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August 2007

Editor:
Michael Bissell, MD, PhD

Value of nadir growth hormone after an octreotide test dose
Detection and diagnosis of hemoglobin A2’ by HPLC
C-reactive protein released from stented coronary arteries
Effects of commonly used drugs on inhibition of pseudocholinesterase activity
Role of adult-onset growth hormone and IGF-1 deficiency in longevity
Detection and monitoring of adenoviruses using a real-time PCR assay
Association between serum GGT, diabetes, and cardiovascular risk
GABA type B receptors and neutrophil chemotaxis during ischemia-reperfusion
Effects of high-cholesterol diets on cardiac parameters

bullet Value of nadir growth hormone after an octreotide test dose

Treatment of acromegaly aims to restore normal growth hormone secretory dynamics and preserve normal anterior pituitary function. Disease remission is achieved when the increased mortality and morbidity associated with active acromegaly is reversed to that of the general population. Epidemiological studies have suggested that disease remission occurs when a growth hormone level of less than 2.5 µg/L (5 mU/L) is achieved, measured as the mean of a growth hormone day profile or as a random growth hormone level, regardless of the therapeutic approach used. However, more recent studies have suggested that suppressing growth hormone to less than 2 µg/L (approximately 5 mU/L), or even less than 1 to 2 µg/L, represents a more appropriate target. The comparative importance of normalization of insulin-like growth factor-1 (IGF-1) for age and gender continues to be debated. Some studies have reported that a normal IGF-1 is associated with reduced mortality. However, other studies have been unable to demonstrate an additional effect of IGF-1 on outcome independent of growth hormone. Somatostatin analogs (SSAs) may be used as primary and adjuvant therapies for acromegaly and seem to be equally effective in either setting. The degree of growth hormone suppression following an octreotide test dose has also been shown in some studies to predict longer term suppression of growth hormone and IGF-1 with subcutaneous multiple injection octreotide therapy. However, Colao, et al., found that growth hormone suppression following an octreotide test dose predicted response to subcutaneous octreotide in only 42.6 percent of patients at three months. It remains unclear what constitutes an adequate suppression of growth hormone in response to an octreotide test dose or the predictive value in determining long-term growth hormone suppression with depot SSA therapy. The authors evaluated the predictive value of the nadir growth hormone and mean growth hormone following an octreotide test dose in identifying subjects who subsequently achieved disease remission with depot SSA therapy. In a retrospective case-control study, 41 patients with acromegaly underwent an octreotide test dose in which growth hormone was measured hourly for six hours following an injection of octreotide 50 µg subcutaneously. Nadir growth hormone and mean growth hormone following the octreotide test dose were determined. Thirty-three patients were subsequently treated with depot SSA therapy, and mean growth hormone and IGF-1 levels were determined at followup. The nadir growth hormone demonstrated superior predictive power compared to mean growth hormone across a range of cutoff values. A nadir growth hormone of less than 5 mU/L demonstrated 80 percent sensitivity and 83 percent specificity in predicting remission with depot SSA therapy. A nadir growth hormone of less than 10 mU/L demonstrated 100 percent sensitivity and 56 percent specificity. The authors concluded that the nadir growth hormone following an octreotide test dose is a useful predictive marker of disease remission, with depot SSA therapy used as a primary or adjuvant agent.

Gilbert JA, Miell JP, Chambers SM, et al. The nadir growth hormone after an octreotide test dose predicts the long-term efficacy of somatostatin analogue therapy in acromegaly. Clin Endocrinol. 2005;62:742–747.

Reprints: Dr. S. J. B. Aylwin, Kings College Hospital, Denmark Hill, London SE5 9RS, United Kingdom; simon.aylwin@kcl.ac.uk

