Increased blood pressure visit-to-visit variability in patients with systemic lupus erythematosus: association with inflammation and comorbidity burden.

BACKGROUND: Blood pressure visit-to-visit variability is a novel risk factor for deleterious long-term cardiac and renal outcomes in the general population. We hypothesized that patients with systemic lupus erythematosus (SLE) have greater blood pressure visit-to-visit variability than control subjects and that blood pressure visit-to-visit variability is associated with a higher comorbidity burden. METHODS: We studied 899 patients with SLE and 4172 matched controls using de-identified electronic health records from an academic medical center. We compared blood pressure visit-to-visit variability measures in patients with SLE and control subjects and examined the association between blood pressure visit-to-visit variability and patients' characteristics. RESULTS: Patients with SLE had higher systolic blood pressure visit-to-visit variability 9.7% (7.8-11.8%) than the control group 9.2% (7.4-11.2%), P < 0.001 by coefficient of variation. Additional measures of systolic blood pressure visit-to-visit variability (i.e. standard deviation, average real variation, successive variation and maximum measure-to-measure change) were also significantly higher in patients with SLE than in control subjects. In patients with SLE, blood pressure visit-to-visit variability correlated significantly with age, creatinine, CRP, triglyceride concentrations and the Charlson comorbidity score (all P < 0.05). Hydroxychloroquine use was associated with reduced blood pressure visit-to-visit variability (P < 0.001), whereas the use of antihypertensives, cyclophosphamide, mycophenolate mofetil and corticosteroids was associated with increased blood pressure visit-to-visit variability (P < 0.05). CONCLUSION: Patients with SLE had higher blood pressure visit-to-visit variability than controls, and this increased blood pressure visit-to-visit variability was associated with greater Charlson comorbidity scores, several clinical characteristics and immunosuppressant medications. In particular, hydroxychloroquine prescription was associated with lower blood pressure visit-to-visit variability.

Outcomes following major emergency gastric surgery: the importance of specialist surgeons.

BACKGROUND: The increasing subspecialisation of general surgeons in their elective work may result in problems for the provision of expert care for emergency cases. There is very little evidence of the impact of subspecialism on outcomes following emergency major upper gastrointestinal surgery. This prospective study investigated whether elective subspecialism of general surgeon is associated with a difference in outcome following major emergency gastric surgery. METHODS: Between February 1994 and June 2010, the data from all emergency major gastric procedures (defined as patients who underwent laparotomy within 12 hours of referral to the surgical service for bleeding gastroduodenal ulcer and/or undergoing major gastric resection) was prospectively recorded. The sub-specialty interest of operating surgeon was noted and related to post-operative outcomes. RESULTS: Over the study period, a total of 63 major gastric procedures were performed of which 23 (37%) were performed by specialist upper gastrointestinal (UGI) consultants. Surgery performed by a specialist UGI surgeon was associated with a significantly lower surgical complication (4% vs. 28% of cases; p=0.04) and in-patient mortality rate (22% vs. 50%; p=0.03). CONCLUSIONS: Major emergency gastric surgery has significantly better clinical outcomes when performed by a specialist UGI surgeon. These results have important implications for provision of an emergency general surgical service.

Acute hernial strangulation following Wii Fit exercises.

The Wii Fit is one the most popular fitness games on the market. Although this device has been linked to a number of injuries, the vast majority of these have been relatively minor musculo-skeletal complaints. We present a case of a patient who presented with an acute strangulation of a pre-existing asymptomatic paraumbilical hernia after completing a series of aerobic exercises on her Wii Fit. She required laparotomy and small bowel resection for infarcted bowel. Although a number of minor mechanical and orthopaedic injurieshave been reported with the Wii Fit, this represents the first case of a life-threatening complication associated with the use of this device.

Long term outcomes following emergency intensive care readmission after elective oesophagectomy.

