Clonal competition with alternating dominance in multiple myeloma

Emerging evidence indicates that tumors can follow several evolutionary paths over a patient's disease course. With the use of serial genomic analysis of samples collected at different points during the disease course of 28 patients with multiple myeloma, we found that the genomes of standard-risk patients show few changes over time, whereas those of cytogenetically high-risk patients show significantly more changes over time. The results indicate the existence of 3 temporal tumor types, which can either be genetically stable, linearly evolving, or heterogeneous clonal mixtures with shifting predominant clones. A detailed analysis of one high-risk patient sampled at 7 time points over the entire disease course identified 2 competing subclones that alternate in a back and forth manner for dominance with therapy until one clone underwent a dramatic linear evolution. With the use of the Vk*MYC genetically engineered mouse model of myeloma we modeled this competition between subclones for predominance occurring spontaneously and with therapeutic selection.     

Status of confocal laser endomicroscopy in gastrointestinal disease

Confocal laser endomicroscopy (CLE) is an advanced imaging technique which combines conventional white light endoscopy (WLE) with an integrated or probe based confocal microscope. This allows microscopic examination of the surface epithelium and in vivo diagnosis during endoscopy. Established CLE applications include the diagnosis of Barrett's oesophagus, gastric intestinal metaplasia, coeliac disease and microscopic colitis. CLE can differentiate hyperplastic from adenomatous polyps in the colon and may obviate the need to biopsy all polyps at endoscopy. CLE is particularly helpful in surveillance endoscopy in inflammatory bowel disease where it has been shown to reduce the number of biopsies required and improve the detection of dysplasia. The future of CLE may be with new contrast agents to allow for molecular tagging and improved endoscopic diagnoses. The aim of this review is to describe the technology and techniques involved in CLE, and discuss the evolving applications in obtaining "virtual biopsy" throughout the GI tract.     

Immunological control of herpes simplex virus infections

Herpes simplex virus type 1 (HSV-1) is capable of causing a latent infection in sensory neurons that lasts for the lifetime of the host. The primary infection is resolved following the induction of the innate immune response that controls replication of the virus until the adaptive immune response can clear the active infection. HSV-1-specific CD8⁺ T cells survey the ganglionic regions containing latently infected neurons and participate in preventing reactivation of HSV from latency. The long-term residence and migration dynamics of the T cells in the trigeminal ganglia appear to distinguish them from the traditional memory T cell subsets. Recently described tissue resident memory (T_RM) T cells establish residence and survive for long periods in peripheral tissue compartments following antigen exposure. This review focuses on the immune system response to HSV-1 infection. Particular emphasis is placed on the evidence pointing to the HSV-1-specific CD8⁺ T cells in the trigeminal belonging to the T_RM class of memory T cells and the role of T_RM cells in virus infection, pathogenesis, latency, and disease.     

Non-invasive imaging of the crystalline structure within a human tooth

The internal crystalline structure of a human molar tooth has been non-destructively imaged in cross-section using X-ray diffraction computed tomography. Diffraction signals from high-energy X-rays which have large attenuation lengths for hard biomaterials have been collected in a transmission geometry. Coupling this with a computed tomography data acquisition and mathematically reconstructing their spatial origins, diffraction patterns from every voxel within the tooth can be obtained. Using this method we have observed the spatial variations of some key material parameters including nanocrystallite size, organic content, lattice parameters, crystallographic preferred orientation and degree of orientation. We have also made a link between the spatial variations of the unit cell lattice parameters and the chemical make-up of the tooth. In addition, we have determined how the onset of tooth decay occurs through clear amorphization of the hydroxyapatite crystal, and we have been able to map the extent of decay within the tooth. The described method has strong prospects for non-destructive probing of mineralized biomaterials.     

Destination healthcare facility of patients with suspected traumatic brain injury in Scotland: Analysis of pre-hospital data

Background

Traumatic brain injury is common. Guidelines from the Brain Trauma Foundation and the Scottish Intercollegiate Guidelines Network recommend that patients with suspected severe traumatic brain injury should be treated in centres with neurosurgical expertise. Scotland does not have a framework for the delivery of trauma care. The aim of this study was to examine the demographic characteristics of incidents involving patients who have suffered a suspected traumatic brain injury, and to evaluate the level of the destination healthcare facility which patients are currently taken to.

Methods

Retrospective analysis of prospectively collected Scottish Ambulance Service data on incidents involving traumatic injury, between Nov 2008 and Oct 2010. Two groups of casualties were analysed: those who had a Glasgow coma scale of less than 14 (GCS < 14), and those who had a Glasgow coma scale of less than 9 (GCS < 9).

Results

126,934 incidents were identified and analysed. 3890 (3.1%) patients had a GCS of less than 14, and 657 (0.5% of total) had a GCS of less than 9. Almost one-third of incidents involving patients with either a GCS < 14 or GCS < 9 occurred in the greater Glasgow health board area. The Lothian health board region had the second-highest number of patients with either a GCS < 14 or GCS < 9. Only 13.8% of patients with a GCS < 14, and 16.7% of those with a GCS < 9, were taken to a hospital with a neurosurgical service.

Conclusions

Many patients who may harbour a traumatic brain injury are taken to a facility which may not be equipped or staffed to deal with such injuries. This mismatch needs to be addressed. However, the care of patients with head injuries is only one aspect of trauma care. The UK has long lagged behind North America in terms of the quality of trauma care provided, although the provision of trauma care in England is currently undergoing major changes. Scotland should consider the development of a similar service delivery framework.     

