[The application of neuroimaging reconstruction technique in evaluating the relationship between skeletal musculature tumors and nerves nearby].

Objective: To analyze the relationship between tumors of the musculoskeletal system and adjacent nerves by reconstructing images of peripheral nerves, and explore its value in surgical treatment. Methods: From May 2016 to April 2019, a total of 27 patients were collected in Department of Imaging,Shougang Hospital, who were with skeletal muscle system tumors, including 15 primary soft tissue tumors, 9 primary bone tumors, 3 metastatic tumors, all of them were closely related to nerves. There were 17 males and 10 females, aged 13-67 years, with an average age of 34 years. Before the operation, CT volume scanning was performed, and curved planar reconstruction (CPR) was used to reconstruct the peripheral nerves. All patients were operated within 2 weeks after the examination. According to the image characteristics before the operation, the nerve invasion was judged. The sensitivity, characteristic, positive predictive value and negative predictive value of the tumor invasion (compression) nerve were calculated according to the intraoperative findings as the gold standard. Result: Of the 27 cases, 25 cases (25/27, 92.6%) could show the relationship between the tumors and the adjacent nerves at the same level, and 22 cases (22/25, 88.0%) had the same preoperative image judgments as the intraoperative findings. In the reconstructed images, the peripheral nerve was a continuous strip-like structure on the same level with the tumor. The invaded nerve became thicker and the edge was blurred. Enhanced scan showed enhancement. The sensitivity, specificity, positive predictive value and negative predictive value of neuroimaging reconstruction were 100.0%, 89.5%, 75.0% and 100.0% respectively. The sensitivity, specificity, positive predictive value and negative predictive value of the nerve compression were 92.3%, 100.0%, 100.0% and 80.0% respectively. Conclusions: Neurological reconstructed images can help clinicians evaluate the relationship between lesions and adjacent nerves quickly and intuitively. They can guide the selection of surgical methods, reduce the risk of intraoperative nerve injury, and have high sensitivity and specificity for nerves invasion.

Genome-wide association study of bipolar I disorder in the Han Chinese population.

We report the first genome-wide association study in 1000 bipolar I patients and 1000 controls, with a replication of the top hits in another 409 cases and 1000 controls in the Han Chinese population. Four regions with most strongly associated single-nucleotide polymorphisms (SNPs) were detected, of which three were not found in previous GWA studies in the Caucasian populations. Among them, SNPs close to specificity protein 8 (SP8) and ST8 α-N-acetyl- neuraminide α-2,8-sialyltransferase (ST8SIA2) are associated with Bipolar I, with P-values of 4.87 × 10(-7) (rs2709736) and 6.05 × 10(-6) (rs8040009), respectively. We have also identified SNPs in potassium channel tetramerization domain containing 12 gene (KCTD12) (rs2073831, P=9.74 × 10(-6)) and in CACNB2 (Calcium channel, voltage-dependent, ß-2 subunit) gene (rs11013860, P=5.15 × 10(-5)), One SNP nearby the rs1938526 SNP of ANK3 gene and another SNP nearby the SNP rs11720452 in chromosome 3 reported in previous GWA studies also showed suggestive association in this study (P=6.55 × 10(-5) and P=1.48 × 10(-5), respectively). This may suggest that there are common and population-specific susceptibility genes for bipolar I disorder.

Type 2 diabetes prevalence and incidence among adults in Taiwan during 1999-2004: a national health insurance data set study.

AIM: To evaluate annual prevalence and incidence of Type 2 diabetes and to examine possible trends among adults in Taiwan. METHODS: A retrospective nationwide longitudinal study using the Taiwan National Health Insurance Research Database collected during 1999-2004. Adult patients aged > or = 20 years old with prevalent and incident Type 2 diabetes were identified using ICD-9-CM diagnostic codes. Age-specific and age-direct-standardized annual incidence and prevalence were calculated to describe their trends in different gender and age group and compared using Poisson regression. RESULTS: During the study years, the age-standardized prevalence of Type 2 diabetes increased from 4.7 to 6.5% for men and from 5.3 to 6.6% for women. The increasing trends in prevalence were significant and higher among people aged < 40 and > or = 80 years. The age-standardized incidence rates of Type 2 diabetes per 1000 person-years were approximately 7.6 and remain stable for men, but decreasing from 7.7 to 6.9 for women. However, the incidence increased significantly in younger adults aged < 40 years whose relative incidence (RI with 95% confidence interval) was 1.31 (1.20-1.42) for men and 1.04 (1.01-1.08) for women. The incidence trends for people aged > or = 40 years were decreased for men and women. The differences in incidence trends between age groups and between genders were all statistically significant (all P < 0.001). CONCLUSIONS: This study demonstrated a substantial increasing trend in Type 2 diabetes prevalence during 1999-2004 among adults in Taiwan. Despite the incidence decreased in older people, young men aged 20-40 years were most susceptible to higher incidence of Type 2 diabetes.

