Research Spotlight

Cordasco, F. A., S. R. Black, M. Price, C. Wixted, M. Heller, L. A. Asaro, J. Nguyen and D. W. Green (2019). “Return to Sport and Reoperation Rates in Patients Under the Age of 20 After Primary Anterior Cruciate Ligament Reconstruction: Risk Profile Comparing 3 Patient Groups Predicated Upon Skeletal Age.” Am J Sports Med Jan 15. [Epub ahead of print].

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BACKGROUND: With sports specialization and level of competition on the rise, anterior cruciate ligament reconstruction (ACLR) in athletes under the age of 20 has increased significantly in recent years. Reports have demonstrated that the revision ACLR rate is higher and return to sport (RTS) rate is lower in this population. PURPOSE:: To evaluate the 2-year clinical outcomes of 3 cohorts of primary ACLR in pediatric and adolescent athletes under the age of 20 based on skeletal age with a focus on RTS and the incidence of second surgery. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: This is a prospective evaluation of 324 athletes younger than 20 years of age who underwent ACLR with minimum 2-year follow-up. The surgical technique was selected predicated on skeletal age, which includes the all-epiphyseal technique with hamstring autograft in the youngest cohort in elementary and middle school (group 1), the partial transphyseal and complete transphyseal with hamstring autograft performed for athletes in the middle cohort (group 2), and bone-tendon-bone autograft in the skeletally mature high school athletes (group 3). RESULTS: The mean chronological age of the entire cohort was 15 years (range, 8-19 years) with 55% males. The 3 cohorts included 49 patients (15%) in group 1 (mean age, 12 years), 66 (20%) in group 2 (mean age, 14.3 years), and 209 (65%) in group 3 (mean age, 16.2 years). Group 2 athletes had a significantly higher revision ACLR rate (20%) compared with group 1 (6%; P = .039) and group 3 (6%; P = .001). Similarly, group 2 athletes had significantly lower RTS rates (85%) compared with group 1 (100%) and group 3 (94%). CONCLUSION:: The rate of revision ACLR was significantly higher and the RTS rates significantly lower in group 2 compared with groups 1 and 3. This age-related risk profile may be used to counsel athletes and parents preoperatively regarding the expectations of surgery with respect to revision ACLR and RTS rates.

Brouwer, W. P., Q. Zhao, B. E. Hansen, D. Lau, M. Khalili, N. A. Terrault, A. M. Di Bisceglie, R. P. Perrillo, M. W. Fried, D. Wong, J. J. Feld, S. H. Belle and H. L. A. Janssen (2019). “Improved Definition of HBV Phenotypes based on Genotype-specific Levels of Hepatitis B s Antigen.” Clin Gastroenterol Hepatol Jan 7. [Epub ahead of print].

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Quantitative HBsAg levels are increasingly important in the management and treatment of CHB. In clinical practice, it is essential to differentiate HBV phenotypes, and previous studies point to quantitative HBsAg as a potential additional serologic marker to this end. However, HBV genotype may influence HBsAg levels as well. Indeed, in the current study we found that HBsAg levels differed across both HBV phenotype and genotype, with highest levels observed in HBV genotype A and lowest in genotype B. The considerable variation in HBsAg levels among different HBV genotypes has important clinical implications, particularly for IC patients, since HBsAg levels >1000 IU/mL are associated with a higher risk of active hepatitis and HCC development. The reason for the observed variation in HBsAg levels between HBV genotypes may be sought in difference in ethnic background, the patient’s age at infection, duration of infection, and different frequencies of HBV precore, basal core and preS mutational patterns. Given the current findings, it is important to assess, also for the future guidelines, whether HBV genotype influences longitudinal HBsAg levels and the probability of HBV phenotype change over time. Moreover, since all IT participants were infected with HBV genotype B or C, further study is needed to elaborate on HBsAg levels of HBV genotype A and D in the IT phase. These patients may however be very rare and this could in fact be one of the reasons of why we found a more even distribution of different HBV genotypes in the IC phase. Overall, it would have been preferable to have a larger subset of non-Asian participants, however our cohort is a non-biased reflection of present clinical practice in North America. Concluding, when using HBsAg levels to assist in determination of HBV phenotype in clinical practice, HBV genotype specific HBsAg level cut-offs will be required. (Excerpt from text of this article in press, p.7.)

Arora, K., J. M. Sequeira, J. M. Alarcon, B. Wasek, E. Arning, T. Bottiglieri and E. V. Quadros (2019). “Neuropathology of vitamin B12 deficiency in the Cd320(-/-) mouse.” FASEB J 33(2): 2563-2573.

