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Breast cancer is a major public health problem throughout the world. In this report, we investigated whether CHM-1, a novel synthetic antimitotic agent could be developed into a potent antitumor agent for treating human breast cancer. CHM-1 induced growth inhibition in MDA-MB-231, MDA-MB-453 and MCF-7 cells in a concentration-dependent manner. Importantly, CHM-1 is less toxic to normal breast (HBL-100) cells. CHM-1 interacted with tubulin, markedly inhibited tubulin polymerization, and disrupted microtubule organization. Proteins from control and CHM-1-treated animal tumor specimens were analyzed by two-dimensional electrophoresis and MALDI-TOF mass spectrometry. Our results indicated that CHM-1 increased the expression of SIRT2 protein, an NAD-dependent tubulin deacetylase. A prodrug strategy was also investigated to address the problem of low aqueous solubility and low bioavailability of the antitumor agent CHM-1. The water-soluble prodrug of CHM-1 (CHM-1-P) was synthesized. After oral and intravenous administration, CHM-1-P induced a dose-dependent inhibition of tumor growth. The aforementioned excellent anti-tumor activity profiles of CHM-1 and its prodrug CHM-1-P, suggests that CHM-1-P deserves to further develop as a clinical trial candidate for treating human breast carcinoma.

// Jui-Wen Ma 1 , Chao-Ming Hung 2, 3 , Ying-Chao Lin 4, 5, 6 , Chi-Tang Ho 7 , Jung-Yie Kao 1 , Tzong-Der Way 8, 9 1 Institute of Biochemistry, College of Life Science, National Chung Hsing University, Taichung, Taiwan 2 Department of General Surgery, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan 3 School of Medicine, I-Shou University, Kaohsiung, Taiwan 4 Division of Neurosurgery, Buddhist Tzu Chi General Hospital, Taichung Branch, Taiwan 5 School of Medicine, Tzu Chi University, Hualien, Taiwan 6 Department of Medical Imaging and Radiological Science, Central Taiwan University of Science and Technology, Taichung, Taiwan 7 Department of Food Science, Rutgers University, New Brunswick, New Jersey, USA 8 Department of Biological Science and Technology, College of Biopharmaceutical and Food Sciences, China Medical University, Taichung, Taiwan 9 Department of Health and Nutrition Biotechnology, College of Health Science, Asia University, Taichung, Taiwan Correspondence to: Tzong-Der Way, email: tdway@mail.cmu.edu.tw Jung-Yie Kao, email: biosjyk@gmail.com Keywords: HER-2-overexpressing breast cancer cells, aloe-emodin, Y-box binding protein-1, ILK/Akt/mTOR signaling pathway, epithelial-mesenchymal transition Received: January 06, 2016 Accepted: June 12, 2016 Published: July 06, 2016 ABSTRACT Human epidermal growth factor receptor-2 (HER-2)-positive breast cancer tends to be aggressive, highly metastatic, and drug resistant and spreads rapidly. Studies have indicated that emodin inhibits HER-2 expression. This study compared the HER-2-inhibitory effects of two compounds extracted from rhubarb roots: aloe-emodin (AE) and rhein. Our results indicated that AE exerted the most potent inhibitory effect on HER-2 expression. Treatment of HER-2-overexpressing breast cancer cells with AE reduced tumor initiation, cell migration, and cell invasion. AE was able to suppress YB-1 expression, further suppressing downstream HER-2 expression. AE suppressed YB-1 expression through the inhibition of Twist in HER-2-overexpressing breast cancer cells. Our data also found that AE inhibited cancer metastasis and cancer stem cells through the inhibition of EMT. Interestingly, AE suppressed YB-1 expression through the downregulation of the intracellular integrin-linked kinase (ILK)/protein kinase B (Akt)/mTOR signaling pathway in HER-2-overexpressing breast cancer cells. In vivo study showed the positive result of antitumor activity of AE in nude mice injected with human HER-2-overexpressing breast cancer cells. These findings suggest the possible application of AE in the treatment of HER-2-positive breast cancer.

