Bilateral vision loss as the initial presentation for central nervous system involvement of mantle cell lymphoma: A case series.

PURPOSE: Mantle cell lymphoma is a rare aggressive subtype of non-Hodgkins B cell lymphoma. It typically presents with asymptomatic monoclonal lymphocytosis, lymphadenopathy or bulky extranodal disease. Mantle cell lymphoma rarely affects the central nervous system. We present two cases in which vision loss was the initial symptom of central nervous system involvement by the malignancy. OBSERVATIONS: Both patients initially received high dose intravenous steroids with notable improvement in their vision. CONCLUSIONS AND IMPORTANCE: Early detection and management of optic nerve infiltration by mantle cell lymphoma is essential as it improves visual outcomes and enables prompt management of the patient's systemic disease.

SOCS1 inhibits migration and invasion of prostate cancer cells, attenuates tumor growth and modulates the tumor stroma.

BACKGROUND: The suppressor of cytokine signaling 1 (SOCS1) gene is repressed in prostate cancer (PCa) by epigenetic silencing and microRNA miR30d. Increased expression of the SOCS1-targeting miR30d correlates with higher biochemical recurrence, suggesting a tumor suppressor role of SOCS1 in PCa, but the underlying mechanisms are unclear. We have shown that SOCS1 inhibits MET receptor kinase signaling, a key oncogenic pathway in cancer progression. Here we evaluated the role of SOCS1 in attenuating MET signaling in PCa cells and tumor growth in vivo. METHODS: MET-overexpressing human DU145 and PC3 PCa cell lines were stably transduced with SOCS1, and their growth, migration and invasion of collagen matrix were evaluated in vitro. Cells expressing SOCS1 or the control vector were evaluated for tumor growth in NOD.scid.gamma mice as xenograft or orthotopic tumors. RESULTS: HGF-induced MET signaling was attenuated in SOCS1-expressing DU145 and PC3 cells. Compared with vector control cells, SOCS1-expressing cells showed reduced proliferation and impaired migration following HGF stimulation. DU145 and PC3 cells showed marked ability to invade the collagen matrix following HGF stimulation and this was attenuated by SOCS1. As xenografts, SOCS1-expressing PCa cells showed significantly reduced tumor growth compared with vector control cells. In the orthotopic tumor model, SOCS1 reduced the growth of primary tumors and metastatic spread. Intriguingly, the SOCS1-expressing DU145 and PC3 tumors showed increased collagen deposition, associated with increased frequency of myofibroblasts. CONCLUSIONS: Our findings support the tumor suppressor role of SOCS1 in PCa and suggest that attenuation of MET signaling is one of the underlying mechanisms. SOCS1 in PCa cells also appears to prevent the tumor-promoting functions of cancer-associated fibroblasts.

Suppressor of cytokine signaling 1-dependent regulation of the expression and oncogenic functions of p21(CIP1/WAF1) in the liver.

The SOCS1 gene coding for suppressor of cytokine signaling 1 is frequently repressed in hepatocellular carcinoma (HCC), and hence SOCS1 is considered a tumor suppressor in the liver. However, the tumor-suppressor mechanisms of SOCS1 are not yet well understood. SOCS1 is known to inhibit pro-inflammatory cytokine production and signaling and to promote activation of the p53 tumor suppressor. However, we observed that SOCS1-deficient mice developed numerous and large liver tumor nodules following treatment with the hepatocarcinogen diethylnitrosamine (DEN) without showing increased interleukin-6 production or activation of p53. On the other hand, the livers of DEN-treated Socs1-null mice showed elevated levels of p21(CIP1/WAF1) protein (p21). Even though p21 generally functions as a tumor suppressor, paradoxically many cancers, including HCC, are known to express elevated levels of p21 that correlate with poor prognosis. We observed elevated p21 expression also in the regenerating livers of SOCS1-deficient mice and in cisplatin-treated Socs1-null hepatocytes, wherein the p21 protein showed increased stability. We show that SOCS1 interacts with p21 and promotes its ubiquitination and proteasomal degradation. Besides, the DEN-treated livers of Socs1-null mice showed increased nuclear and cytosolic p21 staining, and the latter was associated with growth factor-induced, phosphatidylinositol 3-kinase-dependent phosphorylation of p21 in SOCS1-deficient hepatocytes. Cytosolic p21 is often associated with malignancy and chemo-resistance in many cancers. Accordingly, SOCS1-deficient hepatocytes showed increased resistance to apoptosis that was reversed by shRNA-mediated p21 knockdown. In the regenerating livers of Socs1-null mice, increased p21 expression coincided with elevated cyclinD levels. Correspondingly, SOCS1-deficient hepatocytes showed increased proliferation to growth factor stimulation that was reversed by p21 knockdown. Overall, our findings indicate that the tumor-suppressor functions of SOCS1 in the liver could be mediated, at least partly, via regulation of the expression, stability and subcellular distribution of p21 and its paradoxical oncogenic functions, namely, resistance to apoptosis and increased proliferation.

