Successful use of cryocrit for monitoring response to therapeutic plasma exchange in type 1 cryoglobulinemia

Waldenstrom macroglobulinemia (WM) is a clinical syndrome that is defined as lymphoplasmacytic lymphoma with bone marrow involvement and IgM monoclonal gammopathy of any level. In some instances WM can result in a type I cryoglobulinemia with very high cryocrits, which is unusual in type II and III cryoglobulinemia. We describe a case of an 80 year old male with WM, severe type I cryoglobulinemia, and an extremely elevated cryocrit (69%). Over the course of five weeks we performed nine therapeutic plasma exchanges (TPE), and after seven treatments his cryocrit had decreased to 6% with improvement in his symptoms. By monitoring his cryocrit throughout his TPE sessions, we were able to assess his response to treatment, determine the ideal length of treatment in addition to his symptomatic improvement. J. Clin. Apheresis 31:403–404, 2016. © 2015 Wiley Periodicals, Inc.     

Local insulin therapy affects fracture healing in a rat model

A significant number of lower extremity fractures result in mal‐union necessitating effective treatments to restore ambulation. Prior research in diabetic animal fracture models demonstrated improved healing following local insulin application to the fracture site and indicated that local insulin therapy can aid bone regeneration, at least within an insulin‐dependent diabetic animal model. This study tested whether local insulin therapy could accelerate femur fracture repair in normal, non‐diabetic rats. High (20 units) and low (10 units) doses of insulin were delivered in a calcium sulfate carrier which provided sustained release of the exogenous insulin for 7 days after fracture. Histomorphometry, radiographic scoring, and torsional mechanical testing were used to measure fracture healing. The fracture calluses from rats treated with high‐dose insulin had significantly more cartilage than untreated rats after 7 and 14 days of healing. After 4 weeks of healing, femurs from rats treated with low‐dose insulin had significantly higher radiographic scores and mechanical strength (p < 0.05), compared to the no treatment control groups. The results of this study suggest that locally delivered insulin is a potential therapeutic agent for treating bone fractures. Further studies are necessary, such as large animal proof of concepts, prior to the clinical use of insulin for bone fracture treatment. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 776–782, 2013     

Response of bone subjected to optimized high dose irradiation

Allograft tissues are used in over one million musculoskeletal procedures per year. Consequently, it is crucial tissue banks use procedures to militate against allograft associated bacterial and viral infections. Recent studies have identified an important pathogen inactivation technology for musculoskeletal allografts that utilizes high-dose gamma irradiation (50 kGy) under controlled conditions. A total dose of 50 kGy assures that the current standard for medical devices for a microbial sterility assurance level of 10(- 6) is met. Furthermore, the pathogen inactivation technology results in a greater than four log inactivation of enveloped and nonenveloped viruses. Efficacious clinical outcome from musculoskeletal allografts exposed to this innovative sterilization procedure will require that there is no performance decrement in the allograft's biological properties. Therefore, to validate this objective, we executed a study focusing on remodeling and osteoconduction of bone allografts treated with a high dose of gamma irradiation (50 kGy), radioprotectants and well-defined operating parameters of temperature and water content. A rabbit calvarial model was used to test the hypothesis that remodeling and osteoconduction of allogeneic bone treated with the new pathogen inactivation technology would be equivalent to nontreated allogeneic bone. Results indicated treated bone allografts were comparable to nontreated allografts. We conclude, therefore, that based on this outcome and other reports, that high doses of gamma irradiation under optimized conditions designed to reduce free radical damage to tissue will provide safer allografts.     

Characteristics of colorectal cancer in the human immunodeficiency virus-infected African American population

Colorectal Cancer (CRC) is the second leading cause of cancer mortality in the United States. African Americans (AAs) have the highest incidence of CRC of any American ethnic group. Survival from CRC in AAs is lower than in Caucasians, and the mean age of CRC development in AAs is younger. The AA community also has a high rate of HIV infection, accounting for 50.3% of all cases despite making up only 13.6% of the population. This retrospective cohort study identified 17 AA HIV patients with CRC. The patients were matched with 42 HIV-negative CRC patients (controls), based on age, sex, and TNM stage. Data were obtained from 3 hospitals in New Jersey: St. Michael's Medical Center, Trinitas Medical Center and St. Joseph's Medical Center. The age, sex, HIV status, tumor site, stage, drug usage, Hepatitis C status, and survival outcome of subjects and controls were compared. Data from the Surveillance Epidemiology & End Results (SEER) specific to AAs were also compared. The mean age of CRC diagnosis was younger, 50.7 years (median: 52 years, range: 35-71 years), versus 59.42 years (median: 66 years) (P < 0.0001) in the SEER AA population. Of the patients, 29.4% were diagnosed with CRC at less than 45 years of age, versus only 6.35% of the SEER AA population (P < 0.0002). The male-to-female ratio was 11:6. Seven individuals used IV drugs, and 7 had hepatitis C. The mean CD4+ T-cell count was 510.81 cells/mm(3) (median 419). At the time of CRC diagnosis, the average duration of HIV infection was 7.6 years (range 0-22.4 years).Of patients, 87.5% had left-sided CRC, versus 57.55% of the SEER population (P < 0.024). Of the patients, 52.94% had stage III-IV, at diagnosis, versus 43.84% in SEER. There was no statistically significant survival difference between the cases and controls. In our cohort of HIV-infected AA's with CRC, the staging and outcome of CRC did not appear to be affected by the degree of immunosuppression. HIV-infected AA with CRC presented with a higher percentage of left-sided CRC than AA's without HIV. Additionally, AAs with HIV tended to be younger at the time of CRC diagnosis. Our findings suggest that screening for CRC should be offered to HIV-infected AAs before the age of 45, and that sigmoidoscopy with fecal occult blood testing might be an acceptable screening modality. However, the exact age of initiation, optimal frequency, and preferred method of screening (colonoscopy vs. sigmoidoscopy) in this population requires further study.     