OBJECTIVE: The purpose of this study was to analyse the outcomes of patients readmitted to ICU following initial recovery after oesophagectomy. BACKGROUND: Surgery for oesophageal cancer has significant morbidity and poor long-term outcomes. There is limited evidence concerning the long-term outcomes of patients who require readmission to the intensive care unit (ICU) after an initial recovery following resection. METHOD: The case notes of 221 patients who underwent elective oesophagectomy over an eleven-year period were reviewed. Patients who were readmitted to ICU following initial recovery were identified and the clinical and demographic characteristics of these patients were prospectively recorded and their outcomes analysed. RESULTS: A total of 43 patients were readmitted to ICU during the study period mainly for respiratory complications or anastomotic leaks. 17 patients (40%) required a period of mechanical ventilation; 16 patients (37%) required inotropes and 2 patients (5%) required renal support. The mean ICU stay on readmission was 8 days (range 0-49 days) with an in-hospital mortality rate of 33%. In terms of long-term outcomes, the actuarial two- and five-year survival rates were 42.3 +/- 7.7% and 36.7 +/- 8.5% respectively. Multivariate analysis identified both age (Hazard ratio: 1.05 +/- 0.02; p = 0.04) and requirement for renal support (Hazard ratio: 5.63 +/- 0.8; p = 0.03) as independent adverse predictors of survival. CONCLUSIONS: Although ICU readmission following elective oesophagectomy is associated with significant mortality, the overall long-term survival rate for these patients, particularly those who do not require renal support is encouraging.

Impact of training on outcomes following incisional hernia repair.

BACKGROUND: The purpose of this study was to quantify the effect of training on clinical outcomes following elective incisional hernia repair. METHODS: The case notes of 100 consecutive elective open and laparoscopic incisional hernia repair procedures performed between January 2004 and July 2008 were reviewed retrospectively. Cases were performed either by consultant surgeons or trainees operating under direct supervision. The proportion of cases performed by trainees was recorded and the seniority of the operating surgeon related to peri- and post-operative outcomes as well as long-term recurrence rates. RESULTS: Of the 100 cases, 61 were performed by consultants and 39 by trainees. There were no significant demographic differences between the two groups. Trainees undertook a similar proportion of laparoscopic cases as compared with consultants (44% vs. 44%). In addition, the operating time (60 +/- 4 mins vs. 58 +/- 4 mins), length of hospital stay (3.0 +/- 0.3 days vs. 3.3 +/- 0.3 days) and post-operative morbidity rates (18 % vs 10%) were similar between the two groups. At a mean follow-up period of 2.82 +/- 0.17 years, the incidence of recurrent herniae was lower in the trainee group, however this was not statistically significant (8% vs 16% ; p = 0.22). CONCLUSIONS: Supervised trainees can successfully undertake both open and laparoscopic incisional hernia repairs with no detrimental effects on overall hospital costs, post-operative morbidity and long-term recurrence rates.

A phase I study of the safety and tolerability of olaparib (AZD2281, KU0059436) and dacarbazine in patients with advanced solid tumours.

BACKGROUND: Poly adenosine diphosphate (ADP)-ribose polymerase (PARP) is essential in cellular processing of DNA damage via the base excision repair pathway (BER). The PARP inhibition can be directly cytotoxic to tumour cells and augments the anti-tumour effects of DNA-damaging agents. This study evaluated the optimally tolerated dose of olaparib (4-(3--4-fluorophenyl) methyl-1(2H)-one; AZD2281, KU0059436), a potent PARP inhibitor, with dacarbazine and assessed safety, toxicity, clinical pharmacokinetics and efficacy of combination treatment. PATIENTS AND METHODS: Patients with advanced cancer received olaparib (20-200 mg PO) on days 1-7 with dacarbazine (600-800 mg m(-2) IV) on day 1 (cycle 2, day 2) of a 21-day cycle. An expansion cohort of chemonaive melanoma patients was treated at an optimally tolerated dose. The BER enzyme, methylpurine-DNA glycosylase and its substrate 7-methylguanine were quantified in peripheral blood mononuclear cells. RESULTS: The optimal combination to proceed to phase II was defined as 100 mg bd olaparib with 600 mg m(-2) dacarbazine. Dose-limiting toxicities were neutropaenia and thrombocytopaenia. There were two partial responses, both in patients with melanoma. CONCLUSION: This study defined a tolerable dose of olaparib in combination with dacarbazine, but there were no responses in chemonaive melanoma patients, demonstrating no clinical advantage over single-agent dacarbazine at these doses.

