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Comparative analysis of beta-blockers with other antihypertensive agents on cardiovascular outcomes in hypertensive patients with diabetes mellitus: a systematic review and meta-analysis

Saravanan Balamuthusamy, MD - Fri, 01/16/2009 - 05:00

Am J Ther. 2009 Mar-Apr;16(2):133-42. doi: 10.1097/MJT.0b013e31817fd87e.


OBJECTIVES: To analyze the effects of beta-blockers (BBs) on cardiovascular (CV) outcomes in diabetic patients with hypertension.

DATA SOURCE: Literature search was performed with relevant search words using PubMed and Ovid Gateway search engines for trials published in English from June 1996 to July 2007.

REVIEW METHODS: Systematic reviews of randomized control trials that used BBs as treatment or control therapy in diabetic patients with hypertension were included for the analysis. All the included studies use intention-to-treat analysis. Two individual authors procured the data. Myocardial infarction, stroke, CV mortality, and total mortality were the outcomes analyzed. Relative risk across the different groups was calculated using Mantel-Haenszel random- and fixed-effects model. Interstudy heterogeneity was computed by chi(2) test. Results were calculated with 95%confidence intervals (CIs) and were considered significant with double-sided alpha error less than 0.05. Funnel plot was used to assess for publication bias.

RESULTS: Eight trials (N = 130,270) met the inclusion criteria for the analysis. The relative risks for myocardial infarction, stroke, CV mortality, and total mortality were 1.08 (95% CI 0.82-1.42; P = 0.6), 1.13 (95% CI 0.95-1.36; P = 0.1), 1.15 (95% CI 0.83-1.6; P = 0.3), and 1.16 (95% CI 0.92-1.47; P = 0.2), respectively. BBs were associated with increased risk for CV mortality 1.39 (95% CI 1.07-1.804; P ,0.01) when compared with renin angiotensin blockade (RAS) therapy.

CONCLUSION: BBs have increased risk for CV mortality when compared with RAS blockade therapy in diabetic patients with hypertension. BBs do not have increased risk for myocardial infarction, stroke, CV mortality, and total mortality when compared with control antihypertensive therapy in diabetic patients with hypertension.

PMID:19145207 | DOI:10.1097/MJT.0b013e31817fd87e

Pioglitazone and the risk of myocardial infarction and other major adverse cardiac events: a meta-analysis of randomized, controlled trials

Saravanan Balamuthusamy, MD - Thu, 01/08/2009 - 05:00

Am J Ther. 2008 Nov-Dec;15(6):506-11. doi: 10.1097/MJT.0b013e318167180c.


A recent meta-analysis suggested that the use of rosiglitazone increases the risk of myocardial infarction (MI) in patients with type 2 diabetes mellitus. It is unclear whether this is a class effect of thiazolidinediones (TZD). We did a meta-analysis to evaluate cardiovascular outcomes with the use of pioglitazone. Randomized, controlled trials in which pioglitazone was compared with placebo or other hypoglycemic agents were considered for analysis. Studies were included if the data for MI were available. Studies were identified with use of relevant search words in Medline, Pubmed, EMBASE, CINAHL, and Cochrane databases. Data abstraction was done by 2 individual authors using a standardized protocol. The relative risk across all study groups was computed by the Mantel-Haenszel method, and interstudy heterogeneity was assessed by the chi method. All results were computed according to 95% confidence intervals. Five trials (N = 9965) met the inclusion criteria for analysis. The relative risk for MI was 0.86 (0.69-1.07; P = 0.17). The relative risks for stroke and revascularization were 0.79 (0.61-1.02; P = 0.07) and 0.40 (0.13-1.23; P = 0.11), respectively. Pioglitazone does not increase the risk for MI and may decrease the risk for stroke and revascularization.

PMID:19127132 | DOI:10.1097/MJT.0b013e318167180c

Family medicine residency educational characteristics and career satisfaction in recent graduates

Richard Young, MD - Wed, 10/22/2008 - 05:00

Fam Med. 2008 Jul-Aug;40(7):484-91.


BACKGROUND AND OBJECTIVES: Career satisfaction among family physicians has declined over the last 15 years. The purpose of this study was to determine what aspects of residency training are associated with family medicine career satisfaction in recent graduates.

