Lower Lactate Dehydrogenase Levels Research Articles

Pretreatment neutrophilto lynphocyte ratio in ewing sarcoma family of tumors: An analysis of 570 patients.

e22504 Background: Ewing sarcoma family tumor (ESFT) is a systemic disease and inflammatory in nature. Inflammatory biomarkers have been identified as prognostic marker in various malignancies including sarcoma. Here we have evaluated the prognostic implication of pretreatment neutrophil to lymphocyte ratio (NLR) in ESFT. Methods: We have calculated baseline NLR from peripheral blood parameters in 570 patients of ESFT treated with uniform chemotherapy protocol in our institution from June’2003 to Feb’2015. Treatment protocol consists of neoadjuvant chemotherapy followed by surgery and/or radiotherapy as local treatment modality and adjuvant chemotherapy. NLR was dichotomized as high and low with high NLR defined as value over the median. Data was censored on 30th Jan’2016. Results: Median age was 15 years (range: 0.1-55) with male: female ratio of 40:17 and 41% (n = 236) patients had metastasis at presentation. Most common sites of tumor were long bones in 209 (37%), thorax in 108 (19%) and pelvis in 90 (16%) patients. Hundred-one (18%) had a soft tissue primary. Twenty-five percent (n = 144) patients had systemic symptoms at presentation. Median symptom duration was 4 months (range: 0.5-36) with median tumor size 8.8 cm (range: 1.6-26). Median NLR was 1.55 (range: 0.08-12.87). High NLR was associated with older age (p = 0.002), female sex (p = 0.02), low serum albumin (p = 0.003) and high lactate dehydrogenase level (p = 0.03). After median follow-up of 32 months (range: 0.8-152), 5-year event-free survival (EFS) was 25.3% & 35.8% and overall survival (OS) was 38% & 48.7%, respectively in whole cohort and in those with localized disease. In the whole cohort, high NLR ( > 1.55) emerged as independent prognostic factor predicting inferior EFS (Hazard ratio-1.36, p = 0.03) along with metastasis at presentation (p < 0.001) and tumor diameter > 8 cm (p = 0.005), in multivariate analysis. NLR couldn’t predict OS. Conclusions: High pretreatment NLR emerged as independent prognostic factor predicting inferior EFS in patients with ESFT. It is an easily available and cost effective biomarker. Prognostic nature of NLR should be evaluated in a prospective study and if proven, should be included in prognostic model to tailor therapy.

Factors predictive of leg-ulcer healing in sickle cell disease: a multicentre, prospective cohort study.

Leg ulcers (LUs) are a chronic and severe complication of sickle cell disease (SCD). A prospective study in patients with SCD to identify factors associated with complete healing and recurrence of LUs is lacking. To determine clinical and biological factors associated with SCD-LU complete healing and recurrence. This prospective, observational cohort study was conducted at two adult SCD referral-centre sites (2009-2015) and included 98 consecutive patients with at least one LU lasting ≥ 2 weeks. The primary end points compared patients with healed vs. nonhealed LUs at week 24, and patients with vs. without recurrence during follow-up. The median (interquartile range) LU area, duration and follow-up were, respectively, 6·2 cm2 (3-12·8), 9 weeks (4-26) and 65·8 weeks (23·8-122·1). At week 24, LUs were healed in 47% of patients, while 49% of LUs recurred. Univariate analyses identified inclusion LU area < 8 cm2 (82% vs. 35%; P < 0·001), inclusion LU duration < 9 weeks (65% vs. 35%; P = 0·0013) and high median fetal haemoglobin level (P = 0·008) as being significantly associated with complete healing at week 24, and low lactate dehydrogenase level (P = 0·038) as being associated with recurrence. Multivariate analyses retained LU area < 8 cm2 (odds ratio 6·73, 95% confidence interval 2·35-19. 31; P < 0·001) and < 9 weeks' duration (OR 3·19, 95% confidence interval 1·16-8·76; P = 0·024) as being independently associated with healing at week 24. Factors independently associated with recurrence could not be identified. SCD-LU complete healing is independently associated with the clinical characteristics of LUs rather than the clinical or biological characteristics of SCD.

Primary Central Nervous System Lymphomas of the Brain: A Retrospective Analysis in a Single Institution.

