GPIbα-vWF rolling under shear stress shows differences between type 2B and 2M von Willebrand disease.

Both type 2B and type 2M von Willebrand disease result in bleeding disorders; however, whereas type 2B has increased binding affinity between platelet glycoprotein Ibα and von Willebrand factor (vWF), type 2M has decreased binding affinity between these two molecules. We used R687E type 2B and G561S type 2M vWF-A1 mutations to study binding between flowing platelets and insolubilized vWF mutants. We measured rolling velocities, mean stop times, and mean go times at 37°C using high-speed video microscopy. The rolling velocities for wt-wt interactions first decrease, reach a minimum, and then increase with increasing shear stress, indicating a catch-slip transition. By changing the viscosity, we were able to quantify the effects of force versus shear rate for rolling velocities and mean stop times. Platelet interactions with loss-of-function vWF-A1 retain the catch-slip bond transition seen in wt-wt interactions, but at a higher shear stress compared with the wt-wt transition. The mean stop time for all vWF-A1 molecules reveals catch-slip transitions at different shear stresses (gain-of-function vWF-A1 < wt vWF-A1< loss-of-function vWF-A1). The shift in the catch-slip transition may indicate changes in how the different mutants become conformationally active, indicating different mechanisms leading to similar bleeding characteristics.

Congenital myopathy with uniform type 1 fibers.

Congenital myopathy with uniform type 1 fibers is a rare form of nonprogressive congenital neuromuscular disease. We report a 40 year old woman with proximal muscle weakness, waddling gait and decreased deep tendon reflexes. The serum creatine kinase level was decreased. Peripheral nerve conduction velocity as well as electrocardiogram and echocardiogram were normal. The electromyogram showed myopathic changes. A biopsy specimen from the left deltoid muscle revealed a uniformity of type 1 fibers. This is the first case of congenital myopathy with uniform type 1 fibers reported in Serbia.

Decreased brain protein levels of cytochrome oxidase subunits in Alzheimer's disease and in hereditary spinocerebellar ataxia disorders: a nonspecific change?

Controversy exists as to the clinical importance, cause, and disease specificity of the cytochrome oxidase (CO) activity reduction observed in some patients with Alzheimer's disease (AD). Although it is assumed that the enzyme is present in normal amount in AD, no direct measurements of specific CO protein subunits have been conducted. We measured protein levels of CO subunits encoded by mitochondrial (COX I, COX II) and nuclear (COX IV, COX VIc) DNA in autopsied brain of patients with AD whom we previously reported had decreased cerebral cortical CO activity. To assess disease specificity, groups of patients with spinocerebellar ataxia type I and Friedreich's ataxia were also included. As compared with the controls, mean protein concentrations of all four CO subunits were significantly decreased (-19 to -47%) in temporal and parietal cortices in the AD group but were not significantly reduced (-12 to -17%) in occipital cortex. The magnitude of the reduction in protein levels of the CO subunits encoded by mitochondrial DNA (-42 to -47%) generally exceeded that encoded by nuclear DNA (-19 to -43%). In the spinocerebellar ataxia disorders, COX I and COX II levels were significantly decreased in cerebellar cortex (-22 to -32%) but were normal or close to normal in cerebral cortex, an area relatively unaffected by neurodegeneration. We conclude that protein levels of mitochondrial- and nuclear-encoded CO subunits are moderately reduced in degenerating but not in relatively spared brain areas in AD and that the decrease is not specific to this disorder. The simplest explanation for our findings is that CO is decreased in human brain disorders as a secondary event in brain areas having reduced neuronal activity or neuronal/synaptic elements consequent to the primary neurodegenerative process.

Unusual association of multiple sclerosis and tomaculous neuropathy.

We describe two cases in which multiple sclerosis (MS) occurred in association with tomaculous neuropathy, presenting as chronic, distal sensorimotor polyneuropathy. In Case 1, monoclonal gammopathy of undetermined significance with monoclonal IgG lambda reactive against GM1 ganglioside, was also detected. The diagnosis of tomaculous neuropathy was established after sural nerve biopsy. Teased fibers examination revealed focal 'sausage-like' thickenings of the myelin sheaths in intact fibers and in fibers with segmental demyelination. Electron microscopy showed them to be due, mostly, to multiple windings of redundant myelin and concentric apposition of numerous lamellae, in contact with an intact myelin sheath. These are the first reported cases of tomaculous neuropathy in patients with MS. Whether the combination of the two conditions is purely coincidental or suggests the possible causal relation between MS and tomaculous neuropathy, is not certain.

Brain levels of thiamine and its phosphate esters in Friedreich's ataxia and spinocerebellar ataxia type 1.

