Neoadjuvant therapy induces loss of MSH6 expression in colorectal carcinoma

Immunohistochemical stains are routinely used to detect abnormal DNA mismatch repair (MMR) protein expression in colorectal carcinomas, particularly when Lynch syndrome is suspected. Complete loss of MMR protein expression is often associated with underlying microsatellite instability (MSI), and the combined results of mutL homolog 1 (MLH1), postmeiotic segregation increased 2 (PMS2), mutS homolog 2 (MSH2), or mutS homolog 6 (MSH6) immunostains may point to the defective MMR protein in tumors with MSI. We have noted that some neoadjuvantly treated colorectal carcinomas display loss of MMR protein immunoexpression, despite a lack of underlying MSI and preserved staining in pretreatment tumor samples. The purpose of this study was to determine the frequency of this finding. We identified 51 neoadjuvantly treated resected colorectal cancers. Posttreatment tumor samples were immunohistochemically stained with MLH1, PMS2, MSH2, and MSH6 antibodies. Loss of staining for any marker was followed by analysis for MSI and assessment of MMR protein expression in pretreatment tumor samples. All of the 51 posttreatment tumor samples showed preserved MLH1, PMS2, and MSH2, but 10 posttreatment tumor samples (20%) showed decreased MSH6 staining. Of these, 9 posttreatment tumor samples displayed loss of staining in less than 100% of tumor cells, but preserved MSH6 expression in pretreatment tumor samples. One case showed a complete absence of MSH6 staining in both pretreatment and posttreatment tumor samples. All 10 cases were microsatellite stable. We conclude that extensive loss of MSH6 immunoexpression is common among neoadjuvantly treated colorectal carcinomas, but generally does not reflect underlying MSI. Therefore, diminished MSH6 staining in treated tumors should prompt immunohistochemical evaluation of pretreatment biopsy samples before genetic testing for Lynch syndrome.     

Perils of rib fractures

Rib fractures (RF) are noted in 4 to 12 per cent of trauma admissions. To define RF risks at a Level 1 trauma center, investigators conducted a 10-year (1995-2004) retrospective analysis of all trauma patients. Blunt chest trauma was seen in 13 per cent (1,475/11,533) of patients and RF in 808 patients (55% blunt chest trauma, 7% blunt trauma). RF were observed in 26 per cent of children (< 18 years), 56 per cent of adults (18-64 years), and 65 per cent of elderly patients (> or = 65 years). RF were caused by motorcycle crashes (16%, 57/347), motor vehicle crashes (12%, 411/3493), pedestrian-auto collisions (8%, 31/404), and falls (5%, 227/5018). Mortality was 12 per cent (97/808; children 17%, 8/46; adults 9%, 46/522; elderly 18%, 43/240) and was linearly associated with a higher number of RF (5% 1-2 RF, 15% 3-5 RF, 34% > or = 6 RF). Elderly patients had the highest mortality in each RF category. Patients with an injury severity score > or = 15 had 20 per cent mortality versus 2.7 per cent with ISS < 15 (P < 0.0001). Increasing age and number of RF were inversely related to the percentage of patients discharged home. ISS, age, number of RF, and injury mechanism determine patients' course and outcome. Patients with associated injuries, extremes of age, and > or = 3 RF should be admitted for close observation.     

Filiform serrated adenomas: a clinicopathologic and immunophenotypic study of 18 cases

