The cutaneous adverse drug reactions: risk factors, prognosis and economic impacts.

AIMS: The aim of this study was to explore the factors associated with the occurrence, subsequent prognoses and need for additional medications following cutaneous adverse drug reactions (ADRs) among inpatients. METHODS AND MEASURES: This is a case-control study, nested in a large cohort study of 473,446 inpatients hospitalised from 2005 to 2008, examined cutaneous ADRs. A 1 : 5 strategy of individually matching age and principal diagnosis was applied to the data of cases (n = 700) and corresponding controls (n = 3365).The severity of ADRs was evaluated using Naranjo algorithms by senior pharmacists in the medical centre. Medical chart reviews and claim data analyses were analysed to explore risk factors associated with the occurrence and impact of cutaneous ADRs. Economic impacts in terms of length of stay and medical expenses were also analysed. RESULTS: The number of drug prescriptions and secondary diagnoses, and the department to which the patient was admitted, significantly contributed to the risk of cutaneous ADRs and subsequent prognosis. In addition to physician's seniority, the Naranjo score was also positively associated with patients' prognosis. Medical expenses associated with cutaneous ADRs patients ($US 916) were more than 2.5-fold higher than those patients who were not afflicted ($US 318). CONCLUSION: The study identified risk factors for cutaneous ADRs in terms of both patient characteristics and drug complexity. The present analyses indicate characteristics and mechanisms of cutaneous ADRs among inpatients, which provide clues for future intervention strategies and management issues in healthcare settings.

Anterior ilioinguinal incision for drainage of high-located perianal abscess.

Most perianal abscesses originate from infected anal glands at the base of the anal crypts. Most abscesses below are usually drained through perianal incision and can be treated successfully. However, when perianal abscesses extend to the high intrapelvic cavity, it may be inadequate treatment through a single route incision through a perianal approach. The aim of this technical note is to show that combined anterior ilioinguinal and perianal incisions may provide optimal surgical field and multiple drainages. Here, we report a 56-year-old male patient with perianal-originating parapsoas abscesses. Residual abscess still remained after initial perianal incision and drainage after 1-month treatment. We presented combined anterior ilioinguinal and perianal incision technique methods for proper drainage in this complicated case. No recurrent or residual abscess remained after 2 weeks of operation. So, combined anterior ilioinguinal incision is feasible for high-located perianal abscess.

Triglycerides are independently associated with albuminuria in Taiwanese Type 2 diabetic patients.

BACKGROUND: Lipid abnormalities in albuminuria in patients with Type 2 diabetes differ by race. AIM: To perform a biochemical investigation of association between dyslipidemia and albuminuria in Type 2 diabetes in Taiwan. MATERIALS/ SUBJECTS AND METHODS: We recruited a total of 2349 Chinese patients with Type 2 diabetes from two medical centers in Taiwan over a 1-yr period. Patients were categorized into those with normoalbuminuria, microalbuminuria, and macroalbuminuria defined as albumin-to-creatinine ratio of <30, 30- 299, and ≥300 µg/mg. We then investigated the significance of the clinical and biochemical parameters and risk of albuminuria. RESULTS: We found significant differences in total cholesterol (TC) between those with normoalbuminuria and micro/ macroalbuminuria, no significant difference in LDL cholesterol (LDL-C) among the 3 subgroups, a significant difference in HDL cholesterol (HDL-C) between those with normoalbuminuria and macroalbuminuria, and significant increases in triglyceride (TG) paralleling increases in albuminuria. TG was found by logistic regression to be significantly associated with micro/macroalbuminuria in our unadjusted model [odds ratio (OR) = 1.859 (1.596~2.165)], and remained significant after adjusting for various confounders [OR = 1.415 (1.123~1.784)]. Increases in albuminuria paralleled quartile increases in serum TG (p<0.001). CONCLUSIONS: We conclude that TG increases significantly throughout the 3 stages of albuminuria in Taiwanese Type 2 diabetic patients, but TC, HDL-C, and LDL-C do not.

