Tofacitinib use in ulcerative colitis: An expert consensus for day-to-day clinical practice.

Rising number of inflammatory bowel disease (IBD) cases in developing countries necessitate clear guidance for clinicians for the appropriate use of advanced therapies. An expert consensus document was generated to guide the usage of tofacitinib, a Janus kinase inhibitor, in ulcerative colitis. Tofacitinib is a useful agent for the induction and maintenance of remission in ulcerative colitis. It can be used in the setting of biological failure or even steroid-dependent and thiopurine refractory disease. Typically, the induction dose is 10 mg BD orally. Usually, clinical response is evident within eight weeks of therapy. In those with clinical response, the dose can be reduced from 10 mg BD to 5 mg BD. Tofacitinib should be avoided or used cautiously in the elderly, patients with cardiovascular co-morbidity, uncontrolled cardiac risk factors, previous thrombotic episodes and those at high risk for venous thrombosis or previous malignancy. Baseline evaluation should include testing for and management of hepatitis B infection and latent tuberculosis. Where feasible, it is prudent to ensure complete adult vaccination, including Herpes zoster, before starting tofacitinib. The use of tofacitinib may be associated with an increased risk of infections such as herpes zoster and tuberculosis reactivation. Maternal exposure to tofacitinib should be avoided during pre-conception, pregnancy, and lactation. There is emerging evidence of tofacitinib in acute severe colitis, although the exact positioning (first-line with steroids or second-line) is uncertain.

Fat augments leptin-induced uterine contractions by decreasing JAK2 and BKCa channel expressions in late pregnant rats.

Altered lipid metabolism in obesity causes pregnancy complications in humans and animals. Leptin levels increase in pregnancy, as well as obesity. However, the effect of obesity on uterine leptin receptors and its distal signaling is not clear. The present study aimed to understand the effect of increased fat on leptin signaling in rat uterus. Wistar female rats were fed with an HF diet (40% Fat, 17% Sucrose, 1.25% Cholesterol, 0.75% Cholic acid) for 6 weeks before the mating and during pregnancy. HF diet significantly increased the fat depots, liver weight, serum, and tissue cholesterol levels. It produced fatty degeneration in the liver and caused infiltration of inflammatory cells, cystic endometrial glands, and sub endometrial fibrosis of the uterus. In isometric tension experiments, leptin caused a significant increase in uterine contractions in high fat-fed animals compared to control animals. Analysis of receptor expressions revealed no significant difference between the groups. However, a significant decrease in the JAK2 and BKCaα mRNA expression was observed in the uterus of high fat-fed rats. No change in the BKCaß, eNOS, iNOS, MLCP, and MLCK mRNA expressions was noticed in the HF group compared to the control. The findings of the present study suggest that the contractile response to leptin in the uterus of high fat-fed rats may be attributed to reduced signaling through JAK2 and, lowered expressions of BKCa channel α subunits.

Five years review of extraction frequencies at S.D.M. College of dental sciences and Hospital in orthodontic department.

BACKGROUND: To find out the frequency of extraction in general, in Class I, Class II Class III patients, and to compare the frequency of extraction among sex and age. MATERIAL AND METHODS: 550 cases were selected retrospectively having detailed case history, complete records of facial photographs, lateral cephalogram, orthopantomographs and study models. Frequency of extraction was evaluated separately for class I, class II and class III malocclusion and for sex and ages, using the records collected. RESULTS: Show that there was 59.80% of extraction in general. Comparison of sex shows that there were 66.60 of extraction in females. The mean age of males for extraction was 17.85 +/- 4.18 and the mean age of females was 18.36 +/_ 4.89. Among all the groups, Class I malocclusion shows 89% of extraction. CONCLUSIONS: There was higher frequency of extraction comprising in general. Comparison of sex shows that there was higher frequency of extraction in females. Comparison of age shows that extraction frequency is more in late adolescent period. Among all the groups, Class I malocclusion shows higher frequency of extraction. Key words:Extraction, frequency, malocclusion.raumatic neuroma; palisaded encapsulated neuroma; oral palisaded encapsulated neuroma.