Decreased blood and cerebrospinal fluid levels of thiamine have been reported in patients with spinocerebellar ataxia disorders. To determine whether a thiamine deficiency is present in the brain, we measured levels of thiamine and its phosphate esters thiamine monophosphate (TMP) and thiamine diphosphate (TDP), in postmortem cerebellar and cerebral cortices of patients with Friedreich's ataxia (FA) and spinocerebellar ataxia type 1 (SCA1). Brain levels of free (nonphosphorylated) thiamine, TMP, TDP, and total thiamine in FA and SCA1 were, on average, not significantly different from control values. However, a nonsignificant trend was observed for slightly reduced levels of TDP and total thiamine in cerebellar cortex of the SCA1 patients, a finding that might be related to the severe neuronal damage in this brain area. We conclude that in FA, brain thiamine concentrations are normal, whereas in SCA1 the levels are, at most, only slightly reduced.

Association of Krabbe leukodystrophy and congenital fiber type disproportion.

Hypotonia and weakness developed in a 12-month-old boy whose psychomotor development had previously been normal. The muscle biopsy demonstrated a disparity in the mean diameters of type 1 and type 2 fibers and satisfied major histologic criteria for diagnosis of congenital fiber type disproportion (CFTD). However, deterioration of motor and mental function, which developed subsequently, strongly suggested progressive encephalopathy. Examination of leukocyte cerebral enzymes at 15 months of age revealed a complete lack of galactosylceramide-beta-galactosidase. Selective type 1 fiber atrophy with type 1 fiber predominance has been observed in various conditions, including Krabbe disease. We report an additional case of Krabbe leukodystrophy associated with CFTD. The finding on the molecular level will resolve the dilemma of whether CFTD is a congenital myopathy or whether these patterns of disproportion may result from a number of different processes that interfere with the maturation of the developing motor unit.

Immunoreactive levels of alpha-ketoglutarate dehydrogenase subunits in Friedreich's ataxia and spinocerebellar ataxia type 1.

Enzyme activities of a alpha-ketoglutarate dehydrogenase complex (alpha KGDHC) and one of its constituent subunits, dihydrolipoamide dehydrogenase (E3), are reported to be reduced in non-CNS tissues of some patients with Friedreich's ataxia (FA); however, the results are highly conflicting. To determine whether an enzyme abnormality occurs in brain, we measured immunoreactive levels of the three alpha KGDHC subunits, namely, alpha-ketoglutarate dehydrogenase (E1), dihydrolipoamide succinyltransferase (E2) and E3 in postmortem frontal, occipital and cerebellar cortices of 18 control subjects, 9 patients with FA and, for comparison, 12 patients with spinocerebellar ataxia type 1 (SCA1). Decreased (-20 to -31%) levels of E3 were observed in all three examined areas of the patients with FA with the changes statistically significant in cerebellar and frontal cortices. The E3 reduction could be explained by a loss of alpha KGDHC or other dehydrogenase complexes (e.g. pyruvate dehydrogenase complex) which utilize this subunit. In SCA1, enzyme changes were limited to E2 in cerebellar (-26%) and frontal (-19%) cortices. Although the E3 and E2 reductions are only slight, and may represent secondary events, the changes in this key Krebs cycle enzyme could exacerbate degenerative processes in both of the spinocerebellar ataxia disorders.

Association of progressive myoclonic epilepsy and spinal muscular atrophy.

It is well known that certain hereditary diseases of the nervous system sometimes occur concurrently within particular families. This report presents a Yugoslav family of Hungarian origin in whom 2 brothers had progressive myoclonic epilepsy and proximal weakness and atrophy of muscles. Electromyography and muscle biopsy confirmed neurogenic atrophy. Electroencephalography disclosed paroxysmal spike-and-wave and polyspike-and-wave complexes with photic-induced myoclonic jerking. The combination of these clinical features is extremely rare and probably constitutes a clinical syndrome that has not been reported previously.

Brain cytochrome oxidase in Alzheimer's disease.

A recent demonstration of markedly reduced (-50%) activity of cytochrome oxidase (CO; complex 4), the terminal enzyme of the mitochondrial enzyme transport chain, in platelets of patients with Alzheimer's disease (AD) suggested the possibility of a systemic and etiologically fundamental CO defect in AD. To determine whether a CO deficiency occurs in AD brain, we measured the activity of CO in homogenates of autopsied brain regions of 19 patients with AD and 30 controls matched with respect to age, postmortem time, sex, and, as indices of agonal status, brain pH and lactic acid concentration. Mean CO activity in AD brain was reduced in frontal (-26%: p less than 0.01), temporal (-17%; p less than 0.05), and parietal (-16%; not significant, p = 0.055) cortices. In occipital cortex and putamen, mean CO levels were normal, whereas in hippocampus, CO activity, on average, was nonsignificantly elevated (20%). The reduction of CO activity, which is tightly coupled to neuronal metabolic activity, could be explained by hypofunction of neurons, neuronal or mitochondrial loss, or possibly by a more primary, but region-specific, defect in the enzyme itself. The absence of a CO activity reduction in all of the examined brain areas does not support the notion of a generalized brain CO abnormality. Although the functional significance of a 16-26% cerebral cortical CO deficit in human brain is not known, a deficiency of this key energy-metabolizing enzyme could reduce energy stores and thereby contribute to the brain dysfunction and neurodegenerative processes in AD.

