Phenotypic variability in three families with valosin-containing protein mutation.

BACKGROUND AND PURPOSE: The phenotype of IBMPFD [inclusion body myopathy with Paget's disease of the bone and frontotemporal dementia (FTD)] associated with valosin-containing protein (VCP) mutation is described in three families. METHODS: Probands were identified based on a pathological diagnosis of frontotemporal lobar degeneration with TDP-43-positive inclusions type IV. VCP sequencing was carried out. Clinical data on affected family members were reviewed. RESULTS: Ohio family: four subjects presented muscle weakness and wasting. (One subject had both neuropathic and myopathic findings and another subject showed only evidence of myopathy. The etiology of weakness could not be ascertained in the remaining two subjects.) Two individuals also showed Parkinsonism (with associated FTD in one of the two). The proband's brain displayed FTLD-TDP type IV and Braak stage five Parkinson's disease (PD). A VCP R191Q mutation was found. Pennsylvania family: 11 subjects developed IBMPFD. Parkinsonism was noted in two mutation carriers, whilst another subject presented with primary progressive aphasia (PPA). A novel VCP T262A mutation was found. Indiana family: three subjects developed IBMPFD. FTD was diagnosed in two individuals and suspected in the third one who also displayed muscle weakness. A VCP R159C mutation was found. CONCLUSIONS: We identified three families with IBMPFD associated with VCP mutations. Clinical and pathological PD was documented for the first time in members of two families. A novel T262A mutation was found. One individual had PPA: an uncommon presentation of IBMPFD.

The behavioral variant of Alzheimer's disease does not show a selective loss of Von Economo and phylogenetically related neurons in the anterior cingulate cortex.

BACKGROUND: The neurobiological origins of the early and predominant behavioral changes seen in the behavioral variant of Alzheimer's disease (bvAD) remain unclear. A selective loss of Von Economo neurons (VENs) and phylogenetically related neurons have been observed in behavioral variant frontotemporal dementia (bvFTD) and several psychiatric diseases. Here, we assessed whether these specific neuronal populations show a selective loss in bvAD. METHODS: VENs and GABA receptor subunit theta (GABRQ)-immunoreactive pyramidal neurons of the anterior cingulate cortex (ACC) were quantified in post-mortem tissue of patients with bvAD (n = 9) and compared to typical AD (tAD, n = 6), bvFTD due to frontotemporal lobar degeneration based on TDP-43 pathology (FTLD, n = 18) and controls (n = 13) using ANCOVAs adjusted for age and Bonferroni corrected. In addition, ratios of VENs and GABRQ-immunoreactive (GABRQ-ir) pyramidal neurons over all Layer 5 neurons were compared between groups to correct for overall Layer 5 neuronal loss. RESULTS: The number of VENs or GABRQ-ir neurons did not differ significantly between bvAD (VENs: 26.0 ± 15.3, GABRQ-ir pyramidal: 260.4 ± 87.1) and tAD (VENs: 32.0 ± 18.1, p = 1.00, GABRQ-ir pyramidal: 349.8 ± 109.6, p = 0.38) and controls (VENs: 33.5 ± 20.3, p = 1.00, GABRQ-ir pyramidal: 339.4 ± 95.9, p = 0.37). Compared to bvFTD, patients with bvAD showed significantly more GABRQ-ir pyramidal neurons (bvFTD: 140.5 ± 82.658, p = 0.01) and no significant differences in number of VENs (bvFTD: 10.9 ± 13.8, p = 0.13). Results were similar when assessing the number of VENs and GABRQ-ir relative to all neurons of Layer 5. DISCUSSION: VENs and phylogenetically related neurons did not show a selective loss in the ACC in patients with bvAD. Our results suggest that, unlike in bvFTD, the clinical presentation in bvAD may not be related to the loss of VENs and related neurons in the ACC.

Regional and hemispheric susceptibility of the temporal lobe to FTLD-TDP type C pathology.

