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A case of severe cardiac involvement is reported in a patient affected with familial amyloidotic polyneuropathy due to the Portuguese type I variant (Val→Met30) of the transthyretin (prealbumin) molec

The effects of ganglioside treatment on 1,2-diacylglycerol content and on molecular species in 1,2-diacylglycerol, phosphatidic acid and total diacylglycerolipids, as well as Na + ,K + -ATPase activity, were examined in sciatic nerves from streptozotocin-in-duced diabetic rats. Beginning 2 weeks after induction of diabetes, animals were administered mixed bovine brain gangliosides, AGF 1 , an inner ester derivative of this mixture, or saline for 5 weeks. The levels of 1,2-diacylglycerol and arachidonyl-containing molecular species in age-matched non-diabetic animals were not affected by ganglioside treatment. In nerves from saline-treated diabetic animals, 1,2-diacylglycerol levels were not reduced, but both Na + ,K + -ATPase activity and all arachidonoyl-containing species except for 18:0/20:4 1, 2-diacylglycerol were significantly decreased. The content of 1,2-diacylglycerol was lowered by 23 and 16% in bovine brain ganglioside and AGF 1 -treated diabetic animals, respectively, and the quantity of 18:0/20:4 1,2-diacylglycerol was also selectively reduced. Ganglioside administration did not affect the diminished levels of arachidonoyl-containing molecular species in 1,2-diacylglycerol, phosphatidic acid or diacylglycerolipids in nerve from diabetic rats. In the same nerves, bovine brain gangliosides partially and AGF 1 completely restored Na + ,K + -ATPase activity. The results suggest that gangliosides depress the content of total 1,2-diacylglycerol and the quantity of 18:0/20:4 1,2-diacylglycerol, specifically, in diabetic nerve. The possible relationship between the corrective action of gangliosides on Na + ,K + -ATPase activity and the effect of these substances on 1,2-diacylglycerol molecular species composition and metabolism is discussed.

Brainstem acoustic evoked potentials (BAEPs) were studied in streptozotocin (STZ)-diabetic rats and age-matched controls at 3 and 5 months from induction of the pathology. The diabetic status of the animals was kept uncontrolled throughout the study. Body weight and glycosylated hemoglobin were markedly altered in the diabetic animals (− 42% and + 120% of control values, respectively). Neurophysiological results showed an increase in the latency of the major components of BAEPs; this increase was clearly time-dependent for the peripheral component (peak I). The central component (peak IV) was also significantly delayed. However, no significant impairment of the central conduction time was demonstrated by examining the interpeak I–IV latency. In conclusion, BAEPs prove to be a useful non-invasive neurophysiological technique that may help unravel both the relative involvement of the peripheral and central nervous systems in the course of diabetes mellitus, and the evolution of diabetic neuropathy.

A comparative study has been carried out using the freeze-fracture technique on the perineurium of the sciatic nerve from normal and diabetic mice (C57Bl/Ks, BALB/c and CD1 strains) and rats of various ages. The replicas showed that tight junctions connected perineurial cells both within the same cell layer (zonulae occludentes) and between adjacent layers (maculae occludentes). In neonates, a number of zonulae occludentes were characterized by short, incomplete or fragmented ridges at various intervals from each other; in adults, tight junctions appeared as 'mature' networks of interconnected, branching and/or anastomosing strands. Zonulae occludentes of diabetic mice also exhibited frequent interruption of the strands and reduction in the branching of strands. Gap junctions occurred in both zonulae and maculae occludentes of normal and diabetic rats at all ages. In the C57Bl/Ks strain such junctions occurred more frequently in zonulae occludentes of diabetic animals. It is suggested that perineurial cells are coupled by gap junctions to allow fast transfer of ions and small-sized molecules across the layers; under pathological conditions, such as diabetes, the increase in cell-to-cell signalling may be important in controlling the abnormal metabolic situation.