Impaired skin wound healing in lumican-null mice.

BACKGROUND: Previous studies have demonstrated that the lack of lumican delayed corneal wound healing in lumican-null (Lum(-/-) ) mice. This defect is rescued by the addition of glycosylated lumican core protein to the injured corneas. OBJECTIVES: We examined the hypothesis that lumican is also required for the healing of cutaneous wounds using Lum(-/-) mice. METHODS: We demonstrated the basic thinner skin phenotypes in Lum(-/-) mice at different time points and the changes in arrangement of collagen fibres by transmission electron microscopy (TEM). A full skin thickness wound was generated by punch biopsy (6 mm diameter) in experimental Lum(-/-) and wild-type mice. The closure of injured skin was measured after various periods of time (3, 6, 12, 18 days). Specimens of injured and uninjured skin (serving as control) were then subjected to morphological examination with haematoxylin and eosin and Masson trichrome stains, and by TEM. Immunohistochemical staining with anti-CD68 antibody was used to assess the presence of macrophages in injured skin healing for various periods of time. Semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to elucidate the transforming growth factor (TGF)-ß1-induced myofibroblast phenotypic genes. RESULTS: Skin of adult Lum(-/-) mice (3 months and older) was much thinner (40% less) than that of age-matched wild-type mice. This phenomenon was aggravated in older mice. TEM revealed disoriented and irregular collagen fibrils in the dermis of Lum(-/-) mice. Delayed wound healing with an increase in inflammatory macrophages was compatible with the delayed response of the expression of TGF-ß1, type I collagen α1 and fibronectin at the mRNA level by semiquantitative RT-PCR in the Lum(-/-) mice. CONCLUSIONS: Our data demonstrate that lumican plays pivotal roles in skin collagen fibrillogenesis and wound healing.

Serine-385 phosphorylation of inwardly rectifying K+ channel subunit (Kir6.2) by AMP-dependent protein kinase plays a key role in rosiglitazone-induced closure of the K(ATP) channel and insulin secretion in rats.

AIMS/HYPOTHESIS: Rosiglitazone, an insulin sensitiser, not only improves insulin sensitivity but also enhances insulin secretory capacity by ameliorating gluco- and lipotoxicity in beta cells. Rosiglitazone can stimulate insulin secretion at basal and high glucose levels via a phosphatidylinositol 3-kinase (PI3K)-dependent pathway. We hypothesised that regulation of phosphorylation of the ATP-sensitive potassium (K(ATP)) channel might serve as a key step in the regulation of insulin secretion. METHODS: Insulin secretory responses were studied in an isolated pancreas perfusion system, cultured rat islets and MIN6 and RINm5F beta cells. Signal transduction pathways downstream of PI3K were explored to link rosiglitazone to K(ATP) channel conductance with patch clamp techniques and insulin secretion measured by ELISA. RESULTS: Rosiglitazone stimulated AMP-activated protein kinase (AMPK) activity and induced inhibition of the K(ATP) channel conductance in islet beta cells; both effects were blocked by the PI3K inhibitor LY294002. Following stimulation of AMPK by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), a pharmacological activator, both AICAR-stimulated insulin secretion and inhibition of K(ATP) channel conductance were unaffected by LY294002, indicating that AMPK activation occurs at a site downstream of PI3K activity. The serine residue at amino acid position 385 of Kir6.2 was found to be the substrate phosphorylation site of AMPK when activated by rosiglitazone or AICAR. CONCLUSIONS/INTERPRETATION: Our data indicate that PI3K-dependent activation of AMPK is required for rosiglitazone-stimulated insulin secretion in pancreatic beta cells. Phosphorylation of the Ser(385) residue of the Kir6.2 subunit of the K(ATP) channel by AMPK may play a role in insulin secretion.