Post-mortem studies show that focal anterior temporal lobe (ATL) neurodegeneration is most often caused by frontotemporal lobar degeneration TDP-43 type C pathology. Clinically, these patients are described with different terms, such as semantic variant primary progressive aphasia (svPPA), semantic dementia (SD), or right temporal variant frontotemporal dementia (FTD) depending on whether the predominant symptoms affect language, semantic knowledge for object or people, or socio-emotional behaviors. ATL atrophy presents with various degrees of lateralization, with right-sided cases considered rarer even though estimation of their prevalence is hampered by the paucity of studies on well-characterized, pathology-proven cohorts. Moreover, it is not clear whether left and right variants show a similar distribution of atrophy within the ATL cross-sectionally and longitudinally. Here we study the largest cohort to-date of pathology-proven TDP-43-C cases diagnosed during life as svPPA, SD or right temporal variant FTD. We analyzed clinical, cognitive, and neuroimaging data from 30 cases, a subset of which was followed longitudinally. Guided by recent structural and functional parcellation studies, we constructed four bilateral ATL regions of interest (ROIs). The computation of an atrophy lateralization index allowed the comparison of atrophy patterns between the two hemispheres. This led to an automatic, imaging-based classification of the cases as left-predominant or right-predominant. We then compared the two groups in terms of regional atrophy patterns within the ATL ROIs (cross-sectionally) and atrophy progression (longitudinally). Results showed that 40% of pathology proven cases of TDP-43-C diagnosed with a temporal variant presented with right-lateralized atrophy. Moreover, the findings of our ATL ROI analysis indicated that, irrespective of atrophy lateralization, atrophy distribution within both ATLs follows a medial-to-lateral gradient. Finally, in both left and right cases, atrophy appeared to progress to the contralateral ATL, and from the anterior temporal pole to posterior temporal and orbitofrontal regions. Taken together, our findings indicate that incipient right predominant ATL atrophy is common in TDP-43-C pathology, and that distribution of damage within the ATLs appears to be the same in left- and right- sided variants. Thus, regardless of differences in clinical phenotype and atrophy lateralization, both temporal variants of FTD should be viewed as a spectrum presentation of the same disease.

Ethosuximide plasma concentrations: influence of age and associated concomitant therapy.

The relationship between oral dose and plasma concentration of ethosuximide was evaluated retrospectively in 198 epileptic patients aged 2.5 to 34 years. Age appears to be a major factor in determining the ethosuximide plasma level/dose (L/D) ratio. Children younger than 10 years had men L/D ratios significantly lower (p less than 0.0003) than adolescents (10 to 15 years of age) and adults (16 to 34 years of age). Associated antiepileptic therapy reduced the ethosuximide L/D ratio: mean ethosuximide L/D ratios were significantly lower in patients also taking primidone (p less than 0.0005) or valproic acid (p less than 0.02). The correlation between the dose of ethosuximide administered and the plasma concentration was significant in the 3 age groups considered (p less than 0.0004), but the wide scattering of individual plasma concentrations makes it impossible to predict what plasma concentration of ethosuximide will be obtained after a given dose. For this reason, routine monitoring of ethosuximide plasma concentrations still appears to be necessary, especially in children and patients on polytherapy.

[A case of idiopathic multiple calcinosis cutis]. / Un caso di calcinosis cutis multipla, idiopatica.

A case of calcinosis cutis, appeared since childhood in a woman 73-years-old, affected by diabetes mellitus with complications, is described. This uncommon disorder is discussed on the basis of data from recent literature. Calcinosis cutis is a condition characterized by the deposition of crystals of calcium phosphate (hydroxyapatite) in the skin. Calcinosis cutis may be idiopathic or secondary. The idiopathic calcinosis cutis is uncommon, may be solitary or multiple, sporadic or associated with Down syndrome (MICC or "milialike idiopathic calcinosis cutis") and appears more often in childhood or adolescence. Secondary calcinosis cutis may appear in the course of juvenile dermatomyositis or in the form of systemic scleroderma named CREST syndrome (calcinosis cutis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly and telangectasia). Calcinosis cutis may also be seen later in the course of renal failure, associated with hyperphosphatemia and secondary hyperparathyroidism. In this case report, calcinosis cutis appeared early in life and the laboratory data showed normal erythrocyte sedimentation rate and leukocyte count, negative LE test and absence of rheumatoid factor and non-organ-specific auto-antibodies, and multiple localizations. On these grounds, the diagnosis of idiopathic multiple calcinosis cutis was made. This is a rare and benign syndrome, which does not cause any late complication and whose prognosis is therefore favourable.