Continuous low-dose cyclophosphamide and methotrexate combined with celecoxib for patients with advanced cancer.

BACKGROUND: Combined therapy of metronomic cyclophosphamide, methotrexate and high-dose celecoxib targeting angiogenesis was used in a phase II trial. METHODS: Patients with advanced cancer received oral cyclophosphamide 50 mg o.d., celecoxib 400 mg b.d. and methotrexate 2.5 mg b.d. for two consecutive days each week. Response was determined every 8 weeks; toxicity was evaluated according to CTC version 2.0. Plasma markers of inflammation, coagulation and angiogenesis were measured. RESULTS: Sixty-seven of 69 patients were evaluable for response. Twenty-three patients had stable disease (SD) after 8 weeks, but there were no objective responses to therapy. Median time to progression was 57 days. There was a low incidence of toxicities. Among plasma markers, levels of tissue factor were higher in the SD group of patients at baseline, and levels of both angiopoietin-1 and matrix metalloproteinase-9 increased in the progressive disease group only. There were no changes in other plasma markers. CONCLUSION: This metronomic approach has negligible activity in advanced cancer albeit with minimal toxicity. Analysis of plasma markers indicates minimal effects on endothelium in this trial. These data for this particular regimen do not support basic tenets of metronomic chemotherapy, such as the ability to overcome resistant tumours by targeting the endothelium.

Randomized clinical trial of routine on-table cholangiography during laparoscopic cholecystectomy.

BACKGROUND: A randomized clinical trial was undertaken to assess the utility of routine on-table cholangiography (OTC) during laparoscopic cholecystectomy for gallstone disease. METHODS: Some 190 patients with a history of biliary colic or cholecystitis and a low predictive risk for choledocholithiasis were randomized to undergo elective laparoscopic cholecystectomy alone (99 patients) or elective laparoscopic cholecystectomy with OTC (91). Intraoperative findings and postoperative outcomes for the two groups were compared. The primary outcome measure was the incidence of common bile duct (CBD) stones. RESULTS: Of the patients undergoing OTC, ten had abnormal cholangiograms; three had CBD stones and seven had abnormalities without stones. OTC was associated with a significantly longer mean(s.e.m.) operating time (66(2) versus 54(3) min; P < 0·001), but there was no association between performance of OTC and postoperative morbidity. During a 1-year follow-up, no patient in the OTC group re-presented to hospital with recurrent biliary symptoms. In contrast, four of the patients allocated to surgery alone re-presented with symptoms suggestive of CBD obstruction; all settled with conservative treatment and the difference in readmission rate was not significant (P = 0·122). CONCLUSION: Routine cholangiography in patients with a low risk for CBD stones does not seem justified from the results of this trial. REGISTRATION NUMBER: NCT00806780 (http://www.clinicaltrials.gov).

Feasibility of a consultant-led, trainee-delivered urgent laparoscopic cholecystectomy service.

BACKGROUND: Urgent laparoscopic cholecystectomy has become the gold standard for the treatment of acute gallstone disease. Since 2005 we have implemented a consultant-delivered urgent surgical service for this condition. In an attempt to increase the capacity of this service, we have recently introduced a new policy of also allowing selected trainee surgeons to perform urgent laparoscopic cholecystectomy with consultant assistance available on request. The purpose of this study was to audit our initial experience of this new service. METHODS: Patients with acute gallstone disease had their surgery performed by a consultant or a trainee operating independently with consultant assistance available only on request. Allocation was based purely on surgeon availability. The clinical outcomes of 50 consecutive trainee and 50 consecutive consultant cases were compared and an attempt made to identify pre-operative predictors of technically-demanding trainee cases requiring consultant intervention. RESULTS: The mean operating time of trainees was significantly longer than consultants (80 +/- 5 mins vs 55 +/- 4 mins, p <0.001) although the conversion rates for trainees (4%) and consultants (2%) were similar. There were no significant differences between the groups with respect to postoperative morbidity. Of the 50 trainee cases, consultant intervention was required in 12 (24%) cases. There were no statistically significant pre-operative predictors of requirement for consultant assistance. CONCLUSIONS: Urgent laparoscopic cholecystectomy may be performed independently by appropriately skilled trainees within a consultant-led service. Although consultant intervention is often not required, the requirement for consultant assistance cannot be easily predicted based on pre-operative data.

