Alterations in the Fungal Microbiome in Ulcerative Colitis.

BACKGROUND: Although gut fungi have been implicated in the immunopathogenesis of inflammatory bowel disease, the fungal microbiome has not been deeply explored across endohistologic activity and treatment exposure in ulcerative colitis. METHODS: We analyzed data from the SPARC IBD (Study of a Prospective Adult Research Cohort with Inflammatory Bowel Disease) registry. We evaluated the fungal composition of fecal samples from 98 patients with ulcerative colitis across endoscopic activity (n = 43), endohistologic activity (n = 41), and biologic exposure (n = 82). Across all subgroups, we assessed fungal diversity and differential abundance of taxonomic groups. RESULTS: We identified 500 unique fungal amplicon sequence variants across the cohort of 82 patients, dominated by phylum Ascomycota. Compared with endoscopic remission, patients with endoscopic activity had increased Saccharomyces (log2 fold change = 4.54; adjusted P < 5 × 10-5) and increased Candida (log2 fold change = 2.56; adjusted P < .03). After adjusting for age, sex, and biologic exposure among patients with endoscopic activity, Saccharomyces (log2 fold change = 7.76; adjusted P < 1 × 10-15) and Candida (log2 fold change = 7.28; adjusted P< 1 × 10-8) remained enriched during endoscopic activity compared with quiescence. CONCLUSIONS: Endoscopic inflammation in ulcerative colitis is associated with an expansion of Saccharomyces and Candida compared with remission. The role of these fungal taxa as potential biomarkers and targets for personalized approaches to therapeutics in ulcerative colitis should be evaluated.

Gut fungi have been implicated in the pathogenesis of ulcerative colitis. In this retrospective study utilizing deep sequencing of the fecal fungal microbiome, Saccharomyces and Candida were increased during endoscopic inflammation and Penicillium was increased during endoscopic remission.

Clonal-pattern Seborrheic Keratosis: Risk of Recurrence and Progression to Carcinoma.

Seborrheic keratosis is a benign epidermal tumor. Seborrheic keratosis with clonal pattern (CPSK) displays histologic features distinct from other subtypes of SK (non-CPSK). We sought to quantitatively assess the risk of recurrence and progression to squamous cell carcinoma (SCC), either in situ or invasive, of incompletely excised CPSKs. We studied all 244 cases from 238 patients of "seborrheic keratosis, clonal pattern" diagnosed in our institution over a 10-year period (2008-2018). Demographic, clinical, pathologic, and follow-up data were gleaned from electronic health records. Following glass slide review, CPSK lesions were divided into 2 groups: CPSK with cytologic atypia and CPSK without cytologic atypia. For comparison, 107 non-CPSKs were studied as controls. The minimum follow-up period was 2 years (median=4 y). All lesions were incompletely excised. Eighteen of 244 CPSKs (7.4%) recurred at or adjacent to the site of initial partial removal compared with 1.9% of non-CPSKs. Five of the 18 (28%) recurrent CPSKs recurred as CPSK, 11 (61%) as SCC in situ, and 3 (17%) as invasive SCC. The mean time to recurrence was 3.1 years. Two non-CPSKs recurred as non-CPSKs. Overall CPSKs were more likely to recur than non-CPSKs ( P =0.04). CPSKs with atypia were more likely to recur than CPSKs without atypia ( P =0.03). The upgrade rate to SCC at least in situ of all recurrent CPSK lesions with atypia was 78%. Our results suggest that pathologists should report the presence of clonal pattern when observed in seborrheic keratoses, indicate the presence of atypia, and provide lesional margin assessment.

Intravesical electromotive administration of botulinum toxin type A in improving the bladder and bowel functions: Evidence for novel mechanism of action.