The effect of ganglioside administration to nondiabetic and streptozocin-induced diabetic rats on sciatic nerve Na + -K + -ATPase, polyphosphoinositide (PPI) turnover, and protein phosphorylation was investigated. Gangliosides were injected (10 mg/kg body wt i.p.) for 10 or 30 days beginning 20 days after induction of diabetes. Na + -K + -ATPase activity was reduced nearly 50% in diabetic nerve and was restored to normal by both ganglioside treatments. The elevated levels of fructose and sorbitol and depressed content of myo -inositol in diabetic nerve were unaffected by 30 days of ganglioside treatment, indicating that the restoration of Na + -K + -ATPase activity is not dependent on normal concentrations of these compounds. In the same nerves, 32 P incorporation into phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 4-phosphate increased 73–76 and 39–53%, respectively, in diabetic compared with nondiabetic tissue. Ganglioside administration abolished the elevated labeling of PPIs after 30 days but was ineffective after only 10 days. Neither ganglioside regimen was able to reverse enhanced phosphorylation of the major peripheral nerve myelin protein P 0 · The finding that gangliosides can more quickly correct the effects of diabetes on Na + -K + -ATPase activity than on PPI turnover suggests that the mechanisms underlying these two phenomena are not closely related and are distinct from the sequence of events responsible for altered myelin protein phosphorylation.

ATPase activity was investigated in sciatic and optic nerves of female mutant diabetic C57Bl/Ks (db/db) mice and age-matched control mice (db/m and m/m). Nerves from animals aged 50, 70, 125, 180 and 280 days were assayed in vitro for ATPase activity in the presence or absence of ouabain: the ouabain-sensitive fraction contained Na+,K(+)-ATPase. Enzymatic activity was compared within and between age-matched groups. No significant difference in Na+,K(+)-ATPase activity was detected between the diabetic and control mice, whether expressed as mumol Pi/h-1 formed per gramme wet weight or per nerve (protein content). The activity decreased by about 25% in both the sciatic and optic nerves of the oldest animals. These results were strikingly similar in all groups, regardless of the type of nerve examined, confirming that the development of neuropathy in this animal model is unrelated to the postulated derangement of Na+,K(+)-ATPase activity. Among possible explanations, a lack of polyol pathway activation was investigated by staining the sciatic nerves of animals from all groups with the peroxidase-antiperoxidase procedure using a polyclonal antiserum raised against the enzyme aldose reductase. Histological sections of all nerves were consistently negative, suggesting that these animals actually lack the enzyme involved in activating the self-perpetuating metabolic cycle leading to deranged nerve function. The db/db mouse appears to present particular biochemical changes which merit attention with a view to clarifying the pathogenesis of diabetic neuropathy.

Prodynorphin gene expression was investigated in adult ventricular myocytes isolated from normal (F1B) or cardiomyopathic (BIO 14.6) hamsters. Prodynorphin mRNA levels were higher in cardiomyopathic than in control myocytes and were stimulated by treatment of control cells with the protein kinase C (PKC) activator 1, 2-dioctanoyl-sn-glycerol. Both chelerythrine and calphostin C, two PKC inhibitors, abolished the stimulatory effect of the diglyceride and significantly reduced prodynorphin gene expression in cardiomyopathic myocytes. Nuclear run-off experiments indicated that the prodynorphin gene was regulated at the transcriptional level and that treatment of nuclei isolated from control cells with 1, 2-dioctanoyl-sn-glycerol increased prodynorphin gene transcription, whereas chelerythrine or calphostin C abolished this transcriptional effect. Direct exposure of nuclei isolated from cardiomyopathic myocytes to these inhibitors markedly down-regulated the rate of gene transcription. The expression of PKC-alpha, -delta, and -epsilon, as well as PKC activity, were increased in nuclei of cardiomyopathic myocytes compared with nuclei from control cells. The levels of both intracellular and secreted dynorphin B, a biologically active product of the gene, were higher in cardiomyopathic than in control cells and were stimulated or inhibited by cell treatment with 1,2-dioctanoyl-sn-glycerol or PKC inhibitors, respectively.

