Postsecondary and Vocational Education Programs and the Otherwise Qualified Provision of Section 504 of the Rehabilitation Act of 1973

While the Rehabilitation Act defines a handicapped individual,\u27\u27 neither the language of section 504 nor its legislative history sheds much light on the exact meaning of the term \u27\u27otherwise qualified handicapped individual.\u27\u27 This article will argue that the definition of this term must be broad enough to include severely handicapped persons, the primary group that Congress intended to benefit and protect in enacting section 504. Focussing on the area of postsecondary education, this article will argue that the interpretation developed in the Department of Health, Education and Welfare (HEW) Regulation most effectively fulfills the purposes which Congress intended in enacting section 504. The article examines who is a qualified handicapped student entitled to non- . discriminatory admission to and participation in college, university, and vocational programs. The article also examines the challenges to affirmative duties placed upon schools which admit handicapped applicants

Youth is wasted on the young

Amphibians and zebrafish are able to regenerate lost myocardial tissue without loss of cardiac function; whereas mammals, in response to myocardial injury, develop scar and lose cardiac function. This dichotomy of response has been thought to be due to the fact that adult mammalian cardiac myocytes are multinucleated and have limited proliferative capacity. Neonatal mammalian cardiac myocytes do have a limited capacity to proliferate. What has been unknown is whether this limited proliferative capacity is associated with the ability to regenerate myocardial tissue soon after birth. Recently, it has been demonstrated that 1-day-old neonatal mice do have the ability to regenerate resected cardiac tissue, and that the capacity to regenerate cardiac tissue is lost by 7 days after birth. The present commentary reviews these results and attempts to offer perspective as to how these important findings relate to current and future strategies to prevent and treat cardiac dysfunction in clinical populations

Myeloperoxidase and Plasminogen Activator Inhibitor 1 Play a Central Role in Ventricular Remodeling after Myocardial Infarction

Left ventricular (LV) remodeling after myocardial infarction (MI) results in LV dilation, a major cause of congestive heart failure and sudden cardiac death. Ischemic injury and the ensuing inflammatory response participate in LV remodeling, leading to myocardial rupture and LV dilation. Myeloperoxidase (MPO), which accumulates in the infarct zone, is released from neutrophils and monocytes leading to the formation of reactive chlorinating species capable of oxidizing proteins and altering biological function. We studied acute myocardial infarction (AMI) in a chronic coronary artery ligation model in MPO null mice (MPO−/−). MPO−/− demonstrated decreased leukocyte infiltration, significant reduction in LV dilation, and marked preservation of LV function. The mechanism appears to be due to decreased oxidative inactivation of plasminogen activator inhibitor 1 (PAI-1) in the MPO−/−, leading to decreased tissue plasmin activity. MPO and PAI-1 are shown to have a critical role in the LV response immediately after MI, as demonstrated by markedly delayed myocardial rupture in the MPO−/− and accelerated rupture in the PAI-1−/−. These data offer a mechanistic link between inflammation and LV remodeling by demonstrating a heretofore unrecognized role for MPO and PAI-1 in orchestrating the myocardial response to AMI

Searching for a Stochastic Background of Gravitational Waves with LIGO

The Laser Interferometer Gravitational-wave Observatory (LIGO) has performed the fourth science run, S4, with significantly improved interferometer sensitivities with respect to previous runs. Using data acquired during this science run, we place a limit on the amplitude of a stochastic background of gravitational waves. For a frequency independent spectrum, the new limit is $\Omega_{\rm GW} < 6.5 \times 10^{-5}$. This is currently the most sensitive result in the frequency range 51-150 Hz, with a factor of 13 improvement over the previous LIGO result. We discuss complementarity of the new result with other constraints on a stochastic background of gravitational waves, and we investigate implications of the new result for different models of this background.Comment: 37 pages, 16 figure

