Genetic factors influencing the risk of multiple myeloma bone disease.

A major complication of multiple myeloma (MM) is the development of osteolytic lesions, fractures and bone pain. To identify genetic variants influencing the development of MM bone disease (MBD), we analyzed MM patients of European ancestry (totaling 3774), which had been radiologically surveyed for MBD. Each patient had been genotyped for ~6 00 000 single-nucleotide polymorphisms with genotypes for six million common variants imputed using 1000 Genomes Project and UK10K as reference. We identified a locus at 8q24.12 for MBD (rs4407910, OPG/TNFRSF11B, odds ratio=1.38, P=4.09 × 10(-9)) and a promising association at 19q13.43 (rs74676832, odds ratio=1.97, P=9.33 × 10(-7)). Our findings demonstrate that germline variation influences MBD and highlights the importance of RANK/RANKL/OPG pathway in MBD development. These findings will contribute to the development of future strategies for prevention of MBD in the early precancerous phases of MM.

Significance of minimal or no intraperitoneal fluid visible on CT scan associated with blunt liver and splenic injuries: a multicenter analysis.

BACKGROUND: The use of ultrasound (U/S) for the evaluation of patients with blunt abdominal trauma is gaining increasing acceptance. Patients who would have undergone computed tomographic (CT) scan may now be evaluated solely with U/S. Solid organ injuries with minimal or no free fluid may be missed by surgeon sonographers. OBJECTIVE: The purpose of this study was to describe the incidence and clinical importance of liver and splenic injuries with minimal or no free intraperitoneal fluid visible on CT scan. We hypothesized that these solid organ injuries occur infrequently and are of minor clinical significance. METHODS: Patient records and CT scans were reviewed for the presence of and outcome associated with blunt liver and splenic injuries with minimal (<250 mL) or no free fluid detected by an attending radiologist. Data were collected from six major trauma centers during a 4-year period before the introduction of U/S and included demographics, grade of injury (American Association for the Surgery of Trauma scale), need for operative intervention, and outcome. RESULTS: A total of 938 patients with liver and splenic injuries were identified. In this group, 11% of liver injuries and 12% of splenic injuries had no free fluid visible on CT scan and could be missed by diagnostic peritoneal lavage or U/S. Of the 938 patients, 267 (28%) met the inclusion criteria; 161 had injury to the spleen and 125 had injury to the liver. In the 267 patients studied, 97% of the injuries were managed nonoperatively. However, 8 patients (3%) required operative intervention for bleeding. Compared with the liver, the spleen was significantly more likely to bleed (p = 0.01), but the grade of splenic injury was not related to the risk for hemorrhage (p = 0.051). CONCLUSION: Data from this study suggest that injuries to the liver or spleen with minimal or no intraperitoneal fluid visible on CT scan occur more frequently than predicted but usually are of minimal clinical significance. However, patients with splenic injuries may be missed by abdominal U/S. We found a 5% associated risk of bleeding. Therefore, abdominal U/S should not be used as the sole diagnostic modality in all stable patients at risk for blunt abdominal injury.

Overexpression of nerve growth factor in skin increases sensory neuron size and modulates Trk receptor expression.

Sensory neuron development and differentiation is dependent on a family of growth factors known as neurotrophins. Neurotrophins modulate neuron development via trk tyrosine kinase receptor proteins trkA, trkB and trkC. To determine how elevated levels of a target-derived neurotrophin might affect neuronal differentiation, we analysed trk expression in the trigeminal ganglion of transgenic mice that overexpressed nerve growth factor (NGF) in the skin. Increased levels of NGF caused a five-fold increase in neurons expressing trkA mRNA and a two-fold increase in neurons expressing trkC. In control mice, cell size distributions of neuronal subpopulations expressing each trk mRNA showed the three subpopulations distributed over a narrow, overlapping range. In contrast, cell size distribution in NGF-transgenic mice was significantly divergent due in large part to hypertrophy of trkA neurons and, to a lesser extent, trkC neurons. In addition, we examined neurons that bound the isolectin B4 from Bandeiraea simplicifolia (BS-IB4) because most of these neurons do not express any trk receptor in the adult. There was a significant increase in the size of BS-IB4-positive neurons in transgenic mice; however, there was no increase in their number. These studies indicate that an increased level of target-derived NGF affects the development of sensory neurons that in the adult express trkA or trkC, as well as neurons that do not express trk receptors.

Expression of an epidermal keratin protein in liver of transgenic mice causes structural and functional abnormalities.

To examine the role of keratin intermediate filament proteins in cell structure and function, transgenic mice were isolated that express a modified form of the human K14 keratin protein in liver hepatocytes. A modified K14 cDNA (K14.P) sequence was linked downstream of the mouse transthyretin (TTR) gene promoter and enhancer elements to achieve targeted expression in hepatocytes. Hepatocytes expressing high levels of the transgene were found to have abnormal keratin filament networks as detected by indirect immunofluorescence using an antibody specific for the transgene product. Light and electron microscopic level histological analysis of isolated liver tissue showed in many cases degenerative changes that included inflammatory infiltration, ballooning degeneration, an increase in fat containing vacuoles, and glycogen accumulation. These changes were most evident in older mice over four months of age. No indication of typical Mallory body structures were identified at either the light or electron microscopic level. To evaluate secretory function in transgenic livers, bile acid secretion rates were measured in isolated perfused liver and found to be approximately twofold lower than aged-matched controls. These findings indicate that expression of an abnormal keratin in liver epithelial cells in the in vivo setting can alter the structure and function of a tissue and suggest a role of the keratin network in cellular secretion.