Dr. Thomas  Dowling  Dds image

Dr. Thomas Dowling Dds

1771 E Main St
Omro WI 54963
920 852-2121
Medical School: Other - Unknown
Accepts Medicare: No
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License #: 3181
NPI: 1649374273
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Introgressive Hybridization and the Evolution of Lake-Adapted Catostomid Fishes. - PloS one
Hybridization has been identified as a significant factor in the evolution of plants as groups of interbreeding species retain their phenotypic integrity despite gene exchange among forms. Recent studies have identified similar interactions in animals; however, the role of hybridization in the evolution of animals has been contested. Here we examine patterns of gene flow among four species of catostomid fishes from the Klamath and Rogue rivers using molecular and morphological traits. Catostomus rimiculus from the Rogue and Klamath basins represent a monophyletic group for nuclear and morphological traits; however, the Klamath form shares mtDNA lineages with other Klamath Basin species (C. snyderi, Chasmistes brevirostris, Deltistes luxatus). Within other Klamath Basin taxa, D. luxatus was largely fixed for alternate nuclear alleles relative to C. rimiculus, while Ch. brevirostris and C. snyderi exhibited a mixture of these alleles. Deltistes luxatus was the only Klamath Basin species that exhibited consistent covariation of nuclear and mitochondrial traits and was the primary source of mismatched mtDNA in Ch. brevirostris and C. snyderi, suggesting asymmetrical introgression into the latter species. In Upper Klamath Lake, D. luxatus spawning was more likely to overlap spatially and temporally with C. snyderi and Ch. brevirostris than either of those two with each other. The latter two species could not be distinguished with any molecular markers but were morphologically diagnosable in Upper Klamath Lake, where they were largely spatially and temporally segregated during spawning. We examine parallel evolution and syngameon hypotheses and conclude that observed patterns are most easily explained by introgressive hybridization among Klamath Basin catostomids.
Population Structure in the Roundtail Chub (Gila robusta Complex) of the Gila River Basin as Determined by Microsatellites: Evolutionary and Conservation Implications. - PloS one
Ten microsatellite loci were characterized for 34 locations from roundtail chub (Gila robusta complex) to better resolve patterns of genetic variation among local populations in the lower Colorado River basin. This group has had a complex taxonomic history and previous molecular analyses failed to identify species diagnostic molecular markers. Our results supported previous molecular studies based on allozymes and DNA sequences, which found that most genetic variance was explained by differences among local populations. Samples from most localities were so divergent species-level diagnostic markers were not found. Some geographic samples were discordant with current taxonomy due to admixture or misidentification; therefore, additional morphological studies are necessary. Differences in spatial genetic structure were consistent with differences in connectivity of stream habitats, with the typically mainstem species, G. robusta, exhibiting greater genetic connectedness within the Gila River drainage. No species exhibited strong isolation by distance over the entire stream network, but the two species typically found in headwaters, G. nigra and G. intermedia, exhibited greater than expected genetic similarity between geographically proximate populations, and usually clustered with individuals from the same geographic location and/or sub-basin. These results highlight the significance of microevolutionary processes and importance of maintaining local populations to maximize evolutionary potential for this complex. Augmentation stocking as a conservation management strategy should only occur under extreme circumstances, and potential source populations should be geographically proximate stocks of the same species, especially for the headwater forms.
Effect of Common Excipients on the Oral Drug Absorption of Biopharmaceutics Classification System Class 3 Drugs Cimetidine and Acyclovir. - Journal of pharmaceutical sciences
The objective was to assess the impact of larger than conventional amounts of 14 commonly used excipients on Biopharmaceutics Classification System (BCS) class 3 drug absorption in humans. Cimetidine and acyclovir were used as model class 3 drugs across three separate four-way crossover bioequivalence (BE) studies (n = 24 each) in healthy human volunteers, denoted as study 1A, 1B, and 2. In study 1A and 1B, three capsule formulations of each drug were manufactured, collectively involving 14 common excipients. Capsule formulations that incorporated hydroxypropyl methylcellulose (HPMC) or magnesium stearate exhibited lower absorption. The cimetidine commercial solution contained sorbitol and also resulted in lower absorption. Hence, in study 2, two capsule formulations with lower amounts of HPMC and magnesium stearate, the sorbitol-containing commercial solution, and a sorbitol-free solution were assessed for BE. Overall, 12 common excipients were found in large amounts to not impact BCS class 3 drug absorption in humans, such that these excipients need not be qualitatively the same nor quantitatively very similar to reference, but rather simply be not more than the quantities studied here. Meanwhile, for each HPMC and microcrystalline cellulose, BCS class 3 biowaivers require these two excipients to be qualitatively the same and quantitatively very similar to the reference. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.© 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.