bullet Detection and diagnosis of hemoglobin A2’ by HPLC

Hemoglobin A2’, also called HbB2, is a hematologically silent variant of HbA2 that results from substituting arginine for glycine at the 16th amino acid position of the delta-globin chain. HbA2’ is the most common of the HbA2 variants and has been reported to occur in one percent to two percent of African-Americans. HbA2’ has been detected in heterozygous and homozygous states and in combination with other Hb variants and thalassemia. Failure to detect HbA2’ might lead to underestimation of total HbA2 and failure to recognize beta-thalassemia minor. To diagnose or exclude beta-thalassemia minor, the sum of the HbA2 and HbA2’ levels must be considered. The substitution of arginine for glycine confers a net positive charge gain on the delta-globin chain, which accounts for its mobility cathodal to HbA2 on alkaline electrophoresis. In recent years, high-performance liquid chromatography (HPLC) has replaced alkaline electrophoresis as the primary screening method for hemoglobinopathies in many laboratories. HPLC offers the advantages of decreased manual labor, lower cost, and direct quantification of even minor Hb components, including HbA2. HbA2’ is perhaps detected most easily by HPLC, in which it produces a minor peak in the S window. In 2001, the University Hospitals of Cleveland (Ohio) Core Laboratory switched from alkaline electrophoresis to HPLC as the primary screening method for hemoglobin. Shortly afterward, it was observed that some samples had small, unexplained peaks in the S window. The authors suspected that these cases might represent HbA2’, which prompted them to review all of the HPLC tracings retrospectively and prospectively to determine the prevalence of HbA2’ in their patient population and to better define the diagnostic criteria for HbA2’. The authors used the Variant II (Bio-Rad, Hercules, Calif.) to define diagnostic criteria for the HbA2’ trait. They reviewed all Hb screens (n=5,862) performed during a 26-month period for new hemoglobinopathies. The authors identified 57 cases of HbA2’ trait, making it the fourth most prevalent Hb variant detected in this population after HbS, HbC, and beta-thalassemia minor. For HbA2’ trait cases, the mean HbA2 level was 1.7 percent (standard deviation, 0.17%), and the mean HbA2’ level was 1.3 percent (SD, 0.18%). Six possible HbA2’/beta-thalassemia double heterozygotes were identified, for which the sum of the HbA2 and HbA2’ exceeded four percent of total Hb. Hb variants that might interfere with detecting HbA2’ include HbS, glycosylated HbC, and HbG2. Diagnostic criteria proposed for the HbA2’ trait by HPLC are HbA2 of two percent or less, S window peak of one percent to two percent, no previous diagnosis of HbS, and absence of HbG and HbC.

Van Kirk R, Sandhaus LM, Hoyer JD. The detection and diagnosis of hemoglobin A2’ by high-performance liquid chromatography. Am J Clin Pathol. 2005;123:657–661.

Reprints: Dr. Linda M. Sandhaus, Dept. of Pathology, University Hospitals of Cleveland, 11100 Euclid Ave., Cleveland, OH 44106

bullet C-reactive protein released from stented coronary arteries

Human C-reactive protein is an acute-phase reactant and has long been considered merely an innocent bystander in the inflammatory process. High-sensitivity C-reactive protein (hs-CRP) is recognized as a powerful predictor of cardiovascular events, including stroke, coronary heart disease, peripheral vascular disease, and sudden cardiac death. Inflammation plays an essential role in the initiation and progression of coronary atherosclerosis and atherosclerotic plaque rupture that culminates in acute coronary syndromes (ACS). Elevated circulating CRP commonly accompanies ACS, reflecting primary inflammation of vulnerable plaques. In addition, percutaneous coronary intervention (PCI) produces a significant inflammatory reaction in the injured vessel wall that leads to the development of neointimal thickening and restenosis. CRP increases after PCI in a time-dependent manner, with the maximum response at 48 hours. It predicts the occurrence of restenosis. Leukocyte integrin Mac-1 (CD11b/CD18) plays a central role in the inflammatory process at the site of the vessel wall injured by PCI. PCI induces activation and up-regulation of Mac-1 on the surface of neutrophils, with the maximum response at 48 hours after PCI. This is also associated with restenosis. Not only is CRP a powerful inflammatory marker, but evidence suggests that CRP may also directly participate in the inflammatory process of atherogenesis. CRP research has focused on its localization in various tissues, such as atherosclerotic plaques. However, it is not yet known if CRP is produced at the site of the vulnerable plaque or the vessel wall injured by PCI and whether locally released CRP plays a role in Mac-1 activation and restenosis. The authors clinically assessed local CRP production, first at the vulnerable plaque and then at the site of the vessel wall injured by PCI. They also examined the relationship between local CRP production and activation of Mac-1 on the surface of neutrophils leading to restenosis. Their study consisted of two separate protocols. In protocol one, the authors measured serum hs-CRP levels in coronary arterial blood sampled just distal and proximal to the culprit lesions in 36 patients with stable angina and 13 patients with unstable angina. In protocol two, they measured serial serum hs-CRP levels and activated Mac-1 on the surface of neutrophils in coronary sinus and peripheral blood in 20 patients undergoing coronary stenting. In protocol one, CRP was higher in distal blood than proximal blood in stable (P<0.05) and unstable angina (P<0.01). The translesional CRP gradient (distal CRP minus proximal CRP, P<0.05), as well as the proximal CRP (P<0.05) and distal CRP (P<0.05), was higher in unstable angina than in stable angina. In protocol two, the transcardiac CRP gradient (coronary sinus minus peripheral blood) and activated Mac-1 increased gradually after stenting, reaching a maximum at 48 hours (P<0.001 versus baseline for both). The authors noted a positive correlation between the transcardiac CRP gradient and activated Mac-1 at 48 hours (r=0.45, P<0.01). They concluded that C-reactive protein is an excellent marker for plaque instability or poststent inflammatory status, and its source might be the inflammation site of the plaque or the coronary arterial wall injured by stenting.