Enhanced anticancer activity and endocytic mechanisms by polymeric nanocarriers of n-butylidenephthalide in leukemia cells.

PURPOSE: The purpose of this study was to investigate the antitumor mechanisms of n-butylidenephthalide (BP) and to further examine the delivery efficacy of polycationic liposome containing PEI and polyethylene glycol complex (LPPC)-encapsulated BP in leukemia cells. METHODS: MTS, flow cytometric and TUNEL assays were performed to assess cell viability and apoptosis. BP and BP/LPPC complex delivery efficiency was analyzed by full-wavelength fluorescent scanner and fluorescence microscope. The expressions of cell cycle- and apoptosis-related proteins were conducted by Western blotting. RESULTS: The results showed that BP inhibited leukemia cell growth by inducing cell cycle arrest and cell apoptosis. LPPC-encapsulated BP rapidly induced endocytic pathway activation, resulting in the internalization of BP into leukemia cells, causing cell apoptosis within 1 h. CONCLUSIONS: LPPC encapsulation enhanced the cytotoxic activity of BP and did not influence the effects of BP induction that suggested LPPC-encapsulated BP might be developed as anti-leukemia drugs in future.

Abnormal expressions of circadian-clock and circadian clock-controlled genes in the livers and kidneys of long-term, high-fat-diet-treated mice.

OBJECTIVES: Physiological and behavioral circadian rhythmicities are exhibited by all mammals and are generated by intracellular levels of circadian oscillators, which are composed of transcriptional/translational feedback loops involving a set of circadian-clock genes, such as Clock, Per1-3, Cry1-2, Bmal1, Dbp, E4BP4 and CK1varepsilon. These circadian-clock genes play important roles in regulating circadian rhythms and also energy homeostasis and metabolism. Determining whether obesity induced by high-fat diet affected the expressions of circadian-clock genes and their related genes in peripheral tissues, was the main focus of this study. To address this issue, we fed male C57BL/6 mice a high-fat diet for 11 months to induce obesity, hyperglycemic, hypercholesterolemic and hyperinsulinemic symptoms, and used quantitative real-time reverse transcription-PCR to measure gene expression levels. RESULTS: We found that the expressions of circadian-clock genes and circadian clock-controlled genes, including Per1-3, Cry1-2, Bmal1, Dbp, E4BP4, CK1varepsilon, PEPCK, PDK4 and NHE3, were altered in the livers and/or kidneys. CONCLUSIONS: These results indicate that obesity induced by high-fat diet alters the circadian-clock system, and obesity and metabolic syndrome are highly correlated with the expressions of circadian-clock genes and their downstream, circadian clock-controlled genes.

Small ubiquitin-like modifier-4 Met55Val polymorphism is associated with glycemic control of Type 2 diabetes mellitus in Taiwan.

AIM: The development of Type 2 diabetes mellitus (T2DM) has been recognized to be associated with a combination of pancreatic beta-cell dysfunction and insulin resistance. Nuclear factor-kappaB (NF-kappaB) has been recognized as one central mediator in the reaction of inflammation and proapoptotic event in beta-cells. A functional polymorphism at the codon 55 (methionine to valine; A163G) of the small ubiquitin- like modifier-4 (SUMO4) gene may result in higher NF-kappaB activity. This study investigates whether this SUMO4 Met55Val polymorphism also contributes to the development of T2DM. MATERIALS AND METHODS: The study was performed using genomic DNA samples from 574 Type 2 diabetic patients and 323 healthy controls. The SUMO4 Met55Val polymorphism was genotyped using allele-specific real-time PCR. RESULTS: The frequency of the G allele (encoding Val55) was significantly higher in Type 2 diabetic patients and Type 2 diabetic patients with the GG genotype had higher hemoglobin A1c level. Multivariate logistic regression analysis revealed the genotype of GG and GA was an independent risk factor contributing to the development of T2DM. CONCLUSION: This study suggests that in Taiwan the SUMO4 Met 55Val polymorphism is associated with susceptibility to T2DM and Type 2 diabetic patients with GG genotype have worse glycemic control.

