Bone Marrow Microenvironment in Multiple Myeloma Progression

Substantial advances have been made in understanding the biology of multiple myeloma (MM) through the study of the bone marrow (BM) microenvironment. Indeed, the BM niche appears to play an important role in differentiation, migration, proliferation, survival, and drug resistance of the malignant plasma cells. The BM niche is composed of a cellular compartment (stromal cells, osteoblasts, osteoclasts, endothelial cells, and immune cells) and a noncellular compartment including the extracellular matrix (ECM) and the liquid milieu (cytokines, growth factors, and chemokines). In this paper we discuss how the interaction between the malignant plasma cell and the BM microenvironment allowed myeloma progression through cell homing and the new concept of premetastatic niche

Creatine transporter (SLC6A8) knockout mice display an increased capacity for in vitro creatine biosynthesis in skeletal muscle.

The present study aimed to investigate whether skeletal muscle from whole body creatine transporter (CrT; SLC6A8) knockout mice (CrT(-/y)) actually contained creatine (Cr) and if so, whether this Cr could result from an up regulation of muscle Cr biosynthesis. Gastrocnemius muscle from CrT(-/y) and wild type (CrT(+/y)) mice were analyzed for ATP, Cr, Cr phosphate (CrP), and total Cr (TCr) content. Muscle protein and gene expression of the enzymes responsible for Cr biosynthesis L-arginine:glycine amidotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT) were also determined as were the rates of in vitro Cr biosynthesis. CrT(-/y) mice muscle contained measurable (22.3 ± 4.3 mmol.kg(-1) dry mass), but markedly reduced (P < 0.05) TCr levels compared with CrT(+/y) mice (125.0 ± 3.3 mmol.kg(-1) dry mass). AGAT gene and protein expression were higher (~3 fold; P < 0.05) in CrT(-/y) mice muscle, however GAMT gene and protein expression remained unchanged. The in vitro rate of Cr biosynthesis was elevated 1.5 fold (P < 0.05) in CrT(-/y) mice muscle. These data clearly demonstrate that in the absence of CrT protein, skeletal muscle has reduced, but not absent, levels of Cr. This presence of Cr may be at least partly due to an up regulation of muscle Cr biosynthesis as evidenced by an increased AGAT protein expression and in vitro Cr biosynthesis rates in CrT(-/y) mice. Of note, the up regulation of Cr biosynthesis in CrT(-/y) mice muscle was unable to fully restore Cr levels to that found in wild type muscle

International Liver Transplantation Consensus Statement on end-stage liver disease due to nonalcoholic steatohepatitis and liver transplantation

Nonalcoholic steatohepatitis (NASH)-related cirrhosis has become one of the most common indications for liver transplantation (LT), particularly in candidates over the age of 65 years. Typically, NASH candidates have concurrent obesity, metabolic and cardiovascular risks, which directly impact patient evaluation and selection, waitlist morbidity and mortality and eventually posttransplant outcomes. The purpose of these guidelines is to highlight specific features commonly observed in NASH candidates and strategies to optimize pretransplant evaluation and waitlist survival. More specifically, the working group addressed the following clinically-relevant questions providing recommendations based on the GRADE system supported by rigorous systematic reviews and consensus: (1) Is the outcome after LT similar to that of other etiologies of liver disease? (2) Is the natural history of NASH-related cirrhosis different from other etiologies of end-stage liver disease? (3) How should cardiovascular risk be assessed in the candidate for LT? Should the assessment differ from that done in other etiologies? (4) How should comorbidities (hypertension, diabetes, dyslipidemia, obesity, renal dysfunction, etc.) be treated in the candidate for LT? Should treatment and monitoring of these comorbidities differ from that applied in other etiologies? (5) What are the therapeutic strategies recommended to improve the cardiovascular and nutritional status of a NASH patient in the waiting list for LT? (6) Is there any circumstance where obesity should contraindicate LT? (7) What is the optimal time for bariatric surgery: before, during, or after LT? and (8) Donor steatosis: how much relevant is it for LT in NASH patients

Cervical spondylotic myelopathy in the young adult: A review of the literature and clinical diagnostic criteria in an uncommon demographic

Background: Cervical spondylotic myelopathy (CSM) is typically encountered in the elderly population. Significant inconsistencies currently exist regarding the definition of the disorder, the true incidence of CSM in younger populations, and the established diagnostic criteria. Objective: To highlight the lack of standardization in the definition and diagnosis of CSM. Methods: A PubMed literature search was conducted spanning the years 2001 to 2011. The search was limited by the following terms: 1) English language, 2) Adults (19-44 years old), and 3) “cervical spondylotic myelopathy.” Each article was reviewed to determine if the presence of the definition of CSM existed in the article. The clinical characteristics used to make the diagnosis of CSM were recorded for each article. Cochran’s Q statistic was used to determine whether some clinical characteristics were more frequently used than others. Results: 93 papers were reviewed in detail and 16 case reports, reviews, and articles concerning less than three patients were excluded, resulting in 77 articles in the final analysis. The most common clinical definitions were gait disturbance (22/77 articles (28.6%)), upper limb paresthesias or sensory disturbance (21/77 (27.3%)), and clumsy hands (15/77 (19.5%)). Hyperreflexia, spasticity, and pathologically increased reflexes were identified as diagnostic criteria in a minority of patients. Conclusion: The literature employs a wide range of neurologic signs and symptoms to make the diagnosis of CSM, with a majority of studies failing to rely on strict diagnostic criteria. The clinician should not discount CSM as an explanation for the aforementioned findings, as it is well-reported in the literature among the ages 18-44

Anterior Cervical Infection: Presentation and Incidence of an Uncommon Postoperative Complication.