Inoue T, Kato T, Uchida T, et al. Local release of C-reactive protein from vulnerable plaque or coronary arterial wall injured by stenting. J Am Coll Cardiol. 2005;46:239–245.

Reprints: Dr. Teruo Inoue, Dept. of Cardiovascular and Renal Medicine, Saga University Faculty of Medicine, 5-1-1 Nabeshima, Saga 849–8501, Japan; inouete@med.saga-u.ac.jp

bullet Effects of commonly used drugs on inhibition of pseudocholinesterase activity

Several drugs, including chlorpromazine, morphine, procainamide, quinidine, and thioridazine, have been reported to inhibit serum pseudocholinesterase activity in selected studies. Because the catabolism of a variety of drugs is mediated by serum pseudocholinesterase (PCE), including cocaine, cocaethylene, and succinylcholine, coadministering such drugs might be expected to prolong the serum half-life of the drugs, with resulting clinical implications. Earlier studies from the authors’ laboratory have demonstrated inhibition of the degradation of cocaine in human serum by thioridazine and the degradation of cocaethylene in human serum by quinidine. The authors undertook a preliminary study to evaluate the effect of 17 commonly used prescription and over-the-counter drugs on the activity of PCE in vitro. They incubated normal pooled human serum with therapeutic serum concentrations of prescription and over-the-counter drugs for 120 minutes at 37°C and measured the postincubation PCE activity. The authors found that morphine, quinidine, and thioridazine depressed PCE activity by more than five percent, while no effect or negligible effect was noted following incubation with acetaminophen, chlordiazepoxide, chlorpromazine, desipramine, doxepin, imipramine, methamphetamine, nortriptyline, phenobarbital, phenytoin, procainamide, salicylic acid, theophylline, and valproic acid. The authors concluded that depressing PCE activity can prolong the half-life of coadministered agents with metabolism mediated by PCE.

Bailey DN, Briggs JR. Studies of the inhibition of serum pseudocholinesterase activity in vitro by commonly used drugs. Am J Clin Pathol. 2005;124:226–228.

Reprints: Dr. David Bailey, Dept. of Pathology, University of California Medical Center, 200 W. Arbor Drive, San Diego, CA 92103-8320