Epithelioid leiomyosarcoma of the uterus: computed tomography findings.

Uterine epithelioid leiomyosarcoma is a rare neoplasm. There have been no previous reports describing computed tomography (CT) findings for this tumor. A 31-year-old woman presented with a heterogeneous enhancing mass, with internal septa, in the uterus, which was shown on CT images. Histological diagnosis was compatible with epithelioid leiomyosarcoma.

Spontaneous splenic rupture in a patient who received haemodialysis: case report and a review of the literature.

Spontaneous splenic rupture is an extremely rare complication in patients who received haemodialysis. We describe a 51-year-old woman who underwent regular haemodialysis and was admitted because of sudden onset of abdominal pain, hypovolemic shock and dizziness. Haemoperitoneum caused by spontaneous rupture of spleen was found on abdominal CT scan. Emergency splenectomy was performed, and the patient was discharged 9 days after the admission. This report demonstrates that spontaneous splenic rupture requires a high index of suspicion for diagnosis in a patient who received haemodialysis with abdominal pain and should be considered in the differential diagnosis when a patient who received haemodialysis without any trauma history has abdominal pain with unexplained hypovolemic shock.

Early diagnosis of polyomavirus type BK infection in tailoring immunosuppression for kidney transplant patients: screening with urine qualitative polymerase chain reaction assay.

Polyomavirus type BK (BKV) nephropathy is increasingly a significant cause of graft dysfunction and even failure. Early diagnosis followed by reduction of immunosuppression has been associated with an improved prognosis. We screened 250 patients with the urine qualitative polymerase chain reaction (PCR) for BKV DNA. We followed with blood BKV PCR if the urine screen was positive and then reduced immunosuppression in viremic patients. One hundred ninety-nine patients (80%) had no viuria; 43 (17%) viuria; and 8 (3%) both viuria and viremia. Graft biopsy performed in three patients (1%) with viremia and impaired graft function all revealed BKV nephropathy. After 6 months of follow-up, seven out of eight viremic patients (88%) had negative repeat blood PCR and stabilized graft function. An early diagnosis of BKV infection with reduction of immunosuppression may reverse viremia and retard progression of BKV nephropathy. BKV screening by PCR assays should be considered in kidney transplant recipients, especially those with impaired graft function.

Outcome of distal gastric cancer with pyloric stenosis after curative resection.

AIMS: Pyloric stenosis usually presents with symptoms, and this may lead patients to consult their physician. We evaluate whether distal gastric cancer patients with pyloric stenosis had a better outcome than those without. METHODS: A total of 551 distal gastric cancer patients who received curative subtotal gastrectomy between January 1988 and December 2003 at Taipei Veterans General Hospital were analyzed. Among them, 174 patients were sorted into the pyloric stenosis group according to obstructive symptoms. Their clinicopathological features, survival and prognostic factors were evaluated. RESULTS: The 5-year overall and disease-free survival rate of distal third gastric adenocarcinoma for the pyloric stenosis group was significantly lower than those without pyloric stenosis. Multivariate analysis revealed the pyloric stenosis group had deeper cancer invasion (relative to pT1, RR of pT2 3.1, p=0.009; pT3 6.1, p<0.001; pT4 16.5, p<0.001), and more lymph node metastasis (RR 3.6; p=0.001). The pyloric stenosis group had a tendency to lymph node metastasis toward the hepatoduodenal ligament, but this did not reach statistical difference. However, the pyloric stenosis group had significantly higher lymph node metastasis in the retropancreatic region (5.17% vs. 0.53%; p=0.001). CONCLUSIONS: Distal gastric cancers with pyloric stenosis have worse biological behavior than those without, and consequently have a poor outcome.

The preparation and catalytic properties of recombinant human prostate-specific antigen (rPSA).