Objective: To examine the hypothesis that what is the concomitant mechanism of action botulinum toxin type A (BoNTA) administration by intravesical electromotive into the bladder resulting in bladder function improvement. We also tried to confirm the possibility of retrograde trans-axonal transportation of toxin.Design: Animal study.Setting: Ten male rabbits were divided into two groups.Participants: Group 1 (G1) (n = 5) (BoNTA/EMDA), and group 2 (G2) (n = 5) the control group.Interventions: Animals in G1received 10 IU/Kg of intravesical BoNTA through a specific catheter for electromotive drug administration (BoNTA/EMDA). About 0.1-0.15 ml of toxin was diluted in 1 ml of distilled water. The maximum frequency of the device for drug solution delivery was set at 4 mA for 15 min. In G2 as the control group, the same procedure was performed to deliver normal saline to the bladder.Outcome measures: Multiple biopsies were taken from bladder's contiguous structures one month postoperatively. The immunohistochemical (IHC) evaluation was performed with anti-clostridium botulinum toxoid type A mouse IgM monoclonal antibody.Results: In specimens of G1, BoNTA penetrated through muscular layers of the bladder wall and the staining was uniform in the urothelium, interstitium, and muscular layers. Positive IHC staining showed that BoNTA was traced in the upper and lower spinal cord in addition to pelvic nerve, sacral nerve plexus, intestine wall, and pelvic floor muscle. In G2, all the specimens were intact in IHC staining.Conclusions: The presence of BoNTA in lower and upper spinal cord suggests the possibility of retrograde trans-axonal transfer of toxin to lower and upper neural pathways which may result in simultaneous improvement in bladder and bowel functions.

Neoadjuvant-Intensive Androgen Deprivation Therapy Selects for Prostate Tumor Foci with Diverse Subclonal Oncogenic Alterations.

Primary prostate cancer can have extensive microheterogeneity, but its contribution to the later emergence of metastatic castration-resistant prostate cancer (mCRPC) remains unclear. In this study, we microdissected residual prostate cancer foci in radical prostatectomies from 18 men treated with neoadjuvant-intensive androgen deprivation therapy (leuprolide, abiraterone acetate, and prednisone) and analyzed them for resistance mechanisms. Transcriptome profiling showed reduced but persistent androgen receptor (AR) activity in residual tumors, with no increase in neuroendocrine differentiation. Proliferation correlated negatively with AR activity but positively with decreased RB1 expression, and whole-exome sequencing (WES) further showed enrichment for RB1 genomic loss. In 15 cases where 2 or 3 tumor foci were microdissected, WES confirmed a common clonal origin but identified multiple oncogenic alterations unique to each focus. These findings show that subclones with oncogenic alterations found in mCRPC are present in primary prostate cancer and are selected for by neoadjuvant-intense androgen deprivation therapy. In particular, this study indicates that subclonal RB1 loss may be more common than previously appreciated in intermediate- to high-risk primary prostate cancer and may be an early event, independent of neuroendocrine differentiation, in the development of mCRPC. Comprehensive molecular analyses of primary prostate cancer may detect aggressive subclones and possibly inform adjuvant strategies to prevent recurrence.Significance: Neoadjuvant androgen deprivation therapy for prostate cancer selects for tumor foci with subclonal genomic alterations, which may comprise the origin of metastatic castration-resistant prostate cancer. Cancer Res; 78(16); 4716-30. ©2018 AACR.

Breast cancer risk factors in relation to estrogen receptor, progesterone receptor, insulin-like growth factor-1 receptor, and Ki67 expression in normal breast tissue.

Studies have suggested that hormone receptor and Ki67 expression in normal breast tissue are associated with subsequent breast cancer risk. We examined the associations of breast cancer risk factors with estrogen receptor (ER), progesterone receptor (PR), insulin-like growth factor-1 receptor (IGF-1R), and Ki67 expression in normal breast tissue. This analysis included 388 women with benign breast disease (ages 17-67 years) in the Nurses' Health Studies. Immunohistochemical staining was performed on tissue microarrays constructed from benign biopsies containing normal breast epithelium and scored as the percentage of epithelial cells that were positively stained. Ordinal logistic regression (outcomes in tertiles), adjusting for age and potential confounders, was performed to estimate odds ratios (OR) and 95% confidence intervals (CI) for the associations with risk factors. Alcohol consumption was positively associated (≥2.5 vs.<0.4 drink/wk: OR = 2.69, 95% CI = 1.26-5.75, p-trend = 0.008) and breastfeeding was inversely associated (≥6 months vs. never: OR = 0.11, 95% CI = 0.04-0.35, p-trend = 0.0003) with ER expression. Height (≥66 vs.<64 inches: OR = 2.50, 95% CI = 1.34-4.67, p-trend = 0.005) and BMI at age 18 (≥22 vs.<20 kg/m2: OR = 2.33, 95% CI = 1.18-4.62, p-trend = 0.01) were positively associated with PR expression. Body size at age 5-10 years was inversely associated with Ki67 (Level ≥ 2.5 vs. 1: OR = 0.55, 95% CI = 0.30-1.01, p-trend = 0.03). Premenopausal BMI (≥25 vs.<20 kg/m2) was positively associated with cytoplasmic IGF-1R (OR = 5.06, 95% CI = 1.17-21.8, p-trend = 0.04). Our data suggest that anthropometrics, breastfeeding, and alcohol intake may influence the molecular characteristics of normal breast tissue, elucidating the mechanisms by which these risk factors operate. However, larger studies are required to confirm these results.