Primary central nervous system lymphomas (PCNSLs) are relatively rare brain tumors. Accurate diagnosis is usually made by surgical biopsy. In addition to surgical biopsy and decompression, treatment options include high-dose methotrexate and chemotherapy, radiation therapy, and stem cell therapy. Because of the rarity of this disease, guidelines for PCNSL diagnosis and treatment usually are formed from a large series of experiences. We retrospectively reviewed 79 patients in our tertiary referral center during a 13-year period. All patients with PCNSL underwent surgical or bone marrow biopsy procedures, and diagnoses were confirmed by hematologists or neuropathologists. At the time of diagnosis, 44 patients presented with a single lesion. Human immunodeficiency virus was confirmed positive in 1 patient. The standard therapy protocol included high-dose methotrexate (intravenous and intrathecal) and chemotherapy with cytosine arabinoside, followed by external irradiation of the brain. Significant prognostic factors in these patients were low serum lactate dehydrogenase levels and radiation therapy. Multiplicity of lesions at time of diagnosis did not imply a worse outcome, and surgical resection and debulking did not show a significant survival benefit. PCNSL has a poor prognosis. Further clinical trials and diagnostic tools are needed to reveal the complexity of this disease.

Serum lactate dehydrogenase predicts prognosis and correlates with systemic inflammatory response in patients with advanced pancreatic cancer after gemcitabine-based chemotherapy

Serum lactate dehydrogenase (LDH) concentrations correlate with tumor progression and poor outcome. We evaluated the predictive value of serum LDH level for overall survival (OS) of patients with advanced pancreatic cancer after gemcitabine-based chemotherapy. We retrospectively enrolled 364 patients with locally advanced or metastatic pancreatic adenocarcinoma who were then allocated to training (n = 139) and validation cohorts (n = 225). We evaluated the association between serum LDH levels and OS as well as with markers of systemic inflammation, including neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR) and lymphocyte/monocyte ratio (LMR). Kaplan–Meier analyses revealed that low serum LDH levels in the training cohort significantly correlated with longer OS. Multivariate analysis identified the serum LDH levels as an independent prognostic predictor of OS (p = 0.005). Serum LDH levels correlated positively with NLR and PLR and correlated negatively with LMR. Similar results were obtained for the validation cohort, except that multivariate analysis identified the serum LDH level as a significant prognostic predictor and only a statistical trend for OS (p = 0.059). We conclude that serum LDH levels were associated with the systemic inflammatory response and served as a significant prognostic predictor of OS. Serum LDH levels predicted OS in patients with advanced pancreatic cancer after gemcitabine-based palliative chemotherapy.

Higher HOPX expression is associated with distinct clinical and biological features and predicts poor prognosis in de novo acute myeloid leukemia.

Homeodomain-only protein homeobox (HOPX) is the smallest homeodomain protein. It was regarded as a stem cell marker in several non-hematopoietic systems. While the prototypic homeobox genes such as the HOX family have been well characterized in acute myeloid leukemia (AML), the clinical and biological implications of HOPX in the disease remain unknown. Thus we analyzed HOPX and global gene expression patterns in 347 newly diagnosed de novo AML patients in our institute. We found that higher HOPX expression was closely associated with older age, higher platelet counts, lower white blood cell counts, lower lactate dehydrogenase levels, and mutations in RUNX1, IDH2, ASXL1, and DNMT3A, but negatively associated with acute promyelocytic leukemia, favorable karyotypes, CEBPA double mutations and NPM1 mutation. Patients with higher HOPX expression had a lower complete remission rate and shorter survival. The finding was validated in two independent cohorts. Multivariate analysis revealed that higher HOPX expression was an independent unfavorable prognostic factor irrespective of other known prognostic parameters and gene signatures derived from multiple cohorts. Gene set enrichment analysis showed higher HOPX expression was associated with both hematopoietic and leukemia stem cell signatures. While HOPX and HOX family genes showed concordant expression patterns in normal hematopoietic stem/progenitor cells, their expression patterns and associated clinical and biological features were distinctive in AML settings, demonstrating HOPX to be a unique homeobox gene. Therefore, HOPX is a distinctive homeobox gene with characteristic clinical and biological implications and its expression is a powerful predictor of prognosis in AML patients.