Multiple sclerosis susceptibility alleles in African Americans.

Multiple sclerosis (MS) is an autoimmune demyelinating disease characterized by complex genetics and multifaceted gene-environment interactions. Compared to whites, African Americans have a lower risk for developing MS, but African Americans with MS have a greater risk of disability. These differences between African Americans and whites may represent differences in genetic susceptibility and/or environmental factors. SNPs from 12 candidate genes have recently been identified and validated with MS risk in white populations. We performed a replication study using 918 cases and 656 unrelated controls to test whether these candidate genes are also associated with MS risk in African Americans. CD6, CLEC16a, EVI5, GPC5, and TYK2 contained SNPs that are associated with MS risk in the African American data set. EVI5 showed the strongest association outside the major histocompatibility complex (rs10735781, OR=1.233, 95% CI=1.06-1.43, P-value=0.006). In addition, RGS1 seems to affect age of onset whereas TNFRSF1A seems to be associated with disease progression. None of the tested variants showed results that were statistically inconsistent with the effects established in whites. The results are consistent with shared disease genetic mechanisms among individuals of European and African ancestry.

Geographical information systems and tropical medicine.

In terms of their applicability to the field of tropical medicine, geographical information systems (GIS) have developed enormously in the last two decades. This article reviews some of the pertinent and representative applications of GIS, including the use of such systems and remote sensing for the mapping of Chagas disease and human helminthiases, the use of GIS in vaccine trials, and the global applications of GIS for health-information management, disease epidemiology, and pandemic planning. The future use of GIS as a decision-making tool and some barriers to the widespread implementation of such systems in developing settings are also discussed.

A phase II trial of lomeguatrib and temozolomide in metastatic colorectal cancer.

To evaluate the tumour response to lomeguatrib and temozolomide (TMZ) administered for 5 consecutive days every 4 weeks in patients with metastatic colorectal carcinoma. Patients with stage IV metastatic colorectal carcinoma received lomeguatrib (40 mg) and TMZ (50-200 mg m(-2)) orally for 5 consecutive days every 4 weeks. Response was determined every two cycles. Pharmacokinetics of lomeguatrib and TMZ as well as their pharmacodynamic effects in peripheral blood mononuclear cells (PBMC) were determined. Nineteen patients received 49 cycles of treatments. Despite consistent depletion of O(6)-methylguanine-DNA methyltransferase in PBMC, none of the patients responded to treatment. Three patients had stable disease, one for the duration of the study, and no fall in carcinoembryonic antigen was observed in any patient. Median time to progression was 50 days. The commonest adverse effects were gastrointestinal and haematological and these were comparable to those of TMZ when given alone. This combination of lomeguatrib and TMZ is not efficacious in metastatic colorectal cancer. If further studies are to be performed, emerging data suggest that higher daily doses of lomeguatrib and a dosing period beyond that of TMZ should be evaluated.

Training outcomes in colorectal cancer surgery in a district general hospital.

OBJECTIVES: The purpose of this study was to quantify the effect of training on outcomes following colorectal cancer resections in a District General Hospital. PATIENTS AND METHODS: Data on 102 consecutive elective colorectal cancer resections performed at a District General Hospital over a three-year period were prospectively collated. The proportion of cases performed by trainees was recorded and the seniority of the operating surgeon was related to pre-operative morbidity, operative time and postoperative outcome. RESULTS: Consultants, staff grades and registrars performed 46, 35 and 21 procedures respectively. Of the cases performed by registrars, consultant supervision was provided in seven cases, with staff grades providing supervision in 14 cases. As compared with consultants, registrars were less likely to undertake anterior resection (p = 0.001). However, the mean operating times of trainees (145 +/- 8 mins) and consultants (135 +/- 6 mins) were similar. There were no significant differences between the groups with respect to postoperative mortality or morbidity. There was a trend towards more advanced disease in consultant cases, and consultants had a significantly poorer freedom from death or recurrence at two years as compared with trainees (p = 0.03). CONCLUSIONS: In our unit, trainees performed 21% of all elective colorectal resections with no detrimental effect on length of hospital stay, overall hospital costs and early and late patient outcomes. Major colorectal procedures can be successfully accomplished in a District General setting by trainees, with the training burden shared between consultants and staff grade surgeons.

