Reliable assessment of perfusivity and diffusivity from diffusion imaging of the body.

Diffusion-weighted MRI of the body has the potential to provide important new insights into physiological and microstructural properties. The intra-voxel incoherent motion (IVIM) model relates the observed DW-MRI signal decay to parameters that reflect perfusivity (D*) and its volume fraction (f), and diffusivity (D). However, the commonly used voxel-wise fitting of the IVIM model leads to parameter estimates with poor precision, which has hampered their practical usage. In this work, we increase the estimates' precision by introducing a model of spatial homogeneity, through which we obtain estimates of model parameters for all of the voxels at once, instead of solving for each voxel independently. Furthermore, we introduce an efficient iterative solver which utilizes a model-based bootstrap estimate of the distribution of residuals and a binary graph cut to generate optimal model parameter updates. Simulation experiments show that our approach reduces the relative root mean square error of the estimated parameters by 80% for the D* parameter and by 50% for the f and D parameters. We demonstrated the clinical impact of our model in distinguishing between enhancing and nonenhancing ileum segments in 24 Crohn's disease patients. Our model detected the enhanced segments with 91%/92% sensitivity/specificity which is better than the 81%/85% obtained by the voxel-independent approach.

3D multidetector CT angiographic evaluation of extralobar pulmonary sequestration with anomalous venous drainage into the left internal mammary vein in a paediatric patient.

Pulmonary sequestration is a congenital lung malformation, defined by dysplastic and non-functioning lung tissue lacking normal tracheobronchial connections and accompanied by an anomalous systemic blood supply. Recognition of anomalous arteries and veins in pulmonary sequestration is paramount to making the correct diagnosis. In contrast to intralobar pulmonary sequestration, where anomalous venous drainage is usually into the pulmonary venous system, the pattern of anomalous venous drainage is more varied in extralobar pulmonary sequestration. To the best of our knowledge, anomalous venous drainage to the internal mammary vein in extralobar sequestrations has not been reported. We report an anomalous venous drainage into the internal mammary vein in an extralobar sequestration which was evaluated with 3D multidetector CT angiography.

Modeling Alzheimer's disease and other proteopathies in vivo: is seeding the key?

Protein misfolding and aberrant polymerization are salient features of virtually all central neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease, triplet repeat disorders, tauopathies, and prion diseases. In many instances, a single amino acid change can predispose to disease by increasing the production and/or changing the biophysical properties of a specific protein. Possible pathogenic similarities among the cerebral proteopathies suggest that therapeutic agents interfering with the proteopathic cascade might be effective against a wide range of diseases. However, testing compounds preclinically will require disease-relevant animal models. Numerous transgenic mouse models of beta-amyloidosis, tauopathy, and other aspects of AD have now been produced, but none of the existing models fully recapitulates the pathology of AD. In an attempt to more faithfully replicate the human disease, we infused dilute AD-brain extracts into Tg2576 mice at 3-months of age (i.e. 5-6 months prior to the usual onset of beta-amyloid deposition). We found that intracerebral infusion of AD brain extracts results in: 1). Premature deposition of beta-amyloid in eight month-old, beta-amyloid precursor protein ( betaAPP)-transgenic mice (Kane et al., 2000); 2). augmented amyloid load in the injected hemisphere of 15 month-old transgenic mice; 3). evidence for the spread of pathology to other brain areas, possibly by neuronal transport mechanisms; and 4). tau hyperphosphorylation (but not neurofibrillary pathology) in axons passing through the injection site. The seeding of beta-amyloid in vivo by AD brain extracts suggests pathogenic similarities between beta-amyloidoses such as AD and other cerebral proteopathies such as the prionoses, and could provide a new model for studying the proteopathic cascade and its neuronal consequences in neurodegenerative diseases.

Evidence for seeding of beta -amyloid by intracerebral infusion of Alzheimer brain extracts in beta -amyloid precursor protein-transgenic mice.

Many neurodegenerative diseases are associated with the abnormal sequestration of disease-specific proteins in the brain, but the events that initiate this process remain unclear. To determine whether the deposition of the beta-amyloid peptide (Abeta), a key pathological feature of Alzheimer's disease (AD), can be induced in vivo, we infused dilute supernatants of autopsy-derived neocortical homogenates from Alzheimer's patients unilaterally into the hippocampus and neocortex of 3-month-old beta-amyloid precursor protein (betaAPP)-transgenic mice. Up to 4 weeks after the infusion there was no Abeta-deposition in the brain; however, after 5 months, the AD-tissue-injected hemisphere of the transgenic mice had developed profuse Abeta-immunoreactive senile plaques and vascular deposits, some of which were birefringent with Congo Red. There was limited deposition of diffuse Abeta also in the brains of betaAPP-transgenic mice infused with tissue from an age-matched, non-AD brain with mild beta-amyloidosis, but none in mice receiving extract from a young control case. Abeta deposits also were not found in either vehicle-injected or uninjected transgenic mice or in any nontransgenic mice. The results show that cerebral beta-amyloid can be seeded in vivo by a single inoculation of dilute AD brain extract, demonstrating a key pathogenic commonality between beta-amyloidosis and other neurodegenerative diseases involving abnormal protein polymerization. The paradigm can be used to clarify the conditions that initiate in vivo beta-amyloidogenesis in the brain and may yield a more authentic animal model of Alzheimer's disease and other neurodegenerative disorders.