“Triple negative breast cancer” (TNBC) is associated with a higher rate and earlier time of recurrence and worse prognosis after recurrence. In this study, we aimed to examine the crosstalk between fibroblasts and TNBC cells. The fibroblasts were isolated from TNBC patients’ tissue in tumor burden zones, distal normal zones and interface zones. The fibroblasts were indicated as cancer-associated fibroblasts (CAFs), normal zone fibroblasts (NFs) and interface zone fibroblasts (INFs). Our study found that INFs grew significantly faster than NFs and CAFs in vitro. The epithelial BT20 cells cultured with the conditioned medium of INFs (INFs-CM) and CAFs (CAFs-CM) showed more spindle-like shape and cell scattering than cultured with the conditioned medium of NFs (NFs-CM). These results indicated that factors secreted by INFs-CM or CAFs-CM could induce the epithelial-mesenchymal transition (EMT) phenotype in BT20 cells. Using an in vitro co-culture model, INFs or CAFs induced EMT and promoted cancer cell migration in BT20 cells. Interestingly, we found that emodin inhibited INFs-CM or CAFs-CM-induced EMT programming and phenotype in BT20 cells. Previous studies reported that CAFs and INFs-secreted TGF-β promoted human breast cancer cell proliferation, here; our results indicated that TGF-β initiated EMT in BT20 cells. Pretreatment with emodin significantly suppressed the TGF-β-induced EMT and cell migration in BT20 cells. These results suggest that emodin may be used as a novel agent for the treatment of TNBC.

Objectives: Many patients with Crohn’s disease (CD) have low bone mineral density (BMD) that may not be solely attributable to glucocorticoid use. We hypothesised that low BMD in patients with CD is associated with elevated circulating levels of the active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH) 2 D). We further hypothesised that this was secondary to increased synthesis of 1,25(OH) 2 D by inflammatory cells in the intestine. The aim of this study was to examine the relationship between 1,25(OH) 2 D levels and BMD in patients with CD. Methods: An IRB approved retrospective review of medical records from patients with CD (n = 138) or ulcerative colitis (UC, n = 29). Measurements of vitamin D metabolites and immunoreactive parathyroid hormone (iPTH) were carried out. BMD results were available for 88 CD and 20 UC patients. Immunohistochemistry or real time reverse transcription-polymerase chain reaction (RT-PCR) for the enzyme 1α-hydroxylase was performed on colonic biopsies from patients with CD (14) or UC (12) and normal colons (4). Results: Inappropriately high levels of serum 1,25(OH) 2 D (>60 pg/ml) were observed in 42% of patients with CD compared with only 7% in UC, despite no differences in mean iPTH. Serum 1,25(OH) 2 D levels were higher in CD (57 pg/ml) versus UC (41 pg/ml) (p = 0.0001). In patients with CD, there was a negative correlation between 1,25(OH) 2 D levels and lumbar BMD ( r = −0.301, p = 0.005) independent of therapeutic glucocorticoid use. 1,25(OH) 2 D levels also correlated with CD activity. Lastly, immunohistochemistry and RT-PCR demonstrated increased expression of intestinal 1α-hydroxylase in patients with CD. Conclusions: These data demonstrate that elevated 1,25(OH) 2 D is more common in CD than previously appreciated and is independently associated with low bone mineral density. The source of the active vitamin D may be the inflamed intestine. Treatment of the underlying inflammation may improve metabolic bone disease in this subgroup of patients.

