Genetic testing for hereditary nonpolyposis colorectal cancer

Approximately 80 per cent of patients with colorectal cancer have sporadic disease whereas the remaining 20 per cent seem to have a genetic component. Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common autosomal dominant hereditary syndrome predisposing to colorectal cancer. Various methods have been described to screen for HNPCC and to directly test for mismatch repair gene mutations. This study evaluates the initial results of 1) microsatellite instability (MSI) and immunohistochemistry (IHC) staining of tumors and 2) genetic sequencing for mismatch repair gene mutations in patients suspected to have HNPCC. Appropriate patients for HNPCC testing were identified through a high-risk colorectal cancer clinic. Of those patients screened only those who met Amsterdam criteria (AC) for HNPCC or were young age onset (YAO) (<40 years of age) were eligible for testing. The tumors underwent testing for MSI and had IHC performed in those patients with available tumor specimens. MSI was performed on the five markers approved by the NIH consensus conference. MSI-High (MSI-H) was defined as two or more markers being unstable. IHC was done with commercially available stains for MLH1 and MSH2. All patients had sequencing of the MLH1 and MSH2 genes performed to search for mutations by a commercial laboratory. Genetic counseling was provided and written informed consent was obtained. Fourteen patients were part of kindreds that met the AC. An additional 10 patients were <40 years of age at diagnosis of colorectal cancer but lacked any family history. Testing for MSI and IHC was performed on those available tissue blocks. Of the AC patients five had MSH2 mutations and two had MLH1 variants. Of the five with MSH2 mutations three of four had MSI-H tumors and all four had loss of expression of MSH2 on IHC. Of the MLH1 variants only one had MSI-H tumor and lacked expression of MLH-1 on IHC. Of those patients with no mutation identified three of six had MSI-H tumors. For those patients YAO no genetic mutations were identified. Two of the seven had MSI-H tumors. Genetic testing for HNPCC even in those patients fulfilling the rigid AC yielded mutations in only five of 14 patients with variants of unknown significance being found in an additional two patients. Only one MSH2 variant of unknown significance was identified in the 10 YAO patients, which would suggest that screening in this group of patients with MSI and/or IHC would be appropriate.     

Effects of PEEP on residual vascularization in oesophageal substitution gastroplasty by surface oximetry-capnometry and photoplethysmography: an experimental study

OBJECTIVE: To evaluate the effects of positive end-expiratory pressure (PEEP) on residual vascularization in gastric tubes for oesophageal replacement. DESIGN: Experimental open study. MATERIALS: Eleven mongrel dogs. METHODS: Intestinal parietal blood flow was evaluated by photoplethysmography (PPG) and measurement of surface oxygen (PsO(2)) and carbon dioxide (PsCO(2)) tensions under basal conditions. After Akiyama's tubular gastroplasty, three levels of PEEP were administered. At each level, fluids were infused to counter the drop in cardiac output. PPG, surface gas tensions, arterial pressure, cardiac output and arterial blood gas tensions were monitored. Control sections of the bowel were also monitored by PPG. RESULTS: Cardiac output dropped for each level of PEEP and returned to basal levels on volume restabilization and on removal of PEEP. Central venous pressure and pulmonary arterial and capillary pressures increased for each level of PEEP and only returned to basal levels on removal of PEEP. PsO(2) values dropped for each level of PEEP and returned to basal levels on volume restabilization and on removal of PEEP. PsCO(2) levels rose, and PPG wave amplitude dropped, for each level of PEEP; these two variables only returned to basal levels on removal of PEEP. PPG values for the control sections reflected those of the anastomotic area. CONCLUSIONS: PEEP affects surface oxygen values at the level of the gastroplasty by means of its effect on cardiac output. PEEP also creates a venous return compromise and PPG wave amplitude and surface carbon dioxide values are related to this compromise. All three variables could be significant in anastomotic wound healing.     

Children's memory for trauma and positive experiences

Characteristics of children's memory for a trauma and for a positive event were compared and relationships of memory characteristics to trauma symptoms examined in 30 children who experienced a traumatic event. Results revealed that memories for trauma tended to have less sensory detail and coherence, yet have more meaning and impact than did memories for positive experiences. Sexual traumas, offender relationship, and perceived life threat were associated with memory characteristics. Few relationships between memory characteristics and trauma symptoms were found. Therapist ratings of child memory characteristics were correlated with some child trauma memory characteristic reports. These results are consistent with other studies. Possible explanations include divided attention during the traumatic event and cognitive avoidance occurring after the event.     