Delayed massive haemothorax 10 days following percutaneous nephrolithotomy.

A 56-year-old man presented with massive right haemothorax 10 days following percutaneous nephrolithotomy (PCNL) for complex, large-bulk, right renal stones. Antiplatelet medication started following coronary stenting 7 months ago was stopped 5 days prior and resumed 2 days following surgery. Stones were cleared through two tracts, one supracostal, with placement of ureteral stent but no nephrostomy. He was discharged the next day with an unremarkable chest X-ray. He developed cough and fever after 1 week. Three days later he presented with acute dyspnoea, blood pressure of 100/60 mm Hg, pulse of 120/min and haemoglobin of 9.0 g/dL. Chest X-ray and CT scan showed a large right haemothorax. Two-litre haemothorax was drained by intercostal drainage with prompt recovery. Haemothorax is a rare complication following PCNL usually after supracostal access. Most occur at or immediately following surgery. Infection and early resumption of antiplatelet medication might have contributed to his presentation with delayed secondary haemorrhage from a pleural injury.

Vascular endothelial growth factor polymorphisms and a synchronized examination of plasma and tissue expression in epithelial ovarian cancers.

In this study, we have analyzed six genetic polymorphisms of the VEGF-A gene and correlated the genetic data with plasma and tissue expression of VEGF-A in epithelial ovarian carcinomas. A total of 130 cases including 95 malignant carcinomas, 17 low malignant potential and 18 benign tumours were studied. rs699947, rs833061, rs1570360, rs2010963, rs1413711 and rs3025039 were studied by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). Plasma levels of VEGF-A were estimated by enzyme-linked immunosorbent assay (ELISA) and tissue expression of VEGF-A by immunohistochemistry (IHC). Four polymorphisms of the above excluding rs699947 and rs3025039 showed significant association with malignancy, and we observed the presence of positive correlation between haplotype CCGGCC and increased expression of VEGF-A in both plasma and tissues which also correlated with poor prognosis and recurrence suggesting a probable increase in resistance to treatment in such carriers. Highly upregulated tissue expression of VEGF-A was seen in all epithelial ovarian carcinomas with intensity of expression increasing from benign to malignant cases. ELISA data from our study showed an increase in circulating levels of VEGF-A in malignancies. VEGF-A plasma levels can be employed as a biomarker for high-grade malignancy in epithelial ovarian cancers alongside tissue expression and CA-125 levels. This study is unique due to the fact that a simultaneous analysis of plasma and tissue expression has been demonstrated and is a first such study in epithelial ovarian cancers and representing the Indian population (South-east Asian) synchronized with genetic polymorphism data as well.

Comparative study of microwave radiation-induced magnetoresistive oscillations induced by circularly- and linearly- polarized photo-excitation.

A comparative study of the radiation-induced magnetoresistance oscillations in the high mobility GaAs/AlGaAs heterostructure two dimensional electron system (2DES) under linearly- and circularly- polarized microwave excitation indicates a profound difference in the response observed upon rotating the microwave launcher for the two cases, although circularly polarized microwave radiation induced magnetoresistance oscillations observed at low magnetic fields are similar to the oscillations observed with linearly polarized radiation. For the linearly polarized radiation, the magnetoresistive response is a strong sinusoidal function of the launcher rotation (or linear polarization) angle, θ. For circularly polarized radiation, the oscillatory magnetoresistive response is hardly sensitive to θ.

Collagenase-3 expression in periapical lesions: an immunohistochemical study.