Rosiglitazone (BRL 49653) enhances insulin secretory response via phosphatidylinositol 3-kinase pathway.

To elucidate the direct effect of rosiglitazone (RSG), a new thiazolidinedione antihyperglycemic agent, on pancreatic insulin secretion, an in situ investigation by rat pancreatic perfusion was performed. At a basal glucose concentration of 6 mmol/l, RSG (0.045-4.5 micromol/l) stimulated insulin release in a dose-dependent manner. In addition, 4.5 micromol/l RSG potentiated the glucose (10 mmol/l)-induced insulin secretion. Both the first and second phases of glucose-induced insulin secretion were significantly enhanced by RSG, by 80.7 and 52.4%, respectively. The effects of RSG on insulin secretion were inhibited by a phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002. In contrast, the glucose-stimulated insulin secretion was not affected by LY294002. The potentiation effect of RSG on glucose-stimulated insulin secretion, in both the first and second phases, was significantly blocked by LY294002. These results suggest that RSG has a direct potentiation effect on insulin secretion in the presence of 10 mmol/l glucose, mediated through PI3K activity. The inability of LY294002 to inhibit glucose-induced insulin secretion suggests that different pathways are responsible for glucose and RSG signaling.

Inhibition of mouse GATA-1 function by the glucocorticoid receptor: possible mechanism of steroid inhibition of erythroleukemia cell differentiation.

Treatment of mouse erythroleukemia (MEL) cells with hexamethylene bisacetamide induces a program of erythrodifferentiation, as judged by an increase in the synthesis of globins and other erythroid-specific products. This induction can be inhibited by glucocorticoids, e.g. dexamethasone. All globin and other erythroid-specific genes tested contain GATA response elements (GATA-RE) and can be transactivated by GATA-1, a transcription factor. GATA-1 is highly expressed in erythroid cells, including MEL cells. We noted a glucocorticoid receptor (GR) response element motif near a GATA-RE motif in the promoter region of the mouse beta-major and beta-minor globin genes and about 130 bases away from a GATA-RE in the alpha 1-globin gene promoter and, therefore, investigated the possibility that the dexamethasone-induced inhibition of induced MEL cell differentiation may involve effects of the GR on GATA-1 activity. Evidence obtained from transfection assays and DNA electrophoretic mobility shift assays indicates that the GR binds GATA-1 and interferes with its function before any interaction with DNA, but that the presence of a glucocorticoid response element near a GATA-RE augments the GR effect. The N-terminal 106-amino acid domain of the GR was found to be essential for the effect, possibly by binding to GATA-1. Since GATA-1 is autoregulatory, i.e. it has been shown by others to bind to its own promoter and up-regulate its own transcription, the finding that activated GR can interfere with GATA-1 function may provide an explanation for the inhibition by glucocorticoids of the entire program of erythroid differentiation in MEL cells. That is, by interfering with GATA-1 function, the GR inhibits not only the expression of erythroid structural genes, but may also inhibit the expression of a primary erythroid regulatory gene, GATA-1. It was also shown that the GATA-RE in each of the beta-globin promoters responds to mouse GATA-1 in a functional transfection assay.

An integrated inundation model for highly developed urban areas.

A numerical model is developed in this study with various components for simulating the complex flow phenomena in urban drainage basins. The model integrates the HEC-1 model, a 1-D dynamic channel-flow model, a 2-D non-inertia overland-flow model and the SWMM model to reflect the hydraulic processes in areas with different characteristics. The inundation of underground infrastructure during flood is also considered in the model. The typhoon Nari event in 2001, which resulted in severe flood in downtown Taipei, is simulated by the model. The result is compared with the survey records of flooded areas, which reveals the storage effect of underground infrastrucures is significant to the simulation results of highly developed urban areas.

Identification of a pseudorabies virus UL12 (deoxyribonuclease) gene.