METHODS: This was a cross-sectional national survey of 1000 family physicians who graduated within the last 10 years. Questions were primarily Likert type. Exploratory factor analysis was used to identify retained factors. Bivariate and multivariate linear regression analyses were performed to identify residency characteristics, demographics, and current work characteristics that were associated with career satisfaction.

RESULTS: The response rate was 55.8% (558/1000). Exploratory factor analysis found three factors that explained the majority of the variance in career satisfaction: overall work life, rigorous residency training, and demographic factors. Many features of residency training were associated with career satisfaction on bivariate analysis. Multivariate analysis found that training that was exceptionally broad and in-depth was independently associated with career satisfaction. The factors with the largest association with career satisfaction were medical career satisfaction and current work satisfaction.

DISCUSSION: Our findings suggest that residency education that was broad and in-depth was associated with early family medicine career satisfaction. This construct reflected rigorous training that included hands-on procedural experience, breadth of experiences with patients and illness, and care for complex hospitalized patients.


Femoral vs jugular venous catheterization for short-term dialysis access

Saravanan Balamuthusamy, MD - Thu, 10/16/2008 - 05:00

JAMA. 2008 Oct 15;300(15):1760-1; author reply 1761-2. doi: 10.1001/jama.300.15.1760-c.


PMID:18854533 | DOI:10.1001/jama.300.15.1760-c

The role of viscosupplementation in the ankle using hylan G-F 20

Travis Motley, DPM - Sat, 08/30/2008 - 05:00

J Foot Ankle Surg. 2008 Sep-Oct;47(5):377-84. doi: 10.1053/j.jfas.2008.06.013.


The use of intra-articular injections of high molecular weight elastoviscous solutions of hyaluronan or hylans (cross-linked derivatives of hyaluronan) to treat arthritis is termed viscosupplementation. The function of viscosupplementation is to restore the rheologic properties of synovial fluid. Although anecdotal data exist, no long-term studies regarding the use of viscosupplementation in the ankle have been published to date. The goal of this clinical trial was to compare pain reduction following ankle arthroscopy versus that following ankle arthroscopy combined with weekly intra-articular instillation of hylan G-F 20 during the first 3 postoperative weeks. In the series of patients described in this report, we found that both treatment groups experienced statistically significantly decreased pain following the intervention (P = .002 and P = .0009 for the arthroscopy alone and arthroscopy plus hylan groups, respectively), and that those who received 3 intra-articular injections of hylan G-F 20 following ankle arthroscopy improved statistically significantly (P = .0014) more than did those who underwent arthroscopy as a sole therapy. These preliminary results suggest that viscosupplementation combined with arthroscopy may be more beneficial than arthroscopy alone, and provide further insight into the role of viscosupplementation in the treatment of ankle osteoarthritis.


PMID:18725116 | DOI:10.1053/j.jfas.2008.06.013

The effects of body mass index on graft survival in adult recipients transplanted with single pediatric kidneys

Saravanan Balamuthusamy, MD - Tue, 08/12/2008 - 05:00

Am J Nephrol. 2009;29(2):94-101. doi: 10.1159/000151293. Epub 2008 Aug 11.


BACKGROUND: There is insufficient data on the impact of recipient body mass index (BMI) on the long-term graft survival of adult patients transplanted with single pediatric kidneys.

METHODS: We performed a retrospective analysis of adult patients transplanted with single pediatric kidneys at our center. The recipients were classified into 2 groups: group 1 (BMI > or =30) and group 2 (BMI <30). Donor/recipient demographics, postoperative outcomes and survival rates were compared between the 2 groups.

RESULTS: There was no significant difference in donor/recipient demographics between the 2 groups. In group 1, the death-censored graft survival (DCGS) at 1, 3 and 5 years was 90% at all 3 time points, and in group 2 it was 86, 68 and 60%, respectively (p = 0.05). The mean glomerular filtration rate (with standard deviation in parentheses) at 1, 3 and 5 years was, respectively, 55 (15), 59 (19) and 55 (28) ml/min for group 1, compared to 65 (28), 69 (23) and 67 (20) ml/min in group 2 (p = NS). Multivariate analysis revealed a hazard ratio of 5.12 (95% confidence interval 1.06-24.7; p = 0.04) for graft loss in nonobese patients when compared to obese patients. Obese patients had an increased risk for acute rejections within the first month of transplant (p = 0.02).

