervate the heart are in place at birth.     

Differential diagnosis of decreased vision: a case study

Three patients who suffered transitory (from 18 to 49 days) cranial dyskinesias during the course of tubercular meningitis are described. The diagnosis was confirmed by the presence of acid-alcohol resistant bacilli in spinal fluid. Cranial tomography or magnetic resonance images failed to demonstrate anatomical lesions. The blink reflex and brain stem auditory evoked potentials were abnormal, indicating dysfunction of motor nuclei of the cranial nerves, possibly secondary to changes in their regulation by basal ganglia. No recurrences have been observed during follow-up (from 3 to 7 years).     

Effects of long-term monotherapy with enalapril, metoprolol, and digoxin on the progression of left ventricular dysfunction and dilation in dogs with reduced ejection fraction

BACKGROUND: Recent clinical trials have suggested that therapy with angiotensin-converting enzyme inhibitors in asymptomatic patients with reduced left ventricular (LV) function can significantly reduce the incidence of congestive heart failure compared with patients receiving placebo. In the present study, we examined the effects of long-term monotherapy with enalapril, metoprolol, and digoxin on the progression of LV systolic dysfunction and LV chamber enlargement in dogs with reduced LV ejection fraction (EF). METHODS AND RESULTS: LV dysfunction was produced in 28 dogs by multiple sequential intracoronary microembolizations. Embolizations were discontinued when LVEF was 30% to 40%. Three weeks after the last embolization, dogs were randomized to 3 months of oral therapy with enalapril (10 mg twice daily, n = 7), metoprolol (25 mg twice daily, n = 7), digoxin (0.25 mg once daily, n = 7), or no treatment (control, n = 7). As expected, in untreated dogs, LVEF decreased (36 +/- 1% versus 26 +/- 1%, P < .001) and LV end-systolic volume (ESV) and end-diastolic volume (EDV) increased during the 3-month follow-up period (39 +/- 4 versus 57 +/- 6 mL, P < .001, and 61 +/- 6 versus 78 +/- 8 mL, P < .002, respectively). In dogs treated with enalapril or metoprolol, LVEF remained unchanged or increased after therapy compared with before therapy (35 +/- 1% versus 38 +/- 3% and 35 +/- 1% versus 40 +/- 3%, respectively, P < .05), whereas ESV and EDV remained essentially unchanged. In dogs treated with digoxin, EF remained unchanged but ESV and EDV increased significantly. CONCLUSIONS: In dogs with reduced LVEF, long-term therapy with enalapril or metoprolol prevents the progression of LV systolic dysfunction and LV chamber dilation. Therapy with digoxin maintains LV systolic function but does not prevent progressive LV enlargement.     

Rehabilitation of dogs with surgically treated cranial cruciate ligament-deficient stifles by use of electrical stimulation of muscles

OBJECTIVE: To determine effect of electrical muscle stimulation (EMS) on rate and degree of return to function of the limb and development of degenerative joint disease (DJD) after surgical creation and subsequent stabilization of the cranial cruciate ligament (CrCL)-deficient stifle. ANIMALS: 12 clinically normal adult large (19.5 to 31.5 kg) dogs. PROCEDURE: Dogs were anesthetized, and the right CrCL was severed via arthrotomy, destabilizing the stifle. After 3 weeks, the stifle was surgically stabilized. Three weeks later, 6 dogs were subjected to an EMS treatment protocol for the thigh muscles. At 5, 9, 13, and 19 weeks after stifle destabilization, treated (n = 6) and control (n = 6) dogs were evaluated for return of stifle function. Gross and histologic evaluations of the stifles were performed at 19 weeks after stifle destabilization. RESULTS: Treated dogs had significantly (P = 0.001) better lameness score than did control dogs. There was less palpable crepitation of the stifle in treated dogs (P = 0.06); treated dogs also had significantly (P = 0.01) fewer radiographic signs of bone changes. Thigh circumference was significantly (P = 0.02) larger in treated dogs. There was less gross cartilage damage (P = 0.07) in the EMS-treated dogs, but more medial meniscal damage (P = 0.058, cranial pole; P = 0.051, caudal pole). CONCLUSIONS: Improved lameness scores, larger thigh circumference, and decreased radiographically apparent bony changes observed for the treated group of dogs support the hypothesis that dogs treated by EMS after surgical stabilization of the CrCL-deficient stifle had improved limb function, with less DJD, than did dogs treated with the currently accepted clinical protocol of cage rest and slow return to normal activity. However, results of force plate evaluation did not support the hypothesis. Increased meniscal damage in dogs treated by EMS may be cause for concern.     