A case of familial amyloidotic polyneuropathy (FAP) is reported in which peripheral nerve and skeletal muscle biopsies were obtained from the right leg to assess the severity of the relatively late-onset but rapid-evolving neuropathy. The present paper deals with some remarkable features found in the muscular biopsy, taken from peroneus brevis and extensor digitorum longus muscles. Several fibers contained amyloid masses characterized by Congo red positivity and birefringence on polarized light microscopy: histoenzymologic staining revealed that these fibers were always type 2B and appeared grossly hypertrophied. The presence of amyloid inside the muscle fibers was possibly dependent on the internalization of capillaries leading to direct deposition of amyloid fibrils into the sarcoplasm. Fiber vascularization occurred independently of fiber splitting, which appeared to be frequent in both muscles and was characterized by unusual segmental changes in the histochemical properties of the daughter fibers with respect to those of the parent fiber. Target/targetoid and degenerating areas were also observed in a large number of type 2 fibers, usually in close relationship with segmental splitting phenomena. These findings were interpreted as possible secondary myopathic changes accompanying chronic denervation-reinnervation episodes in the course of FAP.

The incidental finding of four ectopic ganglion cells within the pelvic nerve of a normal rat prompted a thorough electron microscopic investigation of the ultrastructural features of these neurons. They were found to enwrap presynaptic terminals inside crater-like invaginations; the appositional surfaces were made more complex by the presence of slender dendritic appendages and sheet-like processes of glial cells. The presynaptic elements contained both clear and dense-cored vesicles, and appeared similar to those characterizing SIF (paraneuronal) cells. In addition, cilia were encountered in both the invaginated processes and most of the Schwann cells associated with the pre- and postsynaptic nerve cells and their processes. Overall, these features were deemed worth reporting because 1) of the unusual features of synaptic input from a SIF cell to a ganglion cell associated with the pelvic plexus, and 2) the ectopic ganglion cells possibly represent the sole example, other than ciliary neurones in the avian ciliary ganglion, of postsynaptic cells encasing presynaptic endings inside their perikarya.

Vascular dementia is usually sporadic and associated with definite risk factors. Several cases also occur in a familial fashion, and may affect middle-aged or even younger subjects. Recently, an autosomal dominant inheritance was demonstrated in two unrelated French families, the members of which were affected by stroke-like episodes culminating in progressive dementia. Genetic linkage analysis assigned the disease locus to chromosome 19q12. We report an additional kindred of Italian origin in which at least 16 subjects presented leukoencephalopathic alterations. Recurrent strokes, psychiatric disturbances, dementia, and in 2 members, tetraplegia and pseudobulbar palsy were the hallmarks of this syndrome. Notably, 5 asymptomatic individuals had neuroradiological signs of leukoencephalopathy. Pathological examination of 1 subject revealed a widespread vasculopathy of the perforating arterioles, characterized by deposition of eosinophilic-congophilic material that did not immunostain with antibodies against prion protein, beta-amyloid, cystatin C, transthyretin, or heat-shock protein 70 and was similar to that described in the French families. Based on the maximum lod score, the most likely location for the disease locus was also mapped to chromosome 19q12, and found to coincide with the CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) locus. The present results confirm the existence of a nosologically distinct, autosomal dominant cerebrovascular disease, presenting with recurrent subcortical ischemic strokes independent of vascular risk factors.

The lack of a suitable animal model for the peripheral neuropathy that often follows the systemic administration of the chemotherapeutic agent vincristine sulfate (VCR) has hampered the correlation between experimental and clinical patterns of this neuropathy. New Zealand rabbits have been recently found to develop, after iv injection of a VCR total dosage similar to that used in humans, a peripheral polyneuropathy characterized by electrophysiological changes that overlap those observed in the clinical setting. The present study was aimed at investigating the ultrastructural features of 3 different nerves (sural, peroneal, and medial gastrocnemius) in rabbits treated with 3 VCR doses that fall within the range (0.2-0.3 mg/kg iv) known to be efficacious chemotherapeutically and active neurotoxicologically. Regardless of the dose and the nerve under examination, histopathologic alterations appeared in the form of an overall loss of myelinated fibers, accompanied by successful attempts of regeneration and remyelination. Fibers undergoing Wallerian degeneration were characterized by an axoplasm, which was either watery-flocculent or divided in 2 or more regions as a consequence of ingrowing Schwann cell processes from the adaxonal surface. These ingrowths tended to isolate axoplasmic areas, retaining a fairly normal structure from other areas already crowded with altered organelles and cytoskeletal elements. In any event, neurofibrillary accumulations were rarely seen. These patterns are discussed with reference to those reported in the ultrastructural studies of human cases and confirm the suitability of rabbit as an animal model for VCR-induced peripheral neuropathy.