The serine proteinase prostate-specific antigen (PSA), and its complex with the serine proteinase inhibitor alpha(1)-antichymotrypsin (ACT), have been used as markers for the diagnosis of prostate cancer. PSA prepared from seminal fluid is typically contaminated with the trypsin-like glandular kallikrein (hK2). Here we describe a convenient and reproducible preparation of catalytically active recombinant PSA (rPSA) and demonstrate an overall similarity in the properties of cloned and refolded rPSA to PSA purified from seminal fluid. We also present results that are relevant for increasing the sensitivity of assays of PSA activity in biological fluids, for the putative role of PSA activity in physiologically important processes, including prostate cancer metastasis, and for the design of PSA inhibitors. Specifically, we find that added salts, in particular NaCl, give rise to dramatic increases in rPSA catalytic activity, as does added glycerol. On the other hand, Zn(2+), spermine, and spermidine, each a major component of seminal and prostatic fluid, strongly inhibit rPSA activity, with Zn(2+) being a non-competitive inhibitor while spermine is a competitive inhibitor. Citrate, also a major component of seminal and prostatic fluid, spermine, and spermidine each protect rPSA from Zn(2+) inhibition, presumably via Zn(2+) sequestration. Finally, rPSA efficiently proteolyzes several protein substrates.

Stage migration influences on stage-specific survival comparison between D1 and D3 gastric cancer surgeries.

AIMS: We evaluate the influency stage migration in a randomised trial comparing D1 (N 1 lymphadenectomy) and D3 (N 1, 2 and 3 lymphadenectomy) dissections. METHODS: Two hundred and thirteen curatively resected patients were analysed, with this TNM data. RESULTS: After applying D3 patients' data according to simulated D1 staging, D3 resections were associated with up-staging to N2-3 levels in 8% of patients according to the N stage. The likelihood of N-status migration increased with increasing depth of invasion into the gastric wall. The increases in the calculated survival rate after stage migration on known 5-year survival rates were: 2% in stage IB, 1% in stage II, 4% in stage IIIA, and 1% in stage IIIB. CONCLUSIONS: Stage migration secondary to meticulous lymph node dissection affects stage-specific survival rates. True therapeutic survival benefit of D3 resection can only be assessed in this context.

Antitumor agents. 174. 2',3',4',5,6,7-Substituted 2-phenyl-1,8-naphthyridin-4-ones: their synthesis, cytotoxicity, and inhibition of tubulin polymerization.

Two series of 2',3',4',5,6,7-substituted 2-phenyl-1,8-naphthyridin-4-ones and 2-phenylpyrido[1,2-alpha]pyrimidin-4-ones have been synthesized and evaluated as cytotoxic compounds and as inhibitors of tubulin polymerization. Most 2-phenyl-1,8-naphthyridin-4-ones showed potent cytotoxic and antitubulin activities, whereas 2-phenylpyrido[1,2-alpha]pyrimidin-4-ones showed no activity in either assay. In general, a good correlation was found between cytotoxicity and inhibition of tubulin polymerization in the 2-phenyl-1,8-naphthyridin-4-one series. The 2-phenyl-1,8-naphthyridin-4-ones (44-49) with a methoxy group at the 3'-position showed potent cytotoxicity against most tumor cell lines with GI50 values in the low micromolar to nanomolar concentration range in the National Cancer Institute's 60 human tumor cell line in vitro screen. Introduction of substituents (e.g. F, Cl, CH3, and OCH3) at the 4'-position led to compounds with reduced or little activity and substitution at the 2'-position resulted in inactive compounds. The effects of various A-ring substitutions on activity depend on the substitution in ring C. Compounds 44-50 were potent inhibitors of tubulin polymerization, with activity nearly comparable to that of the potent antimitotic natural products colchicine, podophyllotoxin, and combretastatin A-4. Compounds 44-49 also inhibited the binding of radiolabeled colchicine to tubulin, but the inhibition was less potent than that obtained with the natural products. Further investigation is underway to determine if substitution at the 3'-position and multisubstitutions in ring C will result in compounds with increased activity.