Image-guided Coring for Large-scale Studies in Molecular Pathology.

Sampling of formalin-fixed paraffin-embedded (FFPE) tissue blocks is a critical initial step in molecular pathology. Image-guided coring (IGC) is a new method for using digital pathology images to guide tissue block coring for molecular analyses. The goal of our study is to evaluate the use of IGC for both tissue-based and nucleic acid-based projects in molecular pathology. First, we used IGC to construct a tissue microarray (TMA); second, we used IGC for FFPE block sampling followed by RNA extraction; and third, we assessed the correlation between nuclear counts quantitated from the IGC images and RNA yields. We used IGC to construct a TMA containing 198 normal and breast cancer cores. Histopathologic analysis showed high accuracy for obtaining tumor and normal breast tissue. Next, we used IGC to obtain normal and tumor breast samples before RNA extraction. We selected a random subset of tumor and normal samples to perform computational image analysis to quantify nuclear density, and we built regression models to estimate RNA yields from nuclear count, age of the block, and core diameter. Number of nuclei and core diameter were the strongest predictors of RNA yields in both normal and tumor tissue. IGC is an effective method for sampling FFPE tissue blocks for TMA construction and nucleic acid extraction. We identify significant associations between quantitative nuclear counts obtained from IGC images and RNA yields, suggesting that the integration of computational image analysis with IGC may be an effective approach for tumor sampling in large-scale molecular studies.

Expression of estrogen receptor, progesterone receptor, and Ki67 in normal breast tissue in relation to subsequent risk of breast cancer.

Although expression of estrogen receptor (ER), progesterone receptor (PR), and cell proliferation marker Ki67 serve as predictive and prognostic factors in breast cancers, little is known about their roles in normal breast tissue. Here in a nested case-control study within the Nurses' Health Studies (90 cases, 297 controls), we evaluated their expression levels in normal breast epithelium in relation to subsequent breast cancer risk among women with benign breast disease. Tissue microarrays were constructed using cores obtained from benign biopsies containing normal terminal duct lobular units and immunohistochemical stained for these markers. We found PR and Ki67 expression was non-significantly but positively associated with subsequent breast cancer risk, whereas ER expression was non-significantly inversely associated. After stratifying by lesion subtype, Ki67 was significantly associated with higher risk among women with proliferative lesions with atypical hyperplasia. However, given the small sample size, further studies are required to confirm these results.

Drainage-related ultrasonography (DRUS): a novel technique for discriminating obstructive and nonobstructive hydroureters in children.

BACKGROUND: Despite advances in urologic imaging, the paucity of an optimal technique that accurately clarifies obstructive and nonobstructive hydroureter exists. OBJECTIVE: This study was conducted to introduce a novel and modified ultrasonographic technique, known as drainage-related ultrasonography (DRUS), discriminating obstructive and nonobstructive, nonrefluxing hydroureter. MATERIALS AND METHODS: A total of 358 children (mean age, 3.7 years) with 418 nonrefluxing hydroureter were included. These children were composed of two groups of obstructive nonrefluxing (141 children with 157 dilated ureters) and nonobstructive, nonrefluxing (217 children with 261 hydroureter). The definite diagnosis regarding the subtype of hydroureter was derived from appropriate investigation. The maximum diameter of the dilated ureter, which was observed on ultrasonography, was recorded before and after 3 h of catheterization, as D1 and D2, respectively. To assess the D ratio, a formula was developed, that is, [(|D1 - D2|)/D1] × 100. Values were recorded and cutoff points were set to discriminate between subtypes. RESULTS: Obstructive versus nonobstructive subtypes of nonrefluxing hydroureter were clarified with 78.5 % sensitivity and 83.4 % specificity, by setting a cutoff point of 22 % for the D ratio. Regardless of the cutoff point assigned to the reduction in D (D2 compared with D1), DRUS revealed 93.9 % sensitivity, 80.6 % specificity, 63.2 % positive predictive value, and 97.4 % negative predictive value in discriminating upper from lower obstruction. CONCLUSION: DRUS affords favorable results in terms of differentiating between obstructive and nonobstructive, nonrefluxing hydroureter, as well as between upper and lower obstruction in obstructive cases. It has the potential to become an efficient imaging modality in the diagnostic algorithm of hydroureter.