Leukotriene receptor blockade in experimental heart failure

The pathophysiological role of endogenous leukotrienes in cardiovascular control and the regulation of renal function in congestive heart failure is not known. Therefore, in six conscious dogs with or without heart failure induced by right ventricular pacing (270/min, 10 days) we studied the effects of the leukotriene receptor antagonist FPL55712 on hemodynamics, plasma hormones and renal function. In healthy dogs, FPL55712 (1 mg kg-1 + 0.01 mg kg-1 min-1 i.v.) had little effect on hemodynamics, only reducing heart rate by 11% and insignificantly increasing systemic vascular resistance. Plasma levels of norepinephrine (-57%), renin (-30%) and aldosterone (-24%) were significantly decreased. Renal function parameters were not changed. In dogs with heart failure, FPL55712 significantly increased systemic vascular resistance (+16%) and decreased cardiac output (-15%). Plasma hormone levels were not changed, but renal plasma flow was decreased (-13%) and glomerular filtration rate (+12%), renal vascular resistance (+13%) and filtration fraction (+23%) were increased. It is concluded that there is no evidence for a contribution of endogenous leukotrienes to the systemic vasoconstriction in experimental heart failure. Whether the increase in systemic and renal vascular resistance induced by the leukotriene antagonist in dogs with heart failure reflects a role for endogenous leukotrienes with vasodilator action is still unclear and deserves further investigation.     

Twenty-four-hour blood pressure profile and blood pressure responses to head-up tilt tests in Parkinson's disease and multiple system atrophy

OBJECTIVE: To investigate the 24 h blood pressure profile in patients with Parkinson's disease with intact autonomic function or with autonomic failure and patients with multiple system atrophy (MSA), and to assess whether these patients exhibit posture-related variations in blood pressure. PATIENTS AND METHODS: We studied 24 patients with Parkinson's disease (11 with autonomic failure) and 13 patients with MSA (all with autonomic failure). Autonomic failure was determined by autonomic tests. An oscillometric recorder was used for ambulatory blood pressure monitoring. Tilt-table tests were performed with a head-up tilt position of 60 degrees. RESULTS: An alteration in the normal 24 h blood pressure profile was observed in 82% of Parkinson's disease patients with autonomic failure and in 85% of those with multiple system atrophy, but not in the patients with intact autonomic function. Head-up tilt tests revealed a significantly higher supine blood pressure in Parkinson's disease patients with autonomic failure and in those with MSA than in Parkinson's disease patients with intact autonomic function. Tilting resulted in a marked fall in blood pressure in patients with MSA; in Parkinson's disease patients with autonomic failure, the fall was comparatively slighter. CONCLUSIONS: We conclude that autonomic failure contributes to the alterations in the day-night blood pressure profile that may possibly be ascribed to postural dysregulation of blood pressure. We hypothesize that nocturnal hypertension is a risk factor in the development of additional cerebrovascular disease in patients with Parkinson's disease or MSA who are affected by autonomic failure.     