Prognostic factors in neuroendocrine carcinoma: biological markers are more useful than histomorphological markers

Gastroenteropancreatic neuroendocrine carcinomas (GEP-NEC) are a very aggressive type of cancer, for which prognostic factors are lacking. We analysed clinical and histomorphological prognostic markers of overall survival (OS), completed with a record of biological and haematological data of patients diagnosed between December 2002 and December 2015. The median OS was 16 months (95% CI 13.9–18.1). After univariate analysis, performance status (PS) ≥ 2 and stage IV were associated with a worse outcome (9 months and 14 months, respectively), as well as patients with lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) levels ≥ 2 ULN (9 months and 8 months, respectively). After multivariate analysis, LDH and AST levels were the only factors that remained significantly associated with better survival: HR 0.36 (p = 0.04) and 0.31 (p = 0.03), respectively. When patients had elevated LDH and AST levels, OS was 20 months, when they had high LDH or AST levels, 13 months and 8 months in the group with low LDH and AST levels (p < 0.001). Therefore, biological data appeared to be more relevant prognostic factors than usual factors described in other studies (PS, stage, and Ki-67). Considering LDH and AST levels at diagnosis could help physicians to predict survival and to stratify patients for clinical trials.

&lt;i&gt;In vitro&lt;/i&gt; oral epithelium cytotoxicity and &lt;i&gt;in vivo&lt;/i&gt; inflammatory inducing effects of anesthetic rice gel

In vitro cytotoxicity of lidocaine hydrochloride (LH) and prilocaine hydrochloride (PH) to oral epithelial cells, isolated from tissue specimens of healthy volunteers, were evaluated. Cell vitality after treating with 1-20% anesthetic solutions for 5 and 30 min was investigated using F-actin and 4',6-diamidino-2-phenylindole staining technique and observed by fluorescence microscopy. Vitality rate of more than 90% was found in all anesthetic groups at both durations whereas no survived cell was found in a positive control group (sodium dodecyl sulfate). Lactate dehydrogenase (LDH) assay was performed to confirm the safety of both anesthetic solutions. Cell culture medium after treating with LH or PH for 5 and 30 min were collected and analyzed using commercial kits. The results showed no significant difference between the test groups and negative control group (untreated culture) with low LDH levels. In vivo inflammatory inducing effect of 5, 10, 20% LH or PH loaded rice gels was investigated in healthy volunteers. Tumor necrosis factor alpha (TNF-α) in gingival cervicular fluid was determined by ELISA technique. It was found that the expression of TNF-α was not different from the baseline. The expression of this inflammatory mediator caused by the commercial gel was higher than those of both anesthetic rice gels. It might be due to the effects of other excipients in the formulation of the commercial product. It is concluded that LH or PH possess no cytotoxicity to oral epithelium and the developed rice gel base and LH and PH rice gels do not induce inflammatory effect to oral tissues.

Serum LDH predicts benefit from bevacizumab beyond progression in metastatic colorectal cancer

Background:Different antiangiogenics are currently indicated in the second-line treatment of metastatic colorectal cancer (mCRC), following a first-line bevacizumab-containing treatment. The magnitude of benefit is limited, but no predictors of benefit have been identified.Methods:A total of 184 mCRC patients progressing to a first-line bevacizumab-containing treatment were randomised in the BEBYP study to continue or not the antiangiogenic in combination with a second-line chemotherapy. A subgroup analysis according to baseline serum lactate dehydrogenase (LDH) levels was carried out.Results:A significant interaction effect between LDH levels and treatment was found in terms of progression-free survival (PFS; P=0.002). Although patients with low LDH levels achieved significant PFS benefit from the continuation of bevacizumab (HR: 0.39 (95% CI: 0.23–0.65)), patients with high levels did not (HR: 1.10 (95% CI: 0.74–1.64)). Consistent results were reported in overall survival (OS; P=0.075).Conclusions:As preclinical evidence suggests that serum LDH may be a marker of tumour angiogenesis activation, low levels may indicate that bevacizumab is still efficacious in inhibiting angiogenesis. Validation of present results in subgroup analyses of other randomised trials of second-line angiogenesis inhibitors is warranted.