Routine pathological analysis of appendicectomy specimens--is it justified?

Appendicectomy for acute appendicitis is one of the most commonly performed surgical procedures. Our unit policy has been to conduct pathological examination of all resected specimens, however this practice has recently been questioned. We therefore sought to analyse the utility of routine histological examination of appendicectomy specimens. A consecutive series of 236 patients who underwent open appendicectomy for clinically suspected appendicitis was reviewed. Examination of the specimens revealed inflammation or necrosis in 175 (74%) of the cases-however unexpected histological findings were seen in 10 (4.2%) specimens. In five of these cases (2.1%), these findings resulted in a change in medical therapy. We conclude that appendicectomy specimens from patients with clinically suspected appendicitis show diversity in their histological characteristics; and that routine histological examination can yield clinically significant information in a significant minority of patients.

Emergency intensive care admission following elective thoracic surgery.

AIM: The aim of this study was to analyse the outcomes of patients admitted to the intensive care unit (ICU) following initial recovery after elective thoracic surgery. METHODS: The case notes of all patients who underwent elective thoracic surgery over a one-year period were reviewed. Patients who were admitted to ICU following an initial recovery on the ward were identified and their postoperative course analysed. The clinical and demographic characteristics of these patients were recorded and their outcomes analysed. RESULTS: A total of 20 patients were admitted to ICU of whom 13 (65%) were admitted for respiratory complication, 5 with sepsis and 2 with cardiovascular instability. Sixteen (80%) patients required CPAP or BIPAP, of whom only 7 (35%) required mechanical ventilation. Renal support was required in 7 patients, with 2 (10%) requiring haemofiltration. ICU survival was 15 patients (75%), whilst overall three-month survival post ICU admission was 65%. Requirement for renal support was the only predictor of mortality on univariate and multivariate analysis. CONCLUSIONS: Salvage ICU admission following elective thoracic surgery is associated with significant mortality, however the outcome is far from hopeless. The majority of patients can be managed without recourse to mechanical ventilation or haemofiltration. The need for renal support is, however, a significant adverse prognostic indicator.

HIV-infected workers deported from the Gulf States: impact on Southern Pakistan.

HIV prevalence is still very low in Pakistan, but its south Asian location and subgroups with recognized lifestyle risk factors suggest that Pakistan will experience expanded diffusion of HIV. We report the frequency of HIV infections identified by the AIDS Control Programme in the Sindh province of Pakistan. Most HIV positive cases currently reported to the Sindh AIDS Control Programme are found among Pakistani workers deported from the Gulf States and among foreigners. The 58 returned workers with HIV represent 61 to 86% of reported cases in any given year during the 1996-1998 period. Five wives of returning workers have been identified with HIV. Expatriate workers in the Gulf States are tested for HIV routinely, unlike other subgroups in Pakistan. Considering the risk of HIV/AIDS due to regular introduction of HIV from returned workers, and the limited awareness surrounding sexual health and HIV/STD transmission issues in Pakistan, intervention programmes targeted at overseas workers need to be implemented to control the expansion of the HIV epidemic in Pakistan (Int J STD AIDS 1999;10:812-14).

Enoxaparin venous thromboembolism prophylaxis in bariatric surgery: A best evidence topic.

A best evidence topic in surgery was written according to a structured protocol. The question addressed was: which is the best regimen of enoxaparin thromboprophylaxis for patients undergoing bariatric surgery? One hundred and twenty-five papers were identified using the reported literature search, of which four represented the best evidence to answer the clinical question. The authors, country and date of publication, patient groups, relevant outcomes and results of these papers were tabulated. All four studies are non-randomized cohort studies examining venous thromboembolism rates and major postoperative bleeding following varying regimens of Enoxaparin thromboprophylaxis. There is no level 1 evidence which significantly favors any particular thromboprophylaxis regimen. There is some evidence that extended duration of treatment of ten days after discharge significantly reduces the incidence of VTE compared to in-hospital treatment only, and that a higher incidence of post-operative bleeding occurs with a regimen that includes a pre-operative dose of Enoxaparin. With regard to dosage, for in-hospital treatment the higher dosage of 40 mg twice daily as opposed to 30 mg seems to significantly reduce the incidence of VTE without significantly affecting bleeding rate.