Thirty-three patients (24 males and nine females) with brain abscesses resulting from infection by aerobic Gram-negative bacilli were identified at Kaohsiung Chang Gung Memorial Hospital over a period of 14 years. Of these, 23 cases developed spontaneously, with the remaining ten postneurosurgery. The organisms most frequently involved were Klebsiella (K.) pneumoniae, Pseudomonas aeruginosa, Escherichia coli and Proteus species and included some rare pathogens, such as Salmonella and Enterobacter species, K. oxytoca, Vibrio and Morganella morganii. Apart from one exception, the locations of the abscess were supratentorial. Twenty-four patients presented with a single abscess, while nine revealed multiple abscesses, with 26 treated surgically and seven with antibiotics exclusively. In total, seven patients died, representing an overall mortality rate of 21%. This study demonstrates that brain abscesses associated with neurosurgical procedures are not rare, accounting for 30% of cases in this study, with K. pneumoniae, Proteus and Enterobacter species the most prevalent of the revealed pathogens. Further, Proteus species were the most prevalent pathogens demonstrated for cases of both otogenic and polymicrobial infections. If brain abscesses are diagnosed for diabetic patients or have a gas-forming appearance, a diagnosis of K. pneumoniae infection should be considered, with particular attention paid to detection of other metastatic septic abscesses. In light of the high mortality rate, early treatment is essential to maximize the chances of survival.

Triple-negative breast cancer (TNBC) is defined by a lack of expression of the estrogen receptor (ER), progesterone receptor (PR), and epidermal growth factor receptor 2 (HER 2). Therefore, targeted therapy agents may not be used, and therapy is largely limited to chemotherapy. Doxorubicin treatment consequently acquires undesired malignance characteristics [i.e., epithelial-mesenchymal transition (EMT) and multi-drug resistance]. Our results illustrated that doxorubicin triggered EMT and resulted in the acquisition of a mesenchymal phenotype in TNBC cells. Moreover, we found that transforming growth factor-β (TGF-β) and PI3K/AKT signaling pathways were acquired for doxorubicin-induced EMT. Interestingly, we found that curcumin suppressed doxorubicin-induced EMT. Curcumin reversed doxorubicin-induced morphological changes, inhibited doxorubicin-induced downregulation of E-cadherin expressions, and inhibited doxorubicin-induced upregulation of vimentin expression. We also found that curcumin inhibited doxorubicin-induced EMT by inhibiting the TGF-β and PI3K/AKT signaling pathways. Moreover, curcumin enhanced the antiproliferative effects of doxorubicin in TNBC cells. In summary, our results suggest that doxorubicin in combination with curcumin may be a potential therapy for TNBC.

Demethoxycurcumin (DMC), curcumin (Cur), and bisdemethoxycurcumin (BDMC) are major forms of curcuminoids found in the rhizomes of turmeric. This study examined the effects of three curcuminoid analogues on breast cancer cells. The results revealed that DMC demonstrated the most potent cytotoxic effects on breast cancer MDA-MB-231 cells. Compared with estrogen receptor (ER)-positive or HER2-overexpressing breast cancer cells, DMC demonstrated the most efficient cytotoxic effects on triple-negative breast cancer (TNBC) cells. However, nonmalignant MCF-10A cells were unaffected by DMC treatment. The study showed that DMC activated AMPK in TNBC cells. Once activated, AMPK inhibited eukaryotic initiation factor 4E-binding protein-1 (4E-BP1) signaling and mRNA translation via mammalian target of rapamycin (mTOR) and decreased the activity and/or expression of lipogenic enzymes, such as fatty acid synthase (FASN) and acetyl-CoA carboxylase (ACC). DMC also targeted multiple AMPK downstream pathways. Among these, the dephosphorylation of Akt is noteworthy because it circumvents the feedback activation of Akt that results from mTOR inhibition. Moreover, DMC suppressed LPS-induced IL-6 production, thereby blocking subsequent Stat3 activation. In addition, DMC also sustained epidermal growth factor receptor (EGFR) activation by suppressing the phosphatases, PP2a and SHP-2. These results suggest that DMC is a potent AMPK activator that acts through a broad spectrum of anti-TNBC activities.