We characterized the gene encoding the pseudorabies virus (PrV) homologue of the herpes simplex virus 1 UL12 open reading frame that encodes the alkaline nuclease. The deduced PrV UL12 product was 492 amino acid residues and exhibited three conserved regions among herpesviruses. Northern blot analysis indicated that three transcripts (3.2, 1.6 and 1 kb) were encoded in this region and the UL12 corresponds to the 1.6-kb transcript. Primer extension and UL12-specific cDNA cloning were performed to verify the precise location of the UL12 transcript. These data indicated that the transcription start site of UL12 was located at 47-62 nucleotides upstream of the UL12 translation start site and the polyadenylation cleavage site was located at 15 or 16 nucleotides downstream the typical polyadenylation signal. Furthermore, the 53-kDa UL12 product, which indeed has deoxyribonuclease activity, was evidenced by in vitro expression.

Analysis of pseudorabies virus genes by cDNA sequencing.

Cloning and sequencing of cDNA could provide a complementary approach to functional analysis of the pseudorabies virus (PrV) genome. Using colony hybridization, Southern hybridization, and DNA sequencing, four species of PrV-specific cDNA were identified. Among these four species of PrV-specific cDNA, three unidentified genes, UL26, UL29, and UL31, were mapped and a novel gI-11K bicistronic cDNA was confirmed. Thus, analysis of PrV-specific transcripts provided a way for identifying genes and a foundation to further study the roles of these transcripts in PrV infection.

Phosphorylation of transcription factor cyclic-AMP response element binding protein mediates c-fos induction elicited by sustained hypertension in rat nucleus tractus solitarii.

We investigated the role of cyclic-AMP response element binding protein signaling in the induction of the immediate-early gene c-fos by baroreceptor activation in neurons of the nucleus tractus solitarii of anesthetized rats. Activation of the arterial baroreceptors with sustained hypertension significantly increased the number of neurons in the caudal nucleus tractus solitarii that were immunoreactive to an antiserum that detects Ser133-phosphorylated cyclic-AMP response element binding protein. This implied increase in phosphorylation of cyclic-AMP response element binding protein was subsequently followed by an elevation in the expression of Fos protein in neurons of the nucleus tractus solitarii. Microinjection bilaterally into the nucleus tractus solitarii of a phosphorothioated antisense oligonucleotide directed against the initiation site of cyclic-AMP response element binding protein messenger RNA discernibly reduced the manifested immunoreactivity of phosphorylated cyclic-AMP response element binding protein in response to baroreceptor activation. This was accompanied by a decline in the transcription of c-fos messenger RNA and the expression of Fos protein, along with an appreciable potentiation of the baroreceptor reflex response. Control injections of the sense oligonucleotide or artificial cerebrospinal fluid were ineffective. These findings suggest that phosphorylation of cyclic-AMP response element binding protein is crucial to Fos expression in the nucleus tractus solitarii elicited by sustained hypertension. As such, phosphorylation of cyclic-AMP response element binding protein may be an important early nuclear event that mediates the long-term inhibitory modulation of the baroreceptor reflex response by Fos protein at the nucleus tractus solitarii.

The recombinant nucleocapsid protein of classical swine fever virus can act as a transcriptional regulator.

The cDNA of the nucleocapsid (core) protein of classical swine fever virus (CSFV) was generated by reverse transcription-polymerase chain reaction (RT-PCR) and cloned into a eukaryotic expression vector. The effect of the recombinant core protein on the transcriptional regulation of cellular as well as viral promoters was studied. Using transient transfection assay, our results demonstrated that the core protein can activate the promoter of human heat shock protein 70 gene, and suppressed the SV40 early promoter. These findings indicate that the core protein appears to function not only as a viral structural protein but also as a regulator of gene expression. The implications of core proteins on the viral maturation are discussed.

Identification, expression, and characterization of the pseudorabies virus DNA-binding protein gene and gene product.

The pseudorabies virus (PRV) gene encoding a DNA-binding protein (DBP) was first identified in this study. The DBP gene has an open reading frame of 3531 nucleotides, capable of coding a 1177-amino-acid polypeptide of 125 kDa. The deduced DBP exhibits a conserved zinc-binding motif and a conserved DNA-binding region, suggesting the similar DNA-binding mechanism occurs among alphaherpesviral DBP homologs. To further identify the biochemical properties of PRV DBP, this protein was expressed in Escherichia coli by using a pET expression vector and purified to homogeneity. The PRV DBP binds cooperatively and preferentially to single-stranded DNA with no significant base preference, judged by agarose gel electrophoresis and competitive nitrocellulose filter binding assays. Taken together, these results suggest that PRV DBP may play an important role in PRV DNA replication by binding cooperatively and nonspecifically to single-stranded DNA that is formed during the replication origin unwinding and replication fork movement.