MERIT40 Is an Akt Substrate that Promotes Resolution of DNA Damage Induced by Chemotherapy.

Resistance to cytotoxic chemotherapy drugs, including doxorubicin, is a significant obstacle to the effective treatment of breast cancer. Here, we have identified a mechanism by which the PI3K/Akt pathway mediates resistance to doxorubicin. In addition to inducing DNA damage, doxorubicin triggers sustained activation of Akt signaling in breast cancer cells. We show that Akt contributes to chemotherapy resistance such that PI3K or Akt inhibitors sensitize cells to doxorubicin. We identify MERIT40, a component of the BRCA1-A DNA damage repair complex, as an Akt substrate that is phosphorylated following doxorubicin treatment. MERIT40 phosphorylation facilitates assembly of the BRCA1-A complex in response to DNA damage and contributes to DNA repair and cell survival following doxorubicin treatment. Finally, MERIT40 phosphorylation in human breast cancers is associated with estrogen receptor positivity. Our findings suggest that combination therapy with PI3K or Akt inhibitors and doxorubicin may constitute a successful strategy for overcoming chemotherapy resistance.

Extensive rewiring of epithelial-stromal co-expression networks in breast cancer.

BACKGROUND: Epithelial-stromal crosstalk plays a critical role in invasive breast cancer pathogenesis; however, little is known on a systems level about how epithelial-stromal interactions evolve during carcinogenesis. RESULTS: We develop a framework for building genome-wide epithelial-stromal co-expression networks composed of pairwise co-expression relationships between mRNA levels of genes expressed in the epithelium and stroma across a population of patients. We apply this method to laser capture micro-dissection expression profiling datasets in the setting of breast carcinogenesis. Our analysis shows that epithelial-stromal co-expression networks undergo extensive rewiring during carcinogenesis, with the emergence of distinct network hubs in normal breast, and estrogen receptor-positive and estrogen receptor-negative invasive breast cancer, and the emergence of distinct patterns of functional network enrichment. In contrast to normal breast, the strongest epithelial-stromal co-expression relationships in invasive breast cancer mostly represent self-loops, in which the same gene is co-expressed in epithelial and stromal regions. We validate this observation using an independent laser capture micro-dissection dataset and confirm that self-loop interactions are significantly increased in cancer by performing computational image analysis of epithelial and stromal protein expression using images from the Human Protein Atlas. CONCLUSIONS: Epithelial-stromal co-expression network analysis represents a new approach for systems-level analyses of spatially localized transcriptomic data. The analysis provides new biological insights into the rewiring of epithelial-stromal co-expression networks and the emergence of epithelial-stromal co-expression self-loops in breast cancer. The approach may facilitate the development of new diagnostics and therapeutics targeting epithelial-stromal interactions in cancer.

NFAT1 promotes intratumoral neutrophil infiltration by regulating IL8 expression in breast cancer.

NFAT transcription factors are key regulators of gene expression in immune cells. In addition, NFAT1-induced genes play diverse roles in mediating the progression of various solid tumors. Here we show that NFAT1 induces the expression of the IL8 gene by binding to its promoter and leading to IL8 secretion. Thapsigargin stimulation of breast cancer cells induces IL8 expression in an NFAT-dependent manner. Moreover, we show that NFAT1-mediated IL8 production promotes the migration of primary human neutrophils in vitro and also promotes neutrophil infiltration in tumor xenografts. Furthermore, expression of active NFAT1 effectively suppresses the growth of nascent and established tumors by a non cell-autonomous mechanism. Evaluation of breast tumor tissue reveals that while the levels of NFAT1 are similar in tumor cells and normal breast epithelium, cells in the tumor stroma express higher levels of NFAT1 compared to normal stroma. Elevated levels of NFAT1 also correlate with increased neutrophil infiltrate in breast tumors. These data point to a mechanism by which NFAT1 orchestrates the communication between breast cancer cells and host neutrophils during breast cancer progression.