This study addressed the question as to whether the reduced activity of Na + ,K + -ATPase reported to occur in diabetic nerves and to play a crucial role in the pathogenesis of diabetic neuropathy could be due to derangements in the axonal transport of the enzyme. A micromethod was developed to evaluate the ATPase accumulation in individual segments of ligated sciatic nerves from streptozotocin-induced diabetic rats. The results confirmed a ∼ 40% decrease in the background activity, but showed that the enzyme was transported at similar rates in both anterograde and retrograde directions, suggesting that the decrease in its activity does not depend on an altered delivery along the axons.

A case of severe cardiac involvement is reported in a patient affected with familial amyloidotic polyneuropathy due to the Portuguese type I variant (Val--Met30) of the transthyretin (prealbumin) molecule. Echocardiographic and hemodynamic studies suggested the presence of a progressive infiltrative cardiomyopathy that was later confirmed by endomyocardial biopsy. Amyloid deposits were found in both intra- and extra-myofiber location and thought to be related to primary involvement of the heart. Norepinephrine content of myocardial bioptic specimens was about threefold lower than normal, indicating that autonomic denervation may contribute to the maintenance and progression of cardiomyopathy. A sample obtained from the sural nerve showed a loss of myelinated fibers along with accumulation of amyloid masses in the endoneurial space. This histopathologic pattern correlated with a sharp decrease in the activity of the enzyme subserving electrochemical conduction through the axonal membrane, Na+, K(+)-ATPase.

This double-blind study assesses the therapeutic efficacy and the safety of oral treatment with phosphatidylserine (BC-PS) vs placebo (300 mg/day for 6 months) in a group of geriatric patients with cognitive impairment. A total of 494 elderly patients (age between 65 and 93 years), with moderate to severe cognitive decline, according to the Mini Mental State Examination and Global Deterioration Scale, were recruited in 23 Geriatric or General Medicine Units in Northeastern Italy. Sixty-nine patients dropped out within the 6-month trial period. Patients were examined just before starting therapy, and 3 and 6 months thereafter. The efficacy of treatment compared to placebo was measured on the basis of changes occurring in behavior and cognitive performance using the Plutchik Geriatric Rating Scale and the Buschke Selective Reminding Test. Statistically significant improvements in the phosphatidylserine-treated group compared to placebo were observed both in terms of behavioral and cognitive parameters. In addition, clinical evaluation and laboratory tests demonstrated that BC-PS was well tolerated. These results are clinically important since the patients were representative of the geriatric population commonly met in clinical practice.

Gangliosides have been shown to modulate autoimmune phenomena in experimental diabetes. The effects of a pancreatic ganglioside preparation or of a commercial brain ganglioside mixture on the insulitis and blood glucose levels in the low-dose streptozotocin mouse model of diabetes have been investigated. Fifty-five C57BL/6J male mice were grouped as follows: Group 1 (n = 20) was injected intraperitoneally with repeated low doses of streptozotocin; Group 2 (n = 10) received streptozotocin as above but was also injected with a pancreatic ganglioside preparation equivalent to 2 micrograms sialic acid 2 h before each streptozotocin dose; Group 3 (n = 15) received streptozotocin and brain-derived gangliosides in the same dose as that of pancreatic gangliosides; Group 4 (n = 10) consisted of normal animals. Half of the mice were killed on day 12 and the others on day 24 from the beginning of treatment. On day 12, among the streptozotocin-injected animals only those treated with pancreatic gangliosides remained normoglycaemic, whereas on day 24 all streptozotocin mice were hyperglycaemic. Such a result paralleled the data pertaining to insulitis scores. In conclusion, pancreatic gangliosides have a short-term protective role on the development of diabetes in the low-dose streptozotocin model, an effect therefore linked to tissue-related differences in the glycosphingolipid composition.

It is reported that 12.5% of the Italian population suffer from cholecystopathy. The Authors carried out a retrospective analysis of the cases observed over an 18-month period. It was found that ultrasonography was the most appropriate screening method to reveal cholecystic pathologies and diseases of the biliary tract since it is specific and sensitive and also enables adjacent organs to be examined (liver, kidneys, aorta, pancreas, spleen).