Validation of a Dosing Strategy for Cefazolin for Surgery Requiring Cardiopulmonary Bypass. - Surgical infections
A prospective, single center, open-label study was conducted to determine if the standard practice for surgical prophylaxis, which includes standardized dosing of cefazolin, at the University of Maryland Medical Center (UMMC) is adequate for patients placed on bypass during cardiac surgery.All patients were given the same standard dosing regimen regardless of weight: two grams of cefazolin administered within 1 h of incision, an additional one gram injected into the bypass circuit at the onset of bypass, and two grams every 3 h after the initial dose. Cefazolin serum concentrations were collected immediately after incision, after the start of bypass, each hour of bypass, at the end of bypass and at sternal closure.Ten patients were consented and completed the study with an average age of 62 y, average weight of 84.7 kg and average cardiopulmonary bypass time of 116 min. The free serum concentrations of cefazolin stayed above the pre-defined inhibitory threshold of 16 mcg/mL throughout the procedure for 100% of participants. The mean total serum concentration in the blood throughout surgery was 160 mcg/mL. No patients were found to have surgical site infections using standard criteria and no adverse events were observed.For patients undergoing cardiac surgery with cardiopulmonary bypass, the UMMC dosing regimen surpassed targeted cefazolin concentrations during the entire surgical procedure for all patients regardless of weight or time on bypass.
Influence of kidney disease on drug disposition: An assessment of industry studies submitted to the FDA for new chemical entities 1999-2010. - Journal of clinical pharmacology
In 1998, the United States Food and Drug Administration (FDA) released the first guidance for industry regarding pharmacokinetic (PK) studies in renally impaired patients. This study aimed to determine if the FDA renal PK guidance influenced the frequency and rigor of renal studies conducted for new chemical entities (NCEs). FDA-approved package inserts (APIs) and clinical pharmacology review documents were analyzed for 194 NCEs approved from 1999 to 2010. Renal studies were conducted in 71.6% of NCEs approved from 1999 to 2010, a significant increase over the 56.3% conducted from 1996 to 1997 (P = .0242). Renal studies were more likely to be completed in highly renally excreted drugs (fe ≥ 30%) compared with drugs with low renal excretion, fe < 30% (89.6% vs 65.8%, P = .0015). PK studies to assess the impact of dialysis were conducted for 31.7% of NCEs that had a renal study: a greater proportion of high fe NCEs were studied (44.2% vs 26.0%, P = .0335). No significant change in frequency or rigor of PK studies was detected over time. The majority of NCEs (76.3%) with a renal study provided specific dosing recommendations in the API. The adoption of the 1998 FDA guidance has resulted in improved availability of PK and drug-dosing recommendations, particularly for high fe drugs.© 2015, The American College of Clinical Pharmacology.
Estimation of Glomerular Filtration Rate in Patients With Cirrhosis by Using New and Conventional Filtration Markers and Dimethylarginines. - Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association
Equations used to estimate glomerular filtration rate (GFR) are not accurate in patients with cirrhosis. We aimed to develop a new equation to estimate the GFR in subjects with cirrhosis and compare its performance with chronic kidney disease epidemiology collaboration (CKD-EPI) cystatin C and creatinine-cystatin C equations, which were derived in populations without cirrhosis.From 2010 through 2014, we measured GFR in 103 subjects with cirrhosis based on non-radiolabeled iothalamate plasma clearance. We measured blood levels of creatinine, cystatin C, β-trace protein, β2-microglobulin, L-arginine, and symmetric and asymmetric dimethylarginines simultaneously with GFR. Multivariate linear regression analysis was performed to develop models to estimate GFR. Overall accuracy, defined by the root mean square error (RMSE) of our newly developed model to estimate GFR, was compared with that of the CKD-EPI equations. To obtain an unbiased estimate of our new equation to estimate GFR, we used a leave-one-out cross-validation strategy.After we considered all the candidate variables and blood markers of GFR, the most accurate equation we identified to estimate GFR included serum levels of creatinine and cystatin C, as well as patients' age, sex, and race. Overall, the accuracy of this equation (RMSE = 22.92) was superior to that of the CKD-EPI cystatin C equation (RMSE = 27.27, P = .004). Among subjects with cirrhosis and diuretic-refractory ascites, the accuracy of the equation we developed to estimate GFR (RMSE = 19.36) was greater than that of the CKD-EPI cystatin C (RMSE = 27.30, P = .003) and CKD-EPI creatinine-cystatin C equations (RMSE = 23.37, P = .004).We developed an equation that estimates GFR in subjects with cirrhosis and diuretic-refractory ascites with greater accuracy than the CKD-EPI cystatin C equation or CKD-EPI creatinine-cystatin C equation.Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.
