Prognosis in DNA Mismatch Repair Deficient Colorectal Cancer: are all MSI Tumours Equivalent?

Microsatellite instability (MSI) in colorectal tumours is the hallmark of defective DNA mismatch repair (MMR) and high level MSI can be detected in up to 15% of incident colorectal cancers. MSI in sporadic colorectal tumours is primarily due to epigenetic silencing of MLH1 while MSI is almost universal in tumours from HNPCC family members due to germline MMR gene mutation with loss or mutational inactivation of the second copy as a somatic event. There is evidence that tumour MSI is associated with a better outcome than the generality of large bowel malignancy. However, although MSI occurs in both sporadic colorectal cancer and in tumours arising in patients with germline MMR gene mutations, cancer survival should not be considered to be equivalent for these two groups with MSI tumours simply because both exhibit similarities in molecular phenotype. Here, we review the evidence on prognosis in patients with sporadic MSI tumours compared to those who have inherited a germline DNA MMR repair gene defect. In addition, we explore whether there are variables that afford opportunity to distinguish three groups on the basis of MSI status, namely: sporadic MSI tumours; MSI tumours in carriers of germline MMR gene defects; microsatellite stable (MSS) tumours. Differences in prognosis between these three groups is important because it underpins the rationale for surveillance and early identification of tumours in MMR gene carriers, as well as refining understanding of the influence of MSI on cancer progression. Furthermore, we discuss the effect of MSI on the effectiveness of chemotherapy regimens.     

Hypopituitarism following cerebral oedema with diabetic ketoacidosis

Clinical evidence of cerebral oedema occurs in approximately 1% of diabetic ketoacidosis episodes. Mortality from this serious complication is falling, but little is known of long term outcome. We describe hypopituitarism and executive dysfunction developing two years after cerebral oedema complicating diabetic ketoacidosis in a 12 year old with type 1 diabetes.     

Utilization across the continuum of long-term care services

PURPOSE: This study presents an analysis of the influence of consumers' predisposing, enabling, and need characteristics on the utilization of long-term care (LTC) services in nursing facilities (NFs), assisted living facilities, or home- and community-based services (HCBS). DESIGN AND METHODS: Data were gathered through a record review of a cross-sectional sample of 1,968 consumers aged 60 years or older receiving formal LTC services. RESULTS: Need contributes the most to differential LTC use. Those with the most need are more likely to be in a NF or HCBS. Enabling characteristics such as Medicaid eligibility and geopolitical region of the state were associated with higher use of NFs. Predisposing and enabling characteristics had a moderating influence on need. IMPLICATIONS:Although high need predicts care in NFs, some of the most impaired elders are also being cared for at home. Because Medicaid increases the likelihood of NF placement, public financing of LTC should reflect the capacity of the system to serve elders at home.     

Training on a visual task improves the outcome of optic nerve regeneration

Optic nerve regeneration in a lizard, Ctenophorus ornatus, is dysfunctional despite survival of most retinal ganglion cells and axon regeneration to the optic tectum. The regenerated retino-tectal projection at 6 months has crude topography but by 1 year is disordered; visually-elicited behavior is absent via the experimental eye. Here, we assess the influence of training on the outcome of optic nerve regeneration. Lizards were trained to catch prey presented within the monocular field of either eye. One optic nerve was then severed and visual stimulation resumed throughout regeneration. In the trained group, presentation was restricted to the eye undergoing optic nerve regeneration; for the untrained group, the unoperated eye was stimulated. Pupil responses returned in trained but not in untrained animals. At 1 year, trained animals oriented to and captured prey; untrained animals demonstrated minimal orienting and failed to capture prey. Regenerated retino-tectal projections were topographic in the trained but not in the untrained group as assessed by in vitro electrophysiological recording and by carbocyanine dye tracing. In vitro electrophysiological recording during application of neurotransmitter antagonists to the tectum revealed that the level of GABAergic inhibition was modest in trained animals but elevated in the untrained group; responses were mainly AMPA-mediated in both groups. We conclude that training improves the behavioral outcome of regeneration, presumably by stabilizing and refining the transient retino-tectal map and preventing a build-up of tectal inhibition. The results suggest that for successful central nerve regeneration to occur in mammals, it may be necessary to introduce training to complement procedures stimulating axon regeneration.     

