Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin [published erratum appears in Hum Mol Genet 1999 May;8(5):943]

Huntington's disease (HD) is an inherited, neurodegenerative disorder caused by the expansion of a glutamine repeat in the N-terminus of the huntingtin protein. To gain insight into the pathogenesis of HD, we generated transgenic mice that express a cDNA encoding an N-terminal fragment (171 amino acids) of huntingtin with 82, 44 or 18 glutamines. Mice expressing relatively low steady-state levels of N171 huntingtin with 82 glutamine repeats (N171-82Q) develop behavioral abnormalities, including loss of coordination, tremors, hypokinesis and abnormal gait, before dying prematurely. In mice exhibiting these abnormalities, diffuse nuclear labeling, intranuclear inclusions and neuritic aggregates, all immunoreactive with an antibody to the N-terminus (amino acids 1-17) of huntingtin (AP194), were found in multiple populations of neurons. None of these behavioral or pathological phenotypes were seen in mice expressing N171-18Q. These findings are consistent with the idea that N-terminal fragments of huntingtin with a repeat expansion are toxic to neurons, and that N-terminal fragments are prone to form both intranuclear inclusions and neuritic aggregates.      

Significance of short tau inversion recovery magnetic resonance sequence in the management of skeletal injuries

The conventional radiographs and urgent short tau inversion recovery (STIR) magnetic resonance image (MRI) examinations of 27 consecutive patients with occult bony injuries were prospectively analysed over a 12 month period. A STIR MRI study was undertaken where the plain films were normal (n=15) or inconclusive (n=12) and where the patients’clinical setting was highly suggestive of an underlying bony injury. In six patients, MRI only revealed soft-tissue injuries or joint effusions and did not demonstrate any bony injury but in the remainder fractures or bone contusions were shown to be present. The MRI studies were performed on a 0.2 Tesla lower field strength unit and the examinations were expeditiously performed, inexpensive, and done on a priority basis between electively booked patients. Radio-isotope studies were not available and hence were not included in the study protocol. Apart from demonstrating the value of STIR MRI (without additional T1-weighted sequences in most patients), the purpose of this study was to highlight the alteration in management in 18/27 patients (66%) and the significant alteration in management in six of these patients.     

Fluorescein labeling of lymphatic vessels for lymphangiography

A simple technique for identification of pedal lymphatic vessels for lymphangiography was developed. A fluorescein-lidocaine mixture is injected subcutaneously into the foot, and within 20 minutes, local lymphatic vessels absorb the solution and fluoresce vividly under ultraviolet light. These labeled lymphatic channels are readily isolated and cannulated. The technique has proved highly successful, with no documented allergic complications after use in more than 1,000 cases.     

Metastic tumor presenting as intracerebral hemorrhage. Report of 6 cases examined by computed tomography

Six patients with intracranial metastases were studied with computed tomography (CT). The initial appearance suggested cerebral hemorrhage. Atypical location, contrast enhancement, or multiplicity proved helpful in differentiating tumors from other causes of intracerebral hemorrhage. Four patients showed contrast enhancement and 3 had multiple lesions. Metastases with associated intracerebral hematoma may simulate a spontaneous hematoma.     

Stage I Adenocarcinoma of the Uterine Cervix: Tumour Size, Grade, Lymph Node Metastases and 5-Year Survival

This study includes 22 cases of Stage I cervical adenocarcinoma. The lymph node metastases and 5-year survival according to the size of lesion and grade of tumour were evaluated. The overall pelvic and para-aortic lymph node metastases were found to be 31.8% and 0% respectively. Metastases in the pelvic lymph nodes were found in 16.6% of patients with lesions less than 2 cm and 50.0% of patients with lesions 2 cm or greater in size. Pelvic lymph node metastases were found to be 0% for Grade 1, 25% for Grade 2 and 46% for Grade 3 tumours. The overall 5-year survival was 68.2%. This figure varied from 60% to 75% according to the size of lesion and from 61.5% to 100% according to the grade of tumour.     