In this study, we describe a previously uncharacterized type of adenomatous polyp of the colorectum that shows prominent, thin, elongated projections of neoplastic epithelium with a serrated contour, which we have termed "filiform serrated adenoma" (SA). Routinely processed polypectomy specimens from 18 patients with filiform SA and 23 controls with traditional (nonfiliform) SA were evaluated for their clinical and pathologic features, and immunohistochemically stained for a variety of markers (O-methylguanine methyltransferase, MLH1, MSH2, CDX2, nuclear beta-catenin, p53, and Ki-67) designed to evaluate their molecular and proliferative characteristics. DNA was extracted from the paraffin-embedded materials, amplified by polymerase chain reaction, and analyzed for microsatellite instability, BRAF, K-ras, and p53 mutational status. Five cases contained sufficient non-neoplastic tissue for dissection and DNA extraction, allowing analysis of loss of heterozygosity. The study group consisted of 7 males and 11 females of mean age 64 years (range: 42 to 89 y). All 18 filiform SAs were located in the left colon, including 15 (83%) that occurred in the rectum, compared with 43% of the control group (P=0.03). Filiform SAs were also larger (1.6 cm) than SAs (mean: 1.2 cm, P=0.02), but no other clinical differences were noted. Most (56%) filiform SAs contained marked stromal edema and tall nonmucinous cells with abundant eosinophilic cytoplasm (61%). High-grade dysplasia was present in 4/18 (22%) cases. Four (22%) filiform SAs also contained nonserrated adenomatous elements with a villous (3 cases) or tubular (1 case) growth pattern. Two (11%) cases contained adjacent areas of sessile SAs and 4 (22%) had hyperplastic areas. None of the polyps in the control group showed stromal edema, high-grade dysplasia, or mixed elements. Polyps in both groups demonstrated comparable staining patterns for O-methylguanine methyltransferase, MLH-1, MSH-2, CDX2, beta-catenin, and Ki-67, and none showed increased nuclear p53 expression. Low-frequency microsatellite instability was present in 5/12 (42%) filiform SAs, 7/12 (58%) were microsatellite stable. Mitogen-activated protein kinase pathway abnormalities were present in 71% of the cases [7/14 (50%) with BRAF and 3/14 (21%) with K-ras mutations]. Four cases showed silent p53 mutations upon direct sequencing and 4 revealed loss of heterozygosity at the loci evaluated, including 1 at D5S346 [adenomatous polyposis coli (APC) gene], 1 at D17S250 (p53 gene), and 2 at MYCL (chromosome 1p34). We conclude that filiform SA potentially represents an unusual variant of SA with a predilection for the left colon, particularly the rectum.     

Telerehabilitation of anomia in primary progressive aphasia

Background: The efficacy of telerehabilitation-based treatment for anomia has been demonstrated in post-stroke aphasia, but the efficacy of this method of anomia treatment delivery has not been established within the context of degenerative illness.

Aims: The current study evaluated the feasibility and efficacy of a telerehabilitation-based approach to anomia treatment within the three subtypes of primary progressive aphasia (PPA).

Methods & Procedures: Each of the three telerehabilitation participants represented a distinct subtype of PPA. Following a baseline evaluation of language and cognition, a phonological treatment and an orthographic treatment were administered to all participants over the course of 6 months. One month after the end of treatment, a post-treatment evaluation began. All treatment sessions and the majority of the evaluation sessions were administered via telerehabilitation. Treatment effects were examined within each subject, and treatment effects were also compared between each telerehabilitation participant and a group of in-person participants who had the same subtype of PPA.

Outcomes & Results: All three telerehabilitation participants exhibited positive treatment effects. CGR (nonfluent/agrammatic variant PPA) and WCH (logopenic variant PPA) showed maintenance of naming for prophylaxis items under both treatment conditions, while ACR (semantic variant PPA) demonstrated increased naming of remediation items under the phonological treatment condition. Compared to in-person participants with the same subtype of PPA, each of the telerehabilitation participants typically showed effects that were either within the expected range or larger than expected.

Conclusions: Telerehabilitation-based anomia treatment is feasible and effective in all three subtypes of PPA.     

Delivery of child health services in Indigenous communities: implications for the federal government's emergency intervention in the Northern Territory