Gabapentin relieves trigeminal neuralgia in multiple sclerosis patients.

This report describes the effectiveness of gabapentin, a recently approved anticonvulsant, in seven patients with MS experiencing trigeminal neuralgia refractory to treatment with conventional medical therapy. Gabapentin relieved pain completely in six and significantly in the seventh patient. Gabapentin may be a valuable addition to pharmacologic therapy in trigeminal neuralgia, particularly in patients with MS and in refractory cases.

Neutralizing antibodies to interferon beta-1a and interferon beta-1b in MS patients are cross-reactive.

OBJECTIVE: To determine whether neutralizing antibodies (NABs) to interferon beta (IFNbeta)-1a (Avonex) and IFNbeta-1b (Betaseron) cross-react. BACKGROUND: A total of 38% of MS patients treated with IFNbeta-1b and 22% of those treated with IFNbeta-1a were reported to develop NABs, which could reduce the clinical efficacy of the drug. METHODS: Blood from 10 MS patients was collected before and at 3 and 6 months after initiating treatment with IFNbeta-1a. ELISA was performed to detect binding antibodies to IFNbeta-1a. Sera from patients who tested positive for binding antibodies to IFNbeta-1a were then screened for NABs to IFNbeta-1a in a biologic assay based on neutralization of antiviral activity. These serum samples were subsequently tested for cross-reactivity with IFNbeta-1b both in the ELISA and the biologic assay. In the second part of the study, sera from patients who participated in the phase III IFNbeta-1b trial at the University of Maryland were examined for cross-reactivity with IFNbeta-1a in the ELISA and the biologic assay. RESULTS: Of the 10 patients treated with IFNbeta-1a, three developed binding as well as NABs to IFNbeta-1a 6 months after treatment, and these antibodies cross-reacted with IFNbeta-1b both in the binding and the biologic assay. Similarly, sera from six patients with NABs to IFNbeta-1b showed cross-reactivity with IFNbeta-1a in the binding assay. Three of these six serum samples tested for neutralizing activity against IFNbeta-1a demonstrated the presence of NABs to IFNbeta-1a. CONCLUSIONS: NABs to IFNbeta-1a (Avonex) and IFNbeta-1b (Betaseron) cross-react, both in the binding and the biologic assays. This suggests that switching to alternate IFNbeta preparation in patients who develop NABs may not be clinically beneficial. Studies examining cross-reactivity between NABs to IFNbeta-1a and IFNbeta-1b in a large number of patients are indicated.

Serum interferon beta-1a (Avonex) levels following intramuscular injection in relapsing-remitting MS patients.

BACKGROUND: The pharmacokinetics of IFNbeta-1a in MS patients are poorly understood. We have previously reported an ELISA sensitive and specific for measuring serum IFNbeta-1b levels in patients with MS. OBJECTIVE: We describe an ELISA to measure interferon beta-1a (Avonex) in the serum of MS patients following IM administration. METHODS: We have developed an ELISA for detecting serum IFNbeta-1a in MS patients receiving 6 million units (MU) of IFNbeta-1a, IM once weekly. The specificity of this ELISA was confirmed by the lack of cross-reactivity with other cytokines except for IFNbeta-1b. RESULTS: Serum IFNbeta-1a levels were measured at 3 and 6 months after initiating treatment with IFNbeta-1a in 10 MS patients. At 3 months, all 10 patients had detectable levels ranging from 68 to 86 IU/mL. At 6 months, IFNbeta-1a could be detected in the serum of all but three patients, with levels ranging from 64 to 81 IU/mL. A kinetic study of IFNbeta-1a serum levels in a separate group of six MS patients who had been receiving IFNbeta-1a for several months was carried out. Blood was drawn before and 2, 4, 6, 8, and 24 hours after IFNbeta-1a injection. Peak serum IFNbeta-1a levels were observed at 8 hours and became undetectable at 24 hours after injection. CONCLUSION: The described ELISA may have useful clinical applications in examining the correlation between serum IFNbeta-1a levels and clinical efficacy.