CONCLUSION: Patients with a BMI > or =30 transplanted with single pediatric kidneys have better DCGS rates when compared to nonobese patients.

PMID:18689988 | DOI:10.1159/000151293

Silencing megalin and cubilin genes inhibits myeloma light chain endocytosis and ameliorates toxicity in human renal proximal tubule epithelial cells

Saravanan Balamuthusamy, MD - Fri, 05/02/2008 - 05:00

Am J Physiol Renal Physiol. 2008 Jul;295(1):F82-90. doi: 10.1152/ajprenal.00091.2008. Epub 2008 Apr 30.


Using target-specific short interfering (si) RNAs, we silenced the tandem endocytic receptors megalin and cubilin genes in cultured human renal proximal tubule epithelial cells. Transfection by siRNA resulted in up to 90% suppression of both megalin and cubilin protein and mRNA expression. In HK-2 cells exposed to kappa-light chain for up to 24 h, light chain endocytosis was reduced in either megalin- or cubilin-silenced cells markedly but incompletely. Simultaneous silencing of both the cubilin and megalin genes, however, resulted in near-complete inhibition of light chain endocytosis, as determined by measuring kappa-light chain protein concentration in cell cytoplasm and by flow cytometry using FITC-labeled kappa-light chain. In these cells, light chain-induced cytokine responses (interleukin-6 and monocyte chemoattractant protein-1) and epithelial-to-mesenchymal transition as well as the associated cellular and morphological alterations were also markedly suppressed. The results demonstrate that light chain endocytosis is predominantly mediated by the megalin-cubilin tandem endocytic receptor and identify endocytosis as a key step in light chain cytotoxicity. Blocking light chain endocytosis prevents its nephrotoxic effects on human kidney proximal tubule cells.

PMID:18448595 | DOI:10.1152/ajprenal.00091.2008

Renin angiotensin system blockade and cardiovascular outcomes in patients with chronic kidney disease and proteinuria: a meta-analysis

Saravanan Balamuthusamy, MD - Tue, 04/29/2008 - 05:00

Am Heart J. 2008 May;155(5):791-805. doi: 10.1016/j.ahj.2008.01.031.


OBJECTIVE: The role of renin angiotensin system (RAS) blockade in controlling hypertension and the positive impact on cardiovascular (CV) outcomes is well known. However, the role of RAS blockade in improving CV outcomes in patients with chronic kidney disease (CKD) is still unclear.

METHODS: Randomized controlled trials that analyzed CV outcomes in patients with CKD/proteinuria treated with RAS blockade (angiotensin-converting enzyme inhibitors/angiotensin receptor blockers) were included in our study. The relative risk across all study groups was computed using Mantel-Hanszel random effects model. Results were calculated with 95% CI and was considered statistically significant if 2-sided alpha error was <.05. Renin angiotensin system blockade-based therapy was compared with placebo and control (beta-blocker, calcium-channel blockers and other antihypertensive-based therapy) therapy in the study.

RESULTS: Twenty-five trials (N = 45758) were used for analysis. Renin angiotensin system blockade decreased the risk for heart failure in patients with diabetic nephropathy when compared with placebo 0.78 (95% CI 0.66-0.92, P = .003) and control therapy (0.63, 95% CI 0.47-0.86, P = .003). The risk for CV outcomes was decreased with RAS blockade (0.56, 95% CI 0.47-0.67, P < .001) in nondiabetic nephropathy patients with CKD when compared with control therapy. There was also a significant reduction of CV outcomes (0.84, 95% CI 0.78-0.91, P < .0001), myocardial infarction (0.78, 95% CI 0.65-0.97, P = .03), and heart failure (0.74, 95% CI 0.58-0.95, P = .02) when we pooled all the patients with CKD and compared RAS blockade to placebo.

CONCLUSIONS: A pooled analysis of all causes of CKD revealed a reduction in the risk for myocardial infarction, heart failure, and total CV outcomes when RAS blockade was compared with placebo. RAS blockade decreases the risk for CV outcomes and heart failure when compared with control therapy in patients with proteinuria. There were also benefits with RAS blockade in reducing the risk of CV outcomes and heart failure in patients with diabetic nephropathy when compared with placebo.

