Association of rheumatic diseases with symptom severity, quality of life, and treatment outcome in patients with fibromyalgia.

OBJECTIVES: To evaluate the frequency of rheumatic diseases and their association with symptom severity, quality of life (QoL), and treatment outcome in patients with fibromyalgia (FM). METHOD: Our study contained 536 FM patients who completed a brief, interdisciplinary fibromyalgia treatment programme (FTP) at our institution, with emphasis on cognitive behavioural therapy (CBT). The Fibromyalgia Impact Questionnaire (FIQ) and the 36-item Short Form Health Status Questionnaire (SF-36) were completed at initial evaluation and at 6 and 12 months after the FTP. The presence of inflammatory rheumatic disease (IRD) was determined by physician diagnoses. A two-sample t-test and multivariate linear regression analyses were performed to compare the rheumatic and non-rheumatic groups. RESULTS: Thirty-six patients (6.7%) had documented IRD. At baseline, the rheumatic group had poorer scores in SF-36 physical functioning (p = 0.02), pain index (p = 0.01), and physical component summary (p = 0.009) than the non-rheumatic group. After treatment, both groups tended to improve; however, the rheumatic group had significantly less improvement on the FIQ subscales in pain (p = 0.01) and missed work days (p = 0.01), as well as in the SF-36 physical functioning (p = 0.01), pain index (p = 0.049), and physical component summary (p = 0.049) compared with the non-rheumatic group. CONCLUSIONS: The frequency of rheumatic diseases in patients with FM seen at FTP was 6.7%. FM patients with rheumatic diseases were found to have worse SF-36-assessed pain and physical health and less improvement in these measures following treatment from FTP than patients without rheumatic diseases. FM patients with rheumatic disease may require additional intervention to address underlying rheumatic disease-related limitations.

Depression and alcohol withdrawal syndrome: is antidepressant therapy associated with lower rates of hospital readmission?

BACKGROUND: Alcohol withdrawal syndrome (AWS) is a frequent cause of admission to acute care hospitals and many of these patients have a history of depression. AIM: Our objective was to determine if antidepressant use in patients with a history of depression is associated with lower rates of hospital readmission for AWS. METHODS: A retrospective study was performed of patients admitted with AWS between January 1, 2006 and December 31, 2008 to an academic tertiary referral hospital. RESULTS: Three hundred and twenty-two patients were admitted with AWS during the study period. One hundred and sixty-one patients (50 %) had no history of depression, 111 patients (34 %) had a history of depression and antidepressant use, and 50 patients (16 %) had a history of depression and no antidepressant use. There was no significant difference in the number of hospitalizations for AWS between these three groups. Patients with a history of depression on antidepressant medication were more likely to be retired or work disabled compared to the other two groups (p < 0.05). The antidepressant class most commonly used was SSRI (63 %). CONCLUSION: Our study highlights the high frequency of depression and antidepressant use in patients admitted with AWS to an acute care hospital. As alcohol withdrawal is associated with increased morbidity and mortality and depression is common in those with alcohol use disorder, further research is necessary to clarify the optimal treatment of comorbid depression and alcohol use disorder in reducing these revolving door admissions.

Pharmacokinetics of daily versus monthly vitamin D3 supplementation in non-lactating women.

This study compared serum cholecalciferol and 25-hydroxyvitamin D (25(OH)D) concentrations over four weeks in healthy, non-pregnant, non-lactating females aged 18-40 years, who were randomized to oral cholecalciferol 5000 international units (IU) daily for 28 days or a single dose of 150 000 IU. The study was conducted in Rochester, MN in March and April of 2010. We found no difference in mean 25(OH)D between treatment groups on study day 0 or day 28 (P=0.14 and 0.28, respectively). The daily group had 11 more days of detectable serum cholecalciferol than the single-dose group (P<0.001). There was no difference observed in cholecalciferol area under the curve (AUC28) between groups (P=0.49). However, the single-dose group had a significantly greater mean 25(OH)D AUC28 compared with the daily group (P<0.001).