The pharmacokinetics and safety of idelalisib in subjects with severe renal impairment.

PURPOSE: Idelalisib is a novel, potent inhibitor of phosphatidylinositol 3-kinase delta (PI3Kδ), which is prominently expressed in cells of hematopoietic origin. Renal excretion plays a minor role in elimination of idelalisib in humans (~15 % of the dose is excreted in urine). This study evaluated the pharmacokinetics (PK) and safety of idelalisib and GS-563117 (its inactive primary metabolite) in subjects with severe renal impairment and healthy subjects. METHODS: Subjects with severe renal impairment were matched in age, sex, and body mass index with healthy subjects who had normal renal function. Each subject received a single oral dose of idelalisib at 150 mg, and safety assessments and PK analyses were performed. RESULTS: Compared with healthy subjects, the geometric least-squares mean ratio of area under the concentration-time curve from zero to last PK observation (AUC(last)), area under the concentration-time curve from zero to infinity (AUC(inf)), and maximum observed plasma concentration (C(max)) were 127, 127, and 105 % for idelalisib and 124, 124, and 96 % for GS-563117, respectively, in subjects with severe renal impairment. CONCLUSIONS: There were no clinically relevant changes of idelalisib or GS-563117 PK in subjects with severe renal impairment versus matched healthy controls. No relevant relationships were identified between idelalisib or GS-563117 exposures and baseline creatinine clearance. Idelalisib dosing was generally well tolerated with most treatment-emergent adverse events and laboratory abnormalities assessed as grade 1 or 2 in severity. Accordingly, dose adjustments for idelalisib are not necessary in subjects with mild, moderate, or severe renal impairment.

Regulation of MET receptor tyrosine kinase signaling by suppressor of cytokine signaling 1 in hepatocellular carcinoma.

Suppressor of cytokine signaling 1 (SOCS1) is considered as a tumor suppressor protein in hepatocellular carcinoma (HCC), but the underlying mechanisms remain unclear. Previously, we have shown that SOCS1-deficient hepatocytes displayed increased responsiveness to hepatocyte growth factor (HGF) due to enhanced signaling via the MET receptor tyrosine kinase. As aberrant MET activation occurs in many tumors including HCC, here we elucidated the mechanisms of SOCS1-mediated regulation. SOCS1 attenuated HGF-induced proliferation of human and mouse HCC cell lines and their growth as tumors in NOD.scid.gamma mice. Tumors formed by SOCS1 expressing HCC cells showed significantly reduced MET expression, indicating that SOCS1 not only attenuates MET signaling but also regulates MET expression. Mechanistically, SOCS1 interacted with MET via the Src homology 2 domain and this interaction was promoted by MET tyrosine kinase activity. The SOCS1-mediated reduction in MET expression does not require the juxtamembrane Y1003 residue implicated in Cbl-mediated downmodulation. Moreover, the proteasome inhibitor MG-132, but not the inhibitors of lysosomal degradation bafilomycin and chloroquine, reversed the SOCS1-mediated reduction in MET expression, indicating that this process is distinct from Cbl-mediated downmodulation. Accordingly, SOCS1 promoted polyubiquitination of MET via K48-dependent but not K63-mediated ubiquitin chain elongation. Furthermore, siRNA-mediated downmodulation of Cbl did not abolish SOCS1-mediated reduction in MET expression in HCC cells. SOCS1-dependent ubiquitination of endogenous MET receptor occurred rapidly following HGF stimulation in HCC cells, leading to proteasomal degradation of phosphorylated MET receptor. These findings indicate that SOCS1 mediates its tumor suppressor functions, at least partly, by binding to MET and interfering with downstream signaling pathways as well as by promoting the turnover of the activated MET receptor. We propose that loss of this control mechanism due to epigenetic repression of SOCS1 could contribute to oncogenic MET signaling in HCC and other cancers, and that MET inhibitors might be useful in treating these patients.

