Hannu Kalimo

A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD

The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal-dominant genes underlying these common neurodegenerative diseases. We have previously shown that a founder haplotype, covering the MOBKL2b, IFNK, and C9ORF72 genes, is present in the majority of cases linked to this region. Here we show that there is a large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 on the affected haplotype. This repeat expansion segregates perfectly with disease in the Finnish population, underlying 46.0% of familial ALS and 21.1% of sporadic ALS in that population. Taken together with the D90A SOD1 mutation, 87% of familial ALS in Finland is now explained by a simple monogenic cause. The repeat expansion is also present in one-third of familial ALS cases of outbred European descent, making it the most common genetic cause of these fatal neurodegenerative diseases identified to date.

Muscle Injuries Biology and Treatment

Muscle injuries are one of the most common traumas occurring in sports. Despite their clinical importance, few clinical studies exist on the treatment of these traumas. Thus, the current treatment principles of muscle injuries have either been derived from experimental studies or been tested only empirically. Although nonoperative treatment results in good functional outcomes in the majority of athletes with muscle injuries, the consequences of failed treatment can be very dramatic, possibly postponing an athletes return to sports for weeks or even months. Moreover, the recognition of some basic principles of skeletal muscle regeneration and healing processes can considerably help in both avoiding the imminent dangers and accelerating the return to competition. Accordingly, in this review, the authors have summarized the prevailing understanding on the biology of muscle regeneration. Furthermore, they have reviewed the existing data on the different treatment modalities (such as medication, therapeutic ultrasound, physical therapy) thought to influence the healing of injured skeletal muscle. In the end, they extend these findings to clinical practice in an attempt to propose an evidence-based approach for the diagnosis and optimal treatment of skeletal muscle injuries.

CADASIL: a Common Form of Hereditary Arteriopathy Causing Brain Infarcts and Dementia

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebrovascular disease leading to cognitive decline and dementia. CADASIL usually begins with migraine in about one third of the patients. More severe manifestations, transient ischemic attacks or recurrent strokes, appear between 30 and 50 years of age. CADASIL, however, may be diagnosed well before the first stroke on the basis of characteristic white matter hyperintensities upon magnetic resonance imaging and presence of pathognomonic granular osmiophilic material in arterial walls, including dermal arteries, since the arteriopathy is generalized. Gradual destruction of vascular smooth muscle cells (VSMC) leads to progressive wall thickening and fibrosis and luminal narrowing in small and medium‐sized penetrating arteries. The reduced cerebral blood flow finally causes lacunar infarcts, mainly in the basal ganglia and fronto‐temporal white matter, which lead to cognitive deficits and dementia of the subcortical vascular type. CADASIL is caused by single missense mutations or small deletions in Notch3 gene encoding a transmembrane receptor Notch3, of which upon ligand binding a nuclear signaling protein is generated by regulated intramembrane proteolysis. Notch signaling is essential during development, regulating cellular differentiation. In adults Notch3 is expressed only in VSMCs and it may promote cell survival by inhibiting apoptosis, but its exact function is unknown. Mutations result in either a gain or loss of one (or rarely, 3) cysteine residue(s) in one of the 34 epidermal growth factor‐like repeats in the extracellular amino‐terminal region of Notch3. It is as yet unclear which disturbance in the Notch signaling pathway leads to the characteristic vascular pathology of CADASIL.

Healing of skeletal muscle injury: an ultrastructural and immunohistochemical study

The healing of gastrocnemius muscle injury induced with a spring-loaded hammer in rats was analysed ultrastructurally and immunohistochemically. The ends of the ruptured myofibers retracted, which resulted in a central blood filled cavity. Central zone (CZ) later becomes occupied by granulation tissue scar. CZ is surrounded by a zone where myofibers are necrotized and phagocytosed by days 2-3. Complete regeneration within the preserved basal lamina (BL) cylinders takes place in 5-7 days. The regeneration of myofibers across the scar follows a pattern different from that within BL cylinders. Thin, often branched, myotubes grow out of the BL cylinders into the granulation tissue, where they extend between fibroblasts and collagen fibrils, in general oriented parallel to the preserved myofibers. The extension of the regenerating myotube seems to take place primarily by local synthesis in the growth cone. Fusing myoblasts provide nuclei, mostly along the sides but also occasionally at the tip of myotubes. Some myoblasts seem to derive from undifferentiated cells in the granulation tissue. By three weeks only a few thin myotubes had extended across the gap between the stumps of the ruptured myofibers. Growing myotubes appear to attach to the surrounding connective tissue by specialized structures, an attachment which evidently transmits contraction force across the gap, allowing use of the injured limb before the healing is complete.

The Arctic Alzheimer mutation facilitates early intraneuronal Aβ aggregation and senile plaque formation in transgenic mice

The Arctic mutation (APP E693G) is unique, since it is located within the amyloid-beta (Abeta) sequence and leads to Alzheimers disease (AD). Arctic Abeta peptides more easily form Abeta protofibrils in vitro, but little is known about the pathogenic mechanism of the Arctic mutation in vivo. Here, we analyzed APP transgenic mice with both the Swedish and Arctic mutations (tg-APPArcSwe) and transgenic mice with the Swedish mutation alone (tg-APPSwe). Intense intraneuronal Abeta-immunoreactive staining was present in young tg-APPArcSwe mice, but not in tg-APPSwe mice. Intracellular Abeta aggregates in tg-APPArcSwe were strongly stained by antibodies recognizing the N-terminus of Abeta, while those recognizing the C-terminus of Abeta stained weakly. The Abeta aggregates inside neurons increased with age and predated extracellular Abeta deposition in both tg-APPArcSwe and tg-APPSwe mice. Senile plaque deposition was markedly accelerated in tg-APPArcSwe mice, as compared to tg-APPSwe mice. We conclude that the Arctic mutation causes AD by facilitating amyloidosis through early accumulation of intracellular Abeta aggregates in association with a rapid onset of senile plaque deposition.