bullet Role of adult-onset growth hormone and IGF-1 deficiency in longevity

Progress in the genetics of life span in invertebrates, primarily through mutagenesis techniques, has allowed researchers to identify specific genes and signaling pathways that modulate longevity. These invertebrate genes exhibit substantial homology to the insulin/IGF-1 receptor and signaling pathways in other species, so the possibility exists that genetic modification to the insulin/IGF-1 signaling cascade may represent a conserved pathway for regulating life span. In contrast, experiments in humans and animals indicate a progressive decrease in growth hormone and insulin-like growth factor-1 (IGF-1) with age. However, replacing growth hormone has been shown to reverse the age-related decline in IGF-1, lean body mass, bone density, skin thickness, immune function, learning and memory, and myocardial function, and the increase in adiposity that is part of aging. The results of these numerous studies suggest that the aged phenotype results from a deficiency in anabolic hormones, of which, a deficiency of growth hormone, and subsequently IGF-1, plays a particularly important role. Using a rodent model with a specific and limited deficiency of growth hormone and IGF-1, the authors reported that growth hormone and IGF-1 deficiency throughout life (GH deficiency [GHD]) has no effect on life span when these animals were compared with normal, heterozygous animals. However, treating GHD animals with growth hormone from four to 14 weeks of age (adult-onset [AO] GHD) increased median and maximal life span by 14 percent and 12 percent, respectively. Analysis of end-of-life pathology indicated that deficiency of these hormones decreased tumor incidence in GHD and AO-GHD animals (18% and 30%, respectively) when compared with heterozygous animals and decreased the severity of, and eliminated deaths from, chronic nephropathy. Total disease burden was reduced by 24 percent in GHD and 16 percent in AO-GHD animals. Interestingly, the incidence of intracranial hemorrhage increased by 154 percent and 198 percent in GHD and AO-GHD animals, respectively, when compared with heterozygous animals. Deaths from intracranial hemorrhage in AO-GHD animals were delayed by 14 weeks, accounting for their increased life span compared with GHD animals. The presence of growth hormone and IGF-1 was necessary to maximize reproductive fitness and growth of offspring early in life and to maintain cognitive function and prevent cartilage degeneration later in life. The diverse effects of growth hormone and IGF-1 are consistent with a model of antagonistic pleiotropy and suggest that, in response to a deficiency of these hormones, increased life span is derived at the risk of functional impairments and tissue degeneration.

Sonntag WE, Carter CS, Ikeno Y, et al. Adult-onset growth hormone and insulin-like growth factor I deficiency reduces neoplastic disease, modifies age-related pathology, and increases life span. Endocrinology. 2005;46:2920–2932.

Reprints: Dr. William Sonntag, Dept. of Physiology and Pharmacology, Wake Forest University Health Sciences, 1 Medical Center Blvd., Winston-Salem, NC 27157-1083; wsonntag@wfubmc.edu

bullet Detection and monitoring of adenoviruses using a real-time PCR assay

Fifty-one human adenovirus serotypes have been identified and divided into six major subgroups—subgenera or species A through F—on the basis of their oncogenic, hemagglutinating, morphological, and DNA sequence properties. Any adenovirus species may cause life-threatening infections. In most clinical situations involving adenovirus infection, species identification of an adenovirus (AdV) isolate is as informative as a finer identification by serotype. Infections can cause localized disease, such as enteritis, upper respiratory tract infection, encephalitis, or cystitis. However, AdV infections in immunocompromised patients tend to become invasive, and disseminated disease is associated with very high mortality rates. Treatment options, which include antiviral agents such as cidofovir and ribavirin, immunomodulation, and cytotoxic T cells, have been reported to work successfully in at least a proportion of patients, emphasizing the importance of adequate diagnostic techniques to quickly detect and monitor the course of infection. Earlier diagnostic approaches to AdV detection relied primarily on serological tests and cell culture. In immunosuppressed patients, however, the use of serological tests is limited due to the impaired immune response, and evaluation of positive cultures is a relatively slow method. The introduction of polymerase chain reaction-based assays has provided new avenues to rapid, specific, and highly sensitive AdV detection. However, many of these diagnostic approaches do not effectively cover all AdV types, or they use lower-stringency conditions to detect the genetically highly diverse adenoviruses. Based on the complete sequence information of the hexon gene, the authors developed a two-reaction real-time PCR assay covering all human adenoviruses with equally high specificity and sensitivity. The detection systems were tested using reference strains for all 51 serotypes and more than 1,000 clinical samples derived from peripheral blood and stool specimens from pediatric patients after allogeneic stem cell transplantation. The authors concluded that the two-reaction assay permits highly specific detection and quantification of adenoviral DNA of any serotype. From the perspective of routine clinical diagnosis, the assay is an improvement over existing approaches because it provides a sensitive and economical technique for the early detection and monitoring of adenoviral infections.

Ebner K, Suda M, Watzinger F, et al. Molecular detection and quantitative analysis of the entire spectrum of human adenoviruses by a two-reaction real-time PCR assay. J Clin Microbiol. 2005;43:3049–3053.