Abnormalities in axonal transport of proteins are thought to play an important role in the pathogenesis of diabetic neuropathy. Gangliosides exert a positive action on numerous alterations in biochemistry and physiology of diabetic nerves. This study was undertaken to assess the effects of exogenous gangliosides on the axonal transport of structural proteins such as actin and tubulin in the sensory fibers of short-term (9-wk) and long-term (6-mo) diabetic rats. Adult Sprague-Dawley rats were made diabetic with a single injection of 70 mg/kg streptozocin i.p. Subgroups were injected daily with either highly purified ganglioside mixture (10 mg/kg i.p.) or saline for 1 mo, beginning either 2 or 17 wk after streptozocin injection. Age-matched rats were used as controls. Axonal transport was studied by the pulse-labeling technique. Three weeks after labeling, sciatic nerves were dissected out and processed for sodium dodecyl sulfate-polyacrylamide gel electrophoresis and fluorography. In diabetic rats of both experimental designs, the transport rate of tubulin and actin was decreased by ∼ 30% compared with control rats. Ganglioside treatment counteracted such alterations in both 9-wk and 6-mo diabetic rats. These data suggest a pharmacological effect that could be correlated with molecular interactions between integral membrane glycolipids and cytoskeletal elements.

Marked (greater than 70%) reduction of the neuropathy target enzyme (NTE) shortly after exposure to organophosphorus compounds heralds the onset of delayed neuropathic damage in animals and humans. One previous study reported that lymphocyte NTE from diabetic patients was depressed by greater than 70%; such a reduction was considered to be a biological marker of diabetic polyneuropathy. To ascertain whether NTE from target tissues might be involved in diabetic neuropathy, we measured NTE activity in the brain, spinal cord and peripheral nerves of streptozotocin-diabetic rats. No reduction in NTE activity was detected in these neural specimens. Therefore, it is concluded that NTE is not involved in diabetic nerve damage and that the meaning of low NTE activity in peripheral lymphocytes of diabetic patients remains unclear.

Murine thymus has been demonstrated to contain both cholinergic receptors and acetylcholinesterase activity. In the present study we have investigated the presence of the enzyme choline acetyltransferase in this organ, which is responsible for the synthesis of acetylcholine. Results reported here demonstrate that (1) an appreciable amount of the enzyme is already present in the thymus on the day of birth; (2) its expression is developmentally regulated; and (3) thymic atrophy, induced in young (2-week-old) and adult (6-week-old) mice by i.p. injection of hydrocortisone for 2 days, is accompanied by significant reduction of choline acetyltransferase activity only in young mice. Altogether these results demonstrate the presence in the murine thymus of functionally relevant markers of the cholinergic system that might interface the interactions between the nervous and immune systems.

In experimental animal studies, exogenous hyaluronan (HA) has been shown to exert beneficial effects on the healing of tympanic membrane perforation. As any other exogenous substance, HA may prove potentially toxic, by filling the middle ear cavity, to the sensory cells of the organ of Corti. Electrophysiological (ABR) and morphological studies were carried out in the rat to examine the auditory function and the structure of the sensory epithelium. Rats received either HA or hydroxy-propyl-methyl-cellulose by trans-tympanic injection (middle ear cavity was completely filled up) and were compared to untreated, age- and weight-matched rats. In both treated groups ABR revealed transitory, mild conduction hearing loss, in particular for high frequencies, until day 7 postinjection. This loss recovered completely within the 15th day. Morphologically, no significant degenerative/necrotic lesions were observed in the organ of Corti, from both treated groups.

To test whether gangliosides (GA) might exert neuritogenic effects in vivo, experimental allergic neuritis (EAN) was studied clinically, neuropathologically, and immunologically in Lewis rats immunized with bovine peripheral nerve, P2 myelin protein, P2 myelin protein plus two different doses of GA, P2 with galactocerebroside (GC), and GA alone, each emulsified in adjuvant. All except the GA-treated group developed signs of EAN between days 11 and 14 after the injection. Rats immunized with P2 alone were the most severely affected. Rats given P2 plus GA and those given P2 plus GC displayed a significantly lower clinical score. Histological analysis revealed a comparable degree of inflammation of the peripheral nervous system and demyelination in the spinal nerve roots of bovine peripheral nerve- and P2-immunized rats. The P2 plus GA and P2 plus GC groups revealed similar degrees of pathology in the spinal nerve roots but the latter group stood apart from the rest in that it showed widespread peripheral nervous system changes extending distally into the sciatic nerve. Serological analysis demonstrated that P2 and GC, but not GA, elicited antibody (IgG) responses, but there was no correlation between antibody titer and clinical or histological involvement. The present data fail to support an enhancing role for gangliosides in the expression of EAN and, by extrapolation, in the Guillain-Barre syndrome, for which EAN serves as the laboratory model, and in which suggestions have been made that antibodies to GA may have pathogenetic significance.

