Development and internal validation of clinical prediction models for outcomes of complicated intra-abdominal infection.

BACKGROUND: Complicated intra-abdominal infections (cIAIs) are associated with significant morbidity and mortality. The aim of this study was to describe the clinical characteristics of patients with cIAI in a multicentre study and to develop clinical prediction models (CPMs) to help identify patients at risk of mortality or relapse. METHODS: A multicentre observational study was conducted from August 2016 to February 2017 in the UK. Adult patients diagnosed with cIAI were included. Multivariable logistic regression was performed to develop CPMs for mortality and cIAI relapse. The c-statistic was used to test model discrimination. Model calibration was tested using calibration slopes and calibration in the large (CITL). The CPMs were then presented as point scoring systems and validated further. RESULTS: Overall, 417 patients from 31 surgical centres were included in the analysis. At 90 days after diagnosis, 17.3 per cent had a cIAI relapse and the mortality rate was 11.3 per cent. Predictors in the mortality model were age, cIAI aetiology, presence of a perforated viscus and source control procedure. Predictors of cIAI relapse included the presence of collections, outcome of initial management, and duration of antibiotic treatment. The c-statistic adjusted for model optimism was 0.79 (95 per cent c.i. 0.75 to 0.87) and 0.74 (0.73 to 0.85) for mortality and cIAI relapse CPMs. Adjusted calibration slopes were 0.88 (95 per cent c.i. 0.76 to 0.90) for the mortality model and 0.91 (0.88 to 0.94) for the relapse model; CITL was -0.19 (95 per cent c.i. -0.39 to -0.12) and - 0.01 (- 0.17 to -0.03) respectively. CONCLUSION: Relapse of infection and death after complicated intra-abdominal infections are common. Clinical prediction models were developed to identify patients at increased risk of relapse or death after treatment, these now require external validation.

Multicentre study of short-course radiotherapy and transanal endoscopic microsurgery for early rectal cancer.

BACKGROUND: Organ-preserving treatment for early-stage rectal cancer may avoid the substantial perioperative morbidity and functional sequelae associated with total mesorectal excision (TME). The initial results of an organ-preserving approach using preoperative short-course radiotherapy (SCRT) and transanal endoscopic microsurgery (TEMS) are presented. METHODS: Patients with cT1-2N0 rectal cancers staged using high-quality MRI and endorectal ultrasonography received SCRT, with TEMS 8-10 weeks later, at four regional referral centres between 2007 and 2013. Patients were generally considered high risk for TME surgery (a small number refused TME). RESULTS: Following SCRT and TEMS, 60 (97 per cent) of 62 patients had an R0 resection. Histopathological staging identified 20 ypT0 tumours, 23 ypT1, 18 ypT2 and one ypT3. Preoperative uT category was significantly associated with a complete pathological response, which was achieved in 13 of 27 patients with uT0/uT1 disease and in five of 29 with uT2 (P = 0·010). Acute complications affected 19 patients, the majority following TEMS. No fistulas occurred and no stomas were formed. Surveillance detected four intraluminal local recurrences at a median follow-up of 13 months, all in patients with tumours staged as ypT2. Salvage TME achieved R0 resection in three patients and a stent was placed in one patient owing to co-morbidities. CONCLUSION: SCRT with TEMS was effective in the majority of patients considered high risk for (or who refused) TME surgery.

Desmoplastic small round cell tumour: a review of literature and treatment options.