Referral and ascertainment bias in patients with synchronous and metachronous endometrial malignancy.

The purpose of this study was to evaluate the frequency in patients with endometrial cancer of other malignancies and the influence of referral and ascertainment biases on these associations. Analysis of 1,028 local and referred patients who had a hysterectomy for endometrial cancer was based on residence at the time of diagnosis. Altogether, 208 patients had a history of another malignancy, most frequently breast, colon, and ovary. At the time of surgery for endometrial cancer, the prevalence of lymphoma and breast and ovarian cancers was greater than expected although the higher prevalence of lymphoma was limited to referred patients. During follow-up after hysterectomy, the incidence of lung cancer was lower than expected, whereas the incidence of lymphoma was higher. Breast, colorectal, and bladder cancers were more common than expected although this finding was limited to local patients. We concluded that results of epidemiologic studies from tertiary care centers may be misleading if they do not account for referral and ascertainment biases.

Association of the bla(CMY-10) gene with a novel complex class 1 integron carrying an ISCR1 element in clinical isolates from Korea.

The bla(CMY-10) gene responsible for ß-lactam resistance was located on a new complex class 1 integron within a conjugative plasmid. The sul1-type class 1 integron, containing an aadA2a gene cassette, was identified upstream of bla(CMY-10). A unique gene array (yqgF-yqgE-gshB-orf97--orf105) was identified downstream of bla(CMY-10.).

A retroperitoneal granular cell tumour that mimics pancreatic cancer.

Granular cell tumour is a rare disorder that is characterised by an oval-shaped tumour that has with eosinophilic granules within the tumour cells. It is extremely rare to find this disease arising from the retroperitoneum. We report here on a case of a 46-year-old man with a retroperitoneal granular cell tumour that mimics pancreatic cancer, and describe the CT and MRI findings.

Use of a palliative care order set to improve resident comfort with symptom management in palliative care.

Although one-fourth of all medicare dollars are spent during the last year of life, symptom management for terminal hospitalized patients has continued to be inadequate. Quality end-of-life care is often overlooked, seldom taught and rarely measured within Internal Medicine Residency Programmes. We studied the effects of a palliative care order set and educational e-mail on resident comfort. Survey of residents showed that only 54% were comfortable across nine aspects of palliative care. Three months after release, 88% of residents were using the order set and 63% believed it increased their comfort with palliative care. Resident comfort managing palliative symptoms increased an average 10% (P = 0.02). First-year residents exposed to this order set increased in comfort from 40% to 65% (P < 0.0001), which significantly surpassed the 48% of second-year residents who reported being comfortable (P = 0.002). Introducing a palliative care order set improves resident comfort with symptom management in dying patients.

Gallbladder adenomyomatosis: imaging findings.

In this pictorial essay, we describe the imaging findings of adenomyomatosis of the gallbladder and emphasize high-resolution ultrasound and magnetic resonance cholangiopancreatography in its diagnosis.

The effect of online status on the impact factors of general internal medicine journals.

BACKGROUND: We sought to determine the effects of becoming available online on impact factors of general medicine journals. METHODS: Through MEDLI NE with an institutional subscription, the 2004 online status of "Medicine, General and Internal" journals listed in the Institute for Scientific Information (ISI ) Journal Citation Reports (JCR) was classified as full text on the Net (FU TON), abstract only, or no abstract available (NAA)/unavailable in MEDLI NE. Similarly, through use of a home computer without an institutional subscription, the 2004 online status of the same journals was determined. For each journal, impact factors for 1992 to 2003 were obtained. RESULTS: Of the 102 "Medicine, General and Internal" journals listed in the ISI JCR, 71 (70%) existed in both pre-Internet (1992) and Internet (2003) eras. Of these 71 journals, those available as FU TON in 2004 had higher median impact factors than non-FU TON journals in 1992 (p < 0.0001> and 2003 (p < 0.0001). Journals that became available online, at least partially, had significant increases in median impact factors from 1992 to 2003 (p< 0.0001 for journals that became available as FUTON and for journals that provided an abstract only. However, journals that became available as FUTON had a greater increase in median impact from 1992 to 2003 than other journals (p = 0.002). Similar results were obtained using impact factor data according to journal online status through use of a home computer without an institutional subscription and for English-language journals only. CONCLUSION: Becoming available online as FUTON is associated with a significant increase in journal impact factor.

