Elevated tryptase levels are associated with greater bone density in a cohort of patients with mastocytosis

BACKGROUND: Mastocytosis is associated with a pathological increase in tissue mast cells. Associated skeletal problems include a decrease in bone density and pathological fractures. METHODS: In order to explore the relationship between bone density and the severity of mastocytosis, 21 patients with mastocytosis who underwent dual-energy X-ray absorptiometry were entered into this study. Correlation coefficients were computed between Z-scores and demographic, clinical and laboratory data. Femoral neck Z-scores correlated with serum tryptase levels when all the patients were considered (p=0.029). RESULTS AND CONCLUSION: Patients with less severe disease had significantly lower values at the L1-L4 spine (p=0.046) and femoral neck (p=0.029) Z-scores compared to patients with more severe disease. Most patients who had low Z-scores (between -1 and -2.5) were under 50 years of age, had less severe disease and had lower serum tryptase levels. A history of gastroesophageal reflux disease and a history of hypotensive episodes correlated with lower L1-L4 spine Z-scores (p<0.05). Thus, patients with less severe disease and lower serum tryptase levels should in particular have their bone density determined with treatment appropriate to the findings.     

Strain differences in allele and expression levels of CD72 on B-lymphocytes from NOD, AKR, NON and C57BL/6 mice

The B-lymphocyte marker CD72 has multiple alleles and serves crucial and nonredundant roles in B-cell development and activation. B-lymphocytes play an important role in development of autoimmune diabetes in NOD mice, therefore we examined the patterns of expression of CD72 and its alloantigens on splenic lymphocytes from 4-week-old NOD/LtJ mice. Comparisons of CD72 expression were made between NOD mice and three non-diabetic strains, NON/LtJ mice, C57BL/6J and AKR/J. Use of allele-specific monoclonal antibodies revealed that the previously uncharacterized NON strain expresses either the a or d allele, whereas NOD and AKR mice were confirmed to express the rare c allele. Flow cytometric analysis revealed differential expression between the strains. Whereas NON, C57BL/6 and AKR mice expressed CD72 on 98, 94 and 92% of their B-lymphocytes (CD19+ cells), the NOD mice only expressed this regulatory marker on 78% of their B-lymphocytes. Furthermore, CD72 expression levels on CD72 positive cells were lower in NOD mice than in other three non-diabetic strains. The presence of the CD72c allele, as well as its low level of expression in NOD mice at 4 weeks of age, may be associated with B-lymphocyte hyper-responsiveness and resistance to activation-induced cell death.     

Progestin-based contraceptive suppresses cellular immune responses in SHIV-infected rhesus macaques

Nine rhesus macaques in groups of three received a single dose of the injectable progestin-based contraceptive Depo-Provera 5 weeks prior to challenge intravaginally with varying doses of a mixture of the pathogenic CXCR4 (X4)-SHIV(SF33A) and CCR5 (R5)-SHIV(SF162P3) isolates. As controls, seven Depo-naive animals were inoculated once with a high-dose of the mixed inoculum. Irrespective of inoculum dose, acute viremia was higher in the Depo-treated than in the Depo-naive animals. Further, genetic complexity of the replicating virus was greater and replication of the X4 virus was favored in dually infected animals treated with Depo-Provera. Analysis of cellular immune responses revealed slower response rates in virus-specific IFN-gamma production to SIV Gag in the Depo-treated macaques. The immunosuppressive effect of Depo-Provera on mounting an antiviral cellular immune response may account for the increase viral burden and diversity, and the predominance of X4 virus replication in SHIV infected macaques that were administered the progestin-based contraceptive.     

Clinical and neuropsychological features of corticobasal degeneration

In this paper, we review the history, clinical, cognitive, imaging and neuropathological features of corticobasal degeneration (CBD). Additionally, we report new findings on the neuropsychological profile of 14 patients with CBD compared to 14 with Alzheimer's disease. Increasing awareness of this disorder has led to the realization that specific cognitive and imaging changes are common with CBD degeneration and that these changes help with clinical diagnosis.     

Fluoxetine induces glucose uptake and modifies glucose transporter palmitoylation in human peripheral blood mononuclear cells

ABSTRACT

Introduction: In line with the monoamine hypothesis of major depressive disorder (MDD), the clinical efficacy of the selective serotonin reuptake inhibitor fluoxetine has classically been ascribed to central serotonin enhancing properties. Current research described disturbances in brain energy metabolism in MDD. Additionally, fluoxetine showed beneficial effects in neuropsychiatric disorders associated with central energy imbalance.