STUDY DESIGN: Retrospective multi-institutional case series. OBJECTIVE: The anterior cervical discectomy and fusion (ACDF) affords the surgeon the flexibility to treat a variety of cervical pathologies, with the majority being for degenerative and traumatic indications. Limited data in the literature describe the presentation and true incidence of postoperative surgical site infections. METHODS: A retrospective multicenter case series study was conducted involving 21 high-volume surgical centers from the AOSpine North America Clinical Research Network, selected for their excellence in spine care and clinical research infrastructure and experience. Medical records for 17 625 patients who received cervical spine surgery (levels from C2 to C7) between January 1, 2005, and December 31, 2011, inclusive, were reviewed to identify the occurrence of 21 predefined treatment complications. Patients who underwent an ACDF were identified in the database and reviewed for the occurrence of postoperative anterior cervical infections. RESULTS: A total of 8887 patients were identified from a retrospective database analysis of 21 centers providing data for postoperative anterior cervical infections (17/21, 81% response rate). A total of 6 postoperative infections after ACDF were identified for a mean rate of 0.07% (range 0% to 0.39%). The mean age of patients identified was 57.5 (SD = 11.6, 66.7% female). The mean body mass index was 22.02. Of the total infections, half were smokers (n = 3). Two patients presented with myelopathy, and 3 patients presented with radiculopathic-type complaints. The mean length of stay was 4.7 days. All patients were treated aggressively with surgery for management of this complication, with improvement in all patients. There were no mortalities. CONCLUSION: The incidence of postoperative infection in ACDF is exceedingly low. The management has historically been urgent irrigation and debridement of the surgical site. However, due to the rarity of this occurrence, guidance for management is limited to retrospective series

Redefining Onyx HD 500 in the Flow Diversion Era

We report the largest US case series results using Onyx HD-500 (EV3), a new liquid embolic agent, in the successful treatment of 21 patients with wide-neck intracranial aneurysms (mean size 4.5 mm), which are at increased risk of incomplete occlusion or recanalization with standard endovascular intervention utilizing detachable platinum coils. All aneurysms were located in the anterior circulation, and three aneurysms presented as acute subarachnoid hemorrhages. Complete aneurysm occlusion was present in 19 of 21 patients (90%). On six-month followup, one patient with an initially small residual neck progressed to total occlusion. Aneurysm recanalization was not detected in any patients on mean follow up of 8.9 months in 11 patients. Four patients experienced transient neurologic deficits in the immediate postoperative period and one in a delayed fashion. Embolization with the liquid embolic agent Onyx appears to be a safe and effective endovascular modality of treatment for wide-neck aneurysms or recurrent aneurysms that had previously failed treatment with detachable coils

The Medical Research Council Myeloma IX trial: the impact on treatment paradigms*

Osteolytic bone disease is a hallmark of symptomatic multiple myeloma. Bisphosphonates have been the mainstay of treatment to preserve skeletal integrity and prevent skeletal-related events in patients with myeloma-related bone disease. Recently, the MRC Myeloma IX trial demonstrated for the first time improved survival and delayed disease progression with the use of an intravenous amino-bisphosphonate, zoledronic acid, vs. an oral agent, clodronate, with intensive and non-intensive anti-myeloma treatment regimens in patients with newly diagnosed multiple myeloma. These results validate a large body of preclinical, translational and other clinical data suggesting anti-myeloma effects of amino-bisphosphonates. In addition, this trial also provided the first head-to-head evidence for superiority of one bisphosphonate over another (zoledronic acid vs. clodronate) for reducing skeletal morbidity in patients with multiple myeloma, as well as a prospective comparison of toxicities. Despite the use of non-bortezomib containing anti-myeloma treatment regimens in the MRC Myeloma IX trial, these results are encouraging and provide an impetus to continue to evaluate current treatment guidelines for myeloma-associated bone disease

Gulf Stream ring water intrusion on the Mid-Atlantic Bight continental shelf break affects microbially driven carbon cycling

Warm core, anticyclonic rings that spin off from the Gulf Stream circulate through the region directly offshore of the Mid-Atlantic Bight. If a warm core ring reaches the continental shelf break, its warm, highly saline water may subduct under cooler, fresher continental shelf surface water, resulting in subsurface waters at the shelf break and over the upper continental slope with high temperatures and salinities and distinct physical and chemical properties characteristic of Gulf Stream water. Such intruding water may also have microbial communities with distinct functional capacities, which may in turn affect the rate and nature of carbon cycling in this coastal/shelf environment. However, the functional capabilities of microbial communities within ring intrusion waters relative to surrounding continental shelf waters are largely unexplored. We investigated microbial community capacity to initiate organic matter remineralization by measuring hydrolysis of a suite of polysaccharide, peptide, and glucose substrates along a transect oriented across the Mid-Atlantic Bight shelf, shelf break, and upper slope. At the outermost sampling site, warm and salty water derived from a Gulf Stream warm core ring was present in the lower portion of the water column. This water exhibited hydrolytic capacities distinct from other sampling sites, and exhibited lower heterotrophic bacterial productivity overall. Warm core rings adjacent to the Mid-Atlantic Bight shelf have increased in frequency and duration in recent years. As the influence of warm core rings on the continental shelf and slope increases in the future, the rate and nature of organic matter remineralization on the continental shelf may also shift