Inhibition of vascular endothelial growth factor in young adult mice causes low bone blood flow and bone strength with no effect on bone mass in trabecular regions.

OBJECTIVE: To determine the effect of an antibody to vascular endothelial growth factor (VEGF) on bone blood flow, bone strength, and bone mass in the young adult mouse. METHODS: Ten-week-old male BALB/cJ mice were body weight-randomized into either a rodent anti-VEGF monoclonal antibody (anti-VEGF, B20-4.1.1; 5 mg/kg 2×/wk.; n = 12) group or a vehicle (VEH; n = 12) group. After 42 days, mice were evaluated for bone blood flow at the distal femur by 18F-NaF-PET/CT and then necropsied. Samples from trabecular and cortical bone regions were evaluated for bone strength by mechanical testing, bone mass by peripheral quantitative computed tomography (pQCT), and micoarchitecture (MicroCT). Hydration of the whole femur was studied by proton nuclear magnetic resonance relaxometry (1H NMR). RESULTS: Distal femur blood flow was 43% lower in anti-VEGF mice than in VEH mice (p = 0.009). Ultimate load in the lumbar vertebral body was 25% lower in anti-VEGF than in VEH mice (p = 0.013). Bone mineral density (BMD) in the trabecular region of the proximal humeral metaphysis by pQCT, and bone volume fraction and volumetric BMD by MicroCT were the same in the two groups. Volume fraction of bound water (BW) of the whole femur was 14% lower in anti-VEGF than in VEH mice (p = 0.003). Finally, BW, but not cortical tissue mineral density, helped section modulus explain the variance in the ultimate moment experienced by the femur in three-point bending. CONCLUSION: Anti-VEGF caused low bone blood flow and bone strength in trabecular bone regions without influencing BMD and microarchitecture. Low bone strength was also associated with low bone hydration. These data suggest that bone blood flow is a novel bone property that affects bone quality.

Osteoarthritis year in review 2016: clinical.

Both epidemiologic and clinical research continues to be performed in osteoarthritis (OA). While epidemiologic studies identify risk factors for incident and progressive disease, clinical studies explore the role of both non-pharmacologic and pharmacologic treatments, including oral and intra-articular therapies. We performed a systematic review of the literature using PubMed for the time period between April 1, 2015 to February 22, 2016. Selected publications in the areas of both epidemiology and treatment are reviewed in this article.

Mortality and cause of death in Japanese patients with rheumatoid arthritis based on a large observational cohort, IORRA.

OBJECTIVES: To investigate mortality, cause of death, and risk factors related to mortality in Japanese patients with rheumatoid arthritis (RA). METHODS: The IORRA cohort is a large observational cohort established in 2000 at the Institute of Rheumatology, Tokyo Women's Medical University. Essentially, all RA patients were registered and clinical parameters were assessed biannually. For patients who failed to participate in subsequent surveys, simple queries were mailed to confirm survival. Standardized mortality ratios (SMRs) were calculated and mortality risk factors were analysed using a Cox proportional hazard model. RESULTS: We analysed 7926 patients (81.9% females; mean age 56.3 ± 13.1 years; mean disease duration 8.5 ± 8.3 years) with RA who enrolled in IORRA from October 2000 to April 2007. During the observational period (35 443.0 person-years), 289 deaths were reported. Major causes of death included malignancies (24.2%), respiratory involvement (24.2%) including pneumonia (12.1%) and interstitial lung disease (ILD) (11.1%), cerebrovascular disease (8.0%), and myocardial infarction (7.6%). As death was not confirmed in all patients, the SMR was deduced to be between 1.46 [95% confidence interval (CI) 1.32-1.60] and 1.90 (95% CI 1.75-2.07) for all patients, between 1.45 (95% CI 1.22-1.70) and 1.70 (95% CI 1.45-1.97) for men, and between 1.46 (95% CI, 1.29-1.65) and 2.02 (95% CI 1.82- 2.24) for women. Factors associated with increased mortality included male gender, older age, worse physical disability, positive rheumatoid factor (RF), corticosteroid use, and presence of ILD. CONCLUSION: The mortality of Japanese RA patients is comparable to that in previous reports from western countries, even though the causes of death were significantly different.

High frequency of p53 abnormality in laryngeal cancers of heavy smokers and its relation to human papillomavirus infection.

A series of 41 laryngeal squamous cell carcinomas was examined for p53 abnormalities and human papillomavirus (HPV) infection by an immunohistochemical and/or molecular approach. Immunohistochemically, p53 over-expression was observed in about 60% of the cancers, of which 12 were revealed to contain point mutations of p53 by a combination of the single-strand conformational polymorphism technique and direct sequencing. The p53 point mutations ranged from codons 157 to 278 and most of these mutations lay in two "hot spots" (codon 157 in four cancers and codon 248 in three cancers). The majority of p53 mutations, both transversions (seven cancers) and transitions (five cancers), occurred at the G nucleotide of the codons. An analysis of the clinical information indicated that p53 point mutation was frequently observed in heavy smokers with an average Brinkman index score of more than 1000. On the other hand, HPV DNA, type 16 or 18, was detected in a quarter of the laryngeal cancers. Of eleven HPV-positive cases, nine were immunohistochemically positive for p53, of which four contained a p53 point mutation. These results suggested no inverse relation between p53 mutation and HPV infection in laryngeal cancers. Our study indicates that p53 abnormalities are related to smoking history and the correlation might be better for smoking and chemical mutagenesis than for HPV.

Lack of synergistic association between human papillomavirus and ras gene point mutation in laryngeal carcinomas.

The spectrum of human papillomavirus (HPV) subtypes in laryngeal carcinomas was investigated by combined polymerase chain reaction (PCR) and restriction fragment length polymorphism analysis. HPV DNA was detected in 11 (24%) of 45 cases, including HPV 16 in 9 cases and HPV 18 in 2 cases. Other HPV subtypes commonly found in the female genital organs were not detected. In addition, the point mutation of codons 12 and 13 in c-Ki-ras-2, c-Ha-ras-1, and N-ras genes was studied by the PCR-single-strand conformational polymorphism (SSCP) method. Of 45 cases tested, only 1 had a point mutation of c-Ki-ras-2 gene at codon 12. These results indicate that the incidence of ras gene point mutation is uncommon and that the synergistic effect of HPV infection and ras gene activation in laryngeal carcinogenesis is probably rare.

Two cases of nasopharyngeal branchial cyst.

Two cases of nasopharyngeal cyst, in a two-year-old girl and a six-year-old boy, are described. The cysts were located in the right lateral wall of the nasopharynx in both cases. Histopathological examinations revealed that the cyst walls were lined with columnar epithelium. The positions of the cysts and pathological features indicated that they were of branchial origin, and they were assumed to originate in the second branchial pouch because of their anatomic location. They differed from previously reported cases in that they extended nearly to the base of the skull, occupying the parapharyngeal space. It was considered that they might have originated from the dorsal part of the second branchial pouch or the layer of endodermal cells cut off from the lower part of the eustachian tube.