Reprints: Thomas Lion, CCRI, Kinderspitalgasse 6, A-1090 Vienna, Austria; thomas.lion@ccri.at

bullet Association between serum GGT, diabetes, and cardiovascular risk

Serum gamma-glutamyltransferase (GGT) concentrations within the physiologic range have been strongly associated with most cardiovascular disease risk factors and have predicted the development of heart disease, hypertension, stroke, and type 2 diabetes. In particular, serum GGT concentrations have shown a strong graded relationship with incident diabetes, suggesting a role in the pathogenesis of diabetes. Although serum GGT activity has commonly been used as a marker for excessive alcohol consumption or liver diseases, neither likely explains the association between serum GGT and diabetes. Microalbuminuria is considered to be a predictor of atherosclerotic diseases. The mechanisms linking microalbuminuria and risk for cardiovascular disease are not fully understood; a recent concept is that microalbuminuria is a marker of endothelial dysfunction. Generalized endothelial dysfunction has been hypothesized to be the underlying factor for microalbuminuria on the one hand and the underlying factor for increased cardiovascular risk on the other. The authors performed a prospective study to examine whether GGT, possibly as a marker of oxidative stress or a generator of oxidative stress, is a predictor of microalbuminuria among young adult black and white men and women. In the study, 2,478 black and white men and women without microalbuminuria at year 10 provided urine samples five years later. Year-10 GGT cutpoints were 12, 18, and 29 U/L. The incidence of microalbuminuria across year-10 GGT categories was U-shaped. Adjusted odds ratios across quartiles of serum GGT were 1.0, 0.39, 0.54, and 0.94 (P<0.01 for quadratic term), but the shape of association depended on the status of hypertension or diabetes (P<0.01 for interaction). Among individuals who ever had hypertension or diabetes, year-10 serum GGT showed a clear positive dose-response association with incident microalbuminuria (P<0.01 for trend), whereas among individuals with neither hypertension nor diabetes during the study, year-10 GGT showed a U-shaped association with it (P=0.01 for quadratic term). When the authors evaluated long-term risk in 3,895 participants based on serum GGT at year zero and prevalence of microalbuminuria at year 10 or year 15, the trends were similar to but weaker than those of short-term incidence risk. The authors concluded that serum GGT within the physiologic range predicted microalbuminuria among patients with hypertension or diabetes and may act as a predictor of microvascular or renal complications, or both, in these vulnerable groups. GGT showed a U-shaped association with microalbuminuria among people who did not develop hypertension or diabetes.

Lee D-H, Jacobs DR, Gross M, et al. Serum γ-glutamyltransferase was differently associated with microalbuminuria by status of hypertension or diabetes: the Coronary Artery Risk Development in Young Adults (CARDIA) study. Clin Chem. 2005;51:1185–1191.

Reprints: David Jacobs, Division of Epidemiology, University of Minnesota School of Public Health, 1300 S. 2nd St., Suite 300, Minneapolis, MN 55454; jacobs@epi.umn.edu

bullet GABA type B receptors and neutrophil chemotaxis during ischemia-reperfusion

Ischemia-reperfusion injury is the underlying mechanism of common and frequently fatal illnesses, such as myocardial infarction, acute renal failure, and stroke. Neutrophils play a central role in ischemia-reperfusion injury. Therefore, identifying proteins that mediate neutrophil functional responses might allow manipulation of signal cascades and potentially modulate specific neutrophil functions. The protein serine/threonine kinase Akt is a significant regulator of neutrophil survival and function. Akt, also known as protein kinase B, is a cellular homologue of a viral oncogene v-Akt. Akt has been shown to regulate a number of neutrophil functions, including chemotaxis, respiratory burst, apoptosis, and actin polymerization. The authors conducted a study to identify Akt binding proteins in neutrophils to better understand the mechanism by which Akt regulates various neutrophil functions. Proteomic and immunoprecipitation studies identified γ-amino butyric acid (GABA) type B receptor 2 (GABABR2) as an Akt binding protein in human neutrophils. Neutrophil lysates subjected to Akt immunoprecipitation followed by immunoblotting with anti-GABABR2 demonstrated Akt association with the intact GABABR. Similar results were obtained from performing reciprocal immunoprecipitations with anti- GABABR2 Ab. Additionally, confocal microscopy demonstrated GABABR2 and Akt colocalization. A GABABR agonist, baclofen, activated Akt and stimulated neutrophil-directed migration in a PI3K-dependent manner, whereas CGP52432, a GABABR antagonist, blocked such effects. Baclofen stimulated neutrophil chemotaxis and tubulin reorganization in a PI3K-dependent manner. Additionally, a GABABR agonist failed to stimulate neutrophil superoxide burst. The authors are unaware of the association of GABABR with Akt in any cell type. They found that the brain-specific receptor GABABR2 is present in human neutrophils and is functionally associated with Akt. Intraventricular baclofen pretreatment in rats subjected to a stroke model showed increased migration of neutrophils to the ischemic lesion. Therefore, the GABABR is functionally expressed in neutrophils and acts as a chemoattractant receptor via an Akt-dependent pathway. The GABABR potentially plays a significant role in the inflammatory response and neutrophil-dependent ischemia-reperfusion injury, such as stroke.