Comparison of Laboratory Data of Patients with Tafro Syndrome and Idiopathic Multicentric Castleman Disease: A Japanese Retrospective Study

Background: First described in 2010, TAFRO syndrome is a clinical disorder presenting as thrombocytopenia, anasarca, fever, reticulin myelofibrosis, renal insufficiency, and organomegaly with unknown etiology. Onset of this syndrome is usually acute or subacute, and disease progression is rapid; a percentage of patients with this disorder have unfavorable clinical courses. Therefore, it is critical to identify an optimal management strategy for this disorder. Histopathological features of lymph nodes from patients with TAFRO syndrome are usually indistinguishable from that of patients with Castleman disease (CD) of mixed type histology. In addition, clinical features of patients with TAFRO syndrome are similar to those of patients with multicentric CD (MCD). Accordingly, some investigators assume TAFRO syndrome as a subcategory of idiopathic MCD (iMCD). However, whether TAFRO syndrome is entirely a part of iMCD category of diseases, or whether these are similar yet distinct disorders has not been clarified.Aims: To elucidate the clinical features of TAFRO syndrome, and to clarify the association between TAFRO syndrome and iMCD.Methods: Since 2013, a multicenter retrospective clinical study has been conducted by the Japanese TAFRO Syndrome Research Group. By July 2016, data of >200 patients with suspected TAFRO syndrome or MCD were collected. Utilizing this database, we compared laboratory data of patients with TAFRO syndrome with those of iMCD patients without TAFRO features. Diagnosis of TAFRO syndrome was defined according to our diagnostic criteria as previously described (Int J Hematol 2016;103:686-692), and the diagnosis of MCD was defined by pathological findings of lymph nodes. HIV or HHV-8 positive patients were excluded from this study. Comparisons between the two groups were performed using the Mann-Whitney U test. P values of <0.05 were considered statistically significant. This study was performed in accordance with the Declaration of Helsinki, and the study protocol was approved by the Ethics Committee of Kanazawa Medical University and by the ethics committee of each participating institution.Results: According to our criteria, 84 patients were diagnosed with TAFRO syndrome, and 88 patients were diagnosed with non-TAFRO iMCD. Male to female ratios and median ages at diagnosis were comparable between these two groups. Hemoglobin, C-reactive protein, creatinine, lactate dehydrogenase (LDH), alkaline phosphatase (ALP), gamma-guanosine triphosphate (ƒÁ-GTP), ferritin, triglyceride, and D-dimer levels were significantly higher in patients with TAFRO syndrome than in patients with iMCD (Table 1). In contrast, platelet count, IgG, and albumin levels were significantly lower in patients with TAFRO syndrome than in patients with iMCD (Table 1). Seventeen of 84 TAFRO patients died due to disease progression, infection, or hemorrhage, whereas only 4 of 88 non-TAFRO iMCD patients died.Discussion: TAFRO syndrome is defined based on clinical manifestations and CD is defined via typical histopathological findings of affected lymph nodes. Consistent with its definition, patients with TAFRO syndrome in our cohort showed low platelet counts and renal dysfunction, which were not commonly observed in non-TAFRO iMCD patients. Serum ALP and ƒÁ-GTP were significantly elevated in patients with TAFRO syndrome, whereas they were within the normal ranges in patients with non-TAFRO iMCD. Interestingly, serum IgG level was not elevated in TAFRO patients, whereas it was remarkably elevated in non-TAFRO iMCD patients. Similarly, low serum LDH level was another characteristic in iMCD patients that was not commonly observed in TAFRO patients. The majority of TAFRO patients showed D-dimer elevation, indicating that this syndrome is frequently accompanied by disseminated intravascular coagulation syndrome. Patients with TAFRO syndrome followed relatively aggressive courses, whereas most patients with non-TAFRO iMCD in our cohort followed indolent clinical courses.Conclusions: Although several clinical and pathological features of TAFRO syndrome resembled those of iMCD, these two conditions manifested distinct laboratory parameters and differing clinical courses. From the results of this study, we postulate that TAFRO syndrome may not be a sub-category of iMCD and that both are distinct diseases with overlapping features. [Display omitted] DisclosuresKinoshita:Zenyaku: Honoraria, Research Funding; Takeda: Research Funding; Chugai: Honoraria, Research Funding; Ono: Research Funding; Gilead: Research Funding; Eisai: Honoraria, Research Funding; Solasia: Research Funding; Janssen: Honoraria; Kyowa Kirin: Honoraria. Aoki:SymBio Pharmaceuticals: Consultancy. Masaki:Takeda: Research Funding; Kyowa Kirin: Research Funding; Chugai: Research Funding.

