Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder that results in retinal degeneration, obesity, cognitive impairment, polydactyly, renal abnormalities, and hypogenitalism. Of the 12 known BBS genes, BBS1 is the most commonly mutated, and a single missense mutation (M390R) accounts for Ϸ80% of BBS1 cases. To gain insight into the function of BBS1, we generated a Bbs1 M390R/M390R knockin mouse model. Mice homozygous for the M390R mutation recapitulated aspects of the human phenotype, including retinal degeneration, male infertility, and obesity. The obese mutant mice were hyperphagic and hyperleptinemic and exhibited reduced locomotor activity but no elevation in mean arterial blood pressure. Morphological evaluation of Bbs1 mutant brain neuroanatomy revealed ventriculomegaly of the lateral and third ventricles, thinning of the cerebral cortex, and reduced volume of the corpus striatum and hippocampus. Similar abnormalities were also observed in the brains of Bbs2 ؊/؊ , Bbs4 ؊/؊ , and Bbs6 ؊/؊ mice, establishing these neuroanatomical defects as a previously undescribed BBS mouse model phenotype. Ultrastructural examination of the ependymal cell cilia that line the enlarged third ventricle of the Bbs1 mutant brains showed that, whereas the 9 ؉ 2 arrangement of axonemal microtubules was intact, elongated cilia and cilia with abnormally swollen distal ends were present. Together with data from transmission electron microscopy analysis of photoreceptor cell connecting cilia, the Bbs1 M390R mutation does not affect axonemal structure, but it may play a role in the regulation of cilia assembly and/or function.B ardet-Biedl syndrome [BBS, Online Mendelian Inheritance in Man (OMIM) 209900] is a genetically heterogeneous autosomal recessive disorder characterized by obesity, retinal degeneration, polydactyly, cognitive impairment, hypogenitalism, and renal abnormalities, as well as susceptibility to hypertension, diabetes mellitus, olfaction deficits, and congenital cardiac defects. Twelve BBS genes (BBS1-12) have been identified to date (1-14). They encode a set of proteins thought to play a role in the structure or function of cilia, basal bodies, and intracellular transport (15, 16). Mutations in BBS1 are the most commonly observed in BBS. A single missense mutation that converts a methionine codon to an arginine codon (M390R) accounts for Ϸ80% of BBS1 mutations and is involved in 25% of all BBS cases (5). The M390R mutation occurs near predicted regions of coiled-coil protein domains and lies within a conserved predicted WD40-like protein motif. These protein motifs are involved in such basic biological processes as signal transduction, RNA synthesis/processing, chromatin assembly, vesicular trafficking, cytoskeletal assembly, cell cycle control, and apoptosis (17).Recently, BBS1, BBS2, BBS4, BBS5, BBS7, BBS8, and BBS9 were shown to form a stable Ϸ450-kDa protein complex called the BBSome in cultured retinal pigment epithelial (RPE) cells and mouse testes. Depletion of some components of the BBSome, ...

Bardet-Biedl syndrome (BBS) is a heterogeneous genetic disorder characterized by many features, including obesity and cardiovascular disease. We previously developed knockout mouse models of 3 BBS genes: BBS2, BBS4, and BBS6. To dissect the mechanisms involved in the metabolic disorders associated with BBS, we assessed the development of obesity in these mouse models and found that BBS-null mice were hyperphagic, had low locomotor activity, and had elevated circulating levels of the hormone leptin. The effect of exogenous leptin on body weight and food intake was attenuated in BBS mice, which suggests that leptin resistance may contribute to hyperleptinemia. In other mouse models of obesity, leptin resistance may be selective rather than systemic; although mice became resistant to leptin's anorectic effects, the ability to increase renal sympathetic nerve activity (SNA) was preserved. Although all 3 of the BBS mouse models were similarly resistant to leptin, the sensitivity of renal SNA to leptin was maintained in Bbs4 -/-and Bbs6 -/-mice, but not in Bbs2 -/-mice. Consequently, Bbs4 -/-and Bbs6 -/-mice had higher baseline renal SNA and arterial pressure and a greater reduction in arterial pressure in response to ganglionic blockade. Furthermore, we found that BBS mice had a decreased hypothalamic expression of proopiomelanocortin, which suggests that BBS genes play an important role in maintaining leptin sensitivity in proopiomelanocortin neurons.