Rane MJ, Gozal D, Butt W, et al. g-amino butyric acid type B receptors stimulate neutrophil chemotaxis during ischemia-reperfusion. J Immunol. 2005;174:7242–7249.

Reprints: Dr. Madhavi J. Rane, University of Louisville, Baxter Research Bldg., 570 S. Preston St., Louisville, KY 40202; mrane@louisville.edu

bullet Effects of high-cholesterol diets on cardiac parameters

An excess of dietary cholesterol promotes coronary plaque formation, which increases a person’s susceptibility to myocardial ischemia and aggravates ischemic heart disease. Moreover, a cholesterol burden closely related to a continuous high-cholesterol diet impairs coronary endothelial nitric oxide synthase (eNOS) activity in small vessels and in conduit vessels by forming complexes of eNOS protein and inhibitory caveolin. Coronary microvascular eNOS dysfunction impairs the regulation of coronary flow and mitochondrial respiration and promotes inflammatory cell infiltration. Although acute myocardial ischemia-reperfusion injury is aggravated by cholesterol burden, it is not clear whether and how cholesterol burden aggravates cardiac function in the infarcted heart and in the ischemic heart with chronic coronary stenosis (CS) without modulating the severity of CS. Myocardial damage induced by a high-cholesterol diet, if any, may not be the same in the two ischemic conditions—that is, infarcted or ischemic but viable myocardium. Therefore, in animal models of these conditions, the authors assessed how different kinds of myocardial ischemia due to CS or myocardial infarction are involved in the worsening of heart failure as a result of a continuous high-cholesterol diet and how such a diet affects endothelial nitric oxide dysfunction. In rats fed a normal chow diet or a high-cholesterol diet, CS or myocardial infarction was created surgically, and the authors assessed left ventricular function by echocardiography and myocardial inflammation by histopathology. In the CS groups, CS severity by histopathology, myocardial perfusion by microspheres, myocardial protein kinase C (PKC) translocation by Western blotting, and myocardial endothelial nitric oxide function were also investigated by the in vitro myocardial oxygen consumption method. The authors found that coronary stenosis impaired myocardial endothelial nitric oxide function and reduced coronary flow reserve, evoking myocardial ischemia, as shown by PKC-e activation, myocardial inflammation, fibrosis, cardiac dysfunction, and remodeling. By itself, a high-cholesterol diet greatly augmented such CS-induced myocardial abnormalities without modulating the severity of CS. These detrimental effects of a high-cholesterol diet were ameliorated by supplying a cofactor of endothelial nitric oxide synthase—tetrahydrobiopterin. In contrast, myocardial infarction-induced heart failure was not aggravated by such a diet. The authors concluded that CS-induced ischemic myocardium seems to be more susceptible to the pro-inflammatory effect of a high-cholesterol diet than infarcted myocardium, leading to aggravation of left ventricular dysfunction and remodeling via modification of the coronary circulation downstream of the epicardial CS site, partly through impairment of endothelial nitric oxide.

Yaoita H, Yoshinari K, Maehara K, et al. Different effects of a high-cholesterol diet on ischemic cardiac dysfunction and remodeling induced by coronary stenosis and coronary occlusion. J Am Coll Cardiol. 2005;45:2078–2087.

Reprints: Dr. Yukio Maruyama, First Dept. of Internal Medicine, Fukushima Medical University, Hikarigaoka 1, Fukushima 960-1295, Japan; maruyama@fmc.ac.jp


Dr. Bissell is Professor and Director of Clinical Services and Vice Chair, Department of Pathology, Ohio State University Medical Center, Columbus.