PMID:18440325 | DOI:10.1016/j.ahj.2008.01.031

Clinical utility of cardiac troponin I in the diagnosis of acute coronary syndrome in patients with renal failure

Saravanan Balamuthusamy, MD - Thu, 08/02/2007 - 05:00

Am J Ther. 2007 Jul-Aug;14(4):356-60. doi: 10.1097/01.mjt.0000212700.86872.3c.


To analyze sensitivity and specificity of cardiac troponin I (cTnI) in detecting obstructive coronary artery disease in African American population with renal insufficiency presenting with acute coronary syndrome. Retrospective analysis of 108 patients who underwent coronary angiography over a 3-year period in a single institution. A troponin I level of 0.1 ng/mL or higher was considered abnormal troponin I. Renal insufficiency was defined as creatinine of 1.2 mg/dL or higher. Obstructive coronary artery disease (CAD) was defined as luminal diameter reduction of 70% or more (or total occlusion) in at least 1 coronary artery. Patients were divided into group 1 (renal insufficiency without need for hemodialysis, n = 76, mean age = 65) and group 2 (patients requiring hemodialysis, n = 32, mean age = 60). Access Accu TnI method was used to quantitate cTnI where murine monoclonal antibodies specifically bind to the C-terminal end of cTnI. In group 1, 41 (54%) patients had abnormal troponin of whom 37 (90%) had CAD and 4 (10%) had normal angiogram; 35 (46%) patients had normal troponin, of whom 25 (71%) had CAD and 10 (29%) had normal angiogram yielding a sensitivity of 60% and specificity of 71% (P = 0.003; 95% confidence interval). In group 2, 20 (63%) had abnormal troponin of whom 19 (95%) had CAD and 1(5%) had normal angiogram; 12 (38%) had normal troponin of whom 7 (59%) had CAD and 5 (41%) had normal angiogram yielding a sensitivity of 73% and specificity of 83% (P = 0.06; 95% confidence interval). cTnI has a sensitivity of 60% and specificity of 71% in acute coronary syndrome patients with renal insufficiency. In patients on hemodialysis, troponin I has a sensitivity of 73% and specificity of 83% for detection of obstructive CAD.

PMID:17667211 | DOI:10.1097/01.mjt.0000212700.86872.3c

Research funding and mentoring in family medicine residencies

Richard Young, MD - Wed, 06/06/2007 - 05:00

Fam Med. 2007 Jun;39(6):410-8.


BACKGROUND AND OBJECTIVES: This study's purpose was to measure the current status of research funding and mentoring in family medicine residencies and to ascertain what resources are needed to increase residencies' research output.

METHODS: This was a cross-sectional survey of family medicine residency program directors in the United States. We measured grant funding sources, availability of mentors, the likelihood programs could qualify for National Institutes of Health (NIH) K awards, barriers to research, and how these factors varied by program type.

RESULTS: The response rate was 66% (298/453). Medical school-based programs were much more likely to report that their family medicine faculty wrote funded research grants than were community-based medical school affiliated programs (76% versus 32%). The majority of both program types reported that research mentors were available (85% versus 60%). Very few programs of either type were likely to meet the minimum requirements for NIH K01, K08, or K23 awards (29% for medical school programs versus 3% for community programs). The most commonly reported specific resources needed to increase research output were time, money, and more faculty (range 86% to 92% between program types).

CONCLUSIONS: The majority of family medicine residencies did not receive grant funding for research, reported that time and money were the most significant barriers to research, but were ineligible to receive support from NIH K awards. More realistic funding mechanisms are needed to support residency-based research faculty.


Caring for a surge of Hurricane Katrina evacuees in primary care clinics

Richard Young, MD - Thu, 03/29/2007 - 05:00

Ann Fam Med. 2007 Mar-Apr;5(2):170-4. doi: 10.1370/afm.646.


Primary care physicians are rarely mentioned in medical disaster plans. We describe how a group of mostly family physicians and administrators of the JPS Health Network (JPS) took primary responsibility for 3,700 evacuees of Hurricane Katrina who came to Tarrant County, Texas. JPS provided medical care to 1,664 (45%) evacuees during a 2-week period. The most common needs were medications for chronic illnesses and treatment of skin infections (primarily on the feet). The JPS Emergency Department saw only 148 evacuees, most of whom arrived by their own transportation and were not seriously ill. JPS created a triage center located several miles from the hospital that referred almost all evacuees with health care needs to a primary care clinic. It was an effective approach for caring for the medical needs of disaster victims and prevented an emergency department and hospital from being overwhelmed. The JPS experience may guide future planning efforts for natural or manmade disasters, especially pandemic threats.