Gemcitabine and oxaliplatin for metastatic pancreatic adenocarcinoma: a North Central Cancer Treatment Group phase II study.

BACKGROUND: This study was performed to determine the efficacy of gemcitabine and oxaliplatin in patients with advanced or metastatic pancreatic adenocarcinoma (ACA). PATIENTS AND METHODS: Pancreatic ACA patients with previously untreated advanced or metastatic disease were enrolled in a phase II study of gemcitabine and oxaliplatin. Oxaliplatin was given i.v. on day 1 and gemcitabine i.v. on days 1 and 8 of a 3-week cycle. The primary end point of the trial was 6-month survival. Secondary end points included response rate, overall survival, median time to progression and toxicity. RESULTS: A total of 47 patients were enrolled, 46 of whom were evaluable. Of those patients assessed for the primary end point 50% lived for > or =6 months. The median time to progression was 4.53 months. Five confirmed responses were seen with a median duration of response of 2.7 months. Overall, the treatment was well tolerated. However, one patient died as a result of treatment-related hemolytic uremic syndrome. CONCLUSIONS: Gemcitabine and oxaliplatin, at doses of 1000 mg/m(2) and 100 mg/m(2), respectively, showed moderate activity in patients with pancreatic ACA. Based on the results of this study further evaluation of this combination is warranted.

Gemcitabine and oxaliplatin for patients with advanced or metastatic pancreatic cancer: a North Central Cancer Treatment Group (NCCTG) phase I study.

BACKGROUND: The study was performed to determine the maximum tolerated dose (MTD) of gemcitabine and oxaliplatin in patients with advanced or metastatic pancreatic adenocarcinoma (ACA). PATIENTS AND METHODS: Pancreatic ACA patients, with previously untreated advanced or metastatic disease, were enrolled in a dose escalation study of gemcitabine and oxaliplatin. Oxaliplatin was given intravenously on day 1 and gemcitabine intravenously on days 1 and 8 of a 3-week cycle. Doses of both drugs were increased with sequential cohorts of patients until dose-limiting toxicity (DLT) was observed. RESULTS: A total of 18 patients were enrolled to three dose levels. DLT of neutropenia and a severe infection was noted at a dose of gemcitabine 1250 mg/m2 and oxaliplatin 130 mg/m2. Hematological toxicity and nausea and vomiting were the most common grade 3/4 toxicities. The MTD, gemcitabine 1000 mg/m2 and oxaliplatin 100 mg/m2, was well tolerated. Three confirmed responses were seen. CONCLUSIONS: The MTD of gemcitabine and oxaliplatin in patients with pancreatic ACA was determined. A phase II study of this combination is ongoing and will be reported separately at a later date.

Maintenance of alpha-helical structures by phenyl rings in the active-site tyrosine triad contributes to catalysis and stability of ketosteroid isomerase from Pseudomonas putida biotype B.