Non-neoplastic hepatic vascular diseases: spectrum of CT and MRI appearances.

The unique dual blood supply of the liver makes it one of the common sites for various vascular neoplastic and non-neoplastic diseases. Increasing use of multiphase contrast-enhanced computed tomography (CT) and dynamic magnetic resonance imaging (MRI) has led to increased identification of numerous non-neoplastic vascular entities apart from already well-known neoplastic lesions. The objective of this review is to describe the causes and clinical features and to familiarize the reader with the key imaging features of various non-neoplastic vascular diseases affecting the liver. Non-neoplastic vascular diseases are classified broadly as those affecting the hepatic veins, portal veins, hepatic artery, intrahepatic shunts, and other miscellaneous conditions.

The mysterious organ. Spectrum of focal lesions within the splenic parenchyma: cross-sectional imaging with emphasis on magnetic resonance imaging.

Incidental splenic lesions are frequently encountered at imaging performed for unrelated causes. Splenic cysts, hemangiomas, and lymphomatous involvement are the most frequently encountered entities. Computed tomography and sonography are commonly used for initial evaluation with magnetic resonance imaging reserved as a useful problem-solving tool for characterizing atypical and uncommon lesions. The value of magnetic resonance imaging lies in classifying these lesions as either benign or malignant by virtue of their signal-intensity characteristics on T1- and T2-weighted imaging and optimal depiction of internal hemorrhage. Dynamic contrast-enhanced sequences may improve the evaluation of focal splenic lesions and allow characterization of cysts, smaller hemangiomas, and hamartomas. Any atypical or unexplained imaging feature related to an incidental splenic lesion requires additional evaluation and/or follow-up. Occasionally, biopsy or splenectomy may be required for definitive assessment given that some of tumours may demonstrate uncertain biologic behavior.

Induction of autoimmune diabetes in non-obese diabetic mice requires interleukin-21-dependent activation of autoreactive CD8⁺ T cells.

Non-obese diabetic (NOD) mice lacking interleukin (IL)-21 or IL-21 receptor do not develop autoimmune type 1 diabetes (T1D). We have shown recently that IL-21 may promote activation of autoreactive CD8(+) T cells by increasing their antigen responsiveness. To investigate the role of IL-21 in activating diabetogenic CD8(+) T cells in the NOD mouse, we generated IL-21-deficient NOD mice expressing the highly pathogenic major histocompatibility complex (MHC) class-I-restricted 8.3 transgenic T cell receptor (TCR). IL-21 deficiency protected 8.3-NOD mice completely from T1D. CD8(+) T cells from the 8.3-NOD.Il21(-/-) mice showed decreased antigen-induced proliferation but displayed robust antigen-specific cytolytic activity and production of effector cytokines. IL-21-deficient 8.3 T cells underwent efficient homeostatic proliferation, and previous antigen stimulation enabled these cells to cause diabetes in NOD.Scid recipients. The 8.3 T cells that developed in an IL-21-deficient environment showed impaired antigen-specific proliferation in vivo even in IL-21-sufficient mice. These cells also showed impaired IL-2 production and Il2 gene transcription following antigen stimulation. However, IL-2 addition failed to reverse their impaired proliferation completely. These findings indicate that IL-21 is required for efficient initial activation of autoreactive CD8(+) T cells but is dispensable for the activated cells to develop effector functions and cause disease. Hence, therapeutic targeting of IL-21 in T1D may inhibit activation of naive autoreactive CD8(+) T cells, but may have to be combined with other strategies to inhibit already activated cells.