INTRODUCTION: Desmoplastic Small Round Cell Tumour (DSRCT) is a rare but aggressive malignancy with poor outcome. AIMS: To review the clinico-pathological features and radiological, histological and tumour markers of the disease and to evaluate the evidence for treatment options available. METHODS: We report a clinical case from our centre and have conducted a review of the literature from Medline (Pubmed) database from 1989 to 2007. RESULTS: DSRCT typically presents with advanced disease and is prevalent in young males. Lack of staging criteria and small numbers of patients make comparison of evidence for its treatment difficult. CONCLUSION: Surgical excision is only recommended for non-metastatic disease with combination chemo-radiotherapy as an adjunct. These modalities used in isolation may have less impact. Furthermore, the side effect profile from radiotherapy may outweigh any survival benefit. For advanced disease, symptom control is most important as these modalities impact survival minimally and palliation of secondary symptoms is paramount. Multi-disciplinary team and specialist centre review for histology and oncology are essential in managing this disease process and will enable greater numbers of patients to be enrolled into therapeutic trials and future evolving therapies.

Impotence: relevance and assessment in the surgical patient.

Two simple methods of assessing the presence and likely cause of impotence are described. The mechanism of sexual dysfunction is discussed with particular relevance to the surgical patient.

A transdisciplinary team approach to perinatal loss.

Pregnancy loss is a unique and life-changing event for the woman and her family. Miscarriages occur in about 15% to 20% of all clinically identified pregnancies in the United States. These pregnancy losses can cause a multitude of problems including physical, emotional, and psychosocial distress. This article discusses how a transdisciplinary team embarked on a 1-year journey to establish a process for providing consistent, high-quality care to women experiencing a pregnancy loss. This team was developed in response to opportunities for improvement at a regional tertiary care center. The team's mission was to develop a uniform standard of compassionate care for these families through a transdisciplinary approach focusing on guidance, support, and information. By sharing the story of our Fetal Demise Task Force, other individuals may be able to identify strengths and weaknesses in their own facilities as they care for women and families experiencing a pregnancy loss.

Urinary incontinence in the disabled elderly male.

A combined approach between Departments of Urology and Geriatric Medicine to the diagnosis and management of urinary incontinence in disabled elderly men with neurological lesions where outflow obstruction is thought to be a contributory factor is described. After a dual out-patient assessment, patients have a planned admission to a geriatric ward where urodynamic studies and cystoscopy are performed, followed, where necessary, by appropriate surgery. The results in 75 patients are presented. Single urodynamic studies alone are effective in establishing the diagnosis in only 20% of cases. The largest group needing surgical treatment are those with combined cerebrovascular disease and prostatic enlargement. The degree of disability, but not age, influences the outcome of surgery in such cases. The benefits of collaboration to such patients and to the departments are discussed.

Cell-specific regulation of gene expression in mitochondria during anther development in sunflower.

Mitochondrial gene expression was characterized during meiosis in sunflower anthers. In situ hybridization experiments showed that there was a marked accumulation of four mitochondrial gene transcripts (atpA, atp9, cob, and rrn26) in young meiotic cells. This pattern of transcript accumulation was only detected for mitochondrial genes and not for transcripts of two nuclear genes (atpB and ANT) encoding mitochondrial proteins or another nuclear gene transcript (25S rRNA). Immunolocalization studies showed that the pattern of accumulation of the protein product of the atpA gene, the F1-ATP synthase alpha subunit, reflects that of the transcript. The expression of the novel mitochondrial orf522, which is associated with the cytoplasmic male-sterile (CMS) phenotype, was also studied by in situ hybridization. The orf522 transcripts were reduced in abundance in meiotic cells in the presence of fertility restorer genes. These results suggest that mitochondrial gene expression is regulated in a cell-specific fashion in developing anthers and that the restorer gene(s) may act cell specifically.

Nuclear restoration of cytoplasmic male sterility in sunflower is associated with the tissue-specific regulation of a novel mitochondrial gene.

