Ip M.S.,University of Wisconsin - Medical School |
Domalpally A.,University of Wisconsin - Medical School |
Sun J.K.,Joslin Diabetes Center |
Ophthalmology | Year: 2015
Purpose To assess the effects of intravitreal ranibizumab on diabetic retinopathy (DR) severity when administered for up to 3 years, evaluate the effect of delayed initiation of ranibizumab therapy on DR severity, and identify baseline patient characteristics associated with the development of proliferative DR (PDR). Design Exploratory analyses of phase III, randomized, double-masked, sham-controlled multicenter clinical trials. Participants Adults with diabetic macular edema (DME) (N = 759), baseline best-corrected visual acuity 20/40 to 20/320 Snellen equivalent, and central foveal thickness ≥275 μm. Methods Patients were randomized to monthly 0.3 or 0.5 mg ranibizumab or sham injections. Sham participants could switch to 0.5 mg ranibizumab during the third year (sham/0.5 mg crossover). Baseline risk factors were evaluated to explore potential associations with development of PDR. Time to first development of PDR was analyzed by Kaplan-Meier methods to calculate cumulative probabilities by group. Main Outcome Measures Study eye change on the Early Treatment Diabetic Retinopathy Study severity scale and a composite clinical outcome evaluating progression to PDR based on photographic changes plus clinically important events defining PDR. Results At month 36, a greater proportion of ranibizumab-treated eyes had ≥2- or ≥3-step DR improvement compared with sham/0.5 mg crossover. A ≥3-step improvement was achieved at 36 months by 3.3%, 15.0%, and 13.2% of sham/0.5 mg, 0.3 mg, and 0.5 mg ranibizumab-treated eyes, respectively (P < 0.0001). Through 36 months, 39.1% of eyes in the sham/0.5 mg group developed PDR, as measured by composite outcome, compared with 18.3% and 17.1% of eyes treated with 0.3 or 0.5 mg ranibizumab, respectively. The presence of macular capillary nonperfusion at baseline seems to be associated with progression to PDR in ranibizumab-treated eyes but did not meaningfully influence visual acuity improvement in eyes with DME after ranibizumab therapy. Conclusions Ranibizumab, as administered to patients with DME for 12 to 36 months in these studies, can both improve DR severity and prevent worsening. Prolonged delays in initiation of ranibizumab therapy may limit this therapeutic effect. Although uncommon, the development of PDR still occurs in a small percentage of eyes undergoing anti-vascular endothelial growth factor therapy and may be related to the presence of macular nonperfusion.
Domalpally A.,University of Wisconsin - Medical School |
Ip M.S.,University of Wisconsin - Medical School |
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.
Capruso D.X.,New York City College of Technology |
Hamsher K.D.,University of Wisconsin - Medical School
Cortex | Year: 2011
Introduction: Clinical evaluation and research on constructional ability have come to rely almost exclusively on two-dimensional tasks such as graphomotor copying or mosaic Block Design (BD). A return to the inclusion of a third dimension in constructional tests may increase the spatial demands of the task, and improve understanding of the relationship between visual perception and constructional ability in patients with cerebral disease. Method: Subjects were patients (n= 43) with focal or multifocal cerebrovascular lesions as determined by CT or MRI. Tests of temporal orientation, verbal intelligence, language, object vision and spatial vision were used to determine which factors were predictive of performance on two-dimensional BD and Three-Dimensional Block Construction (3-DBC) tasks. Results: Stepwise linear regression indicated that spatial vision predicted BD performance, and was even more strongly predictive of 3-DBC. Other cognitive domains did not account for significant additional variance in performance of either BD or 3-DBC. Bilateral cerebral lesions produced more severe deficits on BD than did unilateral cerebral lesions. The presence of a posterior cerebral lesion was the significant factor in producing deficits in 3-DBC. Conclusions: The spatial aspect of a constructional task is enhanced when the patient is required to assemble an object in all three dimensions of space. In the typical patient with cerebrovascular disease, constructional deficits typically occur in the context of a wider syndrome of deficits in spatial vision. © 2010 Elsevier.
