Background: Anterior cruciate ligament (ACL) tears in the pediatric and young adult ACL-deficient knee are often associated with meniscal or chondral injury with delayed time to surgery. The incidence of ACL reconstruction performed in patients aged ≥40 years is rising, and it is unclear if delayed surgery in this cohort similarly affects the health of the meniscus and cartilage. Purpose: To evaluate whether delayed reconstruction in a cohort of patients aged ≥40 years is associated with an increased risk of meniscal or chondral injury. Study Design: Cohort study; Level of evidence, 3. Methods: Records of patients aged ≥40 years who underwent primary arthroscopic ACL reconstruction between 2012 and 2016 at an academic hospital were retrospectively reviewed. Patient characteristic data and time to surgery were recorded. Operative reports were analyzed for meniscal and chondral injuries as well as treatment. Patients were grouped according to time to surgery, defined as early (<90 days) or delayed (≥90 days). Logistic regression modeling was used to form associations between elapsed time to surgery and patient characteristics to meniscal and chondral damage. Additionally, risks for meniscal and chondral injury were analyzed at time points of 180 days and 1 year from injury to surgery. Results: A total of 227 patients met the study criteria: 106 patients underwent early surgery, and 121 underwent delayed surgery. The authors identified 127 medial meniscal tears and 106 lateral meniscal tears. Medial, lateral, and patellofemoral compartment chondral injury was reported in 127, 82, and 130 patients, respectively. Delayed surgery (≥90 days) was not associated with increased risk of medial or lateral meniscal tears or any chondral injury at 90 days. Each year of increased age was associated with an increased odds ratio: 1.09 ( P = .001) for medial meniscal tears, 1.06 ( P = .014) for lateral meniscal tears, 1.10 ( P = .001) for medial compartment chondral injuries, and 1.07 ( P = .007) for patellofemoral compartment chondral injuries. Additionally, each unit of increased body mass index was associated with an increased odds ratio: 1.09 ( P = .039) for medial meniscal tears and 1.14 ( P = .003) for medial compartment cartilage injury. Analysis of 180-day and 1-year time points revealed an increased risk (odds ratio, 3.47; 95% CI, 1.55-7.77; P = .002) for medial meniscal injury when surgery was delayed for >1 year. Conclusion: Delayed ACL reconstruction (≥90 days) among patients aged ≥40 years was not associated with an increased risk of meniscal or chondral injury. Increasing age and body mass index were associated with higher risks of meniscal and chondral injuries in this cohort. Delay in surgery for >1 year was associated with increased risk of medial meniscal tear.

Background Liquid nitrogen spray cryotherapy (LNSCT) has been shown to be a safe, well-tolerated, and effective therapy for Barrett’s esophagus (BE)-associated high grade dysplasia (BE-HGD) and intramucosal adenocarcinoma (IMC). Long-term follow-up is lacking. Aims The authors’ aim was to assess the efficacy, durability, and rate of neoplastic progression after LNSCT in BE-HGD/IMC at 3 and 5 years. Methods In this single-center, retrospective study drawn from a prospective database, patients with BE-HGD/IMC of any length treated with LNSCT were followed with surveillance endoscopy with biopsy for 3 to 5 years. Patients with intramucosal adenocarcinoma completely removed by endoscopic resection were included. Outcome measures included complete eradication of HGD (CE-HGD), dysplasia (CE-D), and intestinal metaplasia (CE-IM), incidence rates (IR), durability of response, location of recurrent IM and dysplasia, and rate of disease progression. Results 50 and 40 patients were included in 3-year and 5-year analyses. Initial CE-HGD, CD-D, and CE-IM were achieved in 98%, 90%, and 60%, respectively. Overall CE-HGD, CE-D, and CE-IM at 3 years were 96% (48/50), 94% (47/50), and 82% (41/50), and at 5 years were 93% (37/40), 88% (35/40), and 75% (30/40). IRs of recurrent IM, dysplasia, and HGD/esophageal adenocarcinoma per person-year of follow-up after initial CE-IM were 12.2%, 4.0%, and 1.4% per person-year for the 5-year cohort. Most recurrences were found immediately below the neosquamocolumnar junction. Two of 7 HGD recurrences occurred later than 4 years after initial eradication, and 2 patients (4%) progressed to adenocarcinoma despite treatment. Conclusion In patients with BE-HGD/IMC, LNSCT is effective in eliminating dysplasia and intestinal metaplasia. Progression to adenocarcinoma was uncommon, and recurrence of dysplasia was successfully treated in most cases. Long-term surveillance is necessary to detect late recurrence of dysplasia.

