Excessive Adventitial Remodeling Leads to Early Aortic Maladaptation in Angiotensin-Induced Hypertension.

The primary function of central arteries is to store elastic energy during systole and to use it to sustain blood flow during diastole. Arterial stiffening compromises this normal mechanical function and adversely affects end organs, such as the brain, heart, and kidneys. Using an angiotensin II infusion model of hypertension in wild-type mice, we show that the thoracic aorta exhibits a dramatic loss of energy storage within 2 weeks that persists for at least 4 weeks. This diminished mechanical functionality results from increased structural stiffening as a result of an excessive accumulation of adventitial collagen, not a change in the intrinsic stiffness of the wall. A detailed analysis of the transmural biaxial wall stress suggests that the exuberant production of collagen results more from an inflammatory response than from a mechano-adaptation, hence reinforcing the need to control inflammation, not just blood pressure. Although most clinical assessments of arterial stiffening focus on intimal-medial thickening, these results suggest a need to measure and control the highly active and important adventitia.

Brain-derived neurotrophic factor in human subjects with function-altering melanocortin-4 receptor variants.

BACKGROUND: In rodents, hypothalamic brain-derived neurotrophic factor (BDNF) expression appears to be regulated by melanocortin-4 receptor (MC4R) activity. The impact of MC4R genetic variation on circulating BDNF in humans is unknown. OBJECTIVE: The objective of this study is to compare BDNF concentrations of subjects with loss-of-function (LOF) and gain-of-function (GOF) MC4R variants with those of controls with common sequence MC4R. METHODS: Circulating BDNF was measured in two cohorts with known MC4R sequence: 148 subjects of Pima Indian heritage ((mean±s.d.): age, 15.7±6.5 years; body mass index z-scores (BMI-Z), 1.63±1.03) and 69 subjects of Hispanic heritage (10.8±3.6 years; BMI-Z, 1.57±1.07). MC4R variants were characterized in vitro by cell surface expression, receptor binding and cyclic AMP response after agonist administration. BDNF single-nucleotide polymorphisms (SNPs) rs12291186, rs6265 and rs7124442 were also genotyped. RESULTS: In the Pima cohort, no significant differences in serum BDNF was observed for 43 LOF subjects versus 65 LOF-matched controls (age, sex and BMI matched; P=0.29) or 20 GOF subjects versus 20 GOF-matched controls (P=0.40). Serum BDNF was significantly associated with genotype for BDNF rs12291186 (P=0.006) and rs6265 (P=0.009), but not rs7124442 (P=0.99); BDNF SNPs did not interact with MC4R status to predict serum BDNF. In the Hispanic cohort, plasma BDNF was not significantly different among 21 LOF subjects, 20 GOF subjects and 28 controls (P=0.79); plasma BDNF was not predicted by BDNF genotype or BDNF-x-MC4R genotype interaction. CONCLUSIONS: Circulating BDNF concentrations were not significantly associated with MC4R functional status, suggesting that peripheral BDNF does not directly reflect hypothalamic BDNF secretion and/or that MC4R signaling is not a significant regulator of the bulk of BDNF expression in humans.

Hyperphagia among patients with Bardet-Biedl syndrome.

BACKGROUND: The importance of hyperphagia as a cause for energy imbalance in humans with Bardet-Biedl syndrome (BBS) has not been established. We therefore compared hyperphagic symptoms in patients with BBS vs. controls. METHODS: We studied 13 patients with BBS and 23 non-syndromic controls with similar age, sex and body mass index (BMI) z-score. A 13-item hyperphagia questionnaire was completed by patients' parents/guardians. RESULTS: Total hyperphagia questionnaire score was higher in BBS than controls (27.6 ± 9.0 vs. 19.1 ± 7.9, P = 0.005). Behaviour and drive subscales were higher for BBS than controls (12.5 ± 4.1 vs. 7.8 ± 3.2, P = 0.001, and 11.2 ± 4.1 vs. 8.3 ± 3.8, P = 0.04, respectively); severity was not significantly different between groups (3.8 ± 1.5 vs. 3.0 ± 1.3, P = 0.072). After adjustment for demographic variables and BMI z-score, total and behaviour subscale scores remained significantly different between groups, suggesting food-seeking activity, rather than preoccupation with food may be the main hyperphagic feature among patients with BBS. CONCLUSION: Appetite dysregulation may contribute to obesity in BBS.