Collagenase-3 (matrix metalloproteinase-13) is a metalloproteinase (MMP) that is associated with bone lesions and exhibits variable expression patterns in odontogenic cysts; it may play a role in regulating focal proliferation and maturation of jaw cyst epithelium. We studied the localization, staining intensity and distribution of collagenase-3 in 13 periapical granulomas with epithelium, 16 periapical granulomas without epithelium and 10 radicular cysts using archived formalin fixed, paraffin embedded tissues. A monoclonal antibody against human collagenase-3 was used to evaluate its expression. Immunohistochemical staining intensities of collagenase-3 in all periapical lesions were (-), 4 (10%); (+), 1 (3%); (++), 22 (56%) and (+++), 12 (31%); differences were not statistically significant. Immunohistochemical distribution of collagenase-3 in epithelial cells was (-), 17 (44%); (+), 17 (44%); (++), 5 (13%); in fibroblasts it was (-), 8 (20%); (+), 23 (59%); (++), 8 (21%); in plasma cells it was (-), 7 (18%); (+), 22 (56%); (++), 10 (26%); in macrophages it was (-), 7 (18%); (+), and 15 (38%); and (++), 17 (44%). Statistically significant differences were found in epithelial cells (p = 0.00) and fibroblasts (p = 0.02), whereas differences were not statistically significant for plasma cells and macrophages. Collagenase-3 may play a role in the conversion of a periapical granuloma with epithelium to radicular cyst. MMP's influence not only epithelial rest cell migration, but also invasion of various stromal cells into granulomatous tissue.

Prevalence of +405G>C,-1154G>A Vascular Endothelial Growth Factor Polymorphism in Breast Cancer.

Vascular endothelial growth factor (VEGF) plays an important role in the development of Breast Cancer. The aim of this study was to investigate the association of polymorphisms in the VEGF gene on prognosis of Breast Cancer patients. This study comprised 200 patients with histologically confirmed cases of Breast cancer and 200 controls. Genotyping of the VEGF gene polymorphisms at +405G>C,-1154G>A, were performed by PCR-RFLP analysis. Preoperative plasma VEGF levels were determined by ELISA. Amongst both cases and controls, the genotypic distribution of the individual SNPs were all in Hardy-Weinberg equilibrium. Mean VEGF level was significantly elevated in cases compared to controls (t = 8.248; P < 0.001). No significant association was found between +405G>C,-1154G>A VEGF polymorphism and Breast Cancer. Logistic regression analysis revealed that 405GG & 1154GG were associated with higher levels of VEGF.

BRCA1 promoter hypermethylation and protein expression in ovarian carcinoma--an Indian study.

Mounting evidences suggest that aberrant methylation of CpG islands is a major pathway leading to the inactivation of tumour suppressor genes and the development of cancer. The aim of the current study was to examine the prevalence of the promoter hypermethylation and protein expression of the BRCA1 gene in epithelial ovarian carcinoma (EOC) to understand the role of epigenetic silencing in ovarian carcinogenesis. We studied the promoter methylation of the BRCA1 gene by methylation-specific PCR in a cohort of 88 patients with EOC, 14 low malignant potential (LMP) tumours and 20 patients with benign tumours of the ovary. The expression of the BRCA1 protein by immunohistochemical analysis was carried out in a subset of 64 EOCs, 10 LMP tumours, 10 benign tumours and 5 normal ovarian tissues. The frequencies of methylation in EOCs and LMP tumours were 51.2 and 57%, respectively, significantly higher (p = 0.000 and p = 0.001) in comparison to benign tumours and normal ovarian tissue where no methylation was seen. Expression of BRCA1 was significantly lower in EOCs (p = 0.003). Lack of protein expression correlated with tumour grade and type. The methylation status correlated well with downregulation of BRCA1 expression. Our results clearly demonstrate that hypermethylation of BRCA1 promoter is a frequent event in ovarian cancer. These data support the hypothesis that BRCA1 promoter methylation plays an important role in the functional inactivation of BRCA1. Follow-up clinical data will reveal the impact of BRCA1 methylation on survival.

Relationship between promoter methylation & tissue expression of MGMT gene in ovarian cancer.