Antitumor agents. 178. Synthesis and biological evaluation of substituted 2-aryl-1,8-naphthyridin-4(1H)-ones as antitumor agents that inhibit tubulin polymerization.

As part of our continuing search for potential anticancer drug candidates in the 2-aryl-1,8-naphthyridin-4(1H)-one series, we have synthesized two series of 3'-substituted 2-phenyl-1,8-naphthyridin-4(1H)-ones and 2-naphthyl-1,8-naphthyridin-4(1H)-ones. All compounds showed significant cytotoxic effects (log GI50 < -4.0; log molar drug concentration required to cause 50% growth inhibition) against a variety of human tumor cell lines of the National Cancer Institute's in vitro screen, including cells derived from solid tumors such as non-small cell lung, colon, central nervous system, melanoma, ovarian, prostate, and breast cancers. All 3'-substituted compounds demonstrated strong cytotoxic effects in almost all tumor cell lines. Introduction of an aromatic ring at the 2'- and 3'-positions also generated compounds with potent antitumor activity. Incorporation of an aromatic ring at the 3'- and 4'-positions produced compounds with reduced activity. Interestingly, introduction of a halogen at the 3'-position yielded compounds with different selectivity for the tumor cell lines tested. All 3'-halogenated compounds (29-36) and compounds 38 and 42-44 were potent inhibitors of tubulin polymerization with activities nearly comparable to those of the potent antimitotic natural products colchicine, podophyllotoxin, and combretastatin A-4. Active agents also inhibited the binding of [3H]colchicine to tubulin.

Virologic factors related to interferon-alpha-induced thyroid dysfunction in patients with chronic hepatitis C.

OBJECTIVE: Hepatitis C virus (HCV), being reported to be associated with a high prevalence of serological markers of autoimmunity in HCV-infected patients, and possibly sharing partial sequences in amino acid segments with thyroid tissue antigens, may be associated with interferon-alpha (IFN-alpha)-induced thyroid dysfunction in chronic hepatitis C patients. We conducted this study to clarify the issue. DESIGN AND METHODS: One hundred and fifty chronic hepatitis C patients with normal baseline thyroid function were treated with IFN-alpha 2a, 2b and n1 (3-6 million Units three times weekly for 24 weeks). Pretreatment sera were tested for HCV genotype and HCV RNA levels. Serum thyrotropin, total thyroxine and free thyroxine index were performed every 4 weeks for 24 weeks followed by every 8 weeks for another 24 weeks. RESULTS: Twenty-one (14.0%) patients developed early thyroid dysfunction (abnormal thyroid function during the first 3 months of therapy). Female gender, lower HCV RNA levels, IFN-alpha n1 and a lower IFN-alpha dose were significantly associated with early thyroid dysfunction. On multivariate analysis, gender, IFN-alpha preparation and HCV RNA levels were the significant factors associated with early thyroid dysfunction. Seven (4.7%) patients developed thyroid dysfunction during the second 3 months of IFN-alpha therapy. Taken together, 18.7% patients developed thyroid dysfunction. Female, mixed HCV genotype infection and lower HCV RNA levels were significantly associated with thyroid dysfunction. However, only gender remained significantly associated with IFN-alpha-induced thyroid dysfunction in multivariate analysis. CONCLUSIONS: The virologic features of HCV may be associated with thyroid dysfunction in chronic hepatitis C patients treated with IFN-alpha. Nevertheless, gender still plays the most important role in IFN-alpha-induced thyroid dysfunction.

Results of curative gastrectomy for carcinoma of the distal third of the stomach.