[Precordial discomfort and ECG changes of repolarization associated with hypomagnesemia in a young women following colectomy for diffuse colonic lipomatosis]. / Oppressione precordiale e turbe elettrocardiografiche della ripolarizzazione associati ad ipomagnesemia in giovane donna colectomizzata per lipomatosi diffusa del colon.

Aim of this paper is to describe and discuss, on the basis of the available literature, the case of a young woman, previously colectomized for diffuse lipomatosis of the colon, showing hypomagnesemia and symptomatic (precordial discomfort) changes of repolarization phase, detected by ECG, probably due to coronary spasm. This hypomagnesemia (1.4 mEq/1) was probably due to altered intestinal absorption of magnesium, linked to a short bowel syndrome. The ECG changes and the precordial symptom were completely reversed by a relative short treatment with magnesium per os, which increased the magnesium level to low borderline value (1.6 mEq/1). The observation of ECG changes with precordial discomfort, probably linked to hypomagnesemia, suggests the need for routinary magnesium determinations to detect deficiency of this electrolyte, with the scope of improving the diagnosis and the treatment of several symptoms, otherwise difficult to interpret.

[Erythropoietin and cisplatin-induced neuropathies in cancer patients]. / Eritropoietina e neuropatie da cisplatino nei pazienti oncologici.

Anaemia commonly occurs in cancer patients on chemotherapy, often necessitating blood transfusion, and, in most recent years, treatment with human recombinant cythropoietin (rHuEPO). However, several extra-hematological effects were reported for EPO, and multi-organ physiological effects on development and repair of tissues are described both on nerves and muscles. Moreover, EPO is presently used in oncological patients with the goal of preventing or limiting anemia secondary to chemotherapy. Ten patients with advanced lung cancer and without neurological impairment assessed by Siegal score and without severe anemia, were studied. Patients (age 56.2 +/- 8.3 years) were random assigned to two groups of 5 patients each: the control group and the EPO treated group. In both groups, at the end of the study, hemoglobin concentration was not different (above 9 mg/dl). In EPO treated group neurological score was 4.00 +/- 1.87, significantly lower (p < 0.004) in comparison with untreated group (score 9.20 +/- 4.32). From these preliminary data we suggest that EPO treatment in cancer patients can exert also a limiting effect on cisplatin peripheral neurotoxicity.

Actin cytoskeleton remodelling by sex steroids in neurones.

Cell morphology and its interaction with the extracellular environment are integrated processes involving a number of intracellular controllers orchestrating cytoskeletal proteins and their interaction with the cell membrane and anchorage proteins. Sex steroids are effective regulators of cell morphology and tissue organisation, and recent evidence indicates that this is obtained through the regulation of the actin cytoskeleton. Intriguingly, many of these regulatory actions related to cell morphology are achieved through the rapid, nonclassical signalling of sex steroid receptors to kinase cascades, independently from nuclear alteration of gene expression or protein synthesis. The identification of the mechanistic basis for these rapid actions on cell cytoskeleton has special relevance for the characterisation of the effects of sex steroids under physiological conditions, such as for the development of neurone/neurone interconnections and dendritic spine density. This is considered to be critical for gender-specific differences in brain function and dysfunction. Recent advancements in the characterisation of the molecular basis of the extranuclear signalling of sex steroids help to clarify the role of oestrogen and progesterone in the brain, and may turn out to be of relevance for clinical purposes. This review highlights the regulatory effects of oestrogens and progesterone on actin cytoskeleton and neurone morphology, as well as recent progresses in the characterisation of these mechanisms, providing insights and working hypotheses on possible clinical applications for the modulation of these pathways in the central nervous system.

Clinicopathologic features of frontotemporal dementia with progranulin sequence variation.