The role of FDG PET/CT in patients treated with neoadjuvant chemotherapy for localized bone sarcomas

PurposeThe histological response to neoadjuvant chemotherapy is an important prognostic factor in patients with osteosarcoma (OS) and Ewing sarcoma (EWS). The aim of this study was to assess baseline primary tumour FDG uptake on PET/CT, and serum values of alkaline phosphatase (ALP) and lactate dehydrogenase (LDH), to establish whether these factors are correlated with tumour necrosis and prognosis.MethodsPatients treated between 2009 and 2014 for localized EWS and OS, who underwent FDG PET/CT as part of their staging work-up, were included. The relationships between primary tumour SUVmax at baseline (SUV1), SUVmax after induction chemotherapy (SUV2), metabolic response calculated as [(SUV1 − SUV2)/SUV1)] × 100, LDH and ALP and tumour response/survival were analysed. A good response (GR) was defined as tumour necrosis >90 % in patients with OS, and grade II-III Picci necrosis (persitence of microscopic foci only or no viable tumor) in patients with Ewing sarcoma.ResultsThe study included 77 patients, 45 with EWS and 32 with OS. A good histological response was achieved in 53 % of EWS patients, and 41 % of OS patients. The 3-year event-free survival (EFS) was 57 % in EWS patients and 48 % OS patients. The median SUV1 was 5.6 (range 0 – 17) in EWS patients and 7.9 (range 0 – 24) in OS patients (p = 0.006). In EWS patients the GR rate was 30 % in those with a high SUV1 (≥6) and 72 % in those with a lower SUV1 (p = 0.0004), and in OS patients the GR rate was 29 % in those with SUV1 ≥6 and 64 % in those with a lower SUV1 (p = 0.05). In the univariate analysis the 3-year EFS was significantly better in patients with a low ALP level (59 %) than in those with a high ALP level (22 %, p = 0.02) and in patients with a low LDH level (62 %) than in those with a high LDH level (37 %, p = 0.004). In EWS patients the 3-year EFS was 37 % in those with a high SUV1 and 75 % in those with a low SUV1 (p = 0.004), and in OS patients the 3-year EFS was 32 % in those with a high SUV1 and 66 % in those with a low SUV1 (p = 0.1). Histology, age and gender were not associated with survival. In the multivariate analysis, SUV1 was the only independent pretreatment prognostic factor to retain statistical significance (p = 0.017). SUV2 was assessed in 25 EWS patients: the median SUV2 was 1.9 (range 1 – 8). The GR rate was 20 % in patients with a high SUV2, and 67 % in those with a low SUV2 (p = 0.02). A good metabolic response (SUV reduction of ≥55 %) was associated with a 3-year EFS of 80 % and a poor metabolic response with a 3-year EFS of 20 % (p = 0.05). In the OS patients the median SUV2 was 2.7 (range 0 – 4.5). Neither SUV2 nor the metabolic response was associated with outcome in OS patients.ConclusionFDG PET/CT is a useful and noninvasive tool for identifying patients who are more likely to be resistant to chemotherapy. If this finding is confirmed in a larger series, SUV1, SUV2 and metabolic response could be proposed as factors for stratifying EWS patients to identify those with high-grade localized bone EWS who would benefit from risk-adapted induction chemotherapy.

Radium-223 Use in Clinical Practice and Variables Associated With Completion of Therapy

BackgroundRadium-223 has shown clinical efficacy in metastatic castration-resistant prostate cancer. Despite improvement in quality of life and survival, practice patterns and utility of this agent outside the context of clinical trials have not been fully characterized. The primary objective in this study was to evaluate variables associated with completion of 5 to 6 radium-223 doses. Patients and MethodsWe conducted retrospective analyses of patients who received radium-223 (n = 135). Patients were classified into 3 cohorts: 1 to 2, 3 to 4, or 5 to 6 radium-223 doses. We evaluated the association of clinical and laboratory variables with the number of cycles administered (5-6 vs. 1-4 doses). ResultsTwenty-five patients (18.5%) received 1 to 2 radium-223 doses, 27 (20.0%) received 3 to 4, and 83 (61.5%) received 5 to 6. The most common reasons for treatment discontinuation included disease progression (61.5%, n = 40), patient preference (15.4%, n = 10), and toxicity (10.8%, n = 7). Factors associated with therapy completion in univariate analysis included previous sipuleucel-T treatment (P = .068), no previous abiraterone or enzalutamide treatment (P = .007), hemoglobin ≥ lower limit of normal (LLN; P = .006), white blood cell count ≥ LLN (P = .045), absolute neutrophil count (ANC) ≥ LLN (P = .049), lower alkaline phosphatase (P = .029), and lower lactate dehydrogenase levels (P = .014). Factors associated with therapy completion in multivariable analysis included previous sipuleucel-T treatment (P = .009), hemoglobin ≥ LLN (P = .037), and ANC ≥ LLN (P = .029). ConclusionSeveral clinical parameters are associated with radium-223 therapy completion. In general, these parameters reflect earlier disease stage. These data are hypothesis-generating and prospective testing of the optimal number of radium-223 doses is warranted.