We report a 29-year-old female patient who developed intracerebral hemorrhage 16 h after endovascular embolization of a brain arteriovenous malformation with a combination of liquid embolic agents of Onyx and n-butyl cyanoacrylate. After emergent craniectomy with evacuation of the hematoma, the patient recovered consciousness with mild expressive aphasia. The possible etiology of postembolization brain hemorrhage was discussed, and the literature was reviewed.

✓ Lipomatous tumors can contain uncommon or rare components (such as fibrolipoma or angiolipoma) that may result in the development of symptoms. To the best of the authors' knowledge, lipoma associated with an osseous component has not been previously reported. A case of intraspinal extradural tumor composed of both adipose and bone tissue is presented. Current theories on the cause of lipoma with an osseous component are discussed. The tumor was histologically confirmed to be an osteolipoma, and the patient recovered well after resection.

Increasing evidence indicates adolescents are likely to occupy their leisure time with online games. This study investigates the influences of leisure satisfaction on life satisfaction among adolescent online gamers. The self-completed market survey questionnaire employed is comprised of two sections: the first is Internet usage frequency, while the second employs two measures-the Leisure Satisfaction Scale (LSS) and the Satisfaction with Life Scale (SWLS), Data were gathered in a medium-sized metropolitan section of north Taiwan and interviews took place at a Cyber Café. Youths (totaling 134) between the ages of 13 and 18 voluntarily participated in the research. Results revealed significant positive relationships between physiological and aesthetic dimensions of leisure satisfaction and life satisfaction. However, the educational dimension of leisure satisfaction has a significant negative influence on life satisfaction. Findings also reveal a significant negative relationship between web surfing frequency and life satisfaction in adolescents. This suggests possible explanations for these results and discusses the implications.

Crohn's disease (CD) is a heterogeneous disorder characterized by diverse clinical phenotypes. Childhood-onset CD has been described as a more aggressive phenotype. Genetic and immune factors may influence disease phenotype and clinical course. We examined the association of immune responses to microbial antigens with disease behavior and prospectively determined the influence of immune reactivity on disease progression in pediatric CD patients.Sera were collected from 196 pediatric CD cases and tested for immune responses: anti-I2, anti-outer membrane protein C (anti-OmpC), anti-CBir1 flagellin (anti-CBir1), and anti-Saccharomyces-cerevisiae (ASCA) using ELISA. Associations between immune responses and clinical phenotype were evaluated.Fifty-eight patients (28%) developed internal penetrating and/or stricturing (IP/S) disease after a median follow-up of 18 months. Both anti-OmpC (p0.0006) and anti-I2 (p0.003) were associated with IP/S disease. The frequency of IP/S disease increased with increasing number of immune responses (p trend = 0.002). The odds of developing IP/S disease were highest in patients positive for all four immune responses (OR (95% CI): 11 (1.5-80.4); p = 0.03). Pediatric CD patients positive foror =1 immune response progressed to IP/S disease sooner after diagnosis as compared to those negative for all immune responses (p0.03).The presence and magnitude of immune responses to microbial antigens are significantly associated with more aggressive disease phenotypes among children with CD. This is the first study to prospectively demonstrate that the time to develop a disease complication in children is significantly faster in the presence of immune reactivity, thereby predicting disease progression to more aggressive disease phenotypes among pediatric CD patients.