Klippel-Trenaunay syndrome and cerebral haemangiopericytoma: a potential association.

Klippel-Trenaunay syndrome (KTS) a rare mesodermal phakomatosis consisting of capillary malformations, varicose veins, and limb hypertrophy, often associated with vascular malformations and benign tumours. A 33-year-old male presented with headaches secondary to a previously diagnosed intracranial tumour. He had a large blanching port-wine stain and hypertrophy of the left side of his body and limbs partial syndactyly of the 2(nd) and 3(rd) digits in all four extremities. The lesion was surgically resected and histology showed a Haemangiopericytoma. Thus KTS may be associated with intracranial Haemangiopericytomas, a malignant vascular tumour.

Brainstem and cortical Lewy bodies in patients presenting clinically with Alzheimer's disease.

In order to study the clinical overlap between neuropathologically defined Lewy body disease (LBD) and Alzheimer's disease, we examined the brains of 37 demented and 13 non-demented subjects. Nigral Lewy bodies (LBs) were present in 16/37 dementia patients, 13 of which had LBD. Eight of these 13 were clinically indistinguishable from AD patients, and in these cases isocortical neurofibrillary tangle (NFT) formation was rare. Thus, although the two conditions were clinically similar in this series, LBD could be distinguished from AD pathologically not only by the presence of nigral LBs but also by the relative paucity of isocortical NFTs.

Astrocytes degenerate in frontotemporal dementia: possible relation to hypoperfusion.

To understand the extent and specificity of astrocyte pathology in sporadic frontotemporal dementia (FTD), we examined several FTD cases for molecular and morphologic characteristics of astrocyte degeneration. We quantified reactive and degenerating astrocytes in sections of frontal, temporal, parietal, and occipital cortex identified using glial fibrillary acidic protein (GFAP) immunoreactivity, terminal deoxynucleotidyl transferase (TdT) labeling, and morphological characteristics and compared them with nondemented, age-matched control brains. Conventional and confocal microscopy revealed that a subpopulation of GFAP(+) astrocytes exhibited positive TdT labeling and beading of their processes in the frontal, temporal, and parietal cortices in 5 of 7 FTD cases that also exhibited gliosis. This morphology was reproduced in cultured astrocytes using ischemic insults. Degenerating astrocytes in FTD correlated inversely with cerebral blood flow as measured by single photon emission computed tomography (SPECT) analysis of (133)Xe inhalation (r = 0.55, p < 0.05). Furthermore, areas of significant astrogliosis corresponded to areas of SPECT hypoperfusion, suggesting that astrocytes may be affected by or perhaps have a causal role in the disturbances of cerebral perfusion in FTD.

Spinal cord infarction following vertebral angiography: clinical and pathological findings.

Spinal cord damage from radiographic contrast material has been known to occur in both spinal and nonspinal angiographic procedures. Reported here is cervical spinal cord injury (SCI) during vertebral angiography. During the procedure, the patient displayed signs of acute cervical spinal cord irritation that should have been taken as a warning of impending injury. Autopsy 9 years later showed evidence of central cervical spinal cord necrosis. The pathological findings are similar to those seen in animal models of contrast media-induced SCI; and the pathophysiological mechanisms of such injury are discussed.

DNA damage and activated caspase-3 expression in neurons and astrocytes: evidence for apoptosis in frontotemporal dementia.