PMID:17389543 | PMC:PMC1838682 | DOI:10.1370/afm.646

Hematologic adverse effects of clopidogrel

Saravanan Balamuthusamy, MD - Sat, 02/17/2007 - 05:00

Am J Ther. 2007 Jan-Feb;14(1):106-12. doi: 10.1097/01.mjt.0000212708.81034.22.


Clopidogrel is used as a frontline antiplatelet agent in patients with coronary artery disease, cerebrovascular disease, and peripheral vascular disease. Hematologic complications and bleeding have been the most feared outcome of antithrombotic and antiplatelet agents. Among the thienopyridines, clopidogrel is considered to be a safer alternative to ticlopidine due to its decreased incidence of hematologic adverse effects. Although thrombotic thrombocytopenia purpura is the most reported hematologic adverse effect of clopidogrel; neutropenia, acquired hemophilia, isolated thrombocytopenia or idiopathic immune thrombocytopenia, and thrombotic thrombocytopenia purpura with hemolytic uremic syndrome are other rare yet recognized hematologic adverse effects of clopidogrel. Patients treated with clopidogrel should be carefully monitored for hematologic adverse effects especially in the first 2 to 3 months after initiation of therapy. Early recognition and prompt initiation of treatment can be life saving in patients who have hematologic adverse effects to clopidogrel. We have drafted this review by performing literature search using Medline, Pubmed, and EMBASE search engine with relevant search words for all reported hematologic adverse effects and manifestations of clopidogrel and their management.

PMID:17303978 | DOI:10.1097/01.mjt.0000212708.81034.22

Statins, diet, and low cholesterol

Saravanan Balamuthusamy, MD - Thu, 06/08/2006 - 05:00

JAMA. 2006 Jun 7;295(21):2479; author reply 2479-80. doi: 10.1001/jama.295.21.2479-b.


PMID:16757717 | DOI:10.1001/jama.295.21.2479-b

Research participation, protected time, and research output by family physicians in family medicine residencies

Richard Young, MD - Fri, 05/05/2006 - 05:00

Fam Med. 2006 May;38(5):341-8.


BACKGROUND AND OBJECTIVES: The Future of Family Medicine project concluded that research must become a greater part of the culture of the specialty. We examined the participation of family physician residency faculty in research, their protected time, and their research output and how these varied by program type.

METHODS: This was a cross-sectional survey of all family medicine residency programs in the United States. The response rate was 66% (298/453).

RESULTS: The majority of programs reported at least one family physician who participates in research, though the medical school-based (MSB) programs reported a higher total number of faculty than the community-based, medical school affiliated (MSA) programs (9.53 versus 2.72) and percentage of faculty (56% versus 37%). Substantially more MSB programs reported that they had at least one family physician with significant protected time for research (48% versus 7% for > 25% protected time) or any protected time (69% for MSB versus 45% for MSA). MSB programs and MSA programs reported similar success at producing at least one poster or paper for national meetings within the last 3 years (63% versus 41%) but not for published papers (86% versus 43%).

CONCLUSIONS: We found that only about half of the family medicine residencies produced any nationally recognized research over a 3-year period and that this represents only a small improvement over the last 10 years. Our findings suggest that more support is needed if research is to become an integral part of the culture of family medicine.


Myocardial infarction in a young African-American male due to myocardial bridging

Saravanan Balamuthusamy, MD - Thu, 02/16/2006 - 05:00

Cardiology. 2006;105(3):165-7. doi: 10.1159/000091400. Epub 2006 Feb 10.


Myocardial bridging is a clinically uncommon congenital anomaly characterized by tunneling of the coronary artery within the myocardial tissue, usually seen in the left anterior descending artery. Myocardial bridging is associated with altered intracoronary hemodynamics during systole and diastole, determined by the severity and the location of the bridging within the coronary artery. Patients with myocardial bridging may present with angina in the absence of other coronary risk factors which may paradoxically improve with exercise due to an increased intrasystolic pressure, preventing vessel compression. It is uncommon to have bridging in the right coronary artery; it is even more uncommon to have right coronary artery bridging with angina and significant ECG changes. We present a case involving bridging of the right coronary artery with significant symptoms and ECG changes.