OBJECTIVE Osteoporosis is a common complication of Crohn's disease (CD). Glucocorticoid use and detrimental effects of inflammatory cytokines including tumor necrosis factor-alpha (TNF-alpha) can lead to osteoporosis. The aim of this study was to assess the ability of treatment with the TNF-alpha antagonist infliximab to increase bone formation as measured by surrogate markers of bone turnover in patients with active CD. METHODS Sera from 38 prospectively enrolled CD patients were examined for levels of bone alkaline phosphatase (BAP), N-telopeptide of type I collagen (NTX), immunoreactive parathyroid hormone (iPTH), calcium, and pro-inflammatory cytokines at baseline and 4 weeks following infliximab infusion. Crohn's Disease Activity Index (CDAI), Inflammatory Bowel Disease Questionnaire (IBDQ), and glucocorticoid dose also were collected. RESULTS In this cohort, CDAI and IBDQ scores were significantly improved at week 4 (P

Although acute pouchitis after ileal pouch-anal anastomosis is common and easily treated, continuous pouch inflammation seen clinically as chronic, antibiotic-dependent pouchitis, and/or Crohn’s disease remains a difficult management problem. Compared with ulcerative colitis, indeterminate colitis patients undergoing ileal pouch-anal anastomosis have a higher incidence of continuous pouch inflammation, which may represent persistent immune reactivity to microbial antigens. Antibody responses to three microbial antigens (oligomannan anti-Saccharomyces cerevisiae, outer membrane porin C of Escherichia coli, and an antigen (I2) from Pseudomonas flourescens) are more commonly seen in Crohn’s disease, whereas antibodies to a cross-reactive antigen (perinuclear antineutrophil cytoplasmic antibodies) is more suggestive of ulcerative colitis. We examined whether preoperative serologic responses to these antigens were associated with Crohn’s disease in indeterminate colitis patients after ileal pouch-anal anastomosis. Twenty-eight indeterminate colitis patients undergoing ileal pouch-anal anastomosis were prospectively assessed for the development of pouchitis or Crohn’s disease. Serologic responses were determined by enzyme-linked immunosorbent assay and immunofluorescence. Patients were classified based on four predominant profiles of antibody expression. Antibody profiles were determined before knowledge of clinical outcome. Median follow-up was 38 (range, 3–75) months. Of 16 patients (61 percent) who developed pouch inflammation, 4 (25 percent) had acute pouchitis and 12 (75 percent) had continuous pouch inflammation (9 had chronic pouchitis, 3 had Crohn’s disease). No preoperative clinical factor predicted the development of these pouch complications. Overall, 16 patients (57 percent) had a positive antibody reactivity profile. Serologic expression of any marker alone did not predict the development of continuous pouch inflammation. However, continuous pouch inflammation developed in 10 of 16 patients (63 percent) who had a positive antibody reactivity profile compared with only 2 of 12 patients (17 percent) who had a negative antibody reactivity profile (P = 0.015). Indeterminate colitis patients who have a positive antibody reactivity profile before ileal pouch-anal anastomosis have a significantly higher incidence of continuous pouch inflammation after surgery than those with a negative profile.

Crohn's disease patients can be characterized by antibody responses against Crohn's disease-related bacterial sequence, Escherichia coli outer membrane porin C, Saccharomyces cerevisiae (oligomannan), and neutrophil nuclear antigens. Our aim was to determine whether expression of antibodies against Crohn's disease-related bacterial sequence and Escherichia coli outer membrane porin C is associated with distinct phenotypic manifestations.Sera from 303 patients were tested for antibodies to the Crohn's disease-related bacterial sequence (I2), anti-Escherichia coli outer membrane porin C, anti-Saccharomyces cerevisiae, and perinuclear antineutrophil cytoplasmic antibodies and for 3 Crohn's disease-associated variants of the NOD2 gene (R702W, G908R, and 1007fs) and compared with clinical data.Patients expressing I2 were more likely to have fibrostenosing Crohn's disease (64.4% vs. 40.7%; P0.001) and to require small bowel surgery (62.2% vs. 37.4%; P0.001). Patients with anti-Escherichia coli outer membrane porin C were more likely to have internal perforating disease (50.0% vs. 30.7%; P = 0.001) and to require small bowel surgery (61.4% vs. 44.2%; P = 0.003). Anti-Crohn's disease-related bacterial sequence was independently associated with fibrostenosis (P = 0.027) and small bowel surgery (P = 0.01), whereas anti-Escherichia coli outer membrane porin C was independently associated with internal perforations (P0.006). Patients positive for I2, anti-Escherichia coli outer membrane porin C, and anti-Saccharomyces cerevisiae were the most likely to have undergone small bowel surgery (72.0%; odds ratio, 8.6; P0.001) compared with patients without reactivity (23.0%). When the presence and magnitude of antibody responses were considered, 90% of patients with small bowel disease who required surgery had high levels of I2, Escherichia coli outer membrane porin C, and oligomannan antibodies, compared with only 18.2% with low-titer responses (P0.001).I2 and anti-Escherichia coli outer membrane porin C are associated with Crohn's disease phenotypes, and patients with the highest level of serum reactivity toward an increasing number of microbiota have the greatest frequency of strictures, internal perforations, and small bowel surgery.