We have previously shown that cytoplasmic male sterility in sunflower is associated with the insertion into the mitochondrial DNA of a novel open reading frame (ORF) located 3' to the atpA gene. Here, we show that in mitochondria from the sterile line, this novel ORF (ORF522) is cotranscribed with atpA. We have identified the product of the ORF522 as being a 15 kDa protein previously observed in sterile plant mitochondria by in organello translation. Both Western blot analysis and in organello translation assays show reduced levels of the 15 kDa polypeptide upon restoration of fertility. Interestingly, this reduction is tissue specific since it is only observed in the male florets from restored hybrid plants. These results suggest that the 15 kDa novel polypeptide is probably responsible for the CMS phenotype. Northern blot analysis using RNA from both seedlings and male florets shows a flower-specific reduction in the level of the ORF522 transcript in the restored hybrid line. The reduction is not due to a reduced transcription rate as demonstrated by 'run-on' experiments using mitochondria isolated from male florets. This suggests that the product of the nuclear restorer gene acts at the post-transcriptional level to destabilize the novel mitochondrial transcript in a tissue-specific manner and restore male fertility.

Specific circulating anti-gliadin IgG-class antibody does not mediate intestinal enteropathy in gliadin-fed mice.

The effects of specific circulating IgG antibody on the uptake of dietary antigen and in the generation of intestinal enteropathy have been investigated in Balb/c mice bred on a gluten-free diet. A monoclonal IgG1 antibody (GD3) was prepared against gliadin. After adoptive transfer into mice, this antibody was capable of mediating a type III hypersensitivity response in vivo to footpad challenge with gliadin. The titres of circulating GD3, as estimated in vitro by ELISA, correlated well with the degree of inflammation at sites of type III responses in vivo. Following footpad challenge with gliadin, titres of circulating GD3 antibody were reduced. GD3 antibody was tested for its ability to mediate inflammatory responses in vivo in the intestinal mucosa of mice fed with gliadin. Circulating GD3 antibody was removed selectively and specifically by dietary gliadin, compared to feeding with bovine serum albumin or maintenance on a gliadin-free diet only. However, we were unable to demonstrate any pathological changes in the intestine as a result of possible local antigen-antibody complex formation or deposition. Using radio-iodinated gliadin as a trace marker, no significant retention of gliadin in the intestinal mucosa was found in mice pre-injected with GD3 antibody. These data suggest that circulating IgG antibody has little effect on dietary antigen uptake in the gut, and alone is insufficient to mediate an enteropathy.

The painful prostate.

A clinical diagnosis of chronic prostatitis was made on 105 adult males who were subsequently admitted and investigated by Stamey localisation techniques, psychological questionnaires, urine flow studies, cysto-urethroscopy and prostatic biopsy or transurethral prostatectomy. From the Stamey localisation studies and cultures of the tissue obtained at transurethral prostatectomy a diagnosis of bacterial prostatitis was made in 50%, of which half were Staphylococcus albus and half were well recognised urinary pathogens. Other significant pathology was found in 25% and, particularly of note, were 2 patients who presented with chronic cystitis (biopsy negative) and subsequently developed carcinoma of the bladder. Also in this group were 5 unsuspected strictures and 5 patients with poor flow rates but normal endoscopy. Investigations in the remaining 25% were all negative except for a significantly higher incidence of neuroticism when compared with the other groups and controls.

Expression of CD6 and the UCHL1-defined CD45 (p180) antigen by human colonic T lymphocytes.

Cryostat sections of histologically normal human colon were studied by double-label immunofluorescence techniques using a panel of monoclonal antibodies to T-lineage antigens and activation markers, with particular reference to the CD6 antigen. In the lamina propria, the majority population of T cells was of the CD3+, CD6+, CD4+ subset, of which virtually all were of the UCHL1+, CD45R-, Leu 8- phenotype of antigen-committed helper T cells. This majority lamina propria population did not express markers associated with blastogenesis (CD7), activation (MHC class II, CD25, CD38) or proliferation (OKT9, Ki67). In both intra-epithelial and lamina propria compartments, a subpopulation of CD3+ T cells was identified which did not express either the CD6 or CD5 peripheral 'pan T' markers. Most of the CD3+, CD6- cells were of the CD8+ (cytotoxic-suppressor) subset which co-expressed the CD7 antigen with a much higher frequency than did the CD6+ subpopulation. Expression of CD25, CD38 and HLA-D antigens, although infrequent, was confined to this CD8+, CD5-, CD6- population. Our data thus imply that the colonic mucosa is largely populated by mature, antigen-committed resting T cells of the helper-inducer phenotype.