Patient satisfaction and functional status after treatment of infection at the site of a total knee arthroplasty with use of the PROSTALAC articulating spacer

BACKGROUND: Two-stage exchange arthroplasty remains the standard treatment of infection at the site of a total knee arthroplasty. The clinical and functional outcomes associated with the use of an articulating antibiotic spacer for two-stage revision for infection are not well established. We conducted a retrospective study to evaluate the outcomes associated with the use of the PROSTALAC articulating spacer between the first and second stages. METHODS: Fifty-eight patients underwent two-stage revision total knee arthroplasty for infection between January 1997 and December 1999. Of these, fifty-four were alive at the time of follow-up and forty-seven were available for inclusion in the present retrospective study. In all patients, a prosthesis of antibiotic-loaded acrylic cement (the PROSTALAC system) was implanted during the first stage after débridement. The amount of osteolysis that occurred between the stages and the range of motion of the knee joint were measured. After two years of follow-up, outcomes were assessed with use of the WOMAC, Oxford-12, and SF-12 instruments as well as a satisfaction questionnaire. RESULTS: At a minimum of two years (average, forty-one months) after revision arthroplasty, two patients (4%) had had a recurrence of infection. The amount of bone loss was unchanged between stages, and the range of movement of the knee improved from 78.2 degrees before the first stage to 87.1 degrees at two years. The average normalized WOMAC function and pain scores were 68.9 and 77.1, respectively; the average Oxford-12 score was 67.3; the average SF-12 mental and physical scores were 53.7 and 41.2, respectively; and the average satisfaction score was 71.7. CONCLUSION: A revision operation for infection at the site of a total knee replacement with use of an articulating spacer was associated with reasonable function and satisfaction scores. These findings may be related to the articulating features of the PROSTALAC system, which permits full active movement of the knee in the early postoperative period.     

Functional calcium coupling with the human metabotropic glutamate receptor subtypes 2 and 4 by stable co-expression with a calcium pathway facilitating G-protein chimera in Chinese hamster ovary cells

The objective of the current study was to facilitate functional calcium assays, compatible with the fluorometric imaging plate reader platform, for the human metabotropic glutamate receptor (mGluR) subtypes 2 and 4, by co-expressing each receptor with a G-protein chimera comprising Galphaq with the C-terminal five amino acids replaced with those from Galphai3 (GqGi3). Transfection of GqGi3 into previously validated stable CHO cell lines expressing mGluR2 or mGluR4 allowed for the selection of new double transfectants in which application of L-glutamate and other mGluR agonists resulted in calcium coupling with a high signal:noise ratio (maximal changes in relative fluorescence units up to 20,000). The rank order of agonist potency for the stimulation of calcium mobilization in the mGluR2/GqGi3 stable cell line was LY354740>L-CCG-I=DCG-IV>L-glutamate>/=(2R,4R)-APDC>/=(1S,3R)-ACPD. In the mGluR4/GqGi3 stable cell line the rank order of agonist potency was L-AP4>L-SOP>/=ACPT-I=L-CCG-I>/=L-glutamate=(R,S)-PPG. By comparison, equivalent potency orders and a significant correlation in functional activities were observed when the same compounds were profiled in [35S]GTPgammaS binding assays for each mGluR subtype. These results validate the use of functional calcium assays, amenable to high-throughput applications on the fluorometric imaging plate reader, for the mGluR2 and mGluR4 subtypes when co-expressed in stable cell lines with the GqGi3 chimera.