Molecular cloning and nucleotide sequence determination of three envelope genes of classical swine fever virus Taiwan isolate p97.

A strain of classical swine fever virus (CSFV) has been isolated in Taiwan. The cDNA coding for three envelope glycoproteins E1, E2 and E3 were molecularly cloned from purified viral particles using the reverse transcription-polymerase chain reaction (RT-PCR) method and sequence-specific primers. The resulting PCR products (1113 bp for E1. 699 bp for E2 and 567 bp for E3) were cloned into the SmaI site of pUC19 and then subjected to DNA sequence analysis. Data showed that nucleotide sequence of the three envelope genes shared a 82-83% homology with the corresponding genes of three other strains (Alfort, Brescia and Weybridge). However, the homology of the deduced amino acid sequence was greater than 90% among the four strains. The potential asparagine-linked glycosylation sites for E1 (5 sites), E2 (7 sites) and E3 (2 sites) were conserved. This suggests that the Taiwan p97 strain is distinct from other three strains described. The variations may have implications for future vaccine development. The sequence has been submitted to GenBank. The accession numbers are U43924 and U03290.

Pseudorabies virus early protein 0 trans-activates the TATA-associated promoter by stimulating the transcription initiation.

Pseudorabies virus (PRV) early protein 0 (EP0) is a transactivator containing a RING finger domain. To assess the transactivation mechanism of PRV EP0, we performed the in vitro transcription by combining HeLa nuclear extract, purified recombinant EP0 and simple promoter constructs, and evaluated the results by primer extension. The data showed that EP0 could significantly activate the TATA-containing synthetic promoters. Moreover, EP0 activated transcription by stabilizing the formation of transcription initiation complex instead of enhancing the elongation rate. To further understand the role of EP0 on assembling the transcription initiation complex, we performed the pull-down assay using affinity precipitation of proteins from HeLa nuclear extracts and bacterially expressed glutathione-S-transferase EP0 RING finger fusion. The data showed that at least six nuclear proteins physically interacted with the EP0 RING finger. Overall, the transactivation of PRV EP0 is accomplished by enhancing the transcription initiation and is associated with at least six nuclear proteins.

Immunolocalization of the pseudorabies virus immediate-early protein IE180 by immunoperoxidase staining.

The immediate-early (1E) gene of pseudorabies virus (PRV) expresses immediately upon infection, a phosphorylated protein (immediate-early protein, IE180) that can transactivate viral other genes and plays an essential role in regulating viral gene expression. In order to detect and localize IE180 in infected cells early on, this gene was cloned for overexpression, and the expressed products were applied to generate specific antibodies against IE180 protein. Two recombinant expression plasmids pN and pNB were constructed by cloning the IE gene onto pET 30a(+) expression vector via NcoI and BamHI sites. Plasmid pN contains the 1.8-kb NcoI-NcoI fragment of IE gene coding for the N-terminus of 616 amino acid residues, while pNB contains the 2.8-kb NcoI-Bam HI fragment coding for the rest of the IE180 protein. Both pN and pNB were transformed, respectively, into E. coli cells and produced large amounts of IE protein products during induction with 1 mM IPTG. The expressed IE proteins for pN and pNB were 60 kDa and 100 kDa in size, respectively. These expression products were purified and then used as antigens to immunize mice for preparing specific antibodies against PRV IE180 protein. The specificities of the mice immune sera were confirmed by their abilities to react with IE180 protein present in the PRV infected cells in the Western immunoblotting assay. Furthermore, immunoperoxidase staining of PRV infected cells undertaken with these antisera revealed the subcellular distribution of the IE proteins in the infected cells and also demonstrated their transportation from the cytoplasm to the nucleus during infection.

Rapid screening of pseudorabies virus-specific cDNAs from a cDNA library.

