A histology-based model for predicting microsatellite instability in colorectal cancers

Identifying colorectal cancers (CRCs) with high levels of microsatellite instability (MSI-H) is clinically important. MSI-H is a positive prognostic marker for CRC, a predictive marker for resistance to standard 5-fluorouracil-based adjuvant chemotherapy, and an important feature for identifying individuals and families with Lynch syndrome. Our aim was to compare and improve upon the existing predictive pathology models for MSI-H CRCs. We tested 2 existing models used to predict MSI-H tumors, (1) Revised Bethesda Guidelines and (2) MsPath, in our population-based cohort of CRCs diagnosed less than 75 years from Newfoundland (N=710). We also scored additional histologic features not described in the other models. From this analysis, we developed a model for the prediction of MSI-H CRCs; Pathologic Role in Determination of Instability in Colorectal Tumors (PREDICT). An independent pathologist validated this model in a second cohort of all CRCs (N=276). Tumor histology was a better predictor of MSI status than was personal and family history of cancer. MsPath identified MSI-H CRCs with a sensitivity of 92.1% and a specificity of 37.8%, whereas the Revised Bethesda Guidelines had a sensitivity of 81.3% and a specificity of 39.5%. PREDICT included some new histology features, including peritumoral lymphocytic reaction and increased proportion of plasma cells in the tumor stroma. PREDICT was superior to both existing models in the development cohort with a sensitivity of 97.4% and a specificity of 53.9%. In the validation cohort, sensitivity was 96.9% and specificity 76.6%. We conclude that PREDICT is a good predictor of MSI-H CRC.     

44Sacral extracorporeal magnetic stimulation is an effective treatment for pelvic floor dyssynergia; Comparative study with biofeedback therapy

Background: Recent development of extracorporeal magnetic stimulation (ECMS) which uses current‐changing magnetic fields allows the induction of electrical stimulation in the desired deep tissue. Recent study showed the sacral nerve stimulation reduces corticoanal excitability that may play a functional role in anal continence mechanisms. Preliminary study shows that ECMS of sacral nerve can modify pelvic floor function and expel rectal balloon in patients with pelvic floor dyssynergia (PFD). Aims: To evaluate the effect of ECMS compared with biofeedback therapy (BF) in patients with PFD. Methods and Materials: Thirty‐eight patients who fulfilled Rome II criteria for PFD by colon transit time and anorectal function tests, were randomly treated with 8 sessions of ECMS (2/weeks; n = 19) at prone position or BF (2/weeks; n = 19) at sitting position. Stimulation parameters were set at 50–80% of maximum intensity, 10 and 50 Hz frequency, 3 s burst length with 3 and 6 s off using arm‐typed stimulator (BioCom‐1000, Mcube Co., Korea). Symptom scores for constipation with/without anorectal function test were repeatedly measured after each treatment. Response was defined as 50% or more decreased symptom score after treatment (partial response: 30–50%, poor: <30%). Results: Fifteen patients (age 49.1 ± 13.4 years, mean ± SD; 4 men) completed 8 session of BF and 14 patients (54.5 ± 17.6 years, 3 men) completed 8 session of ECMS. Four patients of BF group discontinued treatment due to unsatisfactory therapeutic effect (n = 1) and withdrew consent (n = 3) and 5 patients of ECMS group discontinued treatment because of same reasons (n = 1, 4). Total symptom scores were significantly decreased after treatment of 8 session in both treatment groups (13.4 ± 6.6 vs. 4.3 ± 4.0 for BF, p = 0.009; 14.9 ± 5.6 vs. 3.4 ± 4.0 for ECMS, p < 0.001). Bowel movements per week were also significantly increased after treatment in both groups (median 2 vs. 7 for BF, p = 0.035; median 2 vs. 7 for ECMS, p = 0.008). Thirteen out of 15 patients showed response in BF group and 12 out of 14 showed good response in ECMS group. No adverse effects in both groups. Conclusions: ECMS is as effective as BF for the treatment of PFD. Long‐term effect of ECMS for the patients with pelvic floor dyssynergia need to be evaluated in the near future.     