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In humans, vitamin B12 deficiency causes peripheral and CNS manifestations. Loss of myelin in the peripheral nerves and the spinal cord (SC) contributes to peripheral neuropathy and motor deficits. The metabolic basis for the demyelination and brain disorder is unknown. The transcobalamin receptor-knockout mouse ( Cd320(-/-)) develops cobalamin (Cbl) deficiency in the nervous system, with mild anemia. A decreased S-adenosylmethionine: S-adenosylhomocysteine ratio and increased methionine were seen in the brain with no significant changes in neurotransmitter metabolites. The structural pathology in the SC presented as loss of myelin in the axonal tracts with inflammation. The sciatic nerve (SN) showed increased nonuniform, internodal segments suggesting demyelination, and remyelination in progress. Consistent with these changes, the Cd320(-/-) mouse showed an increased latency to thermal nociception. Further, lower amplitude of compound action potential in the SN suggested that the functional capacity of the heavily myelinated axons were preferentially compromised, leading to loss of peripheral sensation. Although the metabolic basis for the demyelination and the structural and functional alterations of the nervous system in Cbl deficiency remain unresolved, the Cd320(-/-) mouse provides a unique model to investigate the pathologic consequences of vitamin B12 deficiency. -Arora, K., Sequeira, J. M., Alarcon, J. M., Wasek, B., Arning, E., Bottiglieri, T., Quadros, E. V. Neuropathology of vitamin B12 deficiency in the Cd320(-/-) mouse.

Anasooya Shaji, C., B. D. Robinson, A. Yeager, M. R. Beeram, M. L. Davis, C. L. Isbell, J. H. Huang and B. Tharakan (2019). “The Tri-phasic Role of Hydrogen Peroxide in Blood-Brain Barrier Endothelial cells.” Sci Rep 9(1): 133.

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Hydrogen peroxide (H2O2) plays an important role physiologically as the second messenger and pathologically as an inducer of oxidative stress in injury, ischemia and other conditions. However, it is unclear how H2O2 influences various cellular functions in health and disease differentially, particularly in the blood-brain barrier (BBB). We hypothesized that the change in cellular concentrations of H2O2 is a major contributor in regulation of angiogenesis, barrier integrity/permeability and cell death/apoptosis in BBB endothelial cells. Rat brain microvascular endothelial cells were exposed to various concentrations of H2O2 (1 nM to 25 mM). BBB tight junction protein (zonula ocludens-1; ZO-1) localization and expression, cytoskeletal organization, monolayer permeability, angiogenesis, cell viability and apoptosis were evaluated. H2O2 at low concentrations (0.001 muM to 1 muM) increased endothelial cell tube formation indicating enhanced angiogenesis. H2O2 at 100 muM and above induced monolayer hyperpermeability significantly (p < 0.05). H2O2 at 10 mM and above decreased cell viability and induced apoptosis (p < 0.05). There was a decrease of ZO-1 tight junction localization with 100 mum H2O2, but had no effect on protein expression. Cytoskeletal disorganizations were observed starting at 1 mum. In conclusion H2O2 influences angiogenesis, permeability, and cell death/apoptosis in a tri-phasic and concentration-dependent manner in microvascular endothelial cells of the blood-brain barrier.

Alsahhar, J. S., R. Idriss and R. Bahirwani (2019). “A Rare Case of Cutaneous Metastases Secondary to Hepatocellular Carcinoma.” Clin Gastroenterol Hepatol 17(3): e17.

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A 54-year-old man presented with a 2-month history of an abdominal rash, initially small papules over the epigastrium that spread medially and subsequently becoming painful. His past medical history included decompensated hepatitis C cirrhosis with hepatocellular carcinoma (HCC) BCLC stage B diagnosed 1 year before presentation (3 lesions, largest measuring 5 cm). He underwent chemoembolization followed by cyberknife radiation 6 months before the current presentation. Physical examination revealed a Sister Mary Joseph nodule surrounded by erythematous tender subcutaneous nodules. His serum α-fetoprotein was 1000 ng/mL. Given the high suspicion for metastases, punch biopsy of a nodule was performed revealing anastomosing cords of highly atypical cells with enlarged hyperchromatic pleomorphic nuclei and atypical mitoses, consistent with high-grade adenocarcinoma of hepatobiliary origin. The patient died of liver failure 2 weeks after presentation. Extrahepatic metastases occur in up to a third of HCC cases, lung being the most common metastatic site. Metastases to skin are rare , primarily occurring because of direct seeding of the tumor at sites of biopsies or biliary drains. Our case highlights an atypical presentation of HCC cutaneous metastases and the importance of biopsy to differentiate HCC from other malignancies with similar presentations. (Text of this image study, p. e17.)