Computational pathology to discriminate benign from malignant intraductal proliferations of the breast.

The categorization of intraductal proliferative lesions of the breast based on routine light microscopic examination of histopathologic sections is in many cases challenging, even for experienced pathologists. The development of computational tools to aid pathologists in the characterization of these lesions would have great diagnostic and clinical value. As a first step to address this issue, we evaluated the ability of computational image analysis to accurately classify DCIS and UDH and to stratify nuclear grade within DCIS. Using 116 breast biopsies diagnosed as DCIS or UDH from the Massachusetts General Hospital (MGH), we developed a computational method to extract 392 features corresponding to the mean and standard deviation in nuclear size and shape, intensity, and texture across 8 color channels. We used L1-regularized logistic regression to build classification models to discriminate DCIS from UDH. The top-performing model contained 22 active features and achieved an AUC of 0.95 in cross-validation on the MGH data-set. We applied this model to an external validation set of 51 breast biopsies diagnosed as DCIS or UDH from the Beth Israel Deaconess Medical Center, and the model achieved an AUC of 0.86. The top-performing model contained active features from all color-spaces and from the three classes of features (morphology, intensity, and texture), suggesting the value of each for prediction. We built models to stratify grade within DCIS and obtained strong performance for stratifying low nuclear grade vs. high nuclear grade DCIS (AUC = 0.98 in cross-validation) with only moderate performance for discriminating low nuclear grade vs. intermediate nuclear grade and intermediate nuclear grade vs. high nuclear grade DCIS (AUC = 0.83 and 0.69, respectively). These data show that computational pathology models can robustly discriminate benign from malignant intraductal proliferative lesions of the breast and may aid pathologists in the diagnosis and classification of these lesions.

Clinical utility of a blood-based BRAF(V600E) mutation assay in melanoma.

BRAF inhibitors (BRAFi) have led to clinical benefit in patients with melanoma. The development of a blood-based assay to detect and quantify BRAF levels in these patients has diagnostic, prognostic, and predictive capabilities that could guide treatment decisions. Blood BRAF(V600E) detection and quantification were performed on samples from 128 patients with stage II (19), III (67), and IV (42) melanoma. Tissue BRAF analysis was performed in all patients with stage IV disease and in selected patients with stage II and III disease. Clinical outcomes were correlated to initial BRAF levels as well as BRAF level dynamics. Serial analysis was performed on 17 stage IV melanoma patients treated with BRAFi and compared with tumor measurements by RECIST. The assay was highly sensitive (96%) and specific (95%) in the stage IV setting, using a blood level of 4.8 pg as "positive." BRAF levels typically decreased following BRAFi. A subset of these patients (5) had an increase in BRAF(V600E) values 42 to 112 days before clinical or radiographic disease progression (PD). From 86 patients with resected, stage II or III melanoma, 39 had evidence of disease relapse (45.3%). Furthermore, BRAF mutation in the blood after surgical resection in these patients was not associated with a difference in relapse risk, although tissue BRAF status was only available for a subset of patients. In summary, we have developed a highly sensitive and specific, blood-based assay to detect BRAF(V600) mutation in patients with melanoma.

Comparison of intradermal injection with iontophoresis of abobotulinum toxin A for the treatment of primary axillary hyperhidrosis: a randomized, controlled trial.

BACKGROUND: Botulinum neurotoxin type A (BTX-A) injection is the treatment of choice for idiopathic axillary hyperhidrosis (IAH) refractory to conventional treatments. OBJECTIVE: This study compared the efficacy of BTX-A injection and iontophoresis for treatment of IAH in a randomized controlled trial. METHODS: In eleven patients with the diagnosis of IAH, one axilla was randomly treated with injections of 1.5 mL (250 MU) of BTX-A, and the other side was treated with BTX-A administered by iontophoresis. The amount of sweating, skin hydration, transepidermal water loss, pain, and patient satisfaction on both axilla were compared with baseline levels, and also between both sides 1 week, 1 month, and 6 months after treatment. RESULTS: The injection side had significantly less sweat production than the iontophoresis side 1 week, 1 month, and 6 months after treatment (84%, 76%, and 50% vs. 73%, 22%, and 32%, respectively). The response to iontophoresis was more stable than that to injection. Participants' pain perception during the procedure score was significantly less on the iontophoresis side compared with the injection side (15.0 vs. 20.0, p < 0.05). CONCLUSION: This study has shown that injection is a more effective method for the administration of BTX-A, though iontophoresis can also be considered a non-invasive and painless method in some patients.