Adrenomedullin and adrenomedullin-binding protein-1 downregulate inflammatory cytokines and attenuate tissue injury after gut ischemia-reperfusion

BACKGROUND: Recent studies have shown that adrenomedullin (AM) and AM-binding protein-1 (AMBP-1) possess anti-inflammatory properties in sepsis. We hypothesized that administration of AM/AMBP-1 after gut ischemia-reperfusion (I/R) downregulates inflammatory cytokines and attenuates tissue injury. METHODS: Male Sprague-Dawley rats (275-325 g) were used. Gut ischemia was induced by placing a microvascular clip across the superior mesenteric artery (SMA) for 90 minutes. Upon release of the SMA clamp, the animals were treated by AM (12 microg per kilogram of body weight) and AMBP-1 (40 microg per kilogram of body weight) in combination, or vehicle (1 mL 0.9% NaCl) over 30 minutes via a femoral vein catheter. The animals undergoing sham operation or ischemia for 90 minutes only, did not receive AM/AMBP-1 treatment. At 60 minutes after the completion of the treatment (ie, 90 minutes after reperfusion), blood samples were collected. Plasma AM and AMBP-1 were measured by radioimmunoassay and Western blot analysis, respectively. Serum levels of TNF-alpha, interleukin (IL)-1beta, IL-6, IL-10, transaminases (ie, alanine aminotransaminase, aspartate aminotransaminase), lactate, and creatinine were determined with the use of enzyme-linked immunosorbent assay and other standard methods. In additional groups of animals, the 10-day survival rate was recorded after gut I/R. RESULTS: Ischemia alone was sufficient to downregulate both AM and AMBP-1. Unlike AMBP-1 that remained decreased, AM levels increased significantly after reperfusion. I/R but not ischemia alone significantly increased serum levels of inflammatory cytokines. Moreover, I/R-induced tissue injury was evidenced by increased levels of transaminases, lactate, and creatinine. Administration of AM/AMBP-1 after ischemia, however, markedly reduced cytokine levels, attenuated tissue injury, and improved survival. CONCLUSIONS: AM/AMBP-1 may be a novel treatment to attenuate the reperfusion injury after gut ischemia.     

Ghrelin down-regulates proinflammatory cytokines in sepsis through activation of the vagus nerve

OBJECTIVE: To test the hypothesis that administration of ghrelin attenuates inflammatory responses in sepsis through vagal nerve stimulation. SUMMARY BACKGROUND DATA: Ghrelin has been demonstrated to possess multiple functions, including stimulation of the vagus nerve. Our recent study has shown that plasma levels of ghrelin were significantly reduced in sepsis; and ghrelin administration improved organ perfusion and function. However, it remained unknown whether ghrelin also decreases proinflammatory cytokines in sepsis and, if so, whether the down-regulatory effect of ghrelin is mediated by activation of the vagus nerve. METHODS: Male rats were subjected to sepsis by cecal ligation and puncture (CLP). At 5 hours after CLP, a bolus intravenous injection of 2 nmol ghrelin was followed by a continuous infusion of 12 nmol ghrelin via a primed 200-microL Alzet mini-pump for 15 hours. At 20 hours after CLP, plasma and peritoneal fluid levels of TNF-alpha and IL-6 were determined. The direct effect of ghrelin on cytokine production was studied using cultured normal rat Kupffer cells or peritoneal macrophages stimulated by lipopolysaccharide (LPS). In additional animals, vagotomy or sham vagotomy was performed in sham and septic animals immediately prior to ghrelin administration and cytokine levels were then measured. RESULTS: Ghrelin significantly reduced TNF-alpha and IL-6 levels in sepsis. In contrast, ghrelin did not inhibit TNF-alpha and IL-6 release from LPS-stimulated Kupffer cells or peritoneal macrophages. However, vagotomy, but not sham vagotomy, prevented ghrelin's down-regulatory effect on TNF-alpha and IL-6 production. CONCLUSIONS: Ghrelin down-regulates proinflammatory cytokines in sepsis through activation of the vagus nerve. Pharmacologic stimulation of the vagus nerve may offer a novel approach of anti-sepsis therapy.     

Nurse endoscopy in a district general hospital

INTRODUCTION: This study describes the first full year of independent practice by a newly appointed nurse endoscopist in a district general hospital. PATIENTS AND METHODS: Patients underwent either 'one stop' flexible sigmoidoscopy and barium enema or flexible sigmoidoscopy alone. Barium enema results, video photography, clinical follow-up, and histology were used to validate the results of the flexible sigmoidoscopy. One stop clinic: 161 endoscopies were performed, with 104 female patients (65%), and a mean age of 64 years. There was one failed endoscopy due to poor bowel preparation. Abnormalities were identified in 84% of endoscopies. Flexible sigmoidoscopy detected abnormalities not seen on the barium enema in 28 cases, all of which were polyps (18%). Barium enema identified one abnormality within reach of the flexible sigmoidoscope not identified at endoscopy (small polyp in sigmoid; 1%). Elective flexible sigmoidoscopy list: 121 endoscopies were performed, with 65 female patients (54%), and a mean age of 59 years. There were two failed endoscopy procedures, both attributed to poor bowel preparation. Two-thirds of patients had an abnormality on investigation. There were no complications in either group of patients. CONCLUSIONS: The nurse-led endoscopy service has been successfully initiated with a high completion rate for flexible sigmoidoscopies. All significant conditions were identified with 99% sensitivity. Nurse endoscopy is a safe, useful and practical procedure in the setting of this district general hospital.     