In order to reduce the time and cost for screening of pseudorabies virus (PRV)-specific cDNAs, a rapid and inexpensive method was developed that involved subtractive hybridization of the plasmid, which contained cDNA fragment, to PRV genomic DNA which was bound to nylon membranes. Ninety percent of DNA background was subtracted successfully by this method and the eluted DNA in the form of plasmid could be used to transform bacteria directly. Applying this technique, 200 colonies were screened from a cDNA library containing 30000 colonies. Furthermore, 17 colonies containing PRV-specific cDNAs, including PRV43, UL42, gII, DNase, EP0, 11K, gX, and RSP40, were identified from the 200 colonies by colony hybridization, Southern hybridization, and DNA sequencing. Thus, the subtractive hybridization can be used to construct and successfully establish the PRV cDNA library from PRV-infected cells.

Analysis of upregulated cellular genes in pseudorabies virus infection: use of mRNA differential display.

Virus infection usually alters the host cell and shuts off the synthesis of cellular macromolecules. In order to screen the upregulated cellular transcripts during pseudorabies virus (PRV) infection, we employed the mRNA differential display technique. The screen is based on positive selection at the mRNA level for genes expressed in normal cells but increased in corresponding PRV-infected cells. Over 14000 species of mRNA, isolated from mock-infected and PRV-infected Madin-Darby bovine kidney cell at 1 h post infection, were screened, and 40 candidate clones were recovered. Southern blot analysis revealed that 17 out of 40 candidate clones, were enhanced in PRV-infected cells. Partial DNA sequences demonstrated that 17 clones were distinct cellular genes, including those encoding the modulators of signal transduction (saposin, 14-3-3, adenylate kinase, adenylyl cyclase, protein kinase C-alpha), those encoding the components of translation (fau, ribosomal proteins S11, L31, L36), other cellular genes (peptidase, cyclin E, rch1, oligo-C-rich single-stranded nucleic acid binding protein, rap, arginyl-tRNA synthetase), and two unknown genes. Thus, this study identifies successfully the transcriptionally regulated cellular genes which are associated with PRV infection. Furthermore, this study provides support for the use of mRNA differential display as a method to rapidly isolate differentially expressed genes in virus infection.

The presence of RNA splicing signals in the cDNA construct of the E2 gene of classical swine fever virus affected its expression.

E2 is the major neutralizing antigen for classical swine fever virus (CSFV) infection. Previously, we have cloned and sequenced the E2 cDNA of Taiwan strain p97 by the reverse transcription-polymerase chain reaction (RT-PCR) method from CSFV-infected tissue. The presence of RNA splicing donor and acceptor sites were found in the cDNA sequence. In this study, transfection of E2 cDNA into mammalian cells resulted in the production of a spliced RNA. Site-directed mutagenesis of the donor and acceptor sites prevented the RNA splicing event and generated a full length transcript in COS7 cells. Although the spliced E2 transcript has not been reported in natural infection of CSFV, this study suggested that the potential splicing sites affected the E2 gene expression when the plasmid-based E2 gene was introduced into mammalian cells.

A comparison of regional versus systemic drug injection. Adriamycin concentration in peripheral blood and gastric stump (post-Billroth II gastrectomy) in the dog.

Gastric stump cancer has a low resection rate and poor response to systemic chemotherapy. This study attempted to achieve higher drug concentrations in target tissues by way of regional arterial injection instead of systemic venous administration. A total of 12 male mongrel dogs that had undergone post-Billroth II gastrectomies were randomly divided into two groups: in group A, 1.27 mg/kg adriamycin (ADM) was injected through the left gastric artery; in group B, the same dose of ADM was injected into a vein in the left front leg. Blood samples were taken at various time intervals, and the dogs were sacrificed 2 h after drug administration. Tissues were removed from various parts of the gastric stump for measurement of the ADM concentration. The ADM content in the jejunum, heart, liver, spleen, and pancreas was also determined. The results were as follows: (1) the ADM concentration in the gastric stump near its lesser curvature and stomal mucosa was significantly higher in group A than in group B (P less than 0.05). (2) The ADM concentrations in the adjacent organs (heart, liver, and pancreas) were also significantly higher in group A than in group B (P less than 0.05). (3) The ADM levels in the venous blood were significantly higher in group B than in group A (P less than 0.05). These results indicate that a chemotherapeutic drug given through the left gastric artery provides a higher drug concentration in the area where gastric stump cancer frequently occurs and that a lower systemic blood level may cause fewer adverse drug effects. The high concentration of ADM in the heart may not be a good indication, but it may serve as an important signal either to select a less cardiotoxic drug or to monitor heart function cautiously during drug therapy.