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Madison, WI, United States

The University of Wisconsin School of Medicine and Public Health is a professional school for the study of medicine and public health at the University of Wisconsin–Madison. Wikipedia.

Schramp M.,University of Wisconsin - Medical School
Sub-cellular biochemistry | Year: 2012

Phosphatidylinositol 4,5-bisphosphate (PIP(2)) is a membrane bound lipid molecule with capabilities to affect a wide array of signaling pathways to regulate very different cellular processes. PIP(2) is used as a precursor to generate the second messengers PIP(3), DAG and IP(3), indispensable molecules for signaling events generated by membrane receptors. However, PIP(2) can also directly regulate a vast array of proteins and is emerging as a crucial messenger with the potential to distinctly modulate biological processes critical for both normal and pathogenic cell physiology. PIP(2) directly associates with effector proteins via unique phosphoinositide binding domains, altering their localization and/or enzymatic activity. The spatial and temporal generation of PIP(2) synthesized by the phosphatidylinositol phosphate kinases (PIPKs) tightly regulates the activation of receptor signaling pathways, endocytosis and vesicle trafficking, cell polarity, focal adhesion dynamics, actin assembly and 3' mRNA processing. Here we discuss our current understanding of PIPKs in the regulation of cellular processes from the plasma membrane to the nucleus. Source

Moss R.L.,University of Wisconsin - Madison | Moss R.L.,University of Wisconsin - Medical School | Fitzsimons D.P.,University of Wisconsin - Madison | Ralphe J.C.,University of Wisconsin - Madison
Circulation Research | Year: 2015

Cardiac myosin-binding protein-C (cMyBP-C) is a thick filament-associated protein that seems to contribute to the regulation of cardiac contraction through interactions with either myosin or actin or both. Several studies over the past several years have suggested that the interactions of cardiac myosin-binding protein-C with its binding partners vary with its phosphorylation state, binding predominantly to myosin when dephosphorylated and to actin when it is phosphorylated by protein kinase A or other kinases. Here, we summarize evidence suggesting that phosphorylation of cardiac myosin binding protein-C is a key regulator of the kinetics and amplitude of cardiac contraction during β-adrenergic stimulation and increased stimulus frequency. We propose a model for these effects via a phosphorylation-dependent regulation of the kinetics and extent of cooperative recruitment of cross bridges to the thin filament: phosphorylation of cardiac myosin binding protein-C accelerates cross bridge binding to actin, thereby accelerating recruitment and increasing the amplitude of the cardiac twitch. In contrast, enhanced lusitropy as a result of phosphorylation seems to be caused by a direct effect of phosphorylation to accelerate cross-bridge detachment rate. Depression or elimination of one or both of these processes in a disease, such as end-stage heart failure, seems to contribute to the systolic and diastolic dysfunction that characterizes the disease. © 2014 American Heart Association, Inc. Source

Tuite M.J.,University of Wisconsin - Medical School
Radiologic Clinics of North America | Year: 2010

Injuries in triathletes are common and are mostly overuse injuries. Rotator cuff tendinitis is the most common complaint from swimming, but the incidence of tendinopathy and rotator cuff tears on magnetic resonance imaging is comparable in triathletes without and with shoulder pain. Cycling injuries are mainly to the knee, including patellar tendinosis, iliotibial band syndrome, and patellofemoral stress syndrome, and to the Achilles tendon and the cervical and lumbar spine. Running is associated with most injuries in triathletes, during both training and racing, causing the athlete to discontinue the triathlon. In addition to knee injuries from running, triathletes may also develop foot and ankle, lower leg, and hip injuries similar to single-sport distance runners. Some injuries in triathletes may be mainly symptomatic during one of the three sports but are exacerbated by one or both of the other disciplines. © 2010 Elsevier Inc. Source

Fowler J.F.,University of Wisconsin - Medical School
British Journal of Radiology | Year: 2010

In 1989 the British Journal of Radiology published a review proposing the term biologically effective dose (BED), based on linear quadratic cell survival in radiobiology. It aimed to indicate quantitatively the biological effect of any radiotherapy treatment, taking account of changes in dose-per-fraction or dose rate, total dose and (the new factor) overall time. How has it done so far? Acceptable clinical results have been generally reported using BED, and it is in increasing use, although sometimes mistaken for "biologically equivalent dose", from which it differs by large factors, as explained here. The continuously bending nature of the linear quadratic curve has been questioned but BED has worked well for comparing treatments in many modalities, including some with large fractions. Two important improvements occurred in the BED formula. First, in 1999, high linear energy transfer (LET) radiation was included; second, in 2003, when time parameters for acute mucosal tolerance were proposed, optimum overall times could then be "triangulated" to optimise tumour BED and cell kill. This occurs only when both early and late BEDs meet their full constraints simultaneously. New methods of dose delivery (intensity modulated radiation therapy, stereotactic body radiation therapy, protons, tomotherapy, rapid arc and cyberknife) use a few large fractions and obviously oppose well-known fractionation schedules. Careful biological modelling is required to balance the differing trends of fraction size and local dose gradient, as explained in the discussion "How Fractionation Really Works". BED is now used for dose escalation studies, radiochemotherapy, brachytherapy, high-LET particle beams, radionuclide-targeted therapy, and for quantifying any treatments using ionising radiation. © 2010 The British Institute of Radiology. Source

Domalpally A.,University of Wisconsin - Medical School | Ip M.S.,University of Wisconsin - Medical School | Ehrlich J.S.,Genentech
Ophthalmology | Year: 2015

Purpose To evaluate the effect of monthly intravitreal ranibizumab on hard exudate (HE) area and the impact of HE on visual acuity (VA) outcomes in diabetic macular edema (DME) patients using data from 2 phase III clinical trials. Design Exploratory analyses of phase III, randomized, double-masked, sham-controlled, multicenter clinical trials. Participants Adults with DME, baseline best-corrected VA 20/40 to 20/320 Snellen equivalent, and central foveal thickness of ≥275 μm. Methods Between the 2 studies, 759 patients with DME were randomized to receive monthly 0.3 or 0.5 mg intravitreal ranibizumab (Lucentis; Genentech, Inc., South San Francisco, CA) or sham injections. Main Outcome Measures Hard exudate area was assessed from color fundus stereophotographs both on an ordinal scale and using continuous estimates of areas within the Early Treatment Diabetic Retinopathy Study grid. Results Data from 739 eyes were available for analysis. Mean baseline HE area was similar across treatment groups, ranging from 0.65 to 0.82 mm2. Through month 24, the percentage of eyes without HE increased from 20.9% to 36.3% in the sham group and from 22.1% to 61.3% and 23.6% to 62.0% in the ranibizumab 0.3-mg and 0.5-mg groups, respectively. Resolution of HE became apparent sometime after month 6 in ranibizumab-treated eyes. At baseline, there was no meaningful correlation between VA and presence or absence of HE. After baseline, there also was no consistent correlation between presence or absence of HE and change in VA over time. Conclusions In this exploratory analysis, monthly intravitreal ranibizumab resulted in significantly greater reduction of HE area compared with sham (P < 0.0001). In contrast to the rapid effects of ranibizumab on macular edema, changes in HE area were more gradual. Contrary to prior expectations, the presence and area of HE did not increase as DME resolved (either in the ranibizumab or sham groups). Importantly, baseline VA was not correlated with presence of HE, nor was the therapeutic benefit of ranibizumab on VA affected negatively by the presence of HE. These data suggest that in the context of intravitreal anti-vascular endothelial growth factor therapy, the presence of HE is not a prognostic indicator of poor visual outcomes. © 2015 American Academy of Ophthalmology. Source

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