Sphingosine kinase 1 regulates the expression of proinflammatory cytokines and nitric oxide in activated microglia

Microglial activation has been implicated as one of the causative factors for neuroinflammation in various neurodegenerative diseases. The sphingolipid metabolic pathway plays an important role in inflammation, cell proliferation, survival, chemotaxis, and immunity in peripheral macrophages. In this study, we demonstrate that sphingosine kinase1 (SphK1), a key enzyme of the sphingolipid metabolic pathway, and its receptors are expressed in the mouse BV2 microglial cells and SphK1 alters the expression and production of proinflammatory cytokines and nitric oxide in microglia treated with lipopolysaccharide (LPS). LPS treatment increased the SphK1 mRNA and protein expression in microglia as revealed by the RT–PCR, Western blot and immunofluorescence. Suppression of SphK1 by its inhibitor, N, N Dimethylsphingosine (DMS), or siRNA resulted in decreased mRNA expression of TNF-α, IL-1β, and iNOS and release of TNF-α and nitric oxide (NO) in LPS-activated microglia. Moreover, addition of sphingosine 1 phosphate (S1P), a breakdown product of sphingolipid metabolism, increased the expression levels of TNF-α, IL-1β and iNOS and production of TNF-α and NO in activated microglia. Hence to summarize, suppression of SphK1 in activated microglia inhibits the production of proinflammatory cytokines and NO and the addition of exogenous S1P to activated microglia enhances their inflammatory responses. Since the chronic proinflammatory cytokine production by microglia has been implicated in neuroinflammation, modulation of SphK1 and S1P in microglia could be looked upon as a future potential therapeutic method in the control of neuroinflammation in neurodegenerative diseases.     

An outbreak of cutaneous anthrax in a non-endemic district--Visakhapatnam in Andhra Pradesh

BACKGROUND: Anthrax is a disease of herbivorous animals, and humans incidentally acquire the disease by handling infected dead animals and their products. Sporadic cases of human anthrax have been reported from Southern India. METHODS: Five tribal men presented with painless ulcers with vesiculation and edema of the surrounding skin on the extremities without any constitutional symptoms. There was a history of slaughtering and consumption of a dead goat ten days prior to the development of skin lesions. Clinically cutaneous anthrax was suspected and smears, swabs and punch biopsies were taken for culture and identification by polymerase chain reaction (PCR). All the cases were treated with intravenous followed by oral antibiotics. Appropriate health authorities were alerted and proper control measures were employed. RESULTS: Smears from the cutaneous lesions of all five patients were positive for Bacillus anthracis and this was confirmed by a positive culture and PCR of the smears in four of the five cases. All the cases responded to antibiotics. CONCLUSION: We report five cases of cutaneous anthrax in a non-endemic district, Visakhapatnam, Andhra Pradesh, for the first time.     

Expression of epidermal growth factor receptor, ezrin, hepatocyte growth factor, and c-Met in uveal melanoma: an immunohistochemical study

The immunoreactivity of epidermal growth factor receptor (EGFR) ezrin, hepatocyte growth factor receptor (HGF), and c-Met was studied in 60 uveal melanomas and was correlated with clinicopathologic parameters. Metastases were diagnosed in the patients with uveal melanoma between 5 years and 8 years (median, 6.5 years) after enucleation. Using Kaplan-Meier statistical analysis, we found a significant association between high c-Met expression and death due to uveal melanoma (p < 0.03). EGFR was expressed in 18 of 60 (30%) tumors; ezrin was expressed in 30 of 60 (50%) tumors. Tumors with liver metastasis (n = 6) showed higher expression of c-Met (p = 0.0009) compared with the tumors with no extension/extrascleral extension without liver metastasis (groups A-45 and B-9). HGF was negative in all the six tumors that had liver metastasis. Further studies are required to understand the possible mechanism of ligand-independent c-Met activation in patients with uveal melanoma.     

Genital tuberculosis: an important cause of Asherman’s syndrome in India

Objective To demonstrate the association between genital endometrial tuberculosis and Asherman's syndrome. Materials and methods A total of 28 women who underwent hysteroscopy with or without laparoscopy for suspected Asherman’s syndrome from symptoms (amenorrhoea or oligomenorrhoea, and or primary or secondary infertility) and who were found to have genital tuberculosis on endometrial biopsy (histopathology or culture) or positive polymerase chain reaction (PCR) on endometrial aspirate or positive findings of tuberculosis on laparoscopy or hysteroscopy were enrolled in this retrospective study. Results The mean age and parity were 26.5 years and 0.3, respectively. There was past history of TB in 67.8% women. All women had menstrual dysfunction, with oligomenorrhoea and hypomenorrhoea in 16 (57%) women and amenorrhoea in 12 (42.8%). All women had primary (n = 19, 67.8%) or secondary (n = 9, 32%) infertility. On hysteroscopy, there were various grades of adhesions in all women, with grade I in 17.8%, grade II in 28.5%, grade III in 28.5% and grade IV in 17.5% women. Only four women (14.3%) had open ostia, while others had bilateral (28.5%) or unilateral (21.3%) blocked ostia or inability to see ostia (28.5%). On laparoscopy performed on 18 women, there were varying grades of adhesions in 16 (88.8%) women, with beading (33.3%), tubercles (33.3%), caseation (11.1%) and tubo-ovarian masses (11.1%). The diagnosis of genital TB was made by histopathology (tuberculous granuloma) on endometrial biopsy in 28.6%, positive culture in 3.6%, positive polymerase chain reaction (PCR) in 46.4% and observation of tubercles, beading or caseation on laparoscopy in 17.8% or shaggy cavity with caseation on hysteroscopy in 3.6% women. Conclusion Genital tuberculosis appears to be an important and common cause of Asherman's syndrome in India, causing oligomenorrhoea or amenorrhoea with infertility.     