Vulvar fibrous hamartoma of infancy: a rare case report and review of literature.

BACKGROUND: Fibrous hamartoma of infancy is a benign mesenchymal tumor occurring infrequently in children, typically involving the axilla. CASE REPORT: An 18-month-old girl with a history of right labium majus enlargement, on examination, had a hard mass that was found strictly adherent to subcutaneous tissue and overlying skin. Postexcision histological examination showed arranged spindle cells, adipose tissue, and nests of immature small cells in a myxoid background, consistent with fibrous hamartoma of infancy. CONCLUSIONS: The main problem in the diagnosis is differentiating this lesion from soft tissue sarcomas, which require an aggressive therapeutic approach. Both surgeons and pathologists need to be aware of the existence of such benign condition in this unusual place to avoid unnecessary therapies.

The expression of heat shock proteins 27 and 105 in squamous cell carcinomaof the tongue and relationship with clinicopathological index

Introduction: In oral cavity, the tongue is the most common site prone to development of squamous cell carcinoma(SCC). Considering malignant transformation as a cellular stress, the expression of heat shock proteins (HSPs)may be affected in this process. In this study we assessed the expression of HSP105 and HSP27 as two of the mostinterested stress proteins and investigated their relationship with grade and stage of the tongue SCC.Material and Methods: Fifty-six specimens including 31 early and 25 advanced tongue SCC were gathered. Allspecimens were graded histologically from I to III. Sixteen sections of normal oral mucosa were used as controlgroup. The cellularity and intensity of HSP105 and HSP27 expression were studied immunohistochemically inboth case and control groups. Results were expressed by histochemical score (HSCORE).Results: Significant differences were observed between expression of HSPs and stage of the disease. From earlyto advanced stage, the expression of HSP105 and HSP27 increased and decreased, respectively. There was norelationship between histological grade of lesion and HSCORE of HSP105 expression (P=0.5), although, HSP27expression had reverse relationship with the SCC histological grade.Conclusion: HSP27 and HSP105 may be indicated for prognostic purposes in evaluation of tongue SCC. HSP 27may be used for more accurate microscopic grading of tongue SCC. Increased expression of HSP105 in advancedstage may lead to using this protein for immunotherapy of tongue SCC (AU)

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Plasma myeloperoxidase activity and apolipoprotein A-1 expression in chronic hepatitis B patients.

BACKGROUND: Hepatitis B virus initiates a complicated cascade process leading to chronic hepatitis B, cirrhosis, and hepatocellular carcinoma. In inflammatory situations, myeloperoxidase is released in plasma and binds to apolipoprotein A-1 in high-density lipoproteins. This study aims to evaluate the level of plasma myeloperoxidase as well as the pattern of plasma proteins in patients with chronic hepatitis B. METHODS: Included in this study were 30 male subjects: 19 chronic hepatitis B patients, 6 HBV-related cirrhotic patients, and 5 healthy controls. Plasma myeloperoxidase was measured using enzyme-linked immunosorbent assay. Proteomic analysis of plasma proteins was performed by two-dimensional gel electrophoresis (2-DE) and mass spectrometry. One way ANOVA was used for data analysis. RESULTS: Mean plasma myeloperoxidase levels were higher in patients with liver cirrhosis (65.5±12.5; P=0.007) and chronic hepatitis B (53.7±10.6; P=0.18) when compared with healthy subjects (45±7.6). Moreover, a positive correlation was found between plasma myeloperoxidase levels and hepatic fibrosis stage (r=0.53, P=0.002; r=0.63, P=0.000). Proteomic analysis showed an altered plasma protein pattern in progressive hepatitis B and down-regulation of the major apolipoprotein A-1 along with the appearance of a variety of spots noted to be apolipoprotein A-1isoforms with different molecular masses. CONCLUSION: In this study, progressive liver injury due to HBV infection correlated with higher plasma myeloperoxidase and an altered plasma apolipoprotein A-1pattern.

Additive anticonvulsant effects of agmatine and lithium chloride on pentylenetetrazole-induced clonic seizure in mice: involvement of α2-adrenoceptor.