The Impact of Diabetes Mellitus on Breast Cancer Outcomes: A Single Center Retrospective Study

Diabetes mellitus has been implicated to affect the prognostic outcomes of patients with various types of cancer. This study explores the impact of diabetes mellitus on the survival outcomes of patients with all stages of breast cancer. We performed a retrospective analysis of 255 patients with all stages of breast cancer. Survival outcomes were compared for diabetic and non-diabetic patients. A greater percent of patients in the non-diabetic group (54.1 %) presented with early-stage (stage 0 and 1) cancer than diabetics for which 41.2 % presented with stage 0 or 1 breast cancer; however this difference did not achieve statistical significance (p?=?0.068). Overall, we observed a significant difference in survival between the diabetics and non-diabetic subjects (p?=?0.001). Even after adjustment for all covariates and after stratification for Body Mass Index (BMI), diabetics were found to have a poorer prognosis in terms of survival time. In patients with breast cancer, diabetes mellitus is an independent predictor of lower overall survival rates, even after adjusting for other comorbidities. Primary caregivers and oncologists alike should aggressively screen breast cancer patients for diabetes mellitus and vice versa.     

Effects of local insulin delivery on subperiosteal angiogenesis and mineralized tissue formation during fracture healing

Local insulin delivery has been shown to improve osseous healing in diabetic animals. The purpose of this study was to quantify the effects of local intramedullary delivery of saline or Ultralente insulin (UL) on various fracture healing parameters using an in vivo non‐diabetic BB Wistar rat model. Quantitation of local insulin levels showed a rapid release of insulin from the fractured femora, demonstrating complete release at 2 days. RT‐PCR analysis revealed that the expression of early osteogenic markers (Col1α2, osteopontin) was significantly enhanced with UL treatment when compared with saline controls (p < 0.05). Significant differences in VEGF + cells and vascularity were evident between the treatment and control groups at day 7 (p < 0.05). At day 21, histomorphometric analysis demonstrated a significant increase in percent mineralized tissue in the UL‐treated animals compared with controls (p < 0.05), particularly within the subperiosteal region of the fracture callus. Mechanical testing at 4 weeks showed significantly greater mechanical strength for UL‐treated animals (p < 0.05), but healing in control animals caught up at 6 weeks post‐fracture. These results suggest that the primary osteogenic effect of UL during the early stages of fracture healing (1–3 weeks) is through an increase in osteogenic gene expression, subperiosteal angiogenesis, and mineralized tissue formation. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 783–791, 2013     

Interleukin‐22 Reduces the Severity of Collagen‐Induced Arthritis in Association With Increased Levels of Interleukin‐10

Objective

The mechanism of action of interleukin‐ 22 (IL‐22) in inflammatory arthritis remains unknown. IL‐22–deficient mice exhibit an intact humoral and cellular immune response to collagen and yet have a reduced incidence of collagen‐induced arthritis (CIA). Further, administration of anti–IL‐22 does not reduce the severity of clinical arthritis but rather improves only certain aspects of joint inflammation as assessed histologically. This study was undertaken to investigate the mechanism of action and role of systemic IL‐22 in modulating target organ inflammation.

Methods

CIA was induced in DBA mice by immunization with collagen and Freund's complete adjuvant. Expression of IL‐22 and its receptor (IL‐22R) in lymphoid organ and target tissues was determined during various phases of arthritis. The effector functions of IL‐22 on induction/regulation of various cytokines in in vitro restimulation cultures were analyzed by enzyme‐linked immunosorbent assay (ELISA). Recombinant IL‐22 with or without anti–IL‐10 antibody was administered to mice following immunization with collagen and prior to the onset of arthritis, and the severity of arthritis was evaluated by clinical scoring and histopathologic assessment. Anticollagen antibodies in mouse sera were analyzed by ELISA.

Results

IL‐22 and IL‐22R were up‐regulated in lymphoid organs and joints during the course of arthritis. IL‐22 augmented IL‐10, IL‐17, and IL‐6 in lymphoid tissues in vitro. Administration of recombinant IL‐22 was associated with an increase in IL‐10 levels in vivo and a significant reduction in the progression of arthritis severity. Anti–IL‐10 antibody treatment was associated with the abrogation of this protective effect of IL‐22.

Conclusion

Our data demonstrate, for the first time, that IL‐22 has a protective role in inflammatory arthritis.