Laparoscopic findings in female genital tuberculosis

OBJECTIVES: To evaluate the laparoscopic findings in genital tuberculosis (TB). METHODS: A total of 85 women of genital TB, who underwent diagnostic laparoscopy for infertility or chronic pelvic pain were enrolled in this retrospective study conducted in our unit at All India Institute of Medical Sciences, New Delhi, India from September 2004 to 2007. RESULTS: The mean age was 28.2 years and the mean parity was 0.24. Most women were from poor socioeconomic status (68.1%). Past history of TB was seen in 29 (34.1%) women with pulmonary TB in 19 (22.35%) women and extrpulmonary in 10 (11.7%) women. Most women presented with infertility (90.6% primary 72.9%; secondary 17.6%) while the rest had chronic pelvic pain (9.4%). The mean duration of infertility was 6.2 years. A total of 49 (57.6%) women had normal menses, while hypomenorrhea, oligomenorrhea, secondary amenorrhea and menorrhagia were seen in 25 (30.1%), 3 (3.5%), 5 (5.9%), and 2 (2.4%) women respectively. Diagnosis of genital TB was made by histopathological evidence of TB granuloma in 16 (18.8%) (Endometrial biopsy in 12.9%, laparoscopy biopsy in 5.9%) women, demonstration of acid fast bacilli (AFB) on microscopy in 2(2.3%), positive AFB culture in 2 (2.3%), positive polymerase chain reaction (PCR) in 55 (64.7%) and laparoscopic findings of genital TB in 40 (47.1%). The various findings on laparoscopy were tubercles on peritoneum (12.9%) or ovary (1.2%), tubovarian masses (7.1%), caseous nodules (5.8%), encysted ascitis in 7.1% women. Various grades of pelvic adhesions were seen in 56(65.8%) women. The various findings on fallopian tubes were normal looking tubes in (7.1%), inability to visualize in 12(14.1%), presence of tubercles on tubes in 3 (3.52%), caseous granuloma in 3 (3.52%), hydrosalpinx in 15 (17.6%) (Right tube 11.7%, left tube 5.9%), pyosalphinx in 3 (3.5%) on right tube and 2 (2.35%) in left tube, beaded tube in 3 (3.5%) on right tube, 4 (4.7%) in left tube with tobacco pouch appearance in 2 (2.35%) women. The right tube was patent in 9 (10.6%) while left tube was patent in 10(11.7%) cases only, while they were either not seen (absent in one case due to previous salphingectomy, inability to see due to adhesion in 14.12%) or blocked at various sites with cornual end being most common in 3 (3.5%) showing multiple block in right tube and 4.7% in left tube. CONCLUSION: There is a significant pelvic morbidity and tubal damage in genital tuberculosis.     

Actinomyces naeslundii as an agent of pelvic actinomycosis in the presence of an intrauterine device.

Actinomyces naeslundii is a saprophyte, sometimes a pathogen, of the human oral cavity. Very few extra-oral infections related to this agent have been described. We report the first instance of A. naeslundii as an etiological agent of pelvic actinomycosis in a user of an intrauterine device, an infection so far exclusively attributed to Actinomyces israelii.     

Outcomes in newly diagnosed localization-related epilepsies.

A total of 558 patients with a range of localization-related epilepsy syndromes starting treatment in a single centre were followed over a period of up to 20 years. Overall, 343 (62%) patients became seizure free for 12 months or more (responders), 92% of whom (57% of total population) remained in remission until the end of follow-up. Only 27 (5%) responders relapsed and subsequently developed refractory epilepsy. The remaining 215 (38%) patients never became seizure free for any 12-month period. There were no significant differences in outcome between cryptogenic (56% remission) and symptomatic (57% remission) epilepsies. Patients with underlying cortical atrophy (71% remission; p<0.05) or cerebrovascular disease (70% remission; p<0.01) did better, while those with traumatic brain injury (35% remission; p<0.001) did worse than the remainder of the symptomatic group. Remission rates in patients with cortical dysplasias (60%), hippocampal atrophy (50%) and primary brain tumors (52%) appeared no different from those with other symptomatic epilepsies. Overall, 20-40% patients with each epilepsy syndrome reported no further seizures after starting AED treatment including 21% with hippocampal atrophy and 33% with cortical dysplasia. More than 50% of patients developing localization-related epilepsy during adolescence or in adulthood had a good outcome. Prognosis in those with underlying hippocampal atrophy or cortical dysplasia was not always bad.     

Circulating matrix modulators (MMP-9 and TIMP-1) and their association with severity of diabetic retinopathy

Aims

Diabetic Retinopathy (DR) is the leading cause of vision loss in the working age population. Matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1), are molecules involved in extracellular tissue matrix remodelling. They are implicated in the loss of retinal tissue integrity, a major cause of DR, that leads to retinal tissue degradation and apoptosis. This study is therefore, conducted to compare the serum levels of MMP-9 and TIMP-1 in T2DM patients without and with retinopathy, and to evaluate their association with the severity of DR.