Frontotemporal dementia (FTD) is a neurodegenerative disease which affects mainly the frontal and anterior temporal cortex. It is associated with neuronal loss, gliosis, and microvacuolation of lamina I to III in these brain regions. In previous studies we have described neurons with DNA damage in the absence of tangle formation and suggested this may result in tangle-independent mechanisms of neurodegeneration in the AD brain. In the present study, we sought to examine DNA fragmentation and activated caspase-3 expression in FTD brain where tangle formation is largely absent. The results demonstrate that numerous nuclei were TdT positive in all FTD brains examined. Activated caspase-3 immunoreactivity was detected in both neurons and astrocytes and was elevated in FTD cases as compared to control cases. A subset of activated caspase-3-positive cells were also TdT positive. In addition, the cell bodies of a subset of astrocytes showed enlarged, irregular shapes, and vacuolation and their processes appeared fragmented. These degenerating astrocytes were positive for activated caspase-3 and colocalized with robust TdT-labeled nuclei. These findings suggest that a subset of astrocytes exhibit degeneration and that DNA damage and activated caspase-3 may contribute to neuronal cell death and astrocyte degeneration in the FTD brain. Our results suggest that apoptosis may be a mechanism of neuronal cell death in FTD as well as in AD (228).

Molecular dating of senile plaques in the brains of individuals with Down syndrome and in aged dogs.

beta-Amyloid (Abeta) is a constituent of senile plaques found with increasing age in individuals with Down syndrome (DS) and in the canine model of aging. Sections of DS and dog brain were immunostained using an affinity-purified polyclonal antibody for a posttranslationally modified Abeta with a racemized aspartate at position 7 (d7C16). The immunostaining characteristics of d7C16 Abeta in DS and dog brain indicate that it is present in all plaque subtypes, including the thioflavin-S-negative diffuse plaques that develop with age in dogs. The youngest DS case exhibited weak immunolabeling for d7C16 but the extent of d7C16-positive plaques increased with age. In addition, d7C16-positive plaques were initially found in clusters in the superficial layers of the frontal and entorhinal cortex but, with advancing age, increasing numbers appeared in deeper layers, suggesting a progression of Abeta deposition from superficial to deeper cortical layers. Ultrastructural studies in DS brain were confirmed using perfused dog brain and provided consistent results; thioflavin-S-negative diffuse plaques consist of fibrillar Abeta and racemized Abeta is associated with thicker and more highly interwoven fibrils than nonracemized Abeta. The use of antibodies to modified forms of the Abeta protein should provide insight into the progression of plaque pathology in DS and Alzheimer's disease brain.

Membranous glomerulopathy with Bowman's capsular and tubular basement membrane deposits.

Bowman's capsular and tubular basement membrane (TBM) deposits are an extremely unusual finding in non-lupus membranous glomerulopathy (MGN). We report three atypical cases of MGN with abundant Bowman's capsular and TBM deposits. In two cases, MGN was idiopathic; in the third case, MGN occurred in the renal allograft in the setting of HCV seropositivity. In addition to the usual glomerular capillary wall deposits, immunofluorescence and electron microscopy revealed extensive immune deposits within Bowman's capsule and TBMs, predominantly at the base of parietal and tubular epithelial cells. These cases suggest a potential pathomechanism of autoantibody to secreted epithelial antigens shared by visceral, parietal, and tubular epithelial cells. In all three cases, indirect immunofluorescence was unable to detect autoantibody to normal renal epithelial or matrix constituents. Furthermore, ELISA was unable to demonstrate circulating antibody to major extracellular matrix components. The implications of these findings for the pathogenesis of MGN are explored.

An error detection and recovery algorithm for compressed video signal using source level redundancy.

The motion compensation-discrete cosine transform (MC-DCT) coding is an efficient compression technique for a digital video sequence. However, the compressed video signal is vulnerable to transmission errors over noisy channels. In this paper, we propose a robust video transmission algorithm, which protects the compressed video signal by inserting redundant information at the source level. The proposed algorithm encodes every lth frame in the semi-intra frame (S-frame) mode, in which the redundant parity-check DC coefficients (PDCs) are systematically inserted into the compressed bitstream. Then, the decoder is capable of recovering very severe transmission errors, such as loss of an entire frame, in addition to detecting the errors effectively without requesting any information from external devices. The proposed algorithm is implemented based on the H.263 coder, and tested intensively in realistic error prone environment. It is shown that the proposed algorithm provides much better objective and subjective performances than the conventional H.263 coder in the error prone environment.

Hybrid estimation of navigation parameters from aerial image sequence.