The use of adjusted ideal body weight for overweight patients undergoing HPC mobilisation for autologous transplantation.

Generally, patients' actual body weight (ABW) is used to calculate the number of CD34⁺ cells to be harvested for autologous haematopoietic progenitor cell (HPC) transplantation. In our institution, 'overweight' patients weighing at least 25% more than their ideal body weight (IBW) have their adjusted ideal body weight (AdjIBW) used for determination of blood volume to be processed to achieve a minimum target of CD34⁺ cells per kilogram, as well as CD34⁺ cell dosage calculation at transplant. AdjIBW is calculated as follows: AdjIBW = IBW + 0.25 × (actual weight - IBW). We have used AdjIBW for 65/153 patients who have had autologous HPC harvests, with a median AdjIBW of 69 kg (range, 50-110 kg). Median actual weight was 90 kg (range, 62-175 kg). Median volume of peripheral blood processed to achieve a minimum 2 × 106 CD34⁺ cells/kg for these patients was 13.2 L (range, 5-35 L), and the median CD34⁺ cells × 106/kg collected for AdjIBW was 6.3 (range, 1.7-33). For normal-weight patients (n = 88; median ABW, 75 kg; range, 49-98 kg), the corresponding median apheresis volume was 16 L (range, 7-24 L), and median CD34⁺ cells × 106/kg harvested was 4.5 (range, 1.4-15.9). In total, 35 in a total transplant cohort of 82 patients had AdjIBW used to determine CD34⁺ cell dose at time of transplant, with a median of 4.5 × 106/kg, (if their ABW was used in the calculation; 3.1 × 106/kg), compared to median dose of 3.2 × 106/kg ABW for the normal-weight patient cohort. All patients engrafted with no significant difference between median times to neutrophil and platelet engraftment for the overweight (13 and 15 days, respectively) compared with normal-weight (12 and 14 days, respectively) patient cohorts. We conclude that the use of AdjIBW is a useful tool for successful harvest and subsequent transplant for overweight patients, with no adverse effect on engraftment times.

Effect of artesunate and mefloquine in combination on the Fridericia corrected QT intervals in Plasmodium falciparum infected adults from Thailand.

OBJECTIVE: To ascertain whether mefloquine (MQ) produces electrocardiogram (ECG) changes that could be a risk for Torsades de Pointe (TdP), a potentially malignant, ventricular tachyarrhythmia. METHODS: We measured the Fridericia corrected QT (QTcF) intervals on 12 lead ECGs on days (D) 0, 3, 7 in Plasmodium falciparum infected adults, treated with oral artesunate (AS) and MQ as a new fixed dose (n = 25) combination or loose tablets (n = 25) over 3 days. Target total doses were 12 mg/kg of AS and 24-25 mg/kg of MQ. MQ concentrations ([MQ]) were measured by HPLC. RESULTS: All ECG intervals were similar between drug arms and were combined for analysis. Mean QTcF values were 389 (D0), 407 (D3) and 399 (D7) ms (Ps < 0.003 vs. D0); corresponding heart rates and [MQ]s were 83, 67 and 73 beats/minute (Ps ≤ 0.0003 vs. D0) and 0, 3095 and 1721 ng/ml. One male patient (loose arm) had a D3 QTcF 504 ms (D0 406 ms, D7 433 ms). In the modelling of QTcF and JTcF from D0 to D7, significant effects were observed individually for [MQ], temperature and heart rate (HR). The MQ AUC(0-∞) was not a significant factor. Using a manual descending, model building approach to select variables, the HR was the only significant variable (P = 0.001) over time in the model that best explained the changes in the QTcF and JTcF intervals. CONCLUSIONS: In this small group of patients, slowing heart rates due to malaria resolution best explained the observed increases in the QTcF intervals.

Influence of sonication on the phenolic content and antioxidant activity of Terminalia catappa L. leaves.