Background We compared the clinical features and therapeutic outcomes of intracranial suppurations (IEs) caused by sub-dural empyema (SDEs) and epidural abscesses (EAs). Methods Twenty-four patients with IE were retrospectively identified at our institution over a period of 14 years. Therapeutic outcomes at 6 months were determined using the Glasgow Outcome Scale. Results Among them, 15 had SDE and nine had EA with or without SDE. The three most frequently encountered clinical features Included fever (79%), disturbed consciousness(58%), and seizures (54%). Postneurosurgical or posttraumatic states (42%) and complication after meningitis (38%) were the two most common modes of infection. The overall mortality rate was 8% (2/24). However, if mortality and severe neurologic sequelae were included in the poor outcome group, then 29% (7/24) of our patients would be considered treatment failures. Conclusion In this study, SDE commonly arose following bacterial meningitis with a more fulminant course, but no deaths occurred. In contrast, EA commonly has a more Indolent course and is postoperatively or post-traumatically related, and therefore may have a higher mortality rate based on primary brain pathophysiology alone. Inpatients with meningitis or who undergo postneurosurgical procedures and develop fever, progressive disturbed consciousness, seizures, and focal neurologic signs, immediate neuroimaging studies should be per-formed to determine whether IE is present. Early surgical drainage and aggressive antimicrobial therapy are necessary.

The clinical manifestations of Crohn's disease (CD) are diverse, ranging from fibrostenosing small-bowel disease to colon-predominant inflammation. These distinctions may represent genetic, immunologic, and microbial heterogeneity. NOD2 gene mutations in CD have been described recently and may alter innate immune responses. We hypothesized that NOD2 mutations may be associated with distinct phenotypic expressions of CD.Two cohorts of consecutively identified patients referred to an inflammatory bowel disease center (n = 142 collected between 1993 and 1996; n = 59 collected between 1999 and 2001) were genotyped for 3 single nucleotide variants of NOD2-R675W, G881R, and 3020insC-and phenotyped for disease behavior, disease location, and serum immune markers.Univariate analysis showed that CD-associated NOD2 variants were significantly associated with fibrostenosing disease in each cohort (P = 0.049 and P = 0.002, respectively). When both cohorts were analyzed together, the association between NOD2 variants and fibrostenosing disease was more significant (P = 0.001). These relationships were observed in both Jews and non-Jews. Forty-six percent of patients with fibrostenosing disease carried at least 1 of these alleles, compared with only 23.5% of patients without fibrostenosing disease (odds ratio, 2.8; 95% confidence interval, 1.6-5.2). Multivariate and conditioning analyses showed a primary association between NOD2 allelic variants and fibrostenosing disease, but not with small-bowel disease.In this description of a genotype/phenotype correlation in CD patients and NOD2 variants, data suggest that variation in this gene contributes to the occurrence of fibrostenotic CD of the small bowel.