BACKGROUND & OBJECTIVES: Epigenetic alterations, in addition to multiple gene abnormalities, are involved in the genesis and progression of human cancers. Aberrant methylation of CpG islands within promoter regions is associated with transcriptional inactivation of various tumour suppressor genes. O 6-methyguanine-DNA methyltransferase (MGMT) is a DNA repair gene that removes mutagenic and cytotoxic adducts from the O 6 -position of guanine induced by alkylating agents. MGMT promoter hypermethylation and reduced expression has been found in some primary human carcinomas. We studied DNA methylation of CpG islands of the MGMT gene and its relation with MGMT protein expression in human epithelial ovarian carcinoma. METHODS: A total of 88 epithelial ovarian cancer (EOC) tissue samples, 14 low malignant potential (LMP) tumours and 20 benign ovarian tissue samples were analysed for MGMT promoter methylation by nested methylation-specific polymerase chain reaction (MSP) after bisulphite modification of DNA. A subset of 64 EOC samples, 10 LMP and benign tumours and five normal ovarian tissue samples were analysed for protein expression by immunohistochemistry. RESULTS: The methylation frequencies of the MGMT gene promoter were found to be 29.5, 28.6 and 20 per cent for EOC samples, LMP tumours and benign cases, respectively. Positive protein expression was observed in 93.8 per cent of EOC and 100 per cent in LMP, benign tumours and normal ovarian tissue samples. Promoter hypermethylation with loss of protein expression was seen only in one case of EOC. INTERPRETATION & CONCLUSIONS: Our results suggest that MGMT promoter hypermethylation does not always reflect gene expression.

Association of vascular endothelial growth factor single nucleotide polymorphisms on the prognosis of breast cancer patients.

BACKGROUND: Vascular endothelial growth factor (VEGF), a major mediator of vascular permeability and angiogenesis, may play a pivotal role in mediating the development and progression of breast cancer. In the present study, we examined the genetic variations of the VEGF gene to assess its possible relation to breast cancer. MATERIALS AND METHODS: A total of 200 patients with histologically confirmed cases of breast cancer and 200 healthy women were genotyped for VEGF single nucleotide polymorphisms (405G > C and -1154G > A) by polymerase chain reaction-restriction fragment length polymorphism analysis. Pre-operative plasma VEGF levels were determined by enzyme-linked immunosorbent assay in 200 women with breast cancer and in 200 normal female controls. RESULTS: The genotype frequencies of the +405G > C, -1154G > A polymorphisms did not show a significant deviation from the Hardy-Weinberg expectation. The minor allele frequencies of the +405G > C and -1154G > A polymorphisms among cases and controls were 33.5% (C allele), 31.5% (A allele) and 35% (C allele), 34.5% (A allele) respectively. +405GG and -1154GG genotypes were associated with higher levels of VEGF among breast cancer cases and controls. Increased plasma VEGF levels were significantly associated with, clinical stage of the disease (P = 0.035). CONCLUSION: Although none of the polymorphisms were significantly associated with breast cancer, some of the VEGF genotypes may influence tumor growth through an altered expression of VEGF and tumor angiogenesis.

Delay in Diagnosis of Upper Gastrointestinal Cancer: whose fault is it?

BACKGROUND: Stomach and esophageal cancers are both deadly and difficult to diagnose early. Stomach cancer is the second most common cancer in Asia. Both these are one of the most common causes of cancer related death in the world. AIM: To determine the mean time delay from appearance of the symptoms to the endoscope procedure [OGDS] and rationalized the reason for this delay in diagnosis. METHOD: This is a cross sectional study of stomach and esophageal cancer data from Jan 2004- July 2008. All patients' records of histologically confirmed stomach or esophageal cancers during the study period were reviewed. RESULT: Total of 112 consecutive patients with stomach and esophageal cancer were analysed. 86 cases of stomach and 26 cases of esophageal cancer were reviewed. The average age for stomach and esophageal cancers are 60.8 years and 58.4 years respectively. The mean duration from the first appearance of cancer symptoms to endoscope procedure was 32.4 weeks for stomach cancer patient and 16.7 weeks for esophageal cancer patients. The reasons for the delays are due to 1) self-medication, 2) Empirical treatment for dyspepsia using antacid and H2 antagonist, 3) Delay in endoscope procedure for high risk patients. CONCLUSION: Reducing the delay in endoscope procedure may lead to early detection of cancer and thereby may improve the prognosis of these patients.