[Clinical heterogeneity in patients with ocular myopathies]. / Heterogenost klinickog ispoljavanja kod bolesnika s okularnom miopatijom.

We present the results of clinical, electrophysiological, and biopsy studies in patients with ocular myopathy. Nine patients (four women and five men) were included in these investigations. According to the biopsy findings the patients were divided into patients with oculocraniosomaltic syndrome (OCSS) and patients with oculopharyngeal muscular dystrophy (OPMD). The presented clinical features, especially in the OCSS groups was more variable. Associated neurological and multisystem disturbances were characteristic of OCSS. Biopsy findings were of essential significance in distinguish these two conditions, especially in cases of the late onset.

Neoplastic angioendotheliomatosis (NAE) of the CNS in a patient with AIDS subacute encephalitis, diffuse leukoencephalopathy and meningo-cerebral cryptococcosis.

A 12-year-old, hemophilic boy died with acquired immune deficiency syndrome (AIDS) after a clinical course characterized by progressive psycho-organic syndrome and opportunistic infections. Postmortem neuropathological examination revealed a cerebral form of neoplastic angioendotheliomatosis (NAE), leukoencephalopathy, giant cell encephalitis and meningo-cerebral cryptococcosis. The most unusual finding was the presence of proliferated neoplastic cells within lumina of some blood vessels throughout the central nervous system (CNS). These cells displayed cytologic features of malignancy and stained positively for common leukocyte antigen. Coronal sections showed diffuse cerebral and cerebellar leukoencephalopathy with most pronounced loss of myelin and axons in deep white matter, while the subcortical arcuate fibers and the corpus callosum were partially spared. In these areas numerous small foci of severe myelin loss were present. Microglial nodules and distinctive multinucleated giant cells (MGC) were numerous. Intracytoplasmic and intranuclear acidophilic inclusions were found in a few multinuclear and mononuclear cells. Close contact between mononuclear and multinuclear cells suggesting their fusion was also observed. As far as we know this is the first case of NAE encountered in AIDS, one of the rare primary cerebral forms and the youngest reported case of NAE up to now. This case could be considered as one proof more that NAE is a special form of malignant lymphoma.

[3H]vesamicol binding in human brain cholinergic deficiency disorders.

We measured the binding of the vesicular acetylcholine transport blocker [3H]vesamicol (2-[4-phenylpiperidino] cyclohexanol; AH-5183) to autopsied frontal cortex and amygdala of patients from 4 disorders having a marked brain cholinergic reduction, namely Alzheimer's disease, Parkinson's disease with dementia, dominantly inherited olivopontocerebellar atrophy and Down's syndrome. Although mean activity of the specific cholinergic marker enzyme choline acetyltransferase (ChAT) was markedly reduced by about 60% in frontal cortex in the 4 patient groups and by 80% or greater in amygdala of the Alzheimer's and Down's syndrome patients, [3H]vesamicol binding density was, on average, either normal or only slightly reduced as compared with the controls. This discrepancy suggests that in human brain [3H]vesamicol binding is either not preferentially localized to cholinergic nerve endings or, in these cholinergic deficiency syndromes, a substantial proportion of the vesamicol binding sites persist on cholinergic nerve terminals despite loss of ChAT activity.

[The surgical anatomy of the sublingual gland]. / Anatomie chirurgicale de la glande sublinguale.

Because of its position, the sublingual gland is clinically important especially in the events of injuries and infections in the anterior part of the sublingual region. The morphology and relationships of this gland were studied by dissection methods applied on 80 fresh or formaldehyde fixed preparations of the mouth floor and of the tongue, which were partly (31 preparations) taken out together with the mandible. As for the shape of the gland, three main types were found: the cuneiform type which was the most frequent (71%), the pyramidal type which was less frequent (16%) and the fusiform type (13%) which comprised the case of a very elongated gland (up to 65 mm). The space in which the gland lied had four walls. Its internal wall consisted of the mylohyoid muscle and it comprised the hyoglossus muscle as well when the gland was very elongated. The inferior wall consisted of the mylohyoid muscle and sometimes it comprised also a narrow part of the superior surface of the geniohyoglossus muscle. An osseous depression on the internal side of the mandible represented the external wall of the sublingual gland space. The superior wall is clinically the most significant. It consists of the sublingual mucosa and a sublingual fold. This wall represents a main surgical access to the gland. In edentulous mandibles this mucous fold may be at the level of the upper mandibular border which may hinder the use of the lower dental prosthesis.