Bovine brain gangliosides have been shown to prevent decay in Na+,K(+)-ATPase activity in sciatic and optic nerves of alloxan- and streptozotocin-diabetic rats. In the search for a drug with greater bioavailability and increased incorporation into neural tissue, ganglioside inner ester derivatives (AGF1) were recently developed. We evaluated the effect of AGF1 treatment on Na+,K(+)-ATPase activity in homogenates of vagus nerve from alloxan-diabetic rats (100 mg/kg s.c.). Animals were treated with AGF1: 10 mg/kg 6 days/week i.p., or 30 mg/kg biweekly i.p. Treatment began 10 d post-alloxan and continued for 8 consecutive weeks. Normal age- and sex-matched rats were used as controls. Alloxan intoxication produced a 39% decrease in Na+,K(+)-ATPase activity of the vagus nerve, which was completely restored (96-97% recovery) by both AGF1 regimes. Results suggest that ganglioside inner ester derivatives may be used in the clinical setting for the management of diabetic autonomic neuropathy.

A nerve guide made of a benzyl ester of hyaluronic acid (HYAFF11p75) was used to bridge 8 mm gaps in rat tibial nerves. Histologic observations indicated that this biomaterial provoked only a transient, modest inflammatory response, and the resorption rate was compatible with the nerve regeneration processes. Phagocytosis of the biomaterial began after neoangiogenesis and cell migration had taken place from both stumps into the nerve guide material. For comparison, the regeneration achieved was evaluated in nerve guides made of either HYAFF11p75 or Silastic, and in nerves repaired with the autograft technique. Recovery was assessed in vivo 90 days after implantation by measuring the nerve compound action potential (CAP) and conduction velocity (NCV) of the regenerated tibial nerve. The results demonstrate that the nerve guide tubes made of HYAFF11p75 were able to support and direct axonal growth, thereby suggesting a possible use for such biomaterial in the management of short nerve gaps in human pathology.

Spontaneous hematoma of the abdominal wall is an unusual event which has an aspecific symptomatology, common to other diseases. There are factors which create a predisposition to the formation of hematoma and others which trigger off this phenomenon. The paper reports 8 patients, aged between 35 and 85 years: predisposition, symptomatology, characteristics of hematoma and therapy are illustrated in a table. Diagnosis was generally made using ultrasonography and the prognosis was always benign.

EDITOR, - Gianluca Landi and colleagues report that 25 cases of the Guillain-Barre syndrome after treatment with gangliosides were seen over four and a half years in Italy, a yearly average of 5.6 cases.1 Their conclusion that these cases represent an excess incidence is incorrect. Their data estimate a yearly exposed population of roughly 2500 000 (4.2% of the Italian population). The 5.6 cases represent a yearly incidence of 0.2/100 000. Eleven of their patients were over 60. The incidence of the Guillain-Barre syndrome is known to be higher in older age groups: an incidence of 3.2/100 000 a year has been reported in people over 60.2 We believe that it is inappropriate to compare the incidence of the Guillain-Barre syndrome in the normal population with that in patients selected for treatment with gangliosides - that is, patients with neuropathy - as the frequency of the syndrome seems to be increased in these patients. This is exemplified by surveys of referrals for generically defined neuropathy3,4: on accurate examination 11-12% of the cases were diagnosed as cases of the Guillain-Barre syndrome. The syndrome may therefore be diagnosed in over 10% of patients with neuropathy (especially elderly patients), who potentially qualify for ganglioside treatment. The authors have not exluded the possibility that gangliosides were prescribed for initial signs of …

The cytoarchitectural analysis of the preoptic-anterior hypothalamic region of the Japanese quail reveals a sexual dimorphism in the total volume of the medial preoptic nucleus (significantly larger in males than in females). Different nuclei of the region (dorsal preopticus, suprachiasmaticus) do not show any statistically significant difference. The sex-related difference is more consistent comparing the distribution of dark volume. This last is due to a larger number of cells containing high amount of Nissl's substance in male than in female. Present findings represent the first example of sexual dimorphism in the avian hypothalamus.