Ketosteroid isomerase (KSI) from Pseudomonas putida biotype B is a homodimeric enzyme catalyzing an allylic rearrangement of Delta5-3-ketosteroids at rates comparable with the diffusion-controlled limit. The tyrosine triad (Tyr14.Tyr55.Tyr30) forming a hydrogen-bond network in the apolar active site of KSI has been characterized in an effort to identify the roles of the phenyl rings in catalysis, stability, and unfolding of the enzyme. The replacement of Tyr14, a catalytic residue, with serine resulted in a 33-fold decrease of kcat, while the replacements of Tyr30 and Tyr55 with serine decreased kcat by 4- and 51-fold, respectively. The large decrease of kcat for Y55S could be due to the structural perturbation of alpha-helix A3, which results in the reorientation of the active-site residues as judged by the crystal structure of Y55S determined at 2.2 A resolution. Consistent with the analysis of the Y55S crystal structure, the far-UV circular dichroism spectra of Y14S, Y30S, and Y55S indicated that the elimination of the phenyl ring of the tyrosine reduced significantly the content of alpha-helices. Urea-induced equilibrium unfolding experiments revealed that the DeltaG(U)H2O values of Y14S, Y30S, and Y55S were significantly decreased by 11.9, 13.7, and 9.5 kcal/mol, respectively, as compared with that of the wild type. A characterization of the unfolding kinetics based on PhiU-value analysis indicates that the interactions mediated by the tyrosine triad in the native state are very resistant to unfolding. Taken together, our results demonstrate that the internal packing by the phenyl rings in the active-site tyrosine triad contributes to the conformational stability and catalytic activity of KSI by maintaining the structural integrity of the alpha-helices.

Intraoperative irradiation for locally recurrent colorectal cancer in previously irradiated patients.

PURPOSE: Information in the literature regarding salvage treatment for patients with locally recurrent colorectal cancer who have previously been treated with high or moderate dose external beam irradiation (EBRT) is scarce. A retrospective review was therefore performed in our institution to determine disease control, survival, and tolerance in patients treated aggressively with surgical resection and intraoperative electron irradiation (IOERT) +/- additional EBRT and chemotherapy. METHODS AND MATERIALS: From 1981 through 1994, 51 previously irradiated patients with recurrent locally advanced colorectal cancer without evidence of distant metastatic disease were treated at Mayo Clinic Rochester with surgical resection and IOERT +/- additional EBRT. An attempt was made to achieve a gross total resection before IOERT if it could be safely accomplished. The median IOERT dose was 20 Gy (range, 10--30 Gy). Thirty-seven patients received additional EBRT either pre- or postoperatively with doses ranging from 5 to 50.4 Gy (median 25.2 Gy). Twenty patients received 5-fluorouracil +/- leucovorin during EBRT. Three patients received additional cycles of 5-fluorouracil +/- leucovorin as maintenance chemotherapy. RESULTS: Thirty males and 21 females with a median age of 55 years (range 31--73 years) were treated. Thirty-four patients have died; the median follow-up in surviving patients is 21 months. The median, 2-yr, and 5-yr actuarial overall survivals are 23 months, 48% and 12%, respectively. The 2-yr actuarial central control (within IOERT field) is 72%. Local control at 2 years has been maintained in 60% of patients. There is a trend toward improved local control in patients who received > or =30 Gy EBRT in addition to IOERT as compared to those who received no EBRT or <30 Gy with 2-yr local control rates of 81% vs. 54%. Distant metastatic disease has developed in 25 patients, and the actuarial rate of distant progression at 2 and 4 years is 56% and 76%, respectively. Peripheral neuropathy was the main IOERT-related toxicity; 16 (32%) patients developed neuropathies (7 mild, 5 moderate, 4 severe). Ureteral narrowing or obstruction occurred in seven patients. All but one patient with neuropathy or ureter fibrosis received IOERT doses > or =20 Gy. CONCLUSION: Long-term local control can be obtained in a substantial proportion of patients with aggressive combined modality therapy, but long-term survival is poor due to the high rate of distant metastasis. Re-irradiation with EBRT in addition to IOERT appears to improve local control. Strategies to improve survival in these poor-risk patients may include the more routine use of conventional systemic chemotherapy or the addition of novel systemic therapies.

Role of catalytic residues in enzymatic mechanisms of homologous ketosteroid isomerases.