Metalloproteinase inhibition reduces lung injury and improves survival after cecal ligation and puncture in rats

BACKGROUND: Neutrophil activation with concomitant matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) release has been implicated in the development of sepsis-induced acute lung injury. We hypothesized that COL-3, a chemically modified tetracycline known to inhibit MMP-2 and MMP-9, would reduce lung injury and improve survival in rats following cecal ligation and puncture (CLP). METHODS: Sprague-Dawley rats were separated into five groups: 1) sham CLP+ carboxymethylcellulose (CMC; vehicle for COL-3, n = 6); 2) sham CLP + COL-3 (n = 6); 3) CLP + CMC (n = 10); 4) CLP + single-dose (SD) COL-3 administered concomitant with CLP (n = 9); and 5) CLP + multiple-dose (MD) COL-3 administered concomitant with CLP and at 24 h after CLP (n = 15). Rats were sacrificed at 168 h (7 days) or immediately after death, with survival defined as hours after CLP. Histological lung assessment was made based on neutrophil infiltration, alveolar wall thickening, and intraalveolar edema fluid. Lung MMP-2 and MMP-9 levels were assessed by immunohistochemistry. MMP-2 and MMP-9 levels were correlated with survival by simple regression analysis. RESULTS: The mortality of rats in the cecal ligation and puncture without treatment group (CLP + CMC) was 70% at 168 h. A single dose of COL-3 in the CLP + COL-3 (SD) group significantly reduced mortality to 54%. Furthermore, with a repeat dose of COL-3 at 24 h after CLP, mortality was significantly reduced to 33%. Pathologic lung changes seen histologically in the CLP + CMC group were significantly reduced by COL-3. A significant reduction in lung tissue levels of MMP-2 and MMP-9 was noted in both groups treated with COL-3. Reduction of MMP-2 and MMP-9 levels correlated with improved survival. CONCLUSION: Inhibition of MMP-2 and MMP-9 by COL-3 in a clinically relevant model of sepsis-induced acute lung injury reduces pulmonary injury and improves survival in a dose-dependent fashion. Our results suggest that prophylactic treatment with COL-3 in high-risk patients may reduce the morbidity and mortality associated with sepsis-induced acute respiratory distress syndrome.     

Cochlear implant benefits in deafness rehabilitation: PET study of temporal voice activations.

Cochlear implants may improve the medical and social prognosis of profound deafness. Nevertheless, some patients have experienced poor results without any clear explanations. One correlate may be an alteration in cortical voice processing. To test this hypothesis, we studied the activation of human temporal voice areas (TVA) using a well-standardized PET paradigm adapted from previous functional MRI (fMRI) studies. METHODS: A PET H(2)(15)O activation study was performed on 3 groups of adult volunteers: normal-hearing control subjects (n = 6) and cochlear-implanted postlingually deaf patients with >2 y of cochlear implant experience, with intelligibility scores in the "Lafon monosyllabic task" >80% (GOOD group; n = 6) or <20% (POOR group; n = 6). Relative cerebral blood flow was measured in 3 conditions: rest, passive listening to human voice, and nonvoice stimuli. RESULTS: Compared with silence, the activations induced by nonvoice stimuli were bilaterally located in the superior temporal regions in all groups. However these activations were significantly and similarly reduced in both cochlear implant groups, whereas control subjects showed supplementary activations. Compared with nonvoice, the voice stimuli induced bilateral activation of the TVA along the superior temporal sulcus (STS) in both the control and the GOOD groups. In contrast, these activations were not detected in the POOR group, which showed only left unilateral middle STS activation. CONCLUSION: These results suggest that PET is an adequate method to explore cochlear implant benefits and that this benefit could be linked to the activation of the TVA.     

Sex differences in response to maximal eccentric exercise

PURPOSE: This study examined sex differences in strength loss, muscle soreness, and serum creatine kinase (CK) and myoglobin (Mb) after high-intensity eccentric exercise of the elbow flexors in a large group of men and women. METHODS: One hundred participants (58 women, 42 men) performed 50 maximal eccentric contractions of the elbow flexor muscles of their nondominant arm. Maximum isometric voluntary contraction (MVC) was recorded at baseline, immediately after exercise, and at 0.5 (12-14 h), 3, 4, 7, and 10 d after exercise. Blood samples for serum CK activity and Mb were taken at baseline and at 4, 7, and 10 d after exercise. Soreness was evaluated at baseline and at 0.5, 3, 4, 7, and 10 d after exercise. RESULTS: Women experienced significantly greater relative strength loss immediately after exercise (-57.8% +/- 19.1) than men (-50.4% +/- 16.9%) (independent t-test; P < or = 0.05), and a greater percentage of women experienced more than 70% strength loss immediately after exercise compared with men (34.4% of women; 7.1% of men). Men exhibited a larger CK response compared with women (ANCOVA; P < or = 0.05), partly because there were more men who were high responders. There were no significant differences between the sexes for serum Mb or soreness measures. Generally, stronger relationships among CK, soreness, and strength-loss measures were found in men compared with women (r = 0.55-0.59 for men; r = 0.12-0.49 for women). CONCLUSION: In response to eccentric exercise, women experienced greater immediate strength loss than men and were more likely to be high responders for immediate strength loss; men experienced greater serum CK activity than women and were more likely to be high responders for increased serum CK. Although the explanation for high responders to eccentric exercise remains unknown, we have shown that there are sex-specific differences in CK and strength-loss response after eccentric exercise.     