High expression of vimentin, a canonical mesenchymal marker, is linked with poor prognosis in triple negative breast cancer (TNBC), implying that vimentin may be a potential biomarker in the application of TNBC therapy. Pterostilbene (PTE) has shown anti-invasion activity, and thus, we investigated whether PTE inhibited the epithelial-mesenchymal transition (EMT) in TNBC. Here, we show that PTE decreases the vimentin expression, but that the effect was transient. PTE stimulated Fas signaling, which drives EMT by the ERK1/2 and GSK3β/β-catenin pathways, supporting Fas signaling induction involved in EMT regulation. PTE also triggered autophagy in TNBC. The treatment of TNBC with 3-methyladenine an autophagy inhibitor, not only sustained PTE-inhibited EMT but also significantly promoted anti-proliferation, which indicates that autophagy plays a cyto-protective role and is associated with EMT. Taken together, these data showed that Fas signaling and autophagy accelerated the aggressiveness of TNBC. Inhibition of autophagy or Fas signaling may provide novel targets for TNBC therapy.

BACKGROUND To assess the clinical features and therapeutic outcomes of brain abscess caused by streptococci. METHODS Twenty patients, 18 males and 2 females, aged 3 to 76 years, collected over a 14-year period, have been identified at Kaohsiung Chang Gung Memorial Hospital. RESULTS Among these 20 patients, 13 had viridans streptococci infection alone, one had non-A, non-B, and non-D streptococci infection alone, and the other 6 had mixed infections each including streptococci. The locations of all of the abscesses were supratentorial. Among these patients, 18 had a single abscess and 2 had multiple abscesses. Underlying conditions were common in our patients, including head trauma, heart disease, otopharyngeal infection, and medical procedures. Nineteen patients were treated surgically and 1 was treated with antibiotics alone. Nineteen survived and 1 died, with an overall mortality rate of 5%. CONCLUSION The clinical presentations and underlying conditions varied according to the different streptococcal species. Streptococcal brain abscesses accounted for 17% of our cases with brain abscesses, and 30% of our streptococcal infections had polymicrobial infections. Although streptococcal brain abscesses were commonly associated with otopharyngeal infections or infectious endocarditis, they also appeared to be often related to neurosurgical events or medical procedures in recent years. Based on our study, prognosis is favorable with early diagnosis and prompt treatment.

The Framingham Heart Study is a very successful longitudinal research for cardiovascular diseases. The completion of a 10-cM genome scan in Framingham families provided an opportunity to evaluate linkage using longitudinal data. Several descriptive traits based on simulated longitudinal data from the Genetic Analysis Workshop 13 (GAW13) were generated, and linkage analyses were performed for these traits. We compared the power of detecting linkage for baseline and slope genes in the simulated data of GAW13 using these traits. We found that using longitudinal traits based on multiple follow-ups may not be more powerful than using cross-sectional traits for genetic linkage analysis.

To evaluate linkage evidence for body mass index (BMI) using both cross-sectional and longitudinal data, we performed genome-wide multipoint linkage analyses on subjects who had complete data at four selected time points (initial, 8th, 12th, and 16th year following the initial visit) from the Framingham Heart Study. The cross-sectional measures included BMI at each of the four selected time points and the longitudinal measure was the within-subject mean of BMI at the above four time points. Using the variance components method, we consistently observed the maximum LOD score out of the genome scan using BMI at each time point and the mean of BMI between 049xd2 and GATA71H05 on chromosome 16. The highest LOD score (3.0) was at time point 1, while the lowest (1.9) was at time point 4. We also observed other suggestive linkages on chromosome 6, 10, and 18 at time point 1 only. The longitudinal measure we studied (mean of BMI) did not provide greater power to identify a positive linkage than some of the cross-sectional measures (e.g., time point 1). The changing of linkage evidence over time provided some insights on the variation of genetic effect on BMI with aging. There may be a QTL on chromosome 16 that contributes to BMI and this locus, and maybe others, is more likely to affect BMI during early adulthood.