Altered expression of ß-catenin, E-cadherin, and E-cadherin promoter methylation in epithelial ovarian carcinoma.

The aim of the study was to evaluate the immunoexpression of E-cadherin, ß-catenin, and Ki-67, as well as the promoter methylation of E-cadherin gene in epithelial ovarian cancer (EOC), as well as to find a possible relationship between the immunoexpression and hypermethylation. Promoter methylation was studied using methylation-specific PCR in 86 malignant cases, 14 low malignant potential (LMP) tumors and 19 benign cystadenomas. Immunohistochemical expression was carried out in 64 malignant cases, 8 LMP tumors, and 11 benign cystadenomas. Immunoexpression of E-cadherin was reduced in EOC, while 100 % expression was seen in LMP tumors and benign cystadenomas. An interesting observation was the nuclear expression of E-cadherin in a high percentage of cancers, which showed a positive correlation with Ki-67. Β-Catenin expression showed heterogeneous localization with increased nuclear localization, which was significantly higher in cases that did not express E-cadherin. Promoter methylation of E-cadherin was 36, 14, and 11 % in EOC, LMP tumors, and benign cystadenomas, respectively. Our results suggest that reduced expression of E-cadherin is associated with promoter methylation of E-cadherin gene, in addition to providing evidence for the aberrant nuclear localization of E-cadherin in EOC.

A rare occurrence and management of familial schwannomatosis.

We are presenting a familial schwannomatosis without the features of neurofibromatosis (NF). We retrospectively reviewed the hospital charts, radiology films, operative notes and pathology slides of the patient. There was a family history of schwannomatosis. The patient had contrast-enhanced MRI, which was negative for vestibular schwannomas. The patient underwent surgical excision of symptomatic lesions. Histopathology confirmed these lesions as schwannomas consisting of areas of Antoni A and B, and immunohistochemical study was positive for S-100 protein. We recommend surgery for symptomatic lesions. Asymptomatic tumours can be monitored. Regular follow-up is essential as they may develop fresh lesions at any time. The relevant literature is discussed.

Aberrant promoter methylation of the RASSF1A and APC genes in epithelial ovarian carcinoma development.

PURPOSE: Tumor suppressor gene (TSG) silencing through promoter hypermethylation plays an important role in cancer development. The aim of this study was to assess the extent of methylation of the RASSF1A and APC TSG promoters in ovarian epithelial adenomas, low malignant potential tumours and carcinomas in order to reveal a role for epigenetic TSG silencing in the development of these ovarian malignancies. METHOD: The promoter methylation status of the RASSF1A and APC genes was assessed in 19 benign cystadenomas, 14 low malignant potential (LMP) tumours, and 86 carcinomas using methylation specific PCR (MSP). RESULTS: The methylation frequencies of the RASSF1A and APC gene promoters in benign cystadenomas were found to be 37 % and 16 %, respectively. The LMP tumours exhibited RASSF1A and APC gene promoter methylation frequencies of 50 % and 28 %, respectively, whereas the carcinomas exhibited methylation frequencies of 58 % and 29 %, respectively. Methylation of either the RASSF1A or the APC gene promoter was encountered in 58 % of the invasive carcinomas. CONCLUSION: The observed aberrant methylation frequencies of the RASSF1A and APC gene promoters indicate that an accumulation of epigenetic events at these specific TSG promoters may be associated with the malignant transformation of benign cystadenomas and LMP tumours to carcinomas.

Ileal ganglioneuromatosis with adenocarcinoma in a patient with multiple neurofibromatosis.