PMID:16479103 | DOI:10.1159/000091400

Evaluation of fibula free flap donor site morbidity

Travis Motley, DPM - Tue, 12/20/2005 - 05:00

Am J Otolaryngol. 2006 Jan-Feb;27(1):29-32. doi: 10.1016/j.amjoto.2005.07.003.


OBJECTIVE: To evaluate foot and ankle function in a series of patients undergoing fibula microvascular free tissue transfer.

STUDY DESIGN: A nonrandomized, nonblinded analysis was performed using the ankle-hindfoot scale as well as radiographic analysis to determine donor site morbidity.

RESULTS: Overall, foot ankle function was deemed to be good in this series of patients. Average ankle-hindfoot score was 84.82 of a possible 100 (range, 55-100). Radiographic analysis of donor and contralateral ankles showed no difference in the syndesmotic space or medial clear space. Only 1 patient had increased talar tilt compared with the contralateral side, although this patient had preservation of stability.

CONCLUSION: Fibula free flap harvest appears to be associated with acceptable donor site morbidity and preservation of good foot and ankle function in most individuals.

PMID:16360820 | DOI:10.1016/j.amjoto.2005.07.003

Protein C deficiency: podiatric medical relevance and case report

Travis Motley, DPM - Sat, 09/17/2005 - 05:00

J Am Podiatr Med Assoc. 2005 Sep-Oct;95(5):491-3. doi: 10.7547/0950491.


We describe the management of a patient who presented to a family-practice clinic with gangrenous digits. After a thorough evaluation, she was found to have protein C deficiency, which produced a hypercoagulable state. Differential diagnosis in the evaluation of the coagulopathic patient with appropriate hematologic tests is briefly discussed.

PMID:16166470 | DOI:10.7547/0950491

Bone matrix therapy for aneurysmal bone cysts

Travis Motley, DPM - Sat, 07/23/2005 - 05:00

J Am Podiatr Med Assoc. 2005 Jul-Aug;95(4):394-7. doi: 10.7547/0950394.


Aneurysmal bone cysts are unique pathologic entities that cause pain and local osseous destruction. Many surgical treatment modalities have been described. This article reports on the case of a 16-year-old high school athlete with left heel pain due to an aneurysmal bone cyst in the calcaneus. Curettage of the bone cyst was performed, and the void was filled with a commercially available mixture of cancellous bone and demineralized bone matrix. Early return to athletic activity was achieved, with no recurrence noted at 3-year follow-up.

PMID:16037557 | DOI:10.7547/0950394

Placement of solid screws with cannulated precision

Travis Motley, DPM - Wed, 11/24/2004 - 05:00

J Surg Orthop Adv. 2004 Fall;13(3):177-9.


Cannulated screws can be inserted in a precise manner with minimal damage to surrounding structures but lack the mechanical strength of solid screws. Our method allows the insertion of a solid screw with the precision of the cannulated technique. With the use of equipment from a variety of operative sets from one manufacturer, a "custom" equipment set can be developed. This "custom" equipment set allows the surgeon to benefit from the strength of solid screws while preserving the precision of a cannulated system.


Adding stability to the crescentic basilar first metatarsal osteotomy

Travis Motley, DPM - Tue, 09/21/2004 - 05:00

J Am Podiatr Med Assoc. 2004 Sep-Oct;94(5):502-4. doi: 10.7547/0940502.


Crescentic basilar osteotomies for metatarsus primus varus and hallux valgus allow for substantial correction of the first intermetatarsal angle and the hallux valgus angle. Crescentic osteotomies have two well-documented pitfalls: sagittal plane instability and difficulty in fixation. We describe the addition of a plantar shelf to crescentic basilar osteotomy that allows for easier fixation and less risk of elevation of the first metatarsal postoperatively. This plantar shelf is made in the metaphyseal portion of the first metatarsal, which provides the benefit of better bone healing. In 20 patients, we found an average reduction in the intermetatarsal angle of 9.3 degrees and an average reduction in the hallux valgus angle of 21.8 degrees. Eight weeks postoperatively, only one patient showed elevation of the first metatarsal.

PMID:15377728 | DOI:10.7547/0940502