Osteochondritis dissecans: analysis of mechanical stability with radiography, scintigraphy, and MR imaging

Twenty-one joints with stable (n = 9) or loose (n = 12) osteochondritis dissecans (OCD) lesions were examined in 15 subjects with plain radiography, three-phase bone scintigraphy, and magnetic resonance (MR) imaging. The lesion size and the thickness of the sclerotic margin as measured on plain radiographs were good parameters for predicting loosening. However, bone scintigraphy was more sensitive and specific in determining the mechanical stability of OCD lesions. MR imaging permitted direct visualization of loosening and fragment displacement; the latter permits differentiation of in situ loosening from a grossly unstable lesion. The noninvasive nature of bone scintigraphy and MR imaging makes them potentially preferable diagnostic modalities to arthrography for evaluating the mechanical status of OCD lesions.     

Some properties of proteolysis by polymorphonuclear leukocyte-granule extracts.

The extracts of granules of human polymorphonuclear leukocytes hydrolyzed a variety of proteins including human and bovine hemoglobin, human fibrinogen, human and bovine serum albumin, bovine elastin, and casein. The hydrolysis of all the proteins except fibrinogen and elastin was increased by addition of urea. Various inhibitors of trypsin, kallikrein, plasmin, Clr, Cls, and other proteolytic enzymes had no inhibitory effect. Slight inhibition was observed with polyanethol sulfonate and strong inhibition with normal human serum. Serum of patients with hereditary angioneurotic edema having no functional C1-esterase inhibitor was as effective in inhibiting the proteolysis as normal serum. The inhibitor was localized in 4S fractions of normal serum fractionated on Sephadex G-200. Fractionation of normal serum by ammonium sulfate precipitation, Sephadex G-200 filtration, and CM-Sephadex chromatography did not result in appearance of inhibitory activity in more than one protein peak, suggesting the possibility that only one inhibitor might be responsible. Since all fractions which contained the inhibitor of proteolysis also contained alpha1-antitrypsin, since sera of patients having low alpha1-antitrypsin levels contained less inhibitory activity, and since antibodies against alpha1-antitrypsin reversed the inhibition obtained from normal serum, the inhibition of proteolysis may be attributed to alpha1-antitrypsin.     

Predictive and prognostic biomarkers for targeted therapy in metastatic colorectal cancer

The use of targeted biologic agents in combination with chemotherapy has increased the overall survival (OS) of metastatic colorectal cancer (mCRC) to 23.5 months. With the assistance of Kirsten-ras (KRAS) mutational status, the subgroup population resistant to the inhibition of epidermal growth factor receptor (EGFR) by monoclonal antibodies (MoAbs) can be identified. However, only up to a third of the KRAS wild-type subpopulation respond to EGFR inhibition. Multiple factors, including relatively low response rates and high costs for targeted agents, are driving the search to identify further biomarkers within the EGFR/Ras/Raf/Mek/Erk and PTEN/PIP3/AKT signaling pathways. Vascular endothelial growth factor (VEGF) is a key player in tumor angiogenesis and the target for the MoAb bevacizumab, which is currently licensed for use in mCRC. Despite numerous studies, an equivalent predictive biomarker for bevacizumab has not been identified. Preclinical work indicates that inhibition of the insulin growth factor receptor (IGFR) pathway stops cellular transformation and tumor regression, thus identifying this pathway as a strong potential target for anticancer drug development and the identification of novel biomarkers. This review focuses on research relating to the roles of biomarkers within the EGF, VEGF, and IGF receptor pathways. The molecules KRAS, BRAF, NRAS, PTEN, PIP3, VEGF, IGF-1R, and IGF binding protein 3 are discussed. Currently, KRAS is the only biomarker used in clinical practice for mCRC. Pending the results of ongoing and future studies, additional biomarkers will be tested, tailoring our approach to targeted therapy in mCRC.