Von Recklinghausen's disease or type 1 neurofibromatosis is an autosomal dominant disease characterized by mucocutaneous neurofibromas, café-au-lait spots and involves many organs including gastrointestinal tract. Gastrointestinal involvement in neurofibromatosis is uncommon and is seen 25% patients and nearly 5% of them are only symptomatic (Shekitka and Sobin, Am J Surg Pathol 18:250-257, 1994; Tomita et al., Int J Colorectal Dis 21: 89-91, 2006).

Changes in BiSpecteral Index (BiS) Values During Cardiopulmonary Bypass (CPB).

BACKGROUND: BiSpecteral Index (BiS) monitoring is standard monitoring regimen in anaesthesia practice. It has also been used in cardiac surgery. It is especially important due to the high incidence of neurological injury or dysfunction that occurs following CPB. This is a retrospective study of 33 cases that were monitored with BiS during the course of coronary artery or valvular surgery, including the period of CPB. METHODS: Thirty three cases monitored with BiS were studied retrospectively. RESULT: From the recordings it was determined that the value of BiS which was ranging between 40 to 60 after induction, dropped below 25 at the onset of CPB. This change was statistically significant (p<0.05). CONCLUSION: This decrease in the BiS value is probably a result of hypo-perfusion and due to clear, oxygen - poor priming fluid reaching the brain. Other periods of hypotension also correlated with the low values of BiS. This cerebral hypoxia which would occur at this time could be the cause of the incidence of neurological dysfunction that is known to occur following CPB.

Laparoscopic staging in gastric cancer: An essential step in its management.

AIM: The role of laparoscopy in staging of gastric cancer is widely accepted; however, in Malaysia its usage has been limited. Patients can be classified as resectable or unresectable, which helps in avoiding an unwanted laparotomy and the morbidities associated with it. The aim of this study was to assess the value of laparoscopy in staging of gastric cancer in comparison with CT scan. MATERIALS AND METHODS: Patients with carcinoma of the stomach after a complete preoperative work-up underwent laparoscopy prior to surgical exploration. TNM staging was used to compare laparoscopy with CT, with the histopathological report used as the gold standard. RESULTS: Forty cases were included in this study. The sensitivity of laparoscopy for T3 tumours appears to be significant when compared to that of CT. Laparoscopy detected 90.3% of the cases as against the 58% detected with CT. There was not much difference in the N factor. With regard to M factor, the sensitivity was 100% for laparoscopy in comparison with CT. CONCLUSIONS: Laparoscopy has been shown to be sensitive in detecting metastasis in gastric cancer in comparison to CT, thus helping in avoiding unwanted laparotomy and thus providing a more systemic approach in managing gastric cancers.

Netrin-1: a novel universal biomarker of human kidney injury.

Currently available diagnostic markers representing kidney injury or function such as serum creatinine and blood urea nitrogen are insensitive and often increased late in the disease process. Netrin-1 protein, a laminin-related secreted molecule, is minimally or not expressed in tubular epithelial cells of normal kidneys. However, it is highly expressed in injured kidneys. Netrin-1 protein has been shown to be detected in urine from mice with acute kidney injury. The current study was carried out to evaluate whether netrin-1 is also induced in human acute kidney injury (AKI) and can serve as a urinary biomarker of the condition. We analyzed netrin-1 levels by sandwich enzyme-linked immunosorbent assay in urine samples from 10 healthy controls, 22 recipients of a renal allograft, 11 patients with ischemic AKI, 13 with AKI associated with sepsis, 9 with radiocontrast-induced AKI, and 8 with drug-induced AKI. Urinary netrin-1 levels normalized for urinary creatinine were significantly higher in all subject groups. The highest values were observed in patients with sepsis and in transplant patients immediately postoperatively. The level of NGAL was similarly increased in transplant patients. In conclusion, urinary netrin-1 levels are increased in patients with various forms of AKI/ATN and may serve as a universal biomarker for AKI.