Investigation of inter-individual variability of the one-carbon folate pathway: a bioinformatic and genetic review.

Genetic polymorphisms in the one-carbon folate pathway have been widely studied in association with a number of conditions. Most of the research has focused on the 677C>T polymorphism in the coding region of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene. However, there are a total of 25 genes in this pathway coding for enzymes, transporters and receptors, which can be investigated using 267 tagging single nucleotide polymorphisms (SNPs); using SNP database (dbSNP), 38 non-synonymous SNPs with a minor allele frequency of >5% are present in these genes. Most of these variants have not been investigated in relation to disease or drug response phenotypes. In addition, their functional consequences are largely unknown. Prediction of the functional effect using six publicly available programs (PolyPhen, SIFT BLink, PMut, SNPs3D, I-Mutant2.0 and LS-SNP) was limited to functionally well-characterized SNPs such as MTHFR c.677C>T and c.1298A>C ranking low. Epigenetic modifications may also be important with some of these genes. In summary, to date, investigation of the one-carbon folate pathway genes has been limited. Future studies should aim for a more comprehensive assessment of this pathway, while further research is also required in determining the functional effects of these genetic variants.

Ovarian cancer in the proteomics era.

Ovarian cancer presents a diagnostic challenge because of its subtle clinical presentation and elusive cell of origin. Two new technologies of proteomics have advanced the dissection of the underlying molecular signaling events and the proteomic characterization of ovarian cancer: mass spectrometry and protein array analysis. Mass spectrometry can provide a snapshot of a proteome in time and space, with sensitivity and resolution that may allow identification of the elusive "needle in the haystack" heralding ovarian cancer. Proteomic profiling of tumor tissue samples can survey molecular targets during treatment and quantify changes using reverse phase protein arrays generated from tumor samples captured by microdissection, lysed and spotted in serial dilutions for high-throughput analysis. This approach can be applied to identify the optimal biological dose of a targeted agent and to validate target to outcome link. The evolution of proteomic technologies has the capacity to advance rapidly our understanding of ovarian cancer at a molecular level and thus elucidate new directions for the treatment of this disease.

Differentiation of tumour-stage mycosis fungoides, psoriasis vulgaris and normal controls in a pilot study using serum proteomic analysis.

BACKGROUND: Serum proteomic analysis is an analytical technique utilizing high-throughput mass spectrometry (MS) in order to assay thousands of serum proteins simultaneously. The resultant 'proteomic signature' has been used to differentiate benign and malignant diseases, enable disease prognosis, and monitor response to therapy. OBJECTIVES: This pilot study was designed to determine if serum protein patterns could be used to distinguish patients with tumour-stage mycosis fungoides (MF) from patients with a benign inflammatory skin condition (psoriasis) and/or subjects with healthy skin. METHODS: Serum was analysed from 45 patients with tumour-stage MF, 56 patients with psoriasis, and 47 controls using two MS platforms of differing resolution. An artificial intelligence-based classification model was constructed to predict the presence of the disease state based on the serum proteomic signature. RESULTS: Based on data from an independent testing set (14-16 subjects in each group), MF was distinguished from psoriasis with 78.6% (or 78.6%) sensitivity and 86.7% (or 93.8%) specificity, while sera from patients with psoriasis were distinguished from those of nonaffected controls with 86.7% (or 93.8%) sensitivity and 75.0% (or 76.9%) specificity (depending on the MS platform used). MF was distinguished from unaffected controls with 61.5% (or 71.4%) sensitivity and 91.7% (or 92.9%) specificity. In addition, a secondary survival analysis using 11 MS peaks identified significant survival differences between two MF groups (all P-values <0.05). CONCLUSIONS: Serum proteomics should be further investigated for its potential to identify patients with neoplastic skin disease and its ability to determine disease prognosis.

Relaparotomy: a five-year review of indications and outcome.

Complications from abdominal surgery may necessitate reoperation and can be associated with significant morbidity and mortality. This review aims to analyse the incidence and outcome of relaparotomy for various indications. In a retrospective review of case notes of patients who had undergone one or more relaparotomies during the same hospitalisation between 1996 and 2000, 55 patients required relaparotomy. Indications included bleeding, infection, anastomotic leakage, wound dehiscence, necrotising pancreatitis, bowel necrosis, bowel obstruction and miscellaneous indications. Relaparotomy for dehiscence and obstruction carried minimal risk; for bleeding and infection entailed moderate risks; and for anastomotic leak had the highest mortality rate. The mortality rate increased in older age groups, multiple system and organ failure and multiple relaparotomies. The overall mortality rate was 38%. Twenty-nine per cent of patients had MRSA infection contributing to sepsis and multiple system and organ failure. Reintervention had brought to evidence technical errors, which could be corrected, and resulted in patient salvage in some cases. The mortality rate of relaparotomy has remained unchanged compared with data published previously, despite improvements in surgical techniques and critical care. Timely relaparotomy is valuable in the identification and treatment of complications following abdominal surgery.

Deterioration of cold-stored tissue specimens due to lipid peroxidation: modulation by antioxidants at high subzero temperatures.

It is often necessary to store tissue specimens in subzero conditions for assay in batches. During storage at -20 degrees C we found that sufficient lipid peroxidation occurred in rat liver homogenates in phosphate-buffered saline to affect subsequent malondialdehyde assays. This peroxidation did not occur at -196 degrees C. The ratio of oxidized to reduced glutathione increased with storage at -20 degrees C and the level of conjugated dienes increased progressively. The addition of a specific free radical scavenger, superoxide dismutase (200 u/ml) reduced the level of malondialdehyde (P < 0.001) during -20 degrees C storage for periods of 28 days but failed to prevent the changes in the glutathione ratio or dienes. Storage in a less specific free radical scavenger, 0.25 molar sucrose/EDTA, instead of phosphate-buffered saline totally prevented the malondialdehyde production over similar storage periods.

Complications of percutaneous endoscopic enterostomy tubes.

Percutaneous endoscopic gastrostomy and jejunostomy tubes have been used clinically for approximately 10 years. They have been used predominantly in patients who cannot sustain their weight by oral intake, such as individuals with abnormalities of swallowing or intestinal peristalsis. The percutaneous endoscopic method of placement confers some advantages over classical surgical placement, especially in poor risk cases. Although several types of tube are commercially available, a substantial complication rate is still directly attributable to the tubes. In some series, complications are reported in 70% of cases. This report describes two complications of endoscopically introduced jejunostomy tubes used in patients with Roux-en-Y reconstructions after previous multiple gastric surgical procedures.

Laparoscopic gastrointestinal surgery.

The growth and scope of laparoscopic gastrointestinal surgery are outstripping the ability of medical journals to print series and reports of experience, and much data remain anectodal and preliminary. Laparoscopic cholecystectomy has become established, although, unfortunately, peroperative cholangiography has not yet become normal practice, despite convincing published evidence that it is likely to reduce the increased number of bile ducts that are damaged by laparoscopic surgeons. Imaging the bile ducts and the overall management of choledocholithiasis need re-evaluation, and the approach will change as more surgeons explore the bile ducts laparoscopically. Laparoscopic hiatal anti-reflux surgery will soon be routine, and a whole range of laparoscopically assisted operations on the oesophagus, colon, and rectum will become commonplace. Operations on the liver remain anecdotal. Throughout this rapid progress, surgeons must not forget the principles of (open) surgical practice, whilst carefully kept registers and regular audit of operations will provide new surgical standards.