Bone Marrow Support of the Heart in Pressure Overload Is Lost with Aging

Exogenous stem cell delivery is under investigation to prevent and treat cardiac dysfunction. It is less studied as to the extent endogenous bone marrow derived stem cells contribute to cardiac homeostais in response to stress and the affects of aging on this stress response.To determine the role of bone marrow (BM) derived stem cells on cardiac homeostasis in response to pressure overload (PO) and how this response is altered by aging.Young (8 weeks) and old (>40 weeks) C57/b6 mice underwent homo- and heterochronic BM transplantation prior to transverse aortic constriction (TAC). We found that older BM is associated with decreased cardiac function following TAC. This decreased function is associated with decrease in BM cell engraftment, increased myocyte apoptosis, decreased myocyte hypertrophy, increased myocardial fibrosis and decreased cardiac function. Additionally, there is a decrease in activation of resident cells within the heart in response to PO in old mice. Interestingly, these effects are not due to alterations in vascular density or inflammation in response to PO or differences in ex vivo stem cell migration between young and old mice.BM derived stem cells are activated in response to cardiac PO, and the recruitment of BM derived cells are involved in cardiac myocyte hypertrophy and maintenance of function in response to PO which is lost with aging

Significance of Thymosin β4 and Implication of PINCH-1-ILK-α-Parvin (PIP) Complex in Human Dilated Cardiomyopathy

Myocardial remodeling is a major contributor in the development of heart failure (HF) after myocardial infarction (MI). Integrin-linked kinase (ILK), LIM-only adaptor PINCH-1, and α-parvin are essential components of focal adhesions (FAs), which are highly expressed in the heart. ILK binds tightly to PINCH-1 and α-parvin, which regulates FA assembly and promotes cell survival via the activation of the kinase Akt. Mice lacking ILK, PINCH or α-parvin have been shown to develop severe defects in the heart, suggesting that these proteins play a critical role in heart function. Utilizing failing human heart tissues (dilated cardiomyopathy, DCM), we found a 2.27-fold (p<0.001) enhanced expression of PINCH, 4 fold for α-parvin, and 10.5 fold (p<0.001) for ILK as compared to non-failing (NF) counterparts. No significant enhancements were found for the PINCH isoform PINCH-2 and parvin isoform β-parvin. Using a co-immunoprecipitation method, we also found that the PINCH-1-ILK-α-parvin (PIP) complex and Akt activation were significantly up-regulated. These observations were further corroborated with the mouse myocardial infarction (MI) and transaortic constriction (TAC) model. Thymosin beta4 (Tβ4), an effective cell penetrating peptide for treating MI, was found to further enhance the level of PIP components and Akt activation, while substantially suppressing NF-κB activation and collagen expression—the hallmarks of cardiac fibrosis. In the presence of an Akt inhibitor, wortmannin, we show that Tβ4 had a decreased effect in protecting the heart from MI. These data suggest that the PIP complex and activation of Akt play critical roles in HF development. Tβ4 treatment likely improves cardiac function by enhancing PIP mediated Akt activation and suppressing NF-κB activation and collagen-mediated fibrosis. These data provide significant insight into the role of the PIP-Akt pathway and its regulation by Tβ4 treatment in post-MI

Inference of Co-Evolving Site Pairs: an Excellent Predictor of Contact Residue Pairs in Protein 3D structures

Residue-residue interactions that fold a protein into a unique three-dimensional structure and make it play a specific function impose structural and functional constraints on each residue site. Selective constraints on residue sites are recorded in amino acid orders in homologous sequences and also in the evolutionary trace of amino acid substitutions. A challenge is to extract direct dependences between residue sites by removing indirect dependences through other residues within a protein or even through other molecules. Recent attempts of disentangling direct from indirect dependences of amino acid types between residue positions in multiple sequence alignments have revealed that the strength of inferred residue pair couplings is an excellent predictor of residue-residue proximity in folded structures. Here, we report an alternative attempt of inferring co-evolving site pairs from concurrent and compensatory substitutions between sites in each branch of a phylogenetic tree. First, branch lengths of a phylogenetic tree inferred by the neighbor-joining method are optimized as well as other parameters by maximizing a likelihood of the tree in a mechanistic codon substitution model. Mean changes of quantities, which are characteristic of concurrent and compensatory substitutions, accompanied by substitutions at each site in each branch of the tree are estimated with the likelihood of each substitution. Partial correlation coefficients of the characteristic changes along branches between sites are calculated and used to rank co-evolving site pairs. Accuracy of contact prediction based on the present co-evolution score is comparable to that achieved by a maximum entropy model of protein sequences for 15 protein families taken from the Pfam release 26.0. Besides, this excellent accuracy indicates that compensatory substitutions are significant in protein evolution.Comment: 17 pages, 4 figures, and 4 tables with supplementary information of 5 figure