The dystrophin gene and cognitive function in the general population

The aim of our study is to investigate whether single-nucleotide dystrophin gene (DMD) variants associate with variability in cognitive functions in healthy populations. The study included 1240 participants from the Erasmus Rucphen family (ERF) study and 1464 individuals from the Rotterdam Study (RS). The participants whose exomes were sequenced and who were assessed for various cognitive traits were included in the analysis. To determine the association between DMD variants and cognitive ability, linear (mixed) modeling with adjustment for age, sex and education was used. Moreover, Sequence Kernel Association Test (SKAT) was used to test the overall association of the rare genetic variants present in the DMD with cognitive traits. Although no DMD variant surpassed the prespecified significance threshold (P<1 × 10⁻⁴), rs147546024:A>G showed strong association (β=1.786, P-value=2.56 × 10⁻⁴) with block-design test in the ERF study, while another variant rs1800273:G>A showed suggestive association (β=−0.465, P-value=0.002) with Mini-Mental State Examination test in the RS. Both variants are highly conserved, although rs147546024:A>G is an intronic variant, whereas rs1800273:G>A is a missense variant in the DMD which has a predicted damaging effect on the protein. Further gene-based analysis of DMD revealed suggestive association (P-values=0.087 and 0.074) with general cognitive ability in both cohorts. In conclusion, both single variant and gene-based analyses suggest the existence of variants in the DMD which may affect cognitive functioning in the general populations.     

Screening, diagnosis and management of early syphilis in genitourinary medicine clinics in the UK

New diagnoses of syphilis in the UK increased eight-fold between 1997 and 2002. This study, conducted in 2002, demonstrated that 31% of clinics were not confident of their expertise to obtain an adequate specimen for dark ground microscopy (DGM), and 35% were not confident of their expertise to detect treponemes on DGM. In all, 64% of clinics had observed adherence problems in HIV-positive patients treated with parenteral regimens, as against 42% with oral regimens. Also, 51% of clinics waited more than a week for the results of initial serological tests for syphilis, and 88% of clinics waited more than a week for confirmatory test results. Other concerns include the failure to perform syphilis serology consistently whenever HIV-positive patients were at risk, and the widespread use of doxycycline as a therapy for syphilis in HIV-positive patients despite concerns that this is not known to be fully treponemicidal in cerebrospinal fluid.     

'My dreams are shuttered down and it hurts lots’–a qualitative study of palliative care needs and their management by HIV outpatient services in Kenya and Uganda

Background

Despite the huge burden of HIV in sub-Saharan Africa, there is little evidence of the multidimensional needs of patients with HIV infection to inform the person-centred care across physical, psychological, social and spiritual domains stipulated in policy guidance. We aimed to describe the problems experienced by people with HIV in Kenya and Uganda and the management of these problems by HIV outpatient services.

Methods

Local researchers conducted in depth qualitative interviews with HIV patients, caregivers and service staff at 12 HIV outpatient facilities (6 in Kenya, 6 in Uganda). Interview data were analysed thematically.

Results

189 people were interviewed (83 patients, 47 caregivers, 59 staff). The impact of pain and symptoms and their causes (HIV, comorbidities, treatment side-effects) were described. Staff reported that effective pain relief was not always available, particularly in Kenya. Psychosocial distress (isolation, loneliness, worry) was exacerbated by stigma and poverty, and detrimentally affected adherence. Illness led to despair and hopelessness. Provision of counselling was reported, but spiritual support appeared to be less common. Neither pain nor psychosocial problems were routinely reported to service staff. Collaboration with local hospices and income-generation activities for patients were highlighted as useful.

Conclusions

The findings demonstrate the multiple and interrelated problems associated with living with HIV and how psychosocial and spiritual distress can contribute to 'total pain’ in this population. In line with the palliative care approach, HIV care requires holistic care and assessment that take into account psychological, socioeconomic and spiritual distress alongside improved access to pain-relieving drugs, including opioids.