BACKGROUND: Frontotemporal lobar degeneration with ubiquitin-immunoreactive (ub-ir) inclusions (FTLD-U) has been associated with frontotemporal dementia (FTD) and ALS. Recently, mutations in Progranulin (PGRN), predicted to cause premature truncation of the PGRN coding sequence, were found in patients with inherited FTLD-U and ub-ir neuronal intranuclear inclusions (NII). OBJECTIVE: To describe clinical, pathologic, and genetic features of three FTD patients having either a family history of FTD (A.III.1 and B.II.1) or of ALS (C.III.1). METHODS: Patients underwent a single clinical assessment, MRI, and [(18)F]fluorodeoxyglucose PET brain scan. Neuropathologic examination and genetic analyses were carried out. RESULTS: Patients presented clinically with the behavioral variant of FTD. Language dysfunctions were marked with comprehension being particularly affected. Neuroimaging revealed frontotemporal atrophy and glucose hypometabolism, with predominant left-side involvement, in Patients A.III.1 and B.II.1. Subject C.III.1 displayed mild atrophy and symmetric anterior hypometabolism. All patients were neuropathologically diagnosed with FTLD-U. Ub-ir NII were noted in Patients A.III.1 and B.II.1 but were absent in Patient C.III.1. The following PGRN sequence variations were found: IVS6-2A-->G (A.III.1), R493X (B.II.1), and R433W (C.III.1). IVS6-2A-->G may lead to skipping of exon 7 with consequent frameshift of the coding sequence and premature termination of PGRN translation. CONCLUSIONS: We have found two PGRN mutations associated with FTD, in affected individuals who are members of families with possible autosomal dominant FTD. A third PGRN sequence variation (R433W) was found in an FTD patient with family history of ALS.

[Dynamic pancreatography with magnetic resonance after functional stimulus with secretin in chronic pancreatitis]. / Pancreatografia dinamica con Risonanza Magnetica dopo stimolo funzionale con secretina nella pancreatite cronica.

AIM OF THE STUDY: Magnetic Resonance pancreatography (MRP) was performed before and after the intravenous injection of secretin to assess the improvement in pancreatic duct visualization and to perform a dynamic study of the pancreatic exocrine function. MATERIAL AND METHODS: 20 MRP examinations were performed in 18 patients with suspected or known chronic pancreatitis. Coronal T2-weighted half-Fourier SSFSE images were obtained with a phased array surface coil. Images were obtained before and up to 10 minutes after the injection of 1 cu/kg b.w. secretin. Quantitative image analysis included main pancreatic duct enlargement over time after secretin injection and the amount of duodenal filling. Qualitative image analysis included: overall image quality improvement, number of pancreatic duct segments visualized, secondary ducts dilation, intraductal filling defects, the presence of pancreas divisum. RESULTS: After secretin injection the overall image quality was judged sufficient in 2 patients and satisfactory in 18 patients. The number of pancreatic duct segments visualized increased from 40/57 (79%) to 57/57 (100%); secondary ducts were visualized in 4 patients before secretin compared to 18 after secretin. The number of stenosis visualized increased from 6 to 9, while intraluminal filling defects increased from 2 to 6. Pancreas divisum was detected in 2 patients after secretin versus 0 before secretin. The main pancreatic duct enlargement was statistically significant in the head of the pancreas (p < .05). Duodenal filling was normal in 13 patients and decreased in 7. DISCUSSION AND CONCLUSIONS: Secretin injection extends the capabilities of MRP in visualizing the morphologic features of pancreatic ducts. The depiction of pancreatic ducts, stenosis, filling defects and pancreas divisum was improved after secretin injection. The exocrine function of the pancreas can be evaluated analyzing the entity and the timing of the duodenal filling.

Hypomagnesemia and smooth muscle contractility: diffuse esophageal spasm in an old female patient.

The aim of this paper is to describe and discuss, on the basis of the available literature, the case of an old female patient, admitted to our university hospital because of a severe dysphagia for solid foods, in whom laboratory data showed a marked hypomagnesemia. She reported a long history (20 years) of allergic bronchial asthma treated with theophylline. Esophagography evidenced a disorder of esophagus motility with diffuse multiple spasm, reminiscent of the 'corkscrew esophagus'. A link with the severe hypomagnesemia (Mg 1.1 mEq/l, normal range 1.6-2.1) was suspected, and a therapy with oral pidolate of Mg (1.5 g/twice a day) was started and continued for 4 months. This was associated with a slow progressive normalization of the Mg plasma level and reverted radiographic esophageal findings with disappearance of dysphagia. Mg is an important element for health and disease, and today Mg deficiency in man has become an accepted medical problem which might complicate many diseases. Neuromuscular disorders, as laryngeal spasm, are recognized complications of hypomagnesemia, but until now only 1 case of motor esophageal disorder associated with a low Mg plasma level was briefly reported in the literature, even if dysphagia is generally included in the symptomatological pattern of hypomagnesemia. Our observation of a severe form of esophageal spasm, associated with hypomagnesemia, in an aged female patient underlines the pathophysiological meaning of the plasma Mg level and suggests the need for routine Mg determination in the clinical setting.