Ketosteroid isomerase (KSI) is one of the most proficient enzymes catalyzing an allylic isomerization reaction at a diffusion-controlled rate. In this study of KSI, we have detailed the structures of its active site, the role of various catalytic residues, and have explained the origin of the its fast reactivity by carrying out a detailed investigation of the enzymatic reaction mechanism. This investigation included the X-ray determination of 15 crystal structures of two homologous enzymes in free and complexed states (with inhibitors) and extensive ab initio calculations of the interactions between the active sites and the reaction intermediates. The catalytic residues, through short strong hydrogen bonds, play the role of charge buffer to stabilize the negative charge built up on the intermediates in the course of the reaction. The hydrogen bond distances in the intermediate analogues are found to be about 0.2 A shorter in the product analogues both experimentally and theoretically.

Phase II study of paclitaxel and cisplatin for advanced urothelial cancer.

PURPOSE: We examined the role of paclitaxel and cisplatin as first line therapy for metastatic urothelial cancer. MATERIALS AND METHODS: A total of 34 patients were enrolled in this study, and all were eligible for treatment and assessable for response. Patients received 135 mg./m.2 paclitaxel intravenously for 3 hours followed by 70 mg./m.2 cisplatin for 2 hours every 3 weeks to a maximum of 6 cycles. RESULTS: Of the patients 70% experienced a major response to treatment, which was partial/regression in 38% and complete in 32%. Toxicity was manageable with no episodes of grade 4 leukopenia or thrombocytopenia. Nonhematological toxicities included primarily nausea, anorexia and neuropathy, which rarely were severe. CONCLUSIONS: This regimen of paclitaxel and cisplatin is effective, safe and convenient to administer in an outpatient setting for advanced urothelial cancer.

T-DNA insertional mutagenesis for functional genomics in rice.

We have produced 22 090 primary transgenic rice plants that carry a T-DNA insertion, which has resulted in 18 358 fertile lines. Genomic DNA gel-blot and PCR analyses have shown that approximately 65% of the population contains more than one copy of the inserted T-DNA. Hygromycin resistance tests revealed that transgenic plants contain an average of 1.4 loci of T-DNA inserts. Therefore, it can be estimated that approximately 25 700 taggings have been generated. The binary vector used in the insertion contained the promoterless beta-glucuronidase (GUS) reporter gene with an intron and multiple splicing donors and acceptors immediately next to the right border. Therefore, this gene trap vector is able to detect a gene fusion between GUS and an endogenous gene, which is tagged by T-DNA. Histochemical GUS assays were carried out in the leaves and roots from 5353 lines, mature flowers from 7026 lines, and developing seeds from 1948 lines. The data revealed that 1.6-2.1% of tested organs were GUS-positive in the tested organs, and that their GUS expression patterns were organ- or tissue-specific or ubiquitous in all parts of the plant. The large population of T-DNA-tagged lines will be useful for identifying insertional mutants in various genes and for discovering new genes in rice.

Crystal structure of TRAIL-DR5 complex identifies a critical role of the unique frame insertion in conferring recognition specificity.

TRAIL is a cytokine that induces apoptosis in a wide variety of tumor cells but rarely in normal cells. It contains an extraordinarily elongated loop because of an unique insertion of 12-16 amino acids compared with the other members of tumor necrosis factor family. Biological implication of the frame insertion has not been clarified. We have determined the crystal structure of TRAIL in a complex with the extracellular domain of death receptor DR5 at 2.2 A resolution. The structure reveals extensive contacts between the elongated loop and DR5 in an interaction mode that would not be allowed without the frame insertion. These interactions are missing in the structures of the complex determined by others recently. This observation, along with structure-inspired deletion analysis, identifies the critical role of the frame insertion as a molecular strategy conferring specificity upon the recognition of cognate receptors. The structure also suggests that a built-in flexibility of the tumor necrosis factor receptor family members is likely to play a general and important role in the binding and recognition of tumor necrosis factor family members.