After 60 years, lithium is still the mainstay in the treatment of mood disorders and widely used in clinic. In addition to its mood stabilizer effects, lithium also shows some anticonvulsant properties. Similar to lithium, agmatine also plays a protective role in the CNS against seizures and has been reported to enhance the effect of different antiepileptic agents. Moreover, both agmatine and lithium have modulatory effects on α(2)-adrenoceptors. So, we designed this study: 1) to investigate whether agmatine and lithium show an additive effect against clonic seizures induced by pentylenetetrazole; 2) to assess whether this additive effect is mediated through the α(2)-adrenoceptor or not. In our study, acute administration of a single effective dose of lithium chloride (30 mg/kg, i.p.) increased the seizure threshold. Pre-treatment with low and, per se, non-effective doses of agmatine (1 and 3mg/kg) potentiated a sub-effective dose of lithium (10mg/kg). Interestingly, the anticonvulsant effects of these effective combinations of lithium and agmatine were prevented by pre-treatment with low and non-effective doses of yohimbine [α(2)-adrenoceptor antagonist] (0.1 and 0.5mg/kg). On the other hand, clonidine [α(2)-adrenoceptor agonist] augmented the anticonvulsant effect of a sub-effective combination of lithium (5mg/kg i.p.) and agmatine (1mg/kg) at relatively low doses (0.1 and 0.25mg/kg). In summary, our findings demonstrate that agmatine and lithium chloride exhibit additive anticonvulsant properties which seem to be mediated through α(2)-adrenoceptor.

A role for opioid system in the proconvulsant effects of sildenafil on the pentylenetetrazole-induced clonic seizure in mice.

There are several lines of evidence that opioidergic and nitrergic systems could modulate the seizure threshold. We previously have shown that sildenafil had proconvulsant effects in a model of clonic seizure induced by pentylenetetrazole (PTZ) or bicuculline. In the present study, we examined whether the opioid system participates in the action of sildenafil on the PTZ-induced clonic seizures in mice. Sildenafil (1, 5, 10 and 20 mg/kg, i.p.) significantly decreased the seizure threshold in a dose-dependent manner, whereas morphine had both anticonvulsant and proconvulsant effects at low (0.5, 1, and 3 mg/kg, s.c.) and high (60 mg/kg, s.c.) doses. A sub-effective dose of sildenafil (5 mg/kg) combined with a dose of morphine (7.5 mg/kg) which was sub-effective for its proconvulsant effects significantly decreased the seizure threshold. Although naltrexone at 0.5 and 1 mg/kg had no effect on the seizure threshold, it significantly prevented both the proconvulsant effects of sildenafil as well as the anticonvulsant and proconvulsant effects of morphine on the PTZ-induced seizure thresholds. Our data suggested a role for opioidergic system in the proconvulsant effects of sildenafil on the PTZ-induced clonic seizures in mice.

The expression of heat shock proteins 27 and 105 in squamous cell carcinoma of the tongue and relationship with clinicopathological index.

INTRODUCTION: In oral cavity, the tongue is the most common site prone to development of squamous cell carcinoma (SCC). Considering malignant transformation as a cellular stress, the expression of heat shock proteins (HSPs) may be affected in this process. In this study we assessed the expression of HSP105 and HSP27 as two of the most interested stress proteins and investigated their relationship with grade and stage of the tongue SCC. MATERIAL AND METHODS: Fifty-six specimens including 31 early and 25 advanced tongue SCC were gathered. All specimens were graded histologically from I to III. Sixteen sections of normal oral mucosa were used as control group. The cellularity and intensity of HSP105 and HSP27 expression were studied immunohistochemically in both case and control groups. Results were expressed by histochemical score (HSCORE). RESULTS: Significant differences were observed between expression of HSPs and stage of the disease. From early to advanced stage, the expression of HSP105 and HSP27 increased and decreased, respectively. There was no relationship between histological grade of lesion and HSCORE of HSP105 expression (P=0.5), although, HSP27 expression had reverse relationship with the SCC histological grade. CONCLUSION: HSP27 and HSP105 may be indicated for prognostic purposes in evaluation of tongue SCC. HSP 27 may be used for more accurate microscopic grading of tongue SCC. Increased expression of HSP105 in advanced stage may lead to using this protein for immunotherapy of tongue SCC.