Lemanske Jr. R.F.,University of Wisconsin - Medical School |
Busse W.W.,University of Wisconsin - Medical School
Journal of Allergy and Clinical Immunology | Year: 2010
Asthma is a complex disorder that displays heterogeneity and variability in its clinical expression both acutely and chronically. This heterogeneity is influenced by multiple factors including age, sex, socioeconomic status, race and/or ethnicity, and gene by environment interactions. Presently, no precise physiologic, immunologic, or histologic characteristics can be used to definitively make a diagnosis of asthma, and therefore the diagnosis is often made on a clinical basis related to symptom patterns (airways obstruction and hyperresponsiveness) and responses to therapy (partial or complete reversibility) over time. Although current treatment modalities are capable of producing control of symptoms and improvements in pulmonary function in the majority of patients, acute and often severe exacerbations still occur and contribute significantly to both the morbidity and mortality of asthma in all age groups. This review will highlight some of the important clinical features of asthma and emphasize recent advances in both pathophysiology and treatment. © 2010 American Academy of Allergy, Asthma & Immunology.
Beurg M.,University of Wisconsin - Medical School |
Kim K.X.,University of Wisconsin - Medical School |
Fettiplace R.,University of Wisconsin - Medical School
Journal of General Physiology | Year: 2014
Transmembrane channel-like (TMC) proteins TMC1 and TMC2 are crucial to the function of the mechanotransducer (MT) channel of inner ear hair cells, but their precise function has been controversial. To provide more insight, we characterized single MT channels in cochlear hair cells from wild-type mice and mice with mutations in Tmc1, Tmc2, or both. Channels were recorded in whole-cell mode after tip link destruction with BAPTA or after attenuating the MT current with GsMTx-4, a peptide toxin we found to block the channels with high affinity. In both cases, the MT channels in outer hair cells (OHCs) of wild-type mice displayed a tonotopic gradient in conductance, with channels from the cochlear base having a conductance (110 pS) nearly twice that of those at the apex (62 pS). This gradient was absent, with channels at both cochlear locations having similar small conductances, with two different Tmc1 mutations. The conductance of MT channels in inner hair cells was invariant with cochlear location but, as in OHCs, was reduced in either Tmc1 mutant. The gradient of OHC conductance also disappeared in Tmc1/Tmc2 double mutants, in which a mechanically sensitive current could be activated by anomalous negative displacements of the hair bundle. This "reversed stimulus-polarity" current was seen with two different Tmc1/Tmc2 double mutants, and with Tmc1/Tmc2/Tmc3 triple mutants, and had a pharmacological sensitivity comparable to that of native MT currents for most antagonists, except dihydrostreptomycin, for which the affinity was less, and for curare, which exhibited incomplete block. The existence in the Tmc1/Tmc2 double mutants of MT channels with most properties resembling those of wild-type channels indicates that proteins other than TMCs must be part of the channel pore. We suggest that an external vestibule of the MT channel may partly account for the channel's large unitary conductance, high Ca2+ permeability, and pharmacological profile, and that this vestibule is disrupted in Tmc mutants. © 2014 Beurg et al.
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.
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.
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.
Barlow C.A.,University of Wisconsin - Medical School |
Laishram R.S.,University of Wisconsin - Medical School |
Anderson R.A.,University of Wisconsin - Medical School
Trends in Cell Biology | Year: 2010
While the presence of phosphoinositides in the nuclei of eukaryotes and the identity of the enzymes responsible for their metabolism have been known for some time, their functions in the nucleus are only now emerging. This is illustrated by the recent identification of effectors for nuclear phosphoinositides. Like the cytosolic phosphoinositide signaling pathway, nuclear phosphatidylinositol 4,5-bisphosphate (PI4,5P2) is at the center of the pathway and acts both as a messenger and as a precursor for many additional messengers. Here, recent advances in the understanding of nuclear phosphoinositide signaling and its functions are reviewed with an emphasis on PI4,5P2 and its role in gene expression. The compartmentalization of nuclear phosphoinositide phosphates (PIPn) remains a mystery, but emerging evidence suggests that phosphoinositides occupy several functionally distinct compartments.
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.