OBJECTIVES: To describe delivery of child health services in Australian Aboriginal communities, and to identify gaps in services required to improve the health of Aboriginal children. DESIGN: Cross-sectional baseline audit for a quality improvement intervention. SETTING AND PARTICIPANTS: 297 children aged at least 3 months and under 5 years in 11 Aboriginal communities in the Northern Territory, Far West New South Wales and Western Australia in 2006. MAIN OUTCOME MEASURES: Adherence to guideline-scheduled services including clinical examinations, brief interventions or advice on health-related behaviour and risks, and enquiry regarding social conditions; and recorded follow-up of identified problems. RESULTS: Documentation of delivery of specific clinical examinations (26%-80%) was relatively good, but was poorer for brief interventions or advice on health-related behaviour and risks (5%-36%) and enquiry regarding social conditions (3%-11%). Compared with children in Far West NSW and WA, those attending NT centres were significantly more likely to have a record of growth faltering, underweight, chronic ear disease, anaemia, or chronic respiratory disease (P < 0.005). Only 11%-13% of children with identified social problems had an assessment report on file. An action plan was documented for 22% of children with growth faltering and 13% with chronic ear disease; 43% of children with chronic respiratory disease and 31% with developmental delay had an assessment report on file. CONCLUSION: Existing systems are not providing for adequate follow-up of identified medical and social problems for children living in remote Aboriginal communities; development of systems for immediate and longer-term sustainable responses to these problems should be a priority. Without effective systems for follow-up, screening children for disease and adverse social circumstances will result in little or no benefit.     

What's hanging around your neck? Pathogenic bacteria on identity badges and lanyards

OBJECTIVE: To determine whether identity badges and lanyards worn by health care workers (HCWs) are capable of harbouring potentially pathogenic bacteria. DESIGN, SETTING AND PARTICIPANTS: Cross-sectional study of 71 HCWs (59 clinical ward staff and 12 infection control staff) at Monash Medical Centre, a university teaching hospital. Samples from lanyards, identity badge surfaces and connections (eg, clips, keys, pens) were cultured. The study was conducted from July to August 2006. MAIN OUTCOME MEASURES: Presence of pathogenic bacteria on identity badges and lanyards; differences in bacterial counts on items carried by nurses and doctors. RESULTS: A total of 27 lanyards were identified with pathogenic bacteria, compared with 18 badges. Analysing lanyards and badges as a combined group, seven had methicillin-resistant Staphylococcus aureus, 29 had methicillin-sensitive S. aureus (MSSA), four had Enterococcus spp and five had aerobic gram-negative bacilli. Lanyards were found to be contaminated with 10 times the median bacterial load per area sampled compared with identity badges. There were no significant differences between nurses and doctors in total median bacterial counts on items carried, but doctors had 4.41 times the risk of carrying MSSA on lanyards (95% CI, 1.14-13.75). CONCLUSION: Identity badges and lanyards worn by HCWs may be contaminated with pathogenic bacteria, which could be transmitted to patients. In view of this finding we suggest appropriate infection control interventions.     

Evaluation of intraocular pressure in the immediate postoperative period after phacoemulsification

PURPOSE: To determine the incidence of hypotony and intraocular pressure (IOP) elevation in the immediate and early postoperative period after temporal posterior limbal phacoemulsification and intraocular lens (IOL) implantation. SETTING: Ambulatory surgical center. METHODS: This prospective analysis comprised 310 eyes that had temporal posterior limbal phacoemulsification with IOL implantation. Surgical parameters included keratome incision of 2.85 mm, incision length of 2.5 mm, peribulbar anesthesia, case-completion IOP of 20 mm Hg, and postoperative lid taping. The IOP measurements were collected preoperatively and 30 minutes and 1 day after surgery. RESULTS: Nineteen eyes (6.1%) had an IOP lower than 5 mm Hg 30 minutes postoperatively in the absence of incision leakage at the paracentesis or keratome sites. Eighteen of the 19 eyes with postoperative hypotony received hydroxypropyl methylcellulose 2% (OcuCoat) and 1 received hypromellose 2% (Cellugel). None of the 23 eyes with an acrylic IOL implanted via a cylindrical lens inserter had an IOP lower than 5 mm Hg postoperatively. Suturing did not significantly affect the incidence of hypotony, and there were no postoperative complications related to hypotony. The mean IOP at 30 minutes was lower than at 1 day in the normal, glaucoma, and glaucoma-suspect groups. Twenty-one normal eyes (8.1%), 5 glaucoma eyes (15.6%), and 1 glaucoma-suspect eye (5%) had an IOP greater than 30 mm Hg 1 day postoperatively. CONCLUSIONS: Postoperative hypotony (IOP <5 mm Hg) occurred in 19 (6.1%) of 310 eyes. At 1 day, IOP higher than 30 mm Hg was more frequent in glaucoma eyes than in normal eyes. Although there were no direct problems related to hypotony at 30 minutes or to elevated IOP (>30 mm Hg) at 1 day, surgeons should be aware of and check for IOP variability (low and high) that can occur in normal, glaucoma, and glaucoma-suspect eyes within the first 24 hours after surgery.     