Hyperpolarized (13)C MR imaging detects no lactate production in mutant IDH1 gliomas: Implications for diagnosis and response monitoring.

Metabolic imaging of brain tumors using 13C Magnetic Resonance Spectroscopy (MRS) of hyperpolarized [1-13C] pyruvate is a promising neuroimaging strategy which, after a decade of preclinical success in glioblastoma (GBM) models, is now entering clinical trials in multiple centers. Typically, the presence of GBM has been associated with elevated hyperpolarized [1-13C] lactate produced from [1-13C] pyruvate, and response to therapy has been associated with a drop in hyperpolarized [1-13C] lactate. However, to date, lower grade gliomas had not been investigated using this approach. The most prevalent mutation in lower grade gliomas is the isocitrate dehydrogenase 1 (IDH1) mutation, which, in addition to initiating tumor development, also induces metabolic reprogramming. In particular, mutant IDH1 gliomas are associated with low levels of lactate dehydrogenase A (LDHA) and monocarboxylate transporters 1 and 4 (MCT1, MCT4), three proteins involved in pyruvate metabolism to lactate. We therefore investigated the potential of 13C MRS of hyperpolarized [1-13C] pyruvate for detection of mutant IDH1 gliomas and for monitoring of their therapeutic response. We studied patient-derived mutant IDH1 glioma cells that underexpress LDHA, MCT1 and MCT4, and wild-type IDH1 GBM cells that express high levels of these proteins. Mutant IDH1 cells and tumors produced significantly less hyperpolarized [1-13C] lactate compared to GBM, consistent with their metabolic reprogramming. Furthermore, hyperpolarized [1-13C] lactate production was not affected by chemotherapeutic treatment with temozolomide (TMZ) in mutant IDH1 tumors, in contrast to previous reports in GBM. Our results demonstrate the unusual metabolic imaging profile of mutant IDH1 gliomas, which, when combined with other clinically available imaging methods, could be used to detect the presence of the IDH1 mutation in vivo.

Successful Continuation of Peritoneal Dialysis after "Sweet" Hydrothorax

Abstract A 44-year-old woman with end-stage renal disease presented with dyspnea on exertion and a vague chest pain about two weeks after commencing continuous ambulatory peritoneal dialysis (CAPD) four months ago. A chest x-ray revealed massive unilateral right-sided pleural effusion. Laboratory analysis of the effusion revealed low protein and lactate dehydrogenase but elevated glucose levels were consistent with transudate and pleuroperitoneal leakage. Pleural glucose concentration was much higher than patients’ serum glucose concentration, which was suggestive of "sweet" hydrothorax because of this high glucose concentration. It is advisable to keep this condition in mind among the differenttial diagnoses of hydrothorax in patients on CAPD.

Serum 25-hydroxyvitamin D Insufficiency in B-Chronic Lymphoid Leukemia at the Time of Disease Presentation in Pakistan

Serum 25-hydroxyvitamin D insufficiency is very common in Pakistan and is often related to inferior prognosis in some cancers but limited data exist for hematopoietic malignancies. This study was conducted to determine the vitamin D insufficiency in B-chronic lymphoid leukemia (CLL) cases at the time of presentation and its possible correlation with clinical staging, hematological parameters and biochemical markers. This descriptive cross sectional study was carried at Liaquat National Hospital from January 2011 to June 2013. Sixty patients with B-chronic lymphoid leukemia were enrolled. Complete blood count, vitamin D levels, serum urea, creatinine, uric acid and LDH levels were assessed. Data were compiled and analyzed using SPSS version 21. Out of 60 patients, 42 (70%) were male and 18 (30%) were female. Mean age was 59.0±9.2 years. The frequency of vitamin D insufficiency was found to be 56.7%. Overall insufficiency was more frequently seen in male gender (40%). Vitamin D insufficiency demonstrated a positive association with low lactate dehydrogenase levels (P=0.005). No links were established with age, clinical stage, hematological and other biochemical markers. Vitamin D insufficiency is high compared with Western studies. Whether normalization of vitamin D insufficiency in deficient B-CLL patients could improve the clinical outcome or delay disease progression will require further studies.