The development of hypertrophic pyloric stenosis in a patient with prostaglandin-induced foveolar hyperplasia.

BACKGROUND: Hypertrophic pyloric stenosis (HPS) has been described in association with several obstructive antropyloric lesions including idiopathic foveolar hyperplasia (gastric mucosal hypertrophy), feeding tubes, eosinophilic gastroenteritis, and hypertrophic antral polyps. Non obstructive antral webs have also been described with HPS. PATIENT AND METHODS: We present a case of gastric-outlet obstruction in association with HPS, namely, prostaglandin-induced foveolar hyperplasia. This entity has been previously described, but rarely in association with HPS. We report a female infant requiring prostaglandin therapy for pulmonary atresia who developed dose-related prostaglandin-induced foveolar hyperplasia and symptoms of progressive non-bilious vomiting. RESULTS: Initially, ultrasonography demonstrated evidence of antral mucosal hypertrophy as the cause for gastric-outlet obstruction. The patient subsequently developed progressive thickening of the antropyloric muscle, resulting in sonographic appearances of hypertrophic pyloric stenosis. Pyloromyotomy was eventually required for treatment of HPS. CONCLUSION: A common denominator of most of the above-described entities is thickening and/or hypertrophy of the antral mucosa. We suggest that the antropyloric musculature may hypertrophy in an effort to overcome the gastric-outlet obstruction caused by the adjacent thickened antral mucosa. In other words, these entities may represent examples of "secondary" hypertrophic pyloric stenosis.

Milameline (CI-979/RU35926): a muscarinic receptor agonist with cognition-activating properties: biochemical and in vivo characterization.

Milameline (E-1,2,5,6-tetrahydro-1-methyl-3-pyridinecarboxaldehyde, O-methyloxime monohydrochloride, CI-979, PD129409, RU35926) was characterized in vitro and evaluated for effects on central and peripheral cholinergic activity in rats and rhesus monkeys. In muscarinic binding studies, milameline displayed nanomolar affinity with an agonist ligand and micromolar affinity with antagonist ligands, with approximately equal affinities determined at the five subtypes of human muscarinic receptors (hM(1)-hM(5)) with whole cells or membranes from stably transfected Chinese hamster ovary (CHO) cells. On binding, milameline stimulated phosphatidylinositol hydrolysis in hM(1) and hM(3) CHO cells and inhibited forskolin-activated cAMP accumulation in hM(2) and hM(4) CHO cells. Additionally, it decreased K(+)-stimulated release of [(3)H]acetylcholine from rat cortical slices. Responses were not caused by the inhibition of acetylcholinesterase, and there was no significant binding to approximately 30 other neurotransmitter binding sites. In rats, milameline decreased spontaneous and scopolamine-induced swimming activity, improved water-maze performance of animals impaired by basal forebrain lesions, increased cortical blood flow, decreased core body temperature, and increased gastrointestinal motility. Electroencephalogram activity in both rats and monkeys was characterized by a predominance of low-voltage desynchronized activity consistent with an increase in arousal. Milameline also reversed a scopolamine-induced impairment of attention on a continuous-performance task in monkeys. Thus, milameline possesses a pharmacological profile consistent with that of a partial muscarinic agonist, with central cholinergic actions being produced in rats and monkeys at doses slightly lower than those stimulating peripheral cholinergic receptors.

Cerebral lipid deposition in aged apolipoprotein-E-deficient mice.

To assess the influence of age and diet on cerebral pathology in mice lacking apolipoprotein E (apoE), four male apoE knockout mice (epsilon -/-), and five male wild-type (epsilon +/+) littermate controls were placed on a high-fat/high-cholesterol diet for 7 weeks beginning at 17 months of age. All four aged knockout mice developed xanthomatous lesions in the brain consisting mostly of crystalline cholesterol clefts, lipid globules, and foam cells. Smaller xanthomas were confined mainly to the choroid plexus and ventral fornix in the roof of the third ventricle, occasionally extending subpially along the choroidal fissure and into the adjacent parenchyma. More advanced xanthomas disrupted adjoining neural tissue in the fornix, hippocampus, and dorsal diencephalon; in one case, over 60% of one telencephalic hemisphere, including nearly the entire neocortex, was obliterated by the lesion. No xanthomas were observed in aged wild-type controls fed the high-fat/high-cholesterol diet. Brains from 42 additional animals, fed only conventional chow, were examined; 3 of 15 aged (15- to 23-month-old) apoE knockout mice developed small choroidal xanthomas. In contrast, no lesions were observed in five young (2- to 4-month-old) apoE knockout mice or in any wild-type controls between the ages of 2 and 23 months. Our findings indicate that disorders of lipid metabolism can induce significant pathological changes in the central nervous system of aged apoE knockout mice, particularly those on a high-fat/high-cholesterol diet. It may be fruitful to seek potential interactions between genetic factors and diet in modulating the risk of Alzheimer's disease and other neurodegenerative disorders in aged humans.