Reported frequencies for microsatellite instability (MSI) in oesophageal cancer differ widely in the literature, perhaps due to the high incidence of loss of heterozygosity (LOH) in this cancer. Using high-resolution fluorescent microsatellite analysis (HRFMA), we analysed microsatellite alterations in detail in 50 Japanese and 50 Chinese patients with squamous cell carcinoma in the oesophagus. In HRFMA, several devices have been developed to improve the detection characteristics, reproducibility of polymerase chain reaction and the migration accuracy of electrophoresis. All the alterations observed were separable into MSI, LOH and alterations ambiguous for both. MSI was rare in these panels of oesophageal carcinomas. The frequencies of MSI in the Japanese and Chinese subjects were 8 and 4%, respectively. All the alterations were mild (within 2 base pairs) and were observed in a limited number of markers. More drastic types of MSI, such as those typical in colorectal cancer, were not observed. On the other hand, the incidence of LOH was high, reaching 50% for the Japanese and 70% for the Chinese subjects. In many of these cases, LOH was observed in multiple microsatellite markers. The frequency of LOH in each marker was not apparently biased. Although in many cases MSI and LOH were clearly distinguished with use of the sensitive and quantitative fluorescent assay, theoretically indistinguishable patterns were noted in some cases. In conclusion, MSI is rare and LOH predominates in squamous cell carcinoma in the oesophagus.

The human BRD2 gene has been linked and associated with a form of common epilepsy and electroencephalographic abnormalities. Disruption of Brd2 in the mouse revealed that it is essential for embryonic neural development and that viable Brd2+/- heterozygotes show both decreased GABAergic neuron counts and increased susceptibility to seizures. To understand the molecular mechanisms by which mis-expression of BRD2 might contribute to epilepsy, we examined its regulation at multiple levels. We discovered that BRD2 expresses distinct tissue-specific transcripts that originate from different promoters and have strikingly different lengths of 5’ untranslated regions (5’UTR). We also experimentally confirmed the presence of a highly conserved, alternatively spliced exon, inclusion of which would result in a premature termination of translation. Downstream of this alternative exon is a polymorphic microsatellite (GT-repeats). Manipulation of the number of the GT-repeats revealed that the length of the GT-repeats affects the ratio of the two alternative splicing products. In vitro translation and expression in cultured cells revealed that among the four different mRNAs (long and short 5’UTR combined with regular and alternative splicing), only the regularly spliced mRNA with the short 5’UTR yields full-length protein. In situ hybridization and immunohistochemical studies showed that although Brd2 mRNA is expressed in both the hippocampus and cerebellum, Brd2 protein only can be detected in the cerebellar Purkinje cells and not in hippocampal cells. These multiple levels of regulation would likely affect the production of functional BRD2 protein during neural development and hence, its role in the etiology of seizure susceptibility.

BackgroundRadiation induced bystander effects are an important component of the overall response of cells to irradiation and are associated with human health risks. The mechanism responsible includes intra-cellular and inter-cellular signaling by which the bystander response is propagated. However, details of the signaling mechanism are not well defined.MethodsWe measured the bystander response of Mrad9+/+ and Mrad9−/− mouse embryonic stem cells, as well as human H1299 cells with inherent or RNA interference-mediated reduced RAD9 levels after exposure to 1 Gy α particles, by scoring chromosomal aberrations and micronuclei formation, respectively. In addition, we used microarray gene expression analyses to profile the transcriptome of directly irradiated and bystander H1299 cells.ResultsWe demonstrated that Mrad9 null enhances chromatid aberration frequency induced by radiation in bystander mouse embryonic stem cells. In addition, we found that H1299 cells with reduced RAD9 protein levels showed a higher frequency of radiation induced bystander micronuclei formation, compared with parental cells containing inherent levels of RAD9. The enhanced bystander response in human cells was associated with a unique transcriptomic profile. In unirradiated cells, RAD9 reduction broadly affected stress response pathways at the mRNA level; there was reduction in transcript levels corresponding to genes encoding multiple members of the UVA-MAPK and p38MAPK families, such as STAT1 and PARP1, suggesting that these signaling mechanisms may not function optimally when RAD9 is reduced. Using network analysis, we found that differential activation of the SP1 and NUPR1 transcriptional regulators was predicted in directly irradiated and bystander H1299 cells. Transcription factor prediction analysis also implied that HIF1α (Hypoxia induced factor 1 alpha) activation by protein stabilization in irradiated cells could be a negative predictor of the bystander response, suggesting that local hypoxic stress experienced by cells directly exposed to radiation may influence whether or not they will elicit a bystander response in neighboring cells.Electronic supplementary materialThe online version of this article (doi:10.1186/1748-717X-9-206) contains supplementary material, which is available to authorized users.