Areas covered: The effect of in vitro fluoxetine exposure on cellular glucose uptake and cerebral glucose transporter function was assessed in human peripheral blood mononuclear cells (PBMC) and murine neuroblastoma N2a cells. Fluoxetine augmented glucose uptake, measured by utilizing the radionuclide-labled glucose analog [18]F-fluorodeoxyglucose, in PBMC without affecting glucose transporter protein content. Analysis of protein palmitoylation using the acyl-biotinyl exchange method revealed GLUT3 to be palmitoylated in PBMC and N2a cells, while palmitoylation of GLUT1 was detected only in N2a cells. Treatment with fluoxetine significantly increased palmitoylation of GLUT3 in PBMC and strongly induced palmitoylation of GLUT1 in PBMC and N2a cells.

Expert opinion: Our findings suggest a novel mechanism exerted by fluoxetine targeting glucose metabolism by regulating glucose transporter palmitoylation. Thus, fluoxetine might evoke its therapeutic effects in neuropsychiatric diseases characterized by disturbances in central energy metabolism at least partly by improving cerebral glucose uptake.     

Protons offer reduced bone marrow,small bowel,and urinary bladder exposure for patients receiving neoadjuvant radiotherapy for resectable rectal cancer

Background

To assess the potential benefit of proton therapy (PT) over photon therapy, we compared 3-dimensional conformal radiotherapy (3DCRT), intensity-modulated radiotherapy (IMRT), and PT plans in patients undergoing neoadjuvant chemoradiation for resectable rectal cancer at our institution.

Methods

Eight consecutive patients with resectable (T2-T3) rectal cancers underwent 3DCRT, IMRT, and 3-dimensional conformal PT treatment planning. Initial target volumes (PTV1) were contoured using the Radiation Therapy Oncology Group anorectal atlas guidelines. Boost target volumes (PTV2) consisted of the gross rectal tumor plus a uniform 2-cm expansion. Plans delivered 45 Gray (Gy) or Cobalt Gray Equivalent (CGE) to the PTV1 and a 5.4-Gy (CGE) boost to the PTV2. Ninety-five percent of the PTVs received 100% of the target dose and 100% of the PTVs received 95% of the target dose. Standard normal-tissue constraints were utilized. Wilcoxon paired t-tests were performed to compare various dosimetric points between the 3 plans for each patient.

Results

All plans met all normal-tissue constraints and were isoeffective in terms of PTV coverage. The proton plans offered significantly reduced median normal-tissue exposure over the 3DCRT and IMRT plans with respect to pelvic bone marrow at the V5Gy, V10Gy, V15Gy, and V20Gy levels and the small bowel space at the V10Gy and V20Gy levels. The proton plans also offered significantly reduced median normal-tissue exposure over the 3DCRT plans with respect to the small bowel at the V30Gy and V40Gy levels and the urinary bladder at the V40Gy level.

Conclusions

By reducing bone marrow exposure, PT may reduce the acute hematologic toxicity of neoadjuvant chemoradiation and increase the likelihood of uninterrupted chemotherapy delivery. Bone marrow sparing may also facilitate the delivery of salvage chemotherapy for patients who subsequently develop hematogenous metastasis. Reduced small bowel exposure using PT may also reduce toxicity and possibly facilitate the use of more-aggressive chemotherapy with radiotherapy.     

Trisomy 8 in B-cell chronic lymphocytic leukemia

Association between trisomy 8 and myeloid disorders/malignancies has been well documented. We report on two patients with a known history of B-cell chronic lymphocytic leukemia (B-CLL) with bone marrow involvement. In addition to the classic B-CLL cytogenetic abnormalities in one of the patients, both showed a trisomy 8 clone in their bone marrow specimens. Using a BioView Duet automated scanning system, which allowed us to combine histology with fluorescence in situ hybridization, we showed that the trisomy 8 clone was restricted to the myeloid lineage. We believe that this finding signifies the development of myelodysplastic syndrome (de novo or therapy related), rather than progression of B-CLL with the occurrence of a new clone, and that in general, it has implications for the finding of trisomy 8 in CLL.     

Microwave ablation for colorectal cancer metastasis to the liver: a single-center retrospective analysis