AIM: This study was designed to evaluate the phenolic content and antioxidant activity of ethanolic extracts from T. catappa leaves obtained by different intervals of sonication. METHODS: Three commonly used methods were followed to evaluate phenolic content and four in vitro methods like 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) radical scavenging assay, ferric reducing antioxidant potency (FRAP), and total antioxidant capacity assays for measuring the antioxidant activities. Antioxidant values of these assays were expressed in terms of milligrams vitamin C equivalent (VCE) antioxidant activities. RESULTS: This study showed that extract obtained with 40 minutes of sonication possessed significant (P < 0.05) polyphenolic contents compared to 20 and 60 minutes sonication and control (24 hour maceration). Moreover, sonication of T. catappa leaf above 40 minutes was found to be unsuitable for extracting out phenolic contents. Even the results of antioxidant assays showed that 40 minutes of the sonicated extract exhibited significant (P < 0.05) VCE values compared to extracts obtained at different intervals of sonication and control. CONCLUSIONS: In sonication extraction method 40 minutes is an ideal time to obtain extract enriched with high polyphenolic content with good antioxidant activity from T. catappa leaves.

Analgesic activity, toxicity study and phytochemical screening of standardized Cinnomomum iners leaves methanolic extract.

Cinnomomum iners standardized leaves methanolic extract (CSLE) was subjected to analgesic, toxicity and phytochemical studies. The analgesic activity of CSLE was evaluated using formalin, hot plate and tail flick tests at doses of 100, 200 and 500 mg/kg. CSLE showed significant activity (P < 0.05) in the formalin model (late phase) on the rats at doses of 200 and 500 mg/kg. However, CSLE did not show activity in the hot plate and tail flick tests. The results obtained suggest that CSLE acts peripherally to relieve pain. For the toxicity study, CSLE was orally administered to the Swiss albino mice according to the Organization for Economic Co-Operation and Development (OECD) guideline 423. There was no lethality or toxic symptoms observed for all the tested doses throughout the 14-day period. Phytochemical screening of CSLE showed the presence of cardiac glycoside, flavonoid, polyphenol, saponin, sugar, tannin and terpenoid.

Challenges in assessing the implementation and effectiveness of physical activity and nutrition policy interventions as natural experiments.

The Ontario (Canada) government has instituted a policy requiring elementary schools to offer at least 20 min of daily physical activity for students in Grades 1-8 and replace non-nutritious vending machine foods with healthier choices. These policy interventions represent 'natural experiments' offering unique opportunities for conducting research and evaluation. The use of natural experiments to contribute evidence on the effectiveness of policy interventions is identified as an underused tool for public health [Tudor-Locke, C., Ainsworth, B. E. and Popkin, B. M. (2001) Active commuting to school: an overlooked source of children's physical activity? Sports Medicine, 31, 309-313; Petticrew, M., Cummins, S., Ferrell, C., Findlay, A., Higgins, C., Hoy, C. et al. (2005) Natural experiments: an underused tool for public health? Public Health, 119, 751-757]. To date, some Canadian school-based food and nutrition policies are being monitored, but their impact on child and youth obesity is unknown [Canadian Institute for Health Information. (2006) Improving the Health of Canadians: Promoting Healthy Weights, Ottawa, ON]. There are a number of challenges to the evaluation of policy interventions as natural experiments. Often, there are little or no baseline data available to use as the basis for assessing change. Government policies that result in the adoption of particular approaches across large jurisdictions, such as provinces, may result in wide variation in the design and implementation of interventions. Thus, in some cases, natural experiments may be at risk of having low potential to be adequately evaluated on key outcomes. In this paper, we discuss the context of these challenges in relation to the Ontario government school physical activity and nutrition policies.

Metastasis of squamous cell carcinoma of the oral tongue is associated with down-regulation of epidermal fatty acid binding protein (E-FABP).

Squamous cell carcinoma (SCC) of the tongue is one of the most common cancers encountered in India, due to the prevalent habits of tobacco chewing and smoking. Up to 40% of the early stage tumours (clinical N0 M0) presenting at the Tata Memorial Hospital have occult cervical lymph node metastasis. Therefore, features in the primary tumour that would predict metastasis would be very useful for designing therapeutic approaches. Hence, we aimed at detecting genotypic markers of the metastatic sub-clones within the heterogeneous primary tumour population. We studied the differential expression of mRNAs between the primary tumour samples of SCC of the oral tongue and their metastasis by differential display analysis and identified a gene, FABP5, coding for Epidermal fatty acid binding protein (E-FABP-GenBank Accession ). Its expression was up to 4-fold higher in the primary tumours (67%) as compared to the corresponding metastatic lymph nodes by northern blot analysis.