Spinal cords of cats treated with the neurotoxic compound beta,beta'-iminodipropionitrile (IDPN) were observed to contain rounded homogeneous bodies, 1-12 microns in diameter, termed "dense microspheres" (DMS). These bodies, absent in control animals, were consistently found only in the ventral horns. No relationship with blood vessels was evident. When stained with PAS and a modified von Kossa's silver nitrate technique, DMS remained negative, showing only very slight metachromasia in some toluidine blue-stained sections. They were consistently acidophilic as evidenced by destaining and differentiation investigations. DMS were observed more frequently in the proximity of nerve cell bodies or closely adjacent to dendrites and their location was mainly extracytoplasmic; with the electron microscope, however, some DMS were also found in glial processes. Rounded osmiophilic bodies, 0.1-0.8 microns in diameter, were noticed in mitochondria of both neurons and glial cells; however, whether they were special forms of DMS or different inclusions was not assessed. Both intra- and extracytoplasmic DMS were similar in ultrastructure, appearing as single membrane-bound spherical or pear-shaped bodies containing a cottony or finely granular matrix. Additionally, both perikaryon and processes of large motoneurons were found to contain pigment granules identified as lipofuscin, which seemed to increase in number and to spread centrifugally in the processes in correlation with duration of the intoxication and size of axonal swellings induced by IDPN.(ABSTRACT TRUNCATED AT 250 WORDS)

Immunohistochemical analysis of the extrahypothalamic distribution of vasotocin-like immunoreactive elements within the brainstem of the domestic fowl revealed several, topographically identifiable, mesencephalic and pontine target areas. In the considered regions numerous nerve endings were surrounding perikarya or large dendritic trunks. No extrahypothalamic immunopositive perikarya have been observed in normal birds.

The importance of sexual hormones in the development of cancers of the large bowel is strongly supported experimentally and epidemiologically. The clinical search for the presence of hormonal receptors in the cells of patients operated for tumours of the colon and rectum has been common since 1975. This investigation ought to have opened up new diagnostic and therapeutic prospects for these tumours which have given such a little curative satisfaction. The present review considered reported data. Unfortunately the emerging picture is irregular in cases and results. It is personally considered that these studies are not for the moment likely to produce important novelties for the treatment of tumours of the large bowel tract.

The efficacy of gangliosides in enhancing axonal regeneration and maturation in the early stages of diabetic neuropathy was assessed by quantitative analysis of immunostained serial sections of the sciatic nerve. Sprague-Dawley rats were made diabetic with a single injection of alloxan (100 mg/kg). One week later they were injected daily intraperitoneally with either a highly purified ganglioside mixture (10 mg/kg) or sterile saline for 4 wk. At the end of the treatment, sciatic nerves were crushed and allowed to regenerate for 1 wk without ganglioside treatment. The animals were then killed, and the nerves were frozen and processed for immunohistochemistry and electron microscopy. The number of regrowing axons was counted with a computerized image-analysis system on cross sections taken at predefined distances along the regenerating stump and stained with monoclonal antibody iC8 specific for the 145,000-Mr subunit of the neurofilaments. In untreated diabetic animals the number of axons able to regenerate and sustain elongation for greater than or equal to 13 mm from the crush point was reduced by 40% with respect to control rats. Ganglioside treatment was effective in compensating almost completely for this dramatic reduction. Electron microscopy confirmed that the immunofluorescence counts corresponded to regenerating axons containing neurofilaments. These results suggest that gangliosides are able to compensate for the derangements of axonal transport of cytoskeletal proteins reported in experimental diabetic neuropathy.