Pituitary hypoplasia and lactotroph dysfunction in mice deficient for cyclin-dependent kinase-4

The lactotroph undergoes dynamic regulation of cell cycle progression during pregnancy, as well as throughout the development of the pituitary. We recently reported that female mice with targeted disruption of Cdk4, one of the G(1)-regulatory cyclin-dependent kinases, are unable to support embryo implantation because of defective progesterone secretion from the corpus luteum. In this study, we demonstrate that this phenotype is not attributable to a primary defect in the corpus luteum but is a consequence of defective prolactin (PRL) production caused by inappropriate development of the pituitary lactotroph population. Specifically, the pituitary of Cdk4-deficient mice is extremely hypoplastic. Lactotrophs and somatotrophs of prepubertal Cdk4-deficient mice were 80% decreased in number, relative to those in wild-type mice, whereas gonadotrophs were unaffected. Lactotrophs of Cdk4-deficient mice did not proliferate in response to estrogen administration, whereas estrogen could induce the expression of galanin, an estrogen-responsive factor required for lactotroph proliferation. The reduction in lactotroph numbers was reflected by markedly diminished serum PRL levels in both prepubertal and postcoital Cdk4-deficient mice. Administration of PRL, after mating, significantly increased serum progesterone levels and restored implantation in Cdk4-deficient female mice. These observations demonstrate that Cdk4 is required for normal proliferation of the lactotroph population.     

Identification of somatic JAK1 mutations in patients with acute myeloid leukemia

Somatic mutations in JAK2 are frequently found in myeloproliferative diseases, and gain-of-function JAK3 alleles have been identified in M7 acute myeloid leukemia (AML), but a role for JAK1 in AML has not been described. We screened the entire coding region of JAK1 by total exonic resequencing of bone marrow DNA samples from 94 patients with de novo AML. We identified 2 novel somatic mutations in highly conserved residues of the JAK1 gene (T478S, V623A), in 2 separate patients and confirmed these by resequencing germ line DNA samples from the same patients. Overexpression of mutant JAK1 did not transform primary murine cells in standard assays, but compared with wild-type JAK1, JAK1^T478S, and JAK1^V623A expression was associated with increased STAT1 activation in response to type I interferon and activation of multiple downstream signaling pathways. This is the first report to demonstrate somatic JAK1 mutations in AML and suggests that JAK1 mutations may function as disease-modifying mutations in AML pathogenesis.     

Mindfulness meditation training alters stress-related amygdala resting state functional connectivity: a randomized controlled trial

Recent studies indicate that mindfulness meditation training interventions reduce stress and improve stress-related health outcomes, but the neural pathways for these effects are unknown. The present research evaluates whether mindfulness meditation training alters resting state functional connectivity (rsFC) of the amygdala, a region known to coordinate stress processing and physiological stress responses. We show in an initial discovery study that higher perceived stress over the past month is associated with greater bilateral amygdala-subgenual anterior cingulate cortex (sgACC) rsFC in a sample of community adults (n = 130). A follow-up, single-blind randomized controlled trial shows that a 3-day intensive mindfulness meditation training intervention (relative to a well-matched 3-day relaxation training intervention without a mindfulness component) reduced right amygdala-sgACC rsFC in a sample of stressed unemployed community adults (n = 35). Although stress may increase amygdala-sgACC rsFC, brief training in mindfulness meditation could reverse these effects. This work provides an initial indication that mindfulness meditation training promotes functional neuroplastic changes, suggesting an amygdala-sgACC pathway for stress reduction effects.