Transient sinus node dysfunction after the Cox-maze III procedure in patients with organic heart disease and chronic fixed atrial fibrillation

OBJECTIVES: This prospective study examined types, frequency and time dependency of the electrophysiologic manifestation of the sinus node dysfunction after the Cox-maze III procedure--the technique of choice for the management of medically refractory atrial fibrillation-in patients with organic heart disease, chronic fixed atrial fibrillation and no preoperatively overt dysfunction of the sinus node. BACKGROUND: The original maze procedure was modified twice in order to reduce the high incidence of the sinus node inability to generate an appropriate sinus tachycardia in response to maximal exercise, and occasional left atrial dysfunction. Despite these modifications, postoperative disturbance of sinus node function can be frequently observed. METHODS: In 15 adult patients, standard electrocardiogram, 24-h Holter monitoring, power spectral analysis of heart variability, exercise testing, Valsalva maneuver and rapid positional changes were performed 3, 6 and 12 months after the Cox-maze III procedure and mitral valve surgery or closure of atrial septal defect. RESULTS: Electrocardiographic manifestations of sinus node dysfunction were identified in 12 patients at 3 months, in 6 patients at 6 months, and in 0 patients at 12 months after surgery. The heart rate response to exercise during the first 6 months was reduced in the maze group and became fully normal at 12 months. Power spectral analysis of heart rate variability showed very low power values at 1 month with inhibited cardiac autonomic activity and no response on sympathetic stress. A potential of recovery of cardiac autonomic activity was documented 12 months after surgery. CONCLUSIONS: The manifestations of sinus node dysfunction following the Cox-maze III procedure were time dependent and their frequency and intensity progressively decreased and disappeared within 12 months after surgery.     

Autonomic control of cardiovascular function: clinical evaluation in health and disease

The high- and low-pressure baroreceptor reflexes are integral to the control of blood pressure by the autonomic nervous system. Tests of the integrity of these baroreflexes make it possible to identify the site of autonomic dysfunction in patients with orthostatic hypotension. Clinical characteristics and typical results of autonomic testing in patients with autonomic failure, with carotid sinus hypersensitivity, and with hyperadrenergic autonomic dysfunction are described in this review.     

Clinical aspects of systemic and localized scleroderma

After the skin, the gastrointestinal tract is the most frequently affected organ in systemic sclerosis. Gastrointestinal symptoms already may be present early in the course of the disease and do not necessarily correlate with objective findings. Esophageal dysmotility is not specific for systemic sclerosis but occurs in other connective tissue diseases as well. Peripheral macrovascular disease was shown to be increased in patients with limited cutaneous sclerosis; signs of autonomic dysfunction were found in patients with the CREST (calcinosis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia) variant. Pulmonary involvement was shown to be moderately or severely decreased in 40% of a large cohort of scleroderma patients. In one study, no support was found for the association between pulmonary involvement and gastroesophageal reflux. Peripheral nerve involvement is often subclinical and might be associated with anti-U1-RNP and anti-topoisomerase I antibodies. Internal organs are seldomly affected in localized scleroderma. When occurring in childhood and involving an extremity, localized scleroderma can cause growth failure, resulting in long-term functional disability.     

Localization of cannabinoid receptor mRNA in rat brain

Cannabinoid receptor mRNA was localized in adult rat brain by 35S-tailed oligonucleotide probes and in situ hybridization histochemistry. Labelling is described as uniform or non-uniform depending on the relative intensities of individual cells expressing cannabinoid receptor mRNA within a given region or nucleus. Uniform labelling was found in the hypothalamus, thalamus, basal ganglia, cerebellum and brainstem. Non-uniform labelling that resulted from the presence of cells displaying two easily distinguishable intensities of hybridization signals was observed in several regions and nuclei in the forebrain (cerebral cortex, hippocampus, amygdala, certain olfactory structures). Olfactory-associated structures, basal ganglia, hippocampus, and cerebellar cortex displayed the heaviest amounts of labelling. Many regions that displayed cannabinoid receptor mRNA could reasonably be identified as sources for cannabinoid receptors on the basis of well documented hodologic data. Other sites that were also clearly labelled could not be assigned as logical sources of cannabinoid receptors. The localization of cannabinoid receptor mRNA indicates that sensory, motor, cognitive, limbic, and autonomic systems should all be influenced by the activation of this receptor by either exogenous cannabimimetics, including marijuana, or the yet unknown endogenous "cannabinoid" ligand.