Activation of myogenic precursor cells after muscle injury.

The time and site of satellite cell activation in contusive myofiber rupture with segmental necrosis were studied in rat by labeling the cells in S phase of mitotic cycle with bromodeoxyuridine. The labeled satellite cell nuclei did not appear before phagocytosis of the necrotized debris had started, usually 1 d after the trauma. Most labeled satellite cell nuclei were found in the necrotized part of the ruptured myofibers, whereas very few of them were detected in the surviving part. The proliferation of satellite cells was extensive during the first 4 d in the regeneration zone; thereafter, it declined and only few labeled nuclei were observed on day 7. These results suggest that necrosis alone is not sufficient as a signal for the satellite cell activation, but it is speculated that (growth?) factors released by the macrophages are needed. A great majority of myoblasts derive from local precursor cells, and satellite cells recruited from the surviving part do not significantly contribute to the regeneration. Most myonuclei needed in regenerating myofibers are produced early within the preserved basal lamina cylinders to be later distributed into those parts of myofibers, which extend into connective tissue between the stumps.

The multifidus muscle in patients with lumbar disc herniation. A histochemical and morphometric analysis of intraoperative biopsies.

Structural changes in the multifidus muscle were analyzed in 41 patients operated on for herniated intervertebral disc. Twelve cadavers served as controls. The two main findings follow: 1) Both in the patients and in the controls the Type 2 muscle fibers were markedly and selectively smaller than the Type 1 fibers, which were of normal size for striated muscles, and 2) the internal structure of Type 1 fibers showed so-called core-targetoid and/or moth-eaten change. Group atrophy or fiber-type grouping (indicators of denervation and reinnervation) were observed only in a few patients. The selective small size of the Type 2 fibers may indicate atrophy due to relative inactivity of the multifidus muscle both in the patients and in the controls, ie, it does not need to be related to the herniated disc. Definite proof for denervation of the multifidus muscle was not observed, but neither the possibility be excluded. The cause of the core-targetoid and/or moth-eaten changes cannot yet be determined with certainty, because these changes are not specific for any single entity but may be due, for example, to denervation, ischemia, or altered use of the muscles because of pain. In any case, because the changes were significantly more common in the patients than in the controls, they signal for a pathologic condition, the character of which remains to be elucidated.

Improvements in the method for the electron microscopic localization of arylsulphatase activity

SummaryThe optimal conditions for the demonstration of arylsulphatase activity in the proximal convoluted tubule cells of the rat kidney were studied at light and electron microscopic level. 8-hydroxyquinoline sulphate, p-nitrophenyl sulphate and 2-hydroxy-5-nitrophenylsulphate were used as substrates and barium and lead as capturing ions. The effect of fixation, capturing ions, substrate concentration and pH was studied biochemically. The results of these biochemical studies were then verified histochemically. Finally a recommended method for the light and electron microscopic demonstration of arylsulphatase activity was presented.

Muscle strain injuries

Muscle injuries--lacerations, contusions or strains--are by far the most common injuries in sports. After first aid following the RICE principle (Rest, Ice, Compression and Elevation), therapy must be tailored according to the severity of the injury and based on the knowledge gained from experimental studies on regeneration of injured muscle. Most muscle injuries can be treated conservatively with excellent recovery, but complete ruptures with complete loss of function should be managed surgically. Immediately after the injury, a short period of immobilization is needed to accelerate formation of the scar between the stumps of the ruptured myofibers, to which the stumps adhere. The optimal length of immobilization depends on the grade of the injury, and should not be longer than needed for the scar to bear the pulling forces without rerupture. Early mobilization is required to invigorate adhesion, orientation of the regenerating muscle fibers, revascularization and resorption of the connective tissue scar. Another important aim of early mobilization, especially in clinical sports medicine, is to minimize inactivity-induced atrophy as well as loss of strength and extensibility, which are rapidly appearing adverse sequelae of prolonged immobilization.

Variant Alzheimer's disease with spastic paraparesis and cotton wool plaques is caused by ps-1 mutations that lead to exceptionally high amyloid-β concentrations

We describe 3 new families affected by Alzheimers disease with spastic paraparesis. In affected individuals, including the earliest known patient with this clinical syndrome, neuropathological examination revealed large “cotton wool” plaques similar to those we have previously described in a Finnish family. In the families in which DNA was available, presenilin‐1 mutations were observed. Transfection of cells with these mutant genes caused exceptionally large increases in secreted Aβ42 levels. Furthermore, brain tissue from individuals with this syndrome had very high amyloid‐β concentrations. These findings define the molecular pathogenesis of an important subgroup of Alzheimers disease and have implications for the pathogenesis of the disease in general. Ann Neurol 2000;48:806–808