This work presents a hybrid method for navigation parameter estimation using sequential aerial images, where navigation parameters represent the position and velocity information of an aircraft for autonomous navigation. The proposed hybrid system is composed of two parts: relative position estimation and absolute position estimation. Computer simulation with two different sets of real aerial image sequences shows the effectiveness of the proposed hybrid parameter estimation algorithm.

Cefazolin in chronic hemodialysis patients: a safe, effective alternative to vancomycin.

Vancomycin use is common in hemodialysis patients, due in part to the ease of dosing, but can lead to the development of resistant organisms, including vancomycin-resistant enterococcus. Alternate antibiotics may be equally effective and allow similar dosing in the chronic hemodialysis population. A retrospective review of culture results from a 217-patient, non-hospital-based outpatient hemodialysis center was performed over a 7-month period. Wound and blood culture sensitivity to cefazolin, vancomycin, cefazolin plus gentamicin, and vancomycin plus gentamicin was analyzed. Cefazolin was equivalent to vancomycin for empiric treatment of clinically significant infections in a population with a low rate of methicillin-resistant Staphylococcus aureus infection. Cefazolin plus gentamicin was superior to vancomycin alone. The vancomycin plus gentamicin combination did provide minimally broader coverage than the cefazolin plus gentamicin combination. A prospective pharmacokinetic analysis of postdialysis cefazolin dosing was performed in anuric chronic hemodialysis patients dialyzed with polysulfone dialyzers. Peak, predialysis, and postdialysis cefazolin levels were obtained. Nondialysis clearance of cefazolin was sufficiently low (k(e), 0.027; t(1/2), 26.4 hours) and dialysis clearance sufficiently high (k(e), 0.254; t(1/2), 3.19 hours) to provide for safe and effective peak and trough cefazolin levels with postdialysis dosing in anuric hemodialysis patients. In conclusion, cefazolin alone or with gentamicin in an appropriate empiric antibiotic choice in chronic hemodialysis patients dialyzed in a nonhospital setting with low methicillin-resistant S. aureus infection rates. For infections with documented sensitivity to cefazolin, a 1 g intravenous dose postdialysis (750 mg in patients weighing <50 kg) is safe and effective.

Repin-induced neurotoxicity in rodents.

Russian knapweed is a perennial weed found in many parts of the world, including southern California. Chronic ingestion of this plant by horses has been reported to cause equine nigropallidal encephalomalacia (ENE), which is associated with a movement disorder simulating Parkinson's disease (PD). Repin, a principal ingredient purified from Russian knapweed, is a sesquiterpene lactone containing an alpha-methylenebutyrolactone moiety and epoxides and is a highly reactive electrophile that can readily undergo conjugation with various biological nucleophiles, such as proteins, DNA, and glutathione (GSH). We show in this study that repin is highly toxic to C57BL/6J mice and Sprague-Dawley rats and acutely induces uncoordinated locomotion associated with postural tremors, hypothermia, and inability to respond to sonic and tactile stimuli. We also show that repin intoxication reduces striatal and hippocampal GSH and increases total striatal dopamine (DA) levels in mice. Striatal microdialysis in rats, however, has demonstrated a significant reduction of extracellular DA levels. These findings, coupled with the absence of any demonstrable change in striatal DOPAC levels, suggest that repin acts by inhibiting DA release, a hypothesis that is further supported by our demonstration that, in cultured PC12 cells, repin inhibits the release of DA without affecting its uptake. We believe, therefore, that inhibition of DA release represents one of the earliest pathogenetic events in ENE, leading eventually to striatal extracellular DA denervation, oxidative stress, and degeneration of nigrostriatal pathways. Since the neurotoxic effects of repin appear to be mediated via oxidative stress, and since repin is a natural product isolated from a plant in our environment that can cause a movement disorder associated with degeneration of nigrostriatal pathways, clarification of the mechanism of repin neurotoxicity may provide new insights into our understanding of the pathogenesis of PD.

A fractal vector quantizer for image coding.

We investigate the relation between VQ (vector quantization) and fractal image coding techniques, and propose a novel algorithm for still image coding, based on fractal vector quantization (FVQ). In FVQ, the source image is approximated coarsely by fixed basis blocks, and the codebook is self-trained from the coarsely approximated image, rather than from an outside training set or the source image itself. Therefore, FVQ is capable of eliminating the redundancy in the codebook without any side information, in addition to exploiting the self-similarity in real images effectively. The computer simulation results demonstrate that the proposed algorithm provides better peak signal-to-noise ratio (PSNR) performance than most other fractal-based coders.