Age-related changes in mouse taste bud morphology, hormone expression, and taste responsivity

Normal aging is a complex process that affects every organ system in the body, including the taste system. Thus, we investigated the effects of the normal aging process on taste bud morphology, function, and taste responsivity in male mice at 2, 10, and 18 months of age. The 18-month-old animals demonstrated a significant reduction in taste bud size and number of taste cells per bud compared with the 2- and 10-month-old animals. The 18-month-old animals exhibited a significant reduction of protein gene product 9.5 and sonic hedgehog immunoreactivity (taste cell markers). The number of taste cells expressing the sweet taste receptor subunit, T1R3, and the sweet taste modulating hormone, glucagon-like peptide-1, were reduced in the 18-month-old mice. Concordant with taste cell alterations, the 18-month-old animals demonstrated reduced sweet taste responsivity compared with the younger animals and the other major taste modalities (salty, sour, and bitter) remained intact.     

Efficacy predictors of lung volume reduction with Zephyr valves in a European cohort

The Endobronchial Valve for Emphysema Palliation Trial (VENT) was a multi-centre, prospective, randomised, controlled trial conducted to evaluate the safety and effectiveness of unilateral endobronchial valve (EBV) treatment. The purpose of this analysis was to assess outcomes in the previously unreported European VENT study cohort. Patients with advanced emphysema were randomly assigned (2:1) to receive Zephyr? (Pulmonx Inc., Redwood City, CA, USA) EBV treatment (n = 111) or medical management (n = 60). At 6 months, EBV patients demonstrated a significant improvement compared with the controls for mean ± SD change in forced expiratory volume in 1 s (7 ± 20% versus 0.5 ± 19%; p = 0.067), cycle ergometry (2 ± 14 W versus -3 ± 10 W; p = 0.04) and St George's Respiratory Questionnaire (-5 ± 14 points versus 0.3 ± 13 points; p = 0.047). At 12 months, the magnitude of the difference between groups for change from baseline was of similar magnitude to the differences seen at 6 months. Rates for complications did not differ significantly. EBV patients with computed tomography (CT) scans suggestive of complete fissure and lobar occlusion had a mean ± SD lobar volume reduction of -80 ± 30% and >50% met minimal clinical difference thresholds. The degree of emphysema heterogeneity did not preclude excellent outcomes. Unilateral lobar volume reduction using EBV treatment is safe and superior clinical results correlated with CT suggestive of complete fissures and successful lobar occlusion. Emphysema heterogeneity was not critical for determining positive outcomes.     

Charlson Co‐morbidity Index and albumin significantly associated with fracture risk in peritoneal dialysis patients

Published literature on fracture in dialysis patients seldom addressed the effect of co‐morbidity and malnutrition. In this study, we reported the incidence and risk factors for fracture in peritoneal dialysis patients. Peritoneal dialysis patients who had fractures between 2006 and 2011 were recruited. Demographic data, details of fracture, Charlson Co‐morbidity Index (CCI) and biochemical parameters were also collected. Non‐fracture controls, matched for age, gender and duration of dialysis, were also recruited at ratio 1:1 for fracture risk analysis. The incidence of fracture was 1 in 37 patient‐years. The commonest site of fracture was neck of femur (n = 16, 55.2%). Twenty‐four patients (82.8%) developed fracture after slip and fall injury. Eight out of 17 self‐ambulatory patients (47.1%) became non‐ambulatory after fracture. Infection was the commonest complication during hospitalization. Univariant analysis demonstrated high CCI (P = 0.001), hypoalbuminaemia (P < 0.001), loss of self autonomy (P = 0.006) and non‐ambulatory state (P = 0.011) significantly associated with increased fracture risk. However, only CCI (odds ratio (OR) 1.373, P = 0.028) and albumin (OR 0.893, P = 0.025) increased fracture risk significantly on multivariant analysis. Bone profile and parathyroid hormone were not significant risk factors. To conclude, fracture associated with adverse outcome in peritoneal dialysis patients. High CCI score and hypoalbuminaemia significantly increase risk of fracture.     

Lumbar lordosis and pelvic inclination in adults with chronic low back pain

BACKGROUND AND PURPOSE: The causes of lumbopelvic imbalances in standing have been widely accepted by physical therapists, but there is a lack of scientific evidence available to support them. We examined the association between 9 variables and pelvic inclination and lumbar lordosis during relaxed standing. SUBJECTS: Thirty men and 30 women with chronic low back pain (CLBP) for at least 4 months were examined (mean age=54.9 years, SD=9, range=40.4-69.8). METHODS: Multiple linear regression modeling was used to assess the association of pelvic inclination and the magnitude of lumbar lordosis in standing with age, sex, body mass index (BMI), Oswestry Back Pain Disability Questionnaire (ODQ) scores, physical activity level, hip flexor muscle length, abdominal muscle force, and range of motion (ROM) for lumbar flexion and extension. RESULTS: In women, age, BMI, and ODQ scores were associated univariately and multivariately with pelvic inclination. In men, lumbar extension ROM was related univariately to pelvic inclination; age, lumbar extension ROM, and ODQ scores were associated multivariately. Lumbar lordosis was associated univariately with only lumbar extension ROM for women and men. A weak correlation was found between angle of pelvic inclination and magnitude of lumbar lordosis in standing (r=. 31 for women, r=.37 for men). CONCLUSION AND DISCUSSION: The odds ratio of having CLBP is increased if the score on the double-leg lowering test for abdominal muscles exceeds 50 degrees for men and 60 degrees for women. In patients with CLBP, the magnitude of the lumbar lordosis and pelvic inclination in standing is not associated with the force production of the abdominal muscles.