We have examined biopsy material from the left m. vastus lateralis of eight patients suffering from rheumatoid arthritis and four patients with progressive systemic sclerosis (scleroderma). All were chosen according to the duration and the severity of disease, so that the broadest possible spectrum of signs and symptoms could be considered. Muscular specimens showed a selective and constant atrophy of the type IIB fibers, as revealed by the myofibrillar ATPase histochemical reaction (both at a pH of 9.4 and with pre-incubation at pH 4.35 and 4.63). Atrophy of the type I fibers was seen only occasionally. Neither structural abnormalities, such as 'motheaten' fibers, nor inflammatory reactions were observed. We think that (1) changes in skeletal muscles of patients with rheumatoid arthritis and progressive systemic sclerosis may be quite selective, and (2) the myopathy associated with rheumatoid arthritis can be differentiated from inflammatory myopathies, even in muscle biopsy specimens, on the basis of histoenzymologic investigations.

The tricyclic antidepressants have a complex interaction with several tissues both in experimental animals and in man. Side effects exerted by these drugs may be so severe as to justify a careful management of each individual depressed patient. The clinician must be aware of these effects above all in treating overdose poisoning and suicide attempts. This paper reviews the tricyclic-induced organic and psychologic disturbances, attention being paid to the antidepressant pharmacodynamics and the importance of biogenic amines-reuptake inhibition. Further studies on the pharmacokinetics of tricyclic antidepressants are needed however to clarify the mechanisms of their side effects. In this situation, increased drug levels should be tried only after lower dosages have proved ineffective in relieving the depressive symptomatology. In any case, the greatest caution should be used in the treatment of patients with cardiovascular diseases, severe hypertension, glaucoma, or a tendency to retain urine. Nevertheless, at present no new antidepressant has been found which may offer more selective therapeutic advantages than the classical tricyclic thymoleptics (imipramine-like drugs).

Beta,beta'-iminodipropionitrile (IDPN) is a synthetic compound known to induce massive focal accumulations of neurofilaments almost exclusively in the proximal segments of motor and sensory axons. The present paper deals with a cat intoxicated with IDPN for five weeks. Swellings filled with skeins of maloriented neurofilaments were observed in the initial (non-myelinated) segment of intraparenchymal spinal axons in addition to the swellings consistently located in the first internodes. Filamentous masses in the initial segment were in some cases intermingled with focal accumulations of mitochondria and smooth vesicles to give the proximal axon the classical appearance of 'spheroid'. In some motoneurons, clumps of neurofilaments occupied the axon hillock and extended well into the perikaryon and some dendritic stems, making the borderlines between cell body and processes undistinguishable. Cytoplasmic organelles were displaced and rearranged in the presence of somal neurofibrillary changes. In a few neurons, regardless of the presence of swellings in the axon initial segment, signs of central chromatolysis were noticed, in the form of nuclear caps of Nissl substance and eccentricity of the nucleus. These findings are discussed with reference to other neurotoxic models of neurofibrillary pathology and the immunochemical differences recently detected between neurofilaments in perikarya, dendrites and axons.

beta,beta'-Iminodipropionitrile (IDPN) causes formation of axonal swellings in the proximal internodes of spinal motor axons. The swellings enlarge and demyelinate with the progression of the neuropathy. The correlation between axonal swellings and electrophysiologic function of motoneurons was examined in cats 2 to 35 days after initial administration of IDPN. Morphologic changes in intraspinal motor axons, occasionally observed 2 days after the first injection, became progressively more evident at later times, with enlargement at the first internode in some axons and appearance of fusiform or balloon-like axonal swellings. At 7 days axonal swellings were infrequently observed and the main structural feature was a reduction in myelin thickness in affected nerve fibers. Despite scant histopathologic changes, motoneuron action potential discharge at this time was significantly altered in latency to onset of spike and rate of rise. Abnormal motoneuron firing patterns were observed at this time. As the neuropathy progressed, both the frequency of occurrence and the size of axonal swellings increased markedly but at no time was there morphologic evidence of chromatolysis. At 14 and 35 days, (after two or five IDPN injections) action potential discharge became further altered in latency to spike onset, rate of rise, initial segment conduction time and somal-dendritic threshold. The incidence of repetitive firing increased and axonal conduction block was observed in several motoneuron recordings. The electrophysiologic changes closely resemble those reported in chromatolytic motoneurons after axotomy. The axonal swellings induced by IDPN may produce an axotomy-like condition which becomes more prominent as the neuropathy progresses but without morphologic evidence of chromatolysis.