Background-Treatment of hyperlipidemia produces functional and structural improvements in atherosclerotic vessels.However, the effects of treating hyperlipidemia on the structure and function of the aortic valve have been controversial, and any effects could be confounded by pleiotropic effects of hypolipidemic treatment. The goal of this study was to determine whether reducing elevated plasma lipid levels with a "genetic switch" in Reversa mice (LdlrϪ/Ϫ/Apob ) reduces oxidative stress, reduces pro-osteogenic signaling, and retards the progression of aortic valve disease. Methods and Results-After 6 months of hypercholesterolemia, Reversa mice exhibited increases in superoxide, lipid deposition, myofibroblast activation, calcium deposition, and pro-osteogenic protein expression in the aortic valve. Maximum aortic valve cusp separation, as judged by echocardiography, was not altered. During an additional 6 months of hypercholesterolemia, superoxide levels, valvular lipid deposition, and myofibroblast activation remained elevated. Furthermore, calcium deposition and pro-osteogenic gene expression became more pronounced, and the aortic cusp separation decreased from 0.85Ϯ0.04 to 0.70Ϯ0.04 mm (meanϮSE; PϽ0.05). Rapid normalization of cholesterol levels at 6 months of age (by inducing expression of Cre recombinase) normalized aortic valve superoxide levels, decreased myofibroblast activation, reduced valvular calcium burden, suppressed pro-osteogenic signaling cascades, and prevented reductions in aortic valve cusp separation. Conclusions-Collectively, these data indicate that reducing plasma lipid levels by genetic inactivation of the mttp gene in hypercholesterolemic mice with early aortic valve disease normalizes oxidative stress, reduces pro-osteogenic signaling, and halts the progression of aortic valve stenosis. Key Words: aortic valve stenosis Ⅲ calcification Ⅲ free radicals Ⅲ hypercholesterolemia Ⅲ valves R eplacement of the aortic valve is the primary treatment for patients with symptomatic calcific aortic valve stenosis and is the second-most-common thoracic surgery procedure in the United States. 1 Risk factors for the development of aortic valve stenosis are similar to those of atherosclerosis and include older age, 2 male sex, hypertension, smoking, diabetes mellitus, 1,2 and hypercholesterolemia. 2 Stenotic aortic valves resemble atherosclerotic lesions pathologically and contain calcium, 3 high levels of matrix-remodeling enzymes, 4 -6 reduced endothelial nitric oxide synthase levels, 7 and increased oxidative stress. 8 -10 Both stenotic valves and atherosclerotic lesions contain a subpopulation of cells with osteoblast-like activity, [11][12][13][14] suggesting that deposition of calcium in these lesions is an active process. Editorial see p 2653 Clinical Perspective on p 2701Reducing plasma cholesterol levels in humans and experimental animals slows the progression and/or reduces the size of atherosclerotic lesions, 15,16 reduces oxidative stress, 17 and improves nitric oxide bioavailability, 15,18 ...

We present a new modeling framework for recognition memory and repetition priming based on signal detection theory. We use this framework to specify and test the predictions of 4 models: (a) a single-system (SS) model, in which one continuous memory signal drives recognition and priming; (b) a multiple-systems-1 (MS1) model, in which completely independent memory signals (such as explicit and implicit memory) drive recognition and priming; (c) a multiple-systems-2 (MS2) model, in which there are also 2 memory signals, but some degree of dependence is allowed between these 2 signals (and this model subsumes the SS and MS1 models as special cases); and (d) a dual-process signal detection (DPSD1) model, 1 possible extension of a dual-process theory of recognition (Yonelinas, 1994) to priming, in which a signal detection model is augmented by an independent recollection process. The predictions of the models are tested in a continuous-identification-with-recognition paradigm in both normal adults (Experiments 1-3) and amnesic individuals (using data from Conroy, Hopkins, & Squire, 2005). The SS model predicted numerous results in advance. These were not predicted by the MS1 model, though could be accommodated by the more flexible MS2 model. Importantly, measures of overall model fit favored the SS model over the others. These results illustrate a new, formal approach to testing theories of explicit and implicit memory.

A single-system computational model of priming and recognition was applied to studies that have looked at the relationship between priming, recognition, and fluency in continuous identification paradigms. The model was applied to 3 findings that have been interpreted as evidence for a multiple-systems account: (a) priming can occur for items not recognized; (b) the pattern of identification reaction times (RTs) to hits, misses, correct rejections, and false alarms can change as a function of recognition performance; and (c) fluency effects (shorter RTs to words judged old vs. judged new) and priming effects (shorter RTs to old vs. new words) can be observed in amnesic patients at levels comparable with healthy adults despite impaired or near-chance recognition. The authors' simulations suggest, contrary to previous interpretations, that these results are consistent with a single-system account.

Objectives: To determine whether patients with suspected heart failure but preserved systolic function, as determined by conventional echocardiographic measures (often said to have "diastolic heart failure), might have subtle left ventricular systolic dysfunction detectable by a new measure of left ventricular systolic function-left ventricular systolic atrioventricular plane displacement. Design: Observational study. Setting: Direct access echocardiography. Patients: 147 patients with suspected heart failure referred by general practitioners. Measurements: Echocardiographic assessment of conventional measures of left ventricular systolic function (fractional shortening, ejection fraction (by Simpson's biplane method) and "eyeball" assessment) and measurement of left ventricular systolic atrioventricular plane displacement. Results: Between 21% and 33% of patients with "normal" left ventricular systolic function by conventional methods were found to have abnormal left ventricular systolic atrioventricular plane displacement.Conclusions: Approximately one quarter of patients with suspected heart failure but preserved systolic function by conventional methods have abnormal atrioventricular plane displacement. These patients with suspected heart failure but preserved systolic function by conventional echocardiographic measures may have heart failure caused by subtle systolic dysfunction rather than isolated "diastolic heart failure". P atients with the signs and symptoms of heart failure but apparently normal left ventricular systolic function (and no other obvious cause of heart failure) present a puzzle. Accumulating reports suggest that up to one third, or even one half, of all patients with a clinical diagnosis of heart failure are of this type.1-5 Recent studies suggest that these patients have a prognosis that is nearly as bad as that for patients with heart failure and reduced left ventricular systolic function.6 7 Despite this, we do not really understand what is wrong with patients who seem to have heart failure and apparently preserved systolic function. Perhaps more important, we do not know how to treat them.Though it has become popular to describe these patients as having "diastolic heart failure" caused by "diastolic dysfunction", it is also possible that unrecognised, subtle left ventricular systolic function may be present. Diastolic dysfunction is usually assumed because some measure of left ventricular systolic function is found to be within a normal range. Typically, this is left ventricular ejection fraction, left ventricular fractional shortening, or, more commonly, an "eyeball" assessment. Recently, what is thought to be a better measurement of predominantly systolic function has been described. Left ventricular systolic atrioventricular (AV) plane displacement, principally a measure of left ventricular systolic function, may be more sensitive than conventional indices. 8-15This technique measures longitudinal rather than circumferential shortening of the left ventricle. METHODS PatientsThe co...

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