Failed regional anesthesia with reduced spinal bupivacaine dosage in a parturient with achondroplasia presenting for urgent cesarean section.

A 36-year-old patient with a history of previous back surgery, asthma, latex allergy and achondroplasia presented for urgent cesarean delivery at 31 weeks' gestation for worsening nonimmune fetal hydrops. The fetus was diagnosed with trisomy 21 and achondroplasia. Because of the urgent clinical situation, the patient was given a spinal anesthetic, which required supplemental intravenous sedation after delivery of the fetus. This case report discusses the controversies in anesthetic management of this complicated patient and compromised fetus regarding general anesthesia, epidural, spinal and combined spinal-epidural anesthesia.

Two cases of refractory warm autoimmune hemolytic anemia treated with rituximab.

Autoimmune hemolytic anemia is thought to be mediated via auto-antibodies produced by lymphoid B cells. This may be an idiopathic process or secondary to an underlying infection or lymphoproliferative disorder. Conventional treatment comprises immunosuppression with corticosteroids and, in some cases, splenectomy. A proportion of patients require lifelong immunosuppression to maintain disease remission. Monoclonal antibody rituximab has gained widespread acceptance in the management of B-cell malignancies. Additionally, it has been used to treat disorders associated with auto-antibody production, such as cold hemagglutinin disease, immune thrombocytopenia, and Evans syndrome. Its use in the treatment of patients with autoimmune hemolytic anemia in the setting of allogeneic bone marrow transplantation as well as in patients with an underlying lymphoproliferative disease has also been reported. We report herein the successful use of rituximab in the treatment of two patients with idiopathic refractory warm autoimmune hemolytic anemia, who are still in remission at 15 and 9 months following treatment.

Inhibitors of hypoxic pulmonary vasoconstriction prevent high-altitude pulmonary edema in rats.

OBJECTIVE: Rapid ascent to high altitude causes hypoxic pulmonary vasoconstriction (HPV) and leads to high-altitude pulmonary edema (HAPE) in susceptible humans. Vasodilating agents lessen HAPE (as evidenced by radiographic and gas exchange measurements), but data establishing their effectiveness on alveolar protein content and hemorrhage are lacking. This study was designed to assess whether preventing HPV reduces the alveolar-capillary barrier leak characteristic of HAPE. METHODS: Rats were pretreated with saline (control group) or acetazolamide (20 mg/kg) or nickel chloride (60 mg/kg) (experimental groups) to prevent HPV and were exposed to high altitude (0.5 atm for 24 hours) in a hypobaric chamber. High-altitude pulmonary edema was then assessed by gravimetric analysis of heart and lung tissue, a visual score of lung hemorrhage, and measurement of protein content in bronchoalveolar lavage fluid. RESULTS: Saline-treated rats developed a mild protein leak indicative of early HAPE that was prevented by inhibition of HPV: protein in bronchoalevolar lavage fluid of saline-treated rats, 21.6 +/- 3.2 mg/dL (mean +/- SEM); HPV-inhibited rats, 12.6 +/- 0.7 mg/dL; air-exposed rats, 13.4 +/- 1.4 mg/ dL (P < .05 saline vs other groups, analysis of variance [ANOVA]). The lungs of saline-treated rats were also mildly hemorrhagic (3.4 +/- 0.9 on a scale of 1-9, where 1 is normal), and the lungs of HPV-inhibited rats appeared normal (1.2 +/- 0.1) (P = .032). Finally, right ventricle weight (adjusted for initial body weight) increased in saline-treated rats: saline-treated, 0.64 +/- 0.02; HPV-inhibited, 0.56 +/- 0.02; air-exposed, 0.59 +/- 0.02 (P < .05, saline vs HPV-inhibited group). CONCLUSION: The results demonstrate that treatment with NiCl2 or acetazolamide prevents HAPE in rats and are consistent with a role for elevated pulmonary artery pressure in the pathogenesis of HAPE.