BackgroundThe purpose of this study is to evaluate the safety and intermediate-term efficacy of percutaneous microwave (MW) ablation for the treatment of colorectal liver metastases (CRLM) at a single institution.MethodsA retrospective review was performed of all CRLM treated with MW ablation from 3/2011 to 7/2020 (102 tumors; 72 procedures; 57 patients). Mean age was 60 years (range, 36–88) and mean tumor size was 1.8 cm (range, 0.5–5.0 cm). The patient population included 19 patients with extra-hepatic disease. Chemotherapy (pre- and/or post-ablation) was given in 98% of patients. Forty-five sessions were preceded by other focal CRLM treatments including resection, ablation, radiation, and radioembolization. Kaplan-Meier curves were used to estimate local tumor progression-free survival (LTPFS), disease-free survival (DFS), and overall survival (OS) and multivariate analysis (Cox Proportional Hazards model) was used to test predictors of OS.ResultsTechnical success (complete ablation) was 100% and median follow-up was 42 months (range, 1–112). There was a 4% major complication rate and an overall complication rate of 8%. Local tumor progression (LTP) rate during the entire study period was 4/98 (4%), in which 2 were retreated with MW ablation for a secondary LTP-rate of 2%. LTP-free survival at 1, 3, and 5 years was 93%, 58%, and 39% and median LTP-free survival was 48 months. OS at 1, 3, and 5 years was 96%, 66%, 47% and median OS was 52 months. There were no statistically significant predictors of OS.ConclusionsMW ablation of hepatic colorectal liver metastases appears safe with excellent local tumor control and prolonged survival compared to historical controls in selected patients. Further comparative studies with other local treatment strategies appear indicated.     

Antinociceptive effect of peripheral serotonin 5-HT2B receptor activation on neuropathic pain

Serotonin is critically involved in neuropathic pain. However, its role is far from being understood owing to the number of cellular targets and receptor subtypes involved. In a rat model of neuropathic pain evoked by chronic constriction injury (CCI) of the sciatic nerve, we studied the role of 5-HT(2B) receptor in dorsal root ganglia (DRG) and the sciatic nerve. We showed that 5-HT(2B) receptor activation both prevents and reduces CCI-induced allodynia. Intrathecal administration of 5-HT(2B) receptor agonist BW723C86 significantly attenuated established mechanical and cold allodynia; this effect was prevented by co-injection of RS127445, a selective 5-HT(2B) receptor antagonist. A single application of BW723C86 on the sciatic nerve concomitantly to CCI dose-dependently prevented mechanical allodynia and significantly reduced cold allodynia 17 days after CCI. This behavioral effect was accompanied with a marked decrease in macrophage infiltration into the sciatic nerve and, in the DRG, with an attenuated abnormal expression of several markers associated with local neuroinflammation and neuropathic pain. CCI resulted in a marked upregulation of 5-HT(2B) receptor expression in sciatic nerve and DRG. In the latter structure, it was biphasic, consisting of a transient early increase (23-fold), 2 days after the surgery and before the neuropathic pain emergence, followed by a steady (5-fold) increase, that remained constant until pain disappeared. In DRG and sciatic nerve, 5-HT(2B) receptors were immunolocalized on sensory neurons and infiltrating macrophages. Our data reveal a relationship between serotonin, immunocytes, and neuropathic pain development, and demonstrate a critical role of 5-HT(2B) receptors in blood-derived macrophages.     

In vivo characterization of several rodent glioma models by 1H MRS

The assessment of metabolites by (1)H MRS can provide information regarding glioma growth, and may be able to distinguish between different glioma models. Rat C6, 9 L/LacZ, F98 and RG2, and mouse GL261, cells were intracerebrally implanted into the respective rodents, and human U87 MG cells were implanted into athymic rats. Ethyl-nitrosourea induction was also used. Glioma metabolites [e.g. total choline (tCho), total creatine (tCr), N-acetylaspartate (NAA), lactate (Lac), glutamine (Gln), glutamate (Glu), aspartate (Asp), guanosine (Gua), mobile lipids and macromolecules (MMs)] were assessed from (1)H MRS using point-resolved spectroscopy (PRESS) [TE = 24 ms; TR = 2500 ms; variable pulse power and optimized relaxation delay (VAPOR) water suppression; 27-μL and 8-μL voxels in rats and mice, respectively] at 7 T. Alterations in metabolites (Totally Automatic Robust Quantitation in NMR, TARQUIN) in tumors were characterized by increases in lipids (Lip1.3: 8.8-54.5 mM for C6 and GL261) and decreases in NAA (1.3-2.0 mM for RG2, GL261 and C6) and tCr (0.8-4.0 mM for F98, RG2, GL261 and C6) in some models. F98, RG2, GL261 and C6 models all showed significantly decreased (p < 0.05) tCr, and RG2, GL261 and C6 models all exhibited significantly decreased (p < 0.05) NAA. The RG2 model showed significantly decreased (p < 0.05) Gln and Glu, the C6 model significantly decreased (p < 0.05) Asp, and the F98 and U87 models significantly decreased (p < 0.05) Gua, compared with controls. The GL261 model showed the greatest alterations in metabolites. (1)H MRS was able to differentiate the metabolic profiles in many of the seven rodent glioma models assessed. These models are considered to resemble certain characteristics of human glioblastomas, and this study may be helpful in selecting appropriate models.