Semi-permeable species boundaries in Iberian barbels (Barbus and Luciobarbus, Cyprinidae). - BMC evolutionary biology
The evolution of species boundaries and the relative impact of selection and gene flow on genomic divergence are best studied in populations and species pairs exhibiting various levels of divergence along the speciation continuum. We studied species boundaries in Iberian barbels, Barbus and Luciobarbus, a system of populations and species spanning a wide degree of genetic relatedness, as well as geographic distribution and range overlap. We jointly analyze multiple types of molecular markers and morphological traits to gain a comprehensive perspective on the nature of species boundaries in these cyprinid fishes.Intraspecific molecular and morphological differentiation is visible among many populations. Genomes of all sympatric species studied are porous to gene flow, even if they are not sister species. Compared to their allopatric counterparts, sympatric representatives of different species share alleles and show an increase in all measures of nucleotide polymorphism (S, Hd, K, π and θ). High molecular diversity is particularly striking in L. steindachneri from the Tejo and Guadiana rivers, which co-varies with other sympatric species. Interestingly, different nuclear markers introgress across species boundaries at various levels, with distinct impacts on population trees. As such, some loci exhibit limited introgression and population trees resemble the presumed species tree, while alleles at other loci introgress more freely and population trees reflect geographic affinities and interspecific gene flow. Additionally, extent of introgression decreases with increasing genetic divergence in hybridizing species pairs.We show that reproductive isolation in Iberian Barbus and Luciobarbus is not complete and species boundaries are semi-permeable to (some) gene flow, as different species (including non-sister) are exchanging genes in areas of sympatry. Our results support a speciation-with-gene-flow scenario with heterogeneous barriers to gene flow across the genome, strengthening with genetic divergence. This is consistent with observations coming from other systems and supports the notion that speciation is not instantaneous but a gradual process, during which different species are still able to exchange some genes, while selection prevents gene flow at other loci. We also provide evidence for a hybrid origin of a barbel ecotype, L. steindachneri, suggesting that ecology plays a key role in species coexistence and hybridization in Iberian barbels. This ecotype with intermediate, yet variable, molecular, morphological, trophic and ecological characteristics is the local product of introgressive hybridization of L. comizo with up to three different species (with L. bocagei in the Tejo, with L. microcephalus and L. sclateri in the Guadiana). In spite of the homogenizing effects of ongoing gene flow, species can still be discriminated using a combination of morphological and molecular markers. Iberian barbels are thus an ideal system for the study of species boundaries, since they span a wide range of genetic divergences, with diverse ecologies and degrees of sympatry.