[Meniscal deformities associated with fractures of the tibial proximal extremity. Considerations in 7 cases]. / Deformazioni meniscali associate a fratture dell'estremo tibiale prossimale. Considerazioni su 7 casi.

Lateral tibial plateau fractures are a fairly frequent event in emergency clinical practice. In these fractures, when bone depression exceeds 5 mm, surgery is indicated. On the rule, conventional plain films combined with tomography can answer diagnostic questions about bone trauma. CT and MRI permit to study associated meniscocapsular injuries for better therapeutical management. Since February, 1991, we have examined 24 patients with tibial plateau fractures with conventional radiography and CT. CT was performed using thin sections, within 0 to 48 hours of the traumatic event. In our series, 7 patients had a lateral meniscal trauma associated with a fracture of the homologous tibial plateau; in all of these 7 women, surgery confirmed complete meniscal avulsion. In these cases, CT showed the following signs of meniscocapsular disinsertion: marked diastasis between capsular structure, popliteal tendon and meniscal profile; associated hypodense hemorrhagic fluid in the popliteal recess; inhomogeneous densitometry of the popliteal tendon resulting from hemorrhagic infarction. Furthermore, CT showed a characteristic and constant morphological alteration of the lateral meniscus with fibrocartilage deformation, that is with a wider or more narrow pattern relative to its normal "C"-like shape. We conclude that this morphological alteration of meniscal fibrocartilage, when associated with a tibial fracture, is a diagnostic CT sign of complete meniscal avulsion. This finding can be a useful integration to other CT signs of this meniscal injury, towards better and more complete therapeutical management.

Pancreas divisum and "santorinicele": diagnosis with dynamic MR cholangiopancreatography with secretin stimulation.

PURPOSE: To evaluate the usefulness of magnetic resonance (MR) cholangiopancreatography (MRCP) before and after secretin administration in diagnosing santorinicele in patients with pancreas divisum. MATERIALS AND METHODS: One hundred seven patients suspected of having pancreatic disease underwent MRCP before and after secretin administration (S-MRCP). S-MRCP images were evaluated for pancreas divisum and santorinicele and for size of the main pancreatic duct and santorinicele. The onset of duodenal filling was calculated on dynamic S-MRCP images. RESULTS: Pancreas divisum was detected in five (5%) of 107 patients at MRCP and in 10 (9%) of 107 patients at S-MRCP. Santorinicele was detected in three (21%) of 14 patients at MRCP and in an additional four (seven [50%] of 14) patients at S-MRCP in patients with pancreas divisum. Santorinicele was confirmed in six of seven patients at endoscopic retrograde cholangiopancreatography (ERCP); in one of seven patients, ERCP was unsuccessful. The duct of Santorini was significantly (P: <.05) larger in the pancreatic head in patients with pancreas divisum and santorinicele (3.6 mm) compared with those with only pancreas divisum (2.2 mm). A noteworthy reduction in size of the pancreatic duct (26%) and of the santorinicele (63%) was observed after sphincterotomy. The onset of duodenal filling was delayed significantly in patients with santorinicele (2.1 vs 1.3 minutes; P: <.05). CONCLUSION: S-MRCP helps in identifying pancreas divisum and santorinicele, which may be the cause of impeded pancreatic outflow.

A large spontaneous splenorenal shunt in a patient with liver cirrhosis and uncomplicated portal hypertension.

The aim of this paper is to describe and discuss, on the basis of a thorough review of the literature, the case of a 70-year-old woman with probable cirrhosis secondary to chronic hepatitis B and C, uncomplicated portal hypertension (without ascites, encephalopathy or bleeding varices), splenomegaly and hypersplenism, and an unusual, spontaneous, large splenorenal shunt and recanalization of the umbilical vein. The tortuous and varicose splenorenal shunt was diagnosed by abdominal ultrasound and CT investigations. A duplex Doppler ultrasonography evaluation was performed to study shunt flow direction and velocity. No gastroesophageal varices were identified on endoscopic examination. The clinical relevance of spontaneous splenorenal shunt, often associated with fundic gastric varices, is discussed.