Cloning, tissue expression and regulation of rat interleukin 1 beta converting enzyme.

Using oligomer primers based on the cDNA sequence of human interleukin 1 beta converting enzyme (ICE), we have employed the RT-PCR method and rat spleen RNA to clone and sequence rat ICE. We report here that the predicted amino acid sequence of rat ICE proenzyme consists of 402 amino acids (p45) and shares 61% and 90% identity, respectively, with human and mouse ICE amino acid sequences. The active site cysteine (Cys284) and 3 or 3 potential processing sites are conserved suggesting that their the rat ICE heterodimer consists of a p22 (Ser104-Asp296) and a p10 (Gly315-His402) subunit or a cryptic processing site creates a smaller heterodimer. Northern blot analysis has revealed a approximately 2.2 kb and a more abundant approximately 1.45 kb ICE transcript both widely expressed in the rat with the highest expression in spleen and intestine and lowest in brain. IL-1 beta mRNA was similarly distributed. Injection of the immunostimulant, lipopolysaccharide (0.2 mg/kg, i.p.), increased rICE mRNA content between 2- to 3-fold in the rat brain with smaller increases measured in testis and spleen. The structural conservation of this enzyme suggests that rat models of inflammation will be useful for evaluating the therapeutic potential of ICE inhibitors in humans.

Electrocardiographic and echocardiographic changes associated with malignant catatonia.

We describe a case of malignant catatonia manifested by catatonic symptoms, fever, hemodynamic instability, and acute neurologic decline that was associated with electrocardiographic and echocardiographic abnormalities similar to those noted in patients with other central nervous system processes. The patient's electrocardiographic and echocardiographic abnormalities resolved after successful electroconvulsive therapy for the underlying neuropsychiatric disorder. The theoretic, physiologic, and clinical significances of this case are discussed.

Cardiopulmonary metastatic lesions of osteosarcoma and associated cerebral infarction.

Osteogenic sarcoma frequently disseminates by hematogenous routes. A 32-year-old patient underwent evaluation for an acute cerebral infarction. Cardiac auscultation disclosed an abnormal diastolic sound. Echocardiographic examination revealed a large left atrial mass, which was found at thoracotomy to be metastatic osteogenic sarcoma. Cerebral computed tomographic scans at the time of initial examination and 3 months later demonstrated new cerebral lesions consistent with metastatic growths. The abrupt cerebral infarction, other clinical findings, and results of diagnostic studies strongly suggested that the acute cerebrovascular event was the result of metastatic cerebral embolization from the tumor material found in the thorax. Cerebral infarction is an unusual and catastrophic complication of thoracic metastatic lesions of osteogenic sarcoma.

Paraneoplastic digital thrombosis: a case report.

Persistent digital ischemia is an uncommon paraneoplastic syndrome. We describe a 71-year-old man whose only manifestation of an underlying adenocarcinoma was digital ischemia. His symptoms responded dramatically to bilateral dorsal sympathectomies. A thorough search for the mechanism producing the ischemia failed to provide an explanation. We assume that unknown neurohumoral factors produced by the tumor were responsible.

Transient atrioventricular block after open-heart surgery for congenital heart disease.

The records of 22 patients with transient atrioventricular (AV) block after open-heart surgery for congenital heart disease from 1972 to 1978 were reviewed to determine the natural history of this entity. Preoperatively, no patient had AV block; 3 had right bundle branch block (BBB), 1 had left BBB and 5 had nonspecific intraventricular conduction delay. Complete AV block developed in 20 patients and Mobitz II AV block in 2. Transient AV block occurred intraoperatively in 14 patients and within 48 hours postoperatively in 8; AV block persisted for greater than or equal to 48 hours postoperatively in all patients, for a mean of 7.3 days (range 2 to 28). During a follow-up of 5.5 years (range 2.5 to 10), late AV block developed in 2 patients. None of the 18 patients whose escape QRS complex morphology during AV block was similar to the final QRS complex during normal sinus rhythm or atrial fibrillation with AV conduction had late AV block, whereas 2 of the 4 in whom it differed did (p less than 0.01). There was no difference in the escape rate between the 2 groups. Thus, late development of high-grade AV block is infrequent among patients with transient postoperative AV block. An escape QRS complex during postoperative AV block that differs from the QRS complex seen on recovery of normal sinus rhythm or atrial fibrillation with anterograde conduction may identify those at high risk of late AV block.