Fractal coding of video sequence using circular prediction mapping and noncontractive interframe mapping.

We propose a novel algorithm for fractal video sequence coding, based on the circular prediction mapping and the noncontractive interframe mapping. The proposed algorithm can effectively exploit the temporal correlation in real image sequences, since each range block is approximated by the domain block in the adjacent frame, which is of the same size as the range block. The computer simulation results demonstrate that the proposed algorithm provides very promising performance at low bit rate, ranging from 40-250 kbyte/s.

Acute hemorrhagic leukoencephalitis during treatment for disseminated tuberculosis in a patient with AIDS.

A 45-year-old man with the acquired immune deficiency syndrome (AIDS) developed disseminated Mycobacterium tuberculosis infection and was started on isoniazid, rifampin, pyrazinamide and ethambutol. The treatment was interrupted because of side effects. On resumption of treatment be developed a rapidly progressive neurological illness characterized by left hemiparesis, right gaze preference, convulsions, coma, evidence of cerebral edema on computed tomography scan and death 9 days later. Autopsy showed the presence of miliary tuberculosis affecting the lungs, liver, spleen, lymph nodes and bone marrow. The brain showed evidence of acute hemorrhagic leukoencephalitis (AHL)-the first such case in a patient with AIDS. We speculate that treatment-induced lysis of mycobacteria with concomitant release of mycobacterial lipoproteins may have activated T-lymphocytes to cause AHL in this patient.

Primary diffuse leptomeningeal gliomatosis with signs of increased intracranial pressure and progressive meningeal enhancement on MRI.

A 21-year-old woman presented with a 5-month history of meningeal signs and evidence of intracranial hypertension and, as shown by magnetic resonance imaging (MRI), progressively more extensive meningeal enhancement, particularly within the spinal canal. Autopsy disclosed the presence of primary diffuse leptomeningeal gliomatosis with spinal cord predominance, possibly arising within heterotopic leptomeningeal glial tissue in the cervical region. No parenchymal primary lesion was identified. MRI with gadolinium appears to be the imaging modality of choice for the early detection of primary diffuse leptomeningeal neoplasia.

Decreases in protease nexins in Alzheimer's disease brain.

A marked and significant reduction of protease nexin-1 (PN-1) and PN-2/amyloid beta protein precursor (A beta PP) was observed in selected regions of Alzheimer's disease (AD) brains as compared to those of aged-matched controls. Correlative analysis indicated a relationship between PN-1 reduction and the severity of pathologic alterations. A statistically significant inverse correlation was noted between the level of PN-1 activity and the density of tau-positive dystrophic neurites in the hippocampus. In view of the ability of thrombin and PN-1 activity to regulate neurite outgrowth, it is possible that abnormal thrombin and PN-1 interactions may play a role in dystrophic neurite formation. The presence of clusters of dystrophic neurites around the capillaries suggests that blood-brain barrier (BBB) dysfunction may enhance such abnormal interactions. The decrease in PN-2/A beta PP levels in AD brains could possibly contribute to neuronal degeneration in AD in view of the ability of PN-2/A beta PP to protect neurons against the toxic effects of the A beta.

Mycobacterium genavense infection presenting as a solitary brain mass in a patient with AIDS: case report and review.

Patients with AIDS are prone to developing infections with opportunistic pathogens. Recently, a new mycobacterium, Mycobacterium genavense, has been found to cause infection in patients with AIDS. Previously published reports indicate that patients who are infected with this organism present with the same clinical features as do patients with disseminated infection due to organisms of the Mycobacterium avium complex. We describe an unusual case of a patient with AIDS who presented with grand mal seizures and a mass lesion in his brain, which was found to be caused by infection with M. genavense. No evidence of disseminated infection could be found in this patient. We discuss the microbiology of this organism and review the literature on M. genavense infections. Clinicians should be aware of this organism so that efforts at culture and identification will be made.