How Similar Are the Mice to Men? Between-Species Comparison of Left Ventricular Mechanics Using Strain Imaging

BACKGROUND: While mammalian heart size maintains constant proportion to whole body size, scaling of left ventricular (LV) function parameters shows a more complex scaling pattern. We used 2-D speckle tracking strain imaging to determine whether LV myocardial strains and strain rates scale to heart size. METHODS: We studied 18 mice, 15 rats, 6 rabbits, 12 dogs and 20 human volunteers by 2-D echocardiography. Relationship between longitudinal or circumferential strains/strain rates (S(Long)/SR(Long), S(Circ)/SR(Circ)), and LV end-diastolic volume (EDV) or mass were assessed by the allometric (power-law) equation Y = kM(β). RESULTS: Mean LV mass in individual species varied from 0.038 to 134 g, LV EDV varied from 0.015 to 102 ml, while RR interval varied from 81 to 1090 ms. While S(Long) increased with increasing LV EDV or mass (β values 0.047±0.006 and 0.051±0.005, p<0.0001 vs. 0 for both) S(Circ) was unchanged (p = NS for both LV EDV or mass). Systolic and diastolic SR(Long) and SR(Circ) showed inverse correlations to LV EDV or mass (p<0.0001 vs. 0 for all comparisons). The ratio between S(Long) and S(Circ) increased with increasing values of LV EDV or mass (β values 0.039±0.010 and 0.040±0.011, p>0.0003 for both). CONCLUSIONS: While S(Circ) is unchanged, S(Long) increases with increasing heart size, indicating that large mammals rely more on long axis contribution to systolic function. SR(Long) and SR(Circ), both diastolic and systolic, show an expected decrease with increasing heart size

Effect of hydrocephalus on rat brain extracellular compartment

<p>Abstract</p> <p>Background</p> <p>The cerebral cortex may be compressed in hydrocephalus and some experiments suggest that movement of extracellular substances through the cortex is impaired. We hypothesized that the extracellular compartment is reduced in size and that the composition of the extracellular compartment changes in rat brains with kaolin-induced hydrocephalus.</p> <p>Methods</p> <p>We studied neonatal (newborn) onset hydrocephalus for 1 or 3 weeks, juvenile (3 weeks) onset hydrocephalus for 3–4 weeks or 9 months, and young adult (10 weeks) onset hydrocephalus for 2 weeks, after kaolin injection. Freeze substitution electron microscopy was used to measure the size of the extracellular compartment. Western blotting and immunohistochemistry with quantitative image densitometry was used to study the extracellular matrix constituents, phosphacan, neurocan, NG2, decorin, biglycan, and laminin.</p> <p>Results</p> <p>The extracellular space in cortical layer 1 was reduced significantly from 16.5 to 9.6% in adult rats with 2 weeks duration hydrocephalus. Western blot and immunohistochemistry showed that neurocan increased only in the periventricular white matter following neonatal induction and 3 weeks duration hydrocephalus. The same rats showed mild decorin increases in white matter and around cortical neurons. Juvenile and adult onset hydrocephalus was associated with no significant changes.</p> <p>Conclusion</p> <p>We conclude that compositional changes in the extracellular compartment are negligible in cerebral cortex of hydrocephalic rats at various ages. Therefore, the functional change related to extracellular fluid flow should be reversible.</p