Contradictory roles of Porphyromonas gingivalis gingipains in caspase-1 activation.

Porphyromonas gingivalis utilizes its major proteases, Arg gingipains (RgpA and RgpB) and Lys gingipain (Kgp), for dysregulation of host immune systems. The aim of this study was to investigate the roles of gingipains in caspase-1 activation and its sequelae in P. gingivalis-infected macrophages. Infection with P. gingivalis at low multiplicity of infections (MOIs), but not at high MOIs, resulted in low levels of interleukin-1β and lactate dehydrogenase without detectable active caspase-1 in the culture supernatants. The proteins released from caspase-1-activated cells were rapidly degraded by gingipains. However, P. gingivalis with gingipains induced higher intracellular caspase-1 activity in the infected cells than the gingipain-null mutant, which was associated with ATP release from the infected cells. In addition, growing the gingipain-null mutant with gingipains enhanced caspase-1 activation by the mutant. In contrast, inhibition of the protease activity of Kgp or Rgps increased the caspase-1-activating potential of wild-type P. gingivalis, indicating an inhibitory effect of the collaborative action of Kgp and Rgps. These results illuminate the contradictory roles of gingipains in the manipulation of host defence systems by P. gingivalis, as they act by both stimulating and inhibiting innate immune responses.

CXCL13, CCL4, and sTNFR as circulating inflammatory cytokine markers in primary and SLE-related autoimmune hemolytic anemia.

BackgroundA considerable proportion of autoimmune hemolytic anemia (AIHA) are secondary to underlying autoimmune disorders, especially syetemic lupus erythematosus (SLE), and the clinical and laboratory index for early discrimination between primary and SLE-related AIHA has yet to be defined. In the present study, we proposed novel cytokine patterns in the pathogenesis of AIHA as well as parameters for the timely identification of SLE-related patients.MethodsAIHA patients confirmed by immunohematology techniques from September 2010 to December 2012 in our facility were consecutively included and categorized into primary (n = 19) and SLE-related (n = 18) groups. Plasma cytokine profiles were measured in a single procedure by Quantibody Human Inflammatory Array 1 (RayBiotech, Norcross, GA).ResultsSLE-related AIHA patients demonstrated younger age (39 ± 20 vs.57 ± 16 years, p = 0.004), poorer reticulocyte compensation (6.8 ± 7.1 vs.12.2 ± 8.6%, p = 0.045), lower levels of lactate dehydrogenase [361 (265-498) vs. 622 (387-1154) U/L, p = 0.004], and higher occurrence of anticardiolipin antibody [9/18 (50%) vs. 2/19 (10.9%), p = 0.009]. MCP-1/CCL2, MIP-1β/CCL4, BLC/CXCL13, IL-8/CXCL8, sTNFRI, and sTNFRII were significantly up-regulated in both groups, while sTNFRII was remarkably higher in SLE-related patients. Among both groups, hemoglobin level was negatively correlated with CXCL13 (r = -0.332, p = 0.044), while reticulocyte count was positively correlated with CCL4 (r = 0.456, p = 0.005).ConclusionCXCL13 and CCL4 could act as circulating biomarkers in AIHA, and indicated disease severity and erythroid compensation, respectively. Higher plasma sTNFRII might favor the diagnosis of SLE-related instead of primary AIHA.

Effects of Contaminated Fish Oil on Hepatic FAS and HMGCR Gene Expression and Liver Function Enzyme Activities

Concerns surrounding contamination with persistent organic pollutants (POPs) prompt caution in the consumption of fish and fish oil, despite their benefits on cardiovascular disease. The present study compared the effects of fish oil spiked with polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCs) to unmodified fish oil on hepatic gene expression of enzymes involved in lipid metabolism. Liver function enzyme levels were also examined. Thirty Sprague-Dawley rats were divided into three groups consuming a diet containing unmodified fish oil, fish oil spiked with POPs, or a control diet without fish oil. After 9 weeks of feeding, gene expression of fatty acid synthase (FAS) was significantly downregulated in both fish oil groups (P = 0.050) compared to control, while the unmodified fish oil group exhibited a tendency towards lower HMG-CoA reductase (HMGCR) transcription. This may explain the significantly lower levels of serum triglycerides in both fish oil groups (P = 0.002), while the unmodified fish oil group showed a tendency towards lower total cholesterol. Rats on the unmodified fish oil diet had significantly lower levels of lactate dehydrogenase (P = 0.040), while rats consuming diets with spiked fish oil exhibited significantly increased levels of alanine aminotransferase (P = 0.029). These findings point to differential genetic regulation from POP contamination and raise concerns surrounding liver damage during the consumption of spiked fish oils. Future studies should investigate the effects of a lengthened feeding time, varying contaminant doses, and interactions between contaminant mixtures and oils of varying composition. Supported by CHNR08-810, SDSU UGP and NUTR 302L class.