Regulation of intestinal immunoglobulin production in response to dietary ovalbumin.

The effects of oral administration of ovalbumin (OVA) on intestinal immunoglobulin production was examined. Balb/c mice, bred and reared on an OVA-free diet, received either one dose or 14 consecutive daily intragastric doses of 25 mg OVA/dose. Single dose administration of OVA resulted in significant suppression of total immunoglobulins in the intestinal mucosa, particularly of the IgA isotype, although a very low titre anti-OVA IgG class antibody response was induced. After multiple peroral immunisations, there was more intestinal anti-OVA antibody induction and less suppression of total immunoglobulins. However, all the anti-OVA antibody was of the IgG isotype. In vitro production of mucosal immunoglobulins was not significantly reduced over 5 days, compared with controls, in either single or multiple administration groups, suggestive of a loss of T suppressor cell function in culture. Prior adoptive transfer of splenic and lymph node cells from mice preimmunised with OVA was capable of abrogating the local suppression of immunoglobulin production in vivo. Although adoptive transfer of bovine serum albumin-sensitised cells could also overcome some of the local suppression, complete restoration of normal immunoglobulin levels was not achieved. These data suggest that single oral administration of a novel dietary antigen induces a transient, non-specific suppression of intestinal immunoglobulin production, which can be overcome by antigen-specific T cells.

The value of permixon in benign prostatic hypertrophy.

A double-blind trial comparing the effect of Permixon (160 mg bd) against placebo in the treatment of benign prostatic hypertrophy is described. In both groups a significant improvement in flow rate and subjective assessment of symptoms was seen. There was no significant difference between the results of treatment in either group.

Confocal microscopy of idarubicin localisation in sensitive and multidrug-resistant bladder cancer cell lines.

Idarubicin is a highly lipophilic anthracycline and appears effective against tumours resistant to conventional anthracyclines. Confocal microscopy demonstrates predominantly cytoplasmic idarubicin accumulation. This distribution is unaltered by resistance status or the resistance reversing agent verapamil. Our results contrast with studies on conventional anthracyclines and suggest that nuclear accumulation may not be a prerequisite for anthracycline cytotoxicity.

Expression of the LFA-1 beta 2 integrin (CD11a/CD18) and ICAM-1 (CD54) in normal and coeliac small bowel mucosa.

The leucocyte adhesion molecules (beta 2 integrins) comprise CD11 alpha-chains and a common beta-chain (CD18). CD11a (leucocyte function-associated antigen 1, LFA-1) is expressed by most T cells, and is involved in antigen presentation by macrophages via its counter-receptor, intercellular adhesion molecule (ICAM-1, CD54). By criteria of double-label immunofluorescence of cryostat tissue sections, virtually all lamina propria T cells of the normal small bowel were found to express LFA-1 strongly. By contrast, only 30-60% of intra-epithelial lymphocytes (IEL) expressed detectable LFA-1, most of which were LFA-1 weak and CD18-. ICAM-1 was expressed strongly only by vascular endothelium. In coeliac disease, there was a modest increase of diffuse ICAM-1 expression in the lamina propria, mainly in the subepithelial zone, where ICAM-1+ macrophages were occasionally seen. There was also a slight overall increase in CD11a expression by IEL, seen predominantly in surface epithelium and mainly by the CD4+ minority subset, but not by CD4-CD8- (TcR gamma delta +) cells. These data suggest that the LFA-1/ICAM-1-dependent antigen presentation pathway is of minor importance to IEL in the normal small bowel, and does not assume a major role in coeliac disease.