Evidence-based radiography

Evidence-based practice (EBP) offers the integration of the best research evidence with clinical knowledge and expertise and patient values. EBP is a well known term in health care. This paper discusses the implementation of EBP into radiography and introduces the term evidence-based radiography. Evidence-based radiography is radiography informed and based on the combination of clinical expertise and the best available research-based evidence, patient preferences and resources available.In Norway, EBP in radiography is being debated and radiographers are discussing the challenges of implementing EBP in both academic and clinical practice. This discussion paper explains why EBP needs to be a basis for a radiography curriculum and a part of radiographers' practice. We argue that Norwegian radiographers must increase participation in research and developing practice within their specific radiographic domain.     

Laparoscopic Treatment of Gastric <Emphasis Type="SmallCaps">Gist</Emphasis>: Report of 21 Cases and Literature’s Review

Background Although the feasibility of laparoscopic resection of gastric gastrointestinal stromal tumors (GISTs) has been established, various aspects are debated. This paper describes the problems of minimally invasive resection of gastric GISTs and compares this experience with an extensive literature review. Study Design Between August 2001 and December 2006, 21 consecutive patients undergoing laparoscopic resection of gastric GISTs were enrolled in a prospective study. A literature review of laparoscopic treatment was performed on Pubmed using keywords GIST and surgery. A comparison with authors’ experience with open wedge-segmental resection of GISTs (25 cases from November 1995 to December 2000) was also carried out. Statistical analysis was based on chi-squared test and t Student evaluation. Results Twenty-one patients, mean age 50.1 years (range, 34–68 years), were submitted to laparoscopic wedge- segmental gastric resections. Mean tumor size was 4.5 cm (range, 2.0–8.5 cm). Mean operative time was 151 min (range, 52–310 min), the mean blood loss was 101 mL (range, 10–250 mL), and the mean hospital stay was 4.8 days (range 3–7 days). There were no major operative complications or mortalities. All lesions had negative resection margins. At a mean follow-up of 35 months, all patients were disease-free. Morbidity, mortality, length of stay, and oncologic outcomes were comparable to the open surgery retrospective evaluation (p = not significant). Conclusions As found also in the literature review, the laparoscopic resection is safe and effective in treating gastric GISTs. Given these findings as well as the advantages afforded by laparoscopic surgery, a minimally invasive approach should be the preferred surgical treatment in patients with small- and medium-sized gastric GISTs.     

Effect of muscle-derived stem cells on the restoration of corpora cavernosa smooth muscle and erectile function in the aged rat

OBJECTIVE

To determine whether skeletal muscle‐derived stem cells (MDSCs) convert into smooth muscle cells (SMCs) both in vitro and in vivo, and in so doing ameliorate the erectile dysfunction (ED) of aged rats, and whether endogenous stem cells are present in the rat corpora cavernosa.

MATERIALS AND METHODS

MDSCs were obtained from mouse muscle, and shown by immunocytochemistry for α‐smooth muscle actin (αSMA) to originate in vitro in myofibroblasts and SMCs, discriminating SMCs by calponin 1 expression. In vivo these MDSCs, labelled with 4′,6‐diamidino‐2‐phenylindole, were implanted into the corpora cavernosa of young adult (5‐month old) and aged (20‐month old) rats for 2 and 4 weeks. Histological changes were assessed by immunohistochemistry and quantitative Western blot. Functional changes were determined by electrical field stimulation (EFS) of the cavernosal nerve.

RESULTS

The exogenous cells replicated and converted into SMCs, as shown in corporal tissue sections by confocal immunofluorescence microscopy for proliferating cell nuclear antigen (PCNA), αSMA, and smoothelin, and also by Western blot for αSMA and PCNA. MDSC differentiation was confirmed by the activation of the αSMA promoter‐linked β‐galactosidase in transfected cells, both in vitro and after implantation in the corpora. Putative endogenous stem cells were shown in corporal tissue sections and Western blots by detecting CD34 and a possible Sca1 variant. EFS showed that implanted MDSCs raised in aged rats the maximal intracavernosal pressure/mean arterial pressure levels above (2 weeks) or up to (4 weeks) those of young adult rats.

CONCLUSIONS

MDSCs implanted into the corpora cavernosa of aged rats converted into SMCs and corrected ED, and endogenous cells expressing stem cell markers were also found in untreated tissue. This suggests that exogenous stem cell implantation and/or endogenous stem cell modulation might be viable therapeutic approaches for ageing‐related ED.