Performance of a divided-load intravenous vancomycin dosing strategy for obese patients. - The Annals of pharmacotherapy
Current guidelines recommend vancomycin trough concentrations of 15 to 20 µg/mL in complicated infections and all trough concentrations >10 µg/mL to avoid developing microbial resistance. To date, no published protocol reliably meets these recommendations for obese patients.We assessed the performance of a novel, obese-specific, divided-load vancomycin protocol for attaining target trough concentrations within 12 to 24 hours of dosing initiation, and during maintenance dosing, in obese patients.The protocol was evaluated through prospective medical record review in 54 consecutive obese patients. Vancomycin serum concentrations were drawn before the third and fifth dose after initiation. Steady-state concentrations were drawn after the third dose once maintenance dosing was achieved and periodically thereafter.Within 12 hours after dosing initiation, 48 (89%) study patients exhibited trough concentrations of 10 to 20 µg/mL averaging 14.5 ± 3.2 µg/mL; 51 (94%) study patients exhibited trough concentrations >10 µg/mL within 12 hours after dosing initiation, and 3 (6%) had trough concentrations >20 µg/mL. Thirty-one participants had second trough concentrations drawn within 24 hours of dosing initiation, averaging 15.0 ± 3.1 µg/mL; 24 patients had a total of 32 trough concentrations drawn during maintenance dosing, averaging 15.1 ± 2.5 µg/mL.Obese-specific, divided-load dosing achieved trough concentrations of 10 to 20 µg/mL for 89% of obese patients within 12 hours of initial dosing and 97% of obese patients within 24 hours of initial dosing while preventing doses given during supratherapeutic trough levels; 97% of troughs measured during steady state were within target range.© The Author(s) 2015.
A pilot study to evaluate renal hemodynamics in cirrhosis by simultaneous glomerular filtration rate, renal plasma flow, renal resistive indices and biomarkers measurements. - American journal of nephrology
Renal hemodynamic measurements are complicated to perform in patients with cirrhosis, yet they provide the best measure of risk to predict hepatorenal syndrome (HRS). Currently, there are no established biomarkers of altered renal hemodynamics in cirrhosis validated by measured renal hemodynamics.In this pilot study, simultaneous measurements of glomerular filtration rate (GFR), renal plasma flow (RPF), renal resistive indices and biomarkers were performed to evaluate renal hemodynamic alterations in 10 patients with cirrhosis (3 patients without ascites, 5 with diuretic-sensitive and 2 diuretic-refractory ascites).Patients with diuretic-refractory ascites had the lowest mean GFR (36.5 ml/min/1.73 m(2)) and RPF (133.6 ml/min/1.73 m(2)) when compared to those without ascites (GFR 82.9 ml/min/1.73 m(2), RPF 229.9 ml/min/1.73 m(2)) and with diuretic-sensitive ascites (GFR 82.3 ml/min/1.73 m(2), RPF 344.1 ml/min/1.73 m(2)). A higher mean filtration fraction (FF) (GFR/RPF 0.36) was noted among those without ascites compared to those with ascites. Higher FF in patients without ascites is most likely secondary to the vasoconstriction in the efferent glomerular arterioles (normal FF ~0.20). In general, renal resistive indices were inversely related to FF. While patients with ascites had lower FF and higher right kidney main and arcuate artery resistive indices, those without ascites had higher FF and lower right kidney main and arcuate artery resistive indices. While cystatin C and β2-microglobulin performed better compared to Cr in estimating RPF, β-trace protein, β2-microglobulin, and SDMA, and (SDMA+ADMA) performed better in estimating right kidney arcuate artery resistive index.The results of this pilot study showed that identification of non-invasive biomarkers of reduced RPF and increased renal resistive indices can identify cirrhotics at risk for HRS at a stage more amenable to therapeutic intervention and reduce mortality from kidney failure in cirrhosis.
Time-series analysis reveals genetic responses to intensive management of razorback sucker (Xyrauchen texanus). - Evolutionary applications
Time-series analysis is used widely in ecology to study complex phenomena and may have considerable potential to clarify relationships of genetic and demographic processes in natural and exploited populations. We explored the utility of this approach to evaluate population responses to management in razorback sucker, a long-lived and fecund, but declining freshwater fish species. A core population in Lake Mohave (Arizona-Nevada, USA) has experienced no natural recruitment for decades and is maintained by harvesting naturally produced larvae from the lake, rearing them in protective custody, and repatriating them at sizes less vulnerable to predation. Analyses of mtDNA and 15 microsatellites characterized for sequential larval cohorts collected over a 15-year time series revealed no changes in geographic structuring but indicated significant increase in mtDNA diversity for the entire population over time. Likewise, ratios of annual effective breeders to annual census size (N b /N a) increased significantly despite sevenfold reduction of N a. These results indicated that conservation actions diminished near-term extinction risk due to genetic factors and should now focus on increasing numbers of fish in Lake Mohave to ameliorate longer-term risks. More generally, time-series analysis permitted robust testing of trends in genetic diversity, despite low precision of some metrics.

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