BACKGROUND: Carcinoma of the distal stomach metastasizes to lymph nodes along the bile duct, pancreatic head, and duodenum. We reviewed the results of patients who underwent operation for carcinoma of the stomach, and placed special emphasis on survival related to lymph node metastasis. STUDY DESIGN: We conducted a prospective study of 258 consecutive patients with adenocarcinoma of the distal third of the stomach who underwent curative gastrectomies. RESULTS: Most of the patients (193 [75 percent]) had advanced cancer (extension beyond the submucosa). A subtotal gastrectomy was the procedure most commonly performed (89 percent). Combined organ resection was performed in 100 patients (39 percent). The operative morbidity was 17 percent; the most frequent complications were chylous leakage, anastomotic insufficiency, and intra-abdominal infection. Ninety-four patients (36 percent) had tumor recurrence, with local recurrence occurring in 45 patients. In 40 of the 45 cases, the local recurrence resulted from remnant lymph nodes (LNs), or soft tissues in the gastric bed. Lymph node metastases were observed in 152 patients (59 percent). Excluding five patients (2 percent) who died, the overall five-year cumulative survival rate was 53 percent. The five year survival rate was 98 percent for patients with TNM stage I disease; 68 percent for patients with stage II disease; 40 percent for patients with stage III disease; and 10 percent for patients with stage IV disease. The survival rate for patients with n0, n1, n2, and n3 disease was respectively 92 percent, 45 percent, 30 percent, and 20 percent. For patients with metastatic LNs in the hepatoduodenal ligament, the five-year survival rate was 20 percent. CONCLUSIONS: These data suggest that survival rate relates to the extent of LN metastasis. It appears that systematic lymph node dissection may have a beneficial effect. However, the efficacy of radical lymph node dissection can only be determined by prospective, randomized clinical trials with a proper study design.

Morbidity and mortality after radical gastrectomy for patients with carcinoma of the stomach.

BACKGROUND: This study sought to analyze the morbidity and mortality rates after radical gastrectomy for carcinoma, since the operation has been criticized as too morbid for the benefits it may provide. STUDY DESIGN: A prospective study of 474 patients who underwent radical gastrectomy was conducted. RESULTS: The overall morbidity and mortality rates were 20.1 and 3.0 percent, respectively. The morbidity and mortality rates fell significantly from 27.0 to 15.7 percent (p = 0.003) and 5.5 to 1.1 percent (p < 0.001), respectively, after the first 200 cases. By logistic regression analysis, it was found that male gender, combined organ(s) resection, extended lymphadenectomy, respiratory system disease, and tumor location were significantly related to postoperative morbidity. In regard to the extent of lymphadenectomy, relative to R2 resection (n = 102), the odds ratio for morbidity after R3 resection (n = 217) was 2.13, and for R4 resection (n = 155) it was 3.12. Age older than 65 years, total gastrectomy, combined organ(s) resection, and respiratory system disease were factors that negatively affected operative mortality. CONCLUSIONS: These observations suggested that radical gastrectomy can be performed with an acceptable risk of morbidity and mortality in a general hospital.

Partial purification and characterization of a soybean beta-glucosidase with high specific activity towards isoflavone conjugates.

A beta-glucosidase with high specific activity towards isoflavone conjugates was purified from soybean [Glycine max] roots by high salt extraction from a low speed centrifugal pellet and subsequent anion and cation exchange chromatography. Purification required stabilization throughout fractionation in 10% glycerol. The enzyme is most likely a dimer (approximate M(r) 165 kDa) with potential subunits of M(r) 80 and/or 75 kDa. The pH and temperature optima are pH 6 and 30 degrees C, respectively. The enzyme was highly heat-stable. Of the various potential effectors examined, silver and mercury ions were the most inhibitory. The IC(50) of silver ions was increased from 140 microM to 14 mM in the presence of 250 microM beta-mercaptoethanol. Glucono-delta-lactone was not strongly inhibitory (IC(50) 24 mM). The activity was highly active against isoflavone conjugates, with a specificity constant 160-1000 fold higher for isoflavone conjugates over the generic chromogenic substrate, p-nitrophenyl beta-glucoside. The enzyme was inactive against the flavonol glycosides tested. The partially purified enzyme had similar K(m) and k(cat) towards 7-O-glucosyl- and 7-O-glucosyl-6"-malonyl-isoflavones, suggesting that it may be able to cleave the esterified glucosyl conjugate. We hypothesize that the enzyme is involved in the release of daidzein and genistein, both of which play central roles in soybean defense.