[Histologic changes in peripheral nerves in rats with chronic copper poisoning]. / Histoloske promene perifernog nerva kod pacova hronicno trovanih bakrom.

The results of histochemical and histopathologic tests of a periphery nerve in rats which were chronically poisoned with copper, are presented. The tests were performed on 45 albino Wistar female rats, which were poisoned with pure copper powder in an inhalation chamber for one year. The control group consisted of 16 rats. By histochemical test the copper pigment was found in 46.66% of the poisoned rats. It was located in epineurium and perineurium, cells and less in the endoneurium. It was also found in cells of the blood vessel media of a periphery nerve. Histopathological changes in a periphery nerve were discrete and they appeared in the form of certain swollen axones.

[Surgical treatment of habitual luxation of the shoulder joint using the Dickson-O'Dell method. Our modification]. / Operativno lijecenje habitualne luksacije ramenog zgloba po metodi Dickson-O'Dell. Nasa modifikacija.

The authors have presented their experience in the treatment of 40 patients with habitual dislocation of the shoulder joints using the method of Dickson-O'Dell during a period of 10 years. They have compared their results with results obtained by other methods and consider their modification as the method of choice on the basis of excellent results obtained in their patients.

[Atherosclerotic changes of the inferior dental artery correlated with those of the carotid bifurcation and the abdominal artery]. / Altérations athéroscléreuses de l'artère dentaire inférieure en corrélation avec celles de la bifurcation carotidienne et de l'aorte abdominale.

50 corpses from adults aged 20 to 75 have been used in order to study the atherosclerotic lesions occurring in typical regions (bifurcation of the common carotid artery and the abdominal aorta) and their relationship to atherosclerotic changes in the inferior alveolar artery. Histological analysis revealed that atherosclerotic alterations of the inferior alveolar artery may appear sometimes earlier than it would be expected on the ground of age. Intima cell proliferation and thickening of elastic elements in the middle layer of the arterial wall, the first signs of atherosclerosis, were found already at the beginning of the third decade of life when the signs of this process in the typical regions were not yet evident. Atherosclerosis affects essentially the functional capacity of the inferior alveolar artery. The development of atherosclerosis in the wall of this artery favours an hypovascularization of the mandible, which must be of certain importance in every operative procedure in oral surgery, especially in those inducing a severe and long traumatism in bone and soft tissues, such as dental implantations.

Maternal translocation t(13:18)(q34:q11) and Edward's syndrome in a fetus: 47,xy,t(13:18)(q34:q11) + 18.

A 32-year-old woman, who presented with four spontaneous abortions, was found to have a balanced translocation: 46,XX,t(13:18)(q34:q11). In the last pregnancy an amniocentesis was done. Abnormal constitution of the fetus had been detected: 47,XY,t(13:18)(q34:q11) + 18, and an abortion was induced. Examination of the fetal tissue confirmed the finding. The fetus showed the characteristics of Edward's syndrome. Through the patient's pedigree it was discovered that balanced translocation appeared in three generations.

Central nicotinic receptors: vomiting, ear twitching and panting.

Vomiting, ear twitching and panting produced by either nicotine or dimethylphenylpiperazinium (DMPP) administered intracerebroventricularly (ICV) to the unanesthetized cat were studied and compared. On a molar basis, nicotine evoked stronger effects overall in terms of the three responses studied, but the DMPP-induced vomiting and ear twitching responses, while weaker, were of longer duration. No significant differences were found in the duration of panting evoked by these nicotinic agonists. The nicotinic blocker hexamethonium injected ICV abolished the vomiting and ear twitching caused by either ICV nicotine or ICV DMPP, but vomiting and ear twitching persisted following the ICV administration of the muscarinic blocker, atropine. Both hexamethonium and atropine depressed or abolished the panting response evoked by either ICV nicotine or ICV DMPP. In cats with ablations of the area postrema, nicotine and DMPP injected ICV did not produce the vomiting response, but ear twitching and panting still occurred. It is concluded that the ICV injection of nicotine or DMPP evoked vomiting and ear twitching in the cat by way of an action on the central nicotinic receptors. However, panting produced by these nicotine agonists is mediated by the mimicking action of acetylcholine on central receptors having mixed nicotinic and muscarinic properties.