Role of the glutamate 332 residue in the transglycosylation activity of ThermusMaltogenic amylase.

A sequence alignment shows that residue 332 is conserved as glutamate in maltogenic amylases (MAases) and in other related enzymes such as cyclodextrinase and neopullulanase, while the corresponding position is conserved as histidine in alpha-amylases. We analyzed the role of Glu332 in the hydrolysis and the transglycosylation activity of Thermus MAase (ThMA) by site-directed mutagenesis. Replacing Glu332 with histidine reduced transglycosylation activity significantly, but enhanced hydrolysis activity on alpha-(1,3)-, alpha-(1,4)-, and alpha-(1,6)-glycosidic bonds relative to the wild-type (WT) enzyme. The mutant Glu332Asp had catalytic properties similar to those of the WT enzyme, but the mutant Glu332Gln resulted in significantly decreased transglycosylation activity. These results suggest that an acidic side chain at position 332 of MAase plays an important role in the formation and accumulation of transfer products by modulating the relative rates of hydrolysis and transglycosylation. From the structure, we propose that an acidic side chain at position 332, which is located in a pocket, is involved in aligning the acceptor molecule to compete with water molecules in the nucleophilic attack of the glycosyl-enzyme intermediate.

Crystal structure of a maltogenic amylase provides insights into a catalytic versatility.

Amylases catalyze the hydrolysis of starch material and play central roles in carbohydrate metabolism. Compared with many different amylases that are able to hydrolyze only alpha-D-(1,4)-glycosidic bonds, maltogenic amylases exhibit catalytic versatility: hydrolysis of alpha-D-(1,4)- and alpha-D-(1,6)-glycosidic bonds and transglycosylation of oligosaccharides to C3-, C4-, or C6-hydroxyl groups of various acceptor mono- or disaccharides. It has been speculated that the catalytic property of the enzymes is linked to the additional approximately 130 residues at the N terminus that are absent in other typical alpha-amylases. The crystal structure of a maltogenic amylase from a Thermus strain was determined at 2.8 A. The structure, an analytical centrifugation, and a size exclusion column chromatography proved that the enzyme is a dimer in solution. The N-terminal segment of the enzyme folds into a distinct domain and comprises the enzyme active site together with the central (alpha/beta)(8) barrel of the adjacent subunit. The active site is a narrow and deep cleft suitable for binding cyclodextrins, which are the preferred substrates to other starch materials. At the bottom of the active site cleft, an extra space, absent in the other typical alpha-amylases, is present whose size is comparable with that of a disaccharide. The space is most likely to host an acceptor molecule for the transglycosylation and to allow binding of a branched oligosaccharide for hydrolysis of alpha-D-(1,4)-glycosidic or alpha-D-(1,6)-glycosidic bond. The (alpha/beta)(8) barrel of the enzyme is the preserved scaffold in all the known amylases. The structure represents a novel example of how an enzyme acquires a different substrate profile and a catalytic versatility from a common active site and represents a framework for explaining the catalytic activities of transglycosylation and hydrolysis of alpha-D-(1,6)-glycosidic bond.

2.8 A resolution crystal structure of human TRAIL, a cytokine with selective antitumor activity.

TRAIL is a newly identified cytokine belonging to the large tumor necrosis factor (TNF) family. TRAIL is a novel molecule inducing apoptosis in a wide variety of tumor cells but not in normal cells. To help in elucidating its biological roles and designing mutants with improved therapeutic potential, we have determined the crystal structure of human TRAIL. The structure reveals that a unique frame insertion of 12-16 amino acids adopts a salient loop structure penetrating into the receptor-binding site. The loop drastically alters the common receptor-binding surface of the TNF family most likely for the specific recognition of cognate partners. A structure-based mutagenesis study demonstrates a critical role of the insertion loop in the cytotoxic activity of TRAIL.