Effect of wood betony (Stachys lavandulifolia Vahl) extract on some serum biochemical changes and acute stress response in juvenile common carp (Cyprinus carpio)

The effects of four different levels of wood betony (WB) (Stachys lavandulifolia Vahl) extract (0, 2, 4 and 8% W/W in the diet) were investigated on some serum enzymatic activities and acute stress response of juvenile common carp (Cyprinus carpio). After 10 weeks post feeding, two groups of fish (0 and 8% WB) were subjected to handling and crowding stress and the stress responses including serum cortisol, glucose and some electrolytes (Na + , K + and Ca +2 ) levels were assayed. The results revealed that the fish fed on 8% WB had significantly lower levels of lactate dehydrogenase (LDH) and alanine transaminase (ALT) compared to the control group (P 0.05). The potassium and calcium levels showed insignificant fluctuations post stress (P>0.05). Dietary inclusion of WB seems to improve liver function and response to acute stress in juvenile common carp.

The effect of high intensity interval training on cardioprotection against ischemia-reperfusion injury in wistar rats.

The aims of the present study were to determine whether short term high intensity interval training (HIIT) could protect the heart against ischemia reperfusion (IR) injury; and if so, to evaluate how long the exercise-associated protection can be lasted. Sixty-three rats were randomly assigned into sedentary (n = 15), sham (n = 7), and exercise groups (n = 41). Rats in the exercise groups performed 5 consecutive days of HIIT on treadmill: 5 min warm up with 50 % VO2max, 6×2 min with 95-105 % VO2max (about 40 to 45 m/min), 5×2 min recovery with 65-75 % VO2max (about 28 to 32 m/min), and 3 min cool down with 50 % VO2max, all at 0 % grade. Animals exposed to an in vivo cardiac IR surgery, performed at days 1, 7, and 14 following the final exercise session. Ischemia-induced arrhythmias, myocardial infarct size (IS), plasma lactate dehydrogenase (LDH) and creatine kinase (CK) activities were measured in all animals. Compared to sedentary rats, exercised animals sustained less IR injury as evidenced by a lower size of infarction and lower levels of LDH and CK at day one and day 7 post exercise. In comparison of sedentary group, IS significantly decreased in EX-IR1 and EX-IR7 groups (50 and 35 %, respectively), but not in EX-IR14 group (19 %). The exercise-induced cardioprotection disappeared 14 days following exercise cessation. There were no significant changes in ischemia-induced arrhythmia between exercised and sedentary rats. The results clearly demonstrate that HIIT protects the heart against myocardial IR injury. This protective effect can be sustained for at least one week following the cessation of the training.

Assessing complement blockade in patients with paroxysmal nocturnal hemoglobinuria receiving eculizumab

AbstractParoxysmal nocturnal hemoglobinuria (PNH) is characterized by intravascular hemolysis, which is effectively controlled with eculizumab, a humanized monoclonal antibody that binds complement protein 5 (C5). The residual functional activity of C5 can be screened using a 50% hemolytic complement (CH50) assay, which is sensitive to the reduction, absence, and/or inactivity of any components of the classical and terminal complement pathway. Little data exist on complement blockade during treatment. From 2010 to 2012, clinical data, hemolysis biomarkers, complement assessment, and free eculizumab circulating levels were systematically measured immediately before every injection given to 22 patients with hemolytic PNH while receiving eculizumab therapy. During the study, 6 patients received ≥1 red blood cell transfusion. Lack of detectable CH50 activity (defined by CH50 ≤ 10% of normal values) was found in 184 samples (51%) and was significantly associated with lower lactate dehydrogenase levels (P = .002). Low levels of circulating free eculizumab (<50 µg/mL) correlated with detectable CH50 activity (CH50 > 10%; P = .004), elevated bilirubin levels (P < .0001), and the need for transfusions (P = .034). This study suggests that both CH50 activity and circulating free eculizumab levels may help physicians to manage PNH patients receiving eculizumab.