Negative regulation of signal transducer and activator of transcription-3 signalling cascade by lupeol inhibits growth and induces apoptosis in hepatocellular carcinoma cells.

BACKGROUND: Constitutive activation of signal transducer and activator of transcription signalling 3 (STAT3) has been linked with survival, proliferation and angiogenesis in a wide variety of malignancies including hepatocellular carcinoma (HCC). METHODS: We evaluated the effect of lupeol on STAT3 signalling cascade and its regulated functional responses in HCC cells. RESULTS: Lupeol suppressed constitutive activation of STAT3 phosphorylation at tyrosine 705 residue effectively in a dose- and time-dependent manner. The phosphorylation of Janus-activated kinases (JAKs) 1 and 2 and Src was also suppressed by lupeol. Pervanadate treatment reversed the downregulation of phospho-STAT3 induced by lupeol, thereby indicating the involvement of a phosphatase. Indeed, we observed that treatment with lupeol increased the protein and mRNA levels of SHP-2, and silencing of SHP-2 abolished the inhibitory effects of lupeol on STAT3 activation. Treatment with lupeol also downregulated the expression of diverse STAT3-regulated genes and decreased the binding of STAT3 to VEGF promoter. Moreover, the proliferation of various HCC cells was significantly suppressed by lupeol, being associated with substantial induction of apoptosis. Depletion of SHP-2 reversed the observed antiproliferative and pro-apoptotic effects of lupeol. CONCLUSIONS: Lupeol exhibited its potential anticancer effects in HCC through the downregulation of STAT3-induced pro-survival signalling cascade.

Single stage repair of tetralogy of fallot associated with left pulmonary artery sling and tracheal stenosis.

We report a rare case of tetralogy of Fallot (TOF) with left pulmonary artery (LPA) sling with tracheal stenosis. The patient underwent successful surgery in one stage involving intracardiac repair of TOF, LPA reimplantation and resection of tracheal stenosis with end-to-end anastomosis.

Perinatal tuberculosis: four cases and use of broncho-alveolar lavage.

Despite the high prevalence of tuberculosis in adults and children, congenital and perinatal forms of tuberculosis are rare. Four patients with perinatal tuberculosis are described. Diagnosis was made by demonstration of acid-fast bacilli (AFB) on broncho-alveolar lavage (BAL) specimens (two cases), gastric aspirate smear (one case) and lymph node fine-needle aspirate (one case). All of the above specimens were subsequently positive on culture. Two infants died of progressive pulmonary failure, and one of the mothers died, despite the institution of anti-tuberculous therapy. BAL specimen examination for AFB is useful in the diagnosis of perinatal tuberculosis, especially in infants with smear-negative gastric aspirate.

Immunosuppression among HIV-1-positive patients attending for care: experience from two large HIV centres in the United Kingdom.

OBJECTIVES: The aim of the study was to describe the prevalence of and examine the factors associated with immunosuppression (CD4 < 200 cells/microL) among HIV-infected patients attending two large inner London treatment centres. METHODS: Patients attending for care who had a CD4 count < 200 cells/microL during a 6-month period (1 January to 30 June 2007) were identified from the UK national CD4 surveillance database. Corresponding case notes were reviewed and factors associated with the most recent immunosuppressive episode examined. Patients either previously had a CD4 count > 200 cells/microL at any time under follow-up which had decreased (group A) or never had a CD4 count > 200 cells/microL (group B; late presenters). RESULTS: Of 4589 patients, 10.2% (467) had at least one CD4 count < 200 cells/microL. In group A (60.1% of patients), 70.4% were not receiving antiretroviral therapy (ART) at the time at which the CD4 count fell to < 200 cells/microL. Reasons included: treatment interruption (TI; 32.6%), patient declined ART (20.2%), infrequent attendance (19.1%), physician delay in offer (23.1%) and transient CD4 cell count decrease (3.9%). Among those receiving ART, one in three had poor adherence. In group B, 92.3% had started ART after presentation: most had recently started and were responding virologically. AIDS-defining diagnoses occurred in the year preceding the decrease in CD4 cell count in 12.6% of patients in group A and 33.3% of those in group B. CONCLUSION: The majority of patients became immunosuppressed while under care. Our findings suggest that, in addition to strategies aimed at earlier diagnosis, there are further opportunities to reduce severe immunosuppression in patients already attending for HIV care.

Evaluation of the immunogenicity and safety of an indigenously developed DTwP-Hib tetravalent combination vaccine (Shan 4) with EasyFourTM in Indian infants administered per EPI schedule: a phase III trial.

The study was planned to assess and compare immunogenicity and safety of an indigenous DTPw-Hib combination vaccine (Shan 4) with EasyFour, the available DTwP-Hib vaccine in India. Overall 210 healthy infants, six to eight weeks of age, were randomized to receive three doses of either Shan 4 or EasyFour at 6, 10 and 14 weeks of age. Antibodies were analyzed prior to and four to six weeks post third vaccine dose. Solicited and unsolicited local and systemic events in the follow up period after each dose were recorded. Post vaccination 100% of the infants in Shan 4 and EasyFour groups had seroprotective concentrations of Anti PRP-T IgG antibodies, IgG anti-diphtheria toxoid antibodies and IgG anti-tetanus toxoid antibodies. Following third dose of vaccination 86.99% subjects in the Shan 4 group and 73.85% subjects in the EasyFour group seroconverted for anti-pertussis antibody titres. Two Serious Adverse Events (SAE s) were reported during the course of the study, all unrelated to the respective vaccine administered. Most commonly reported adverse events in both the groups were pain at injection site, mild fever (<103°F) and minor swelling at injection site. The study proved that Shan 4 was safe and immunogenic compared to the available licensed vaccine.

Lymphogranuloma venereum presenting as genital ulceration and inguinal syndrome in men who have sex with men in London, UK.

OBJECTIVES: To describe a series of lymphogranuloma venereum (LGV) cases presenting as inguinal syndrome and/or genital ulceration seen among men who have sex with men (MSM) in London, UK. METHODS: Collaborative retrospective case note review. Clinicians from three London genitourinary medicine (GUM) clinics accessed by large populations of MSM within the current LGV outbreak collected clinical data from confirmed cases of LGV inguinal syndrome or genital ulcer. LGV was confirmed by the detection of LGV-specific DNA from specimens such as bubo aspirates, ulcer swabs, urethral swabs, first void urine and rectal biopsy material. RESULTS: There were 13 cases detected overall: 5 cases of urethral LGV infection with inguinal adenopathy, 3 cases of genital ulcer with LGV inguinal adenopathy, 3 cases of isolated LGV-associated inguinal buboes, 1 case of a solitary LGV penile ulcer and 1 case with a penile ulcer and bubonulus. Only 6 of the 13 were HIV positive and all tested negative for hepatitis C. The majority of cases reported few sexual contacts in the 3 months preceding their diagnosis. CONCLUSIONS: Clinical manifestations of LGV in MSM have not been confined to proctitis in the current outbreak in the UK and a small but significant number of inguinogenital cases of LGV have been observed. Epidemiologically, many of the cases described seem to have occurred at the periphery of the current MSM LGV epidemic. Clinicians need to be vigilant for these less common presentations of LGV among MSM and specific diagnostic tests should be done from the relevant lesions.

UK National Audit of Sexual History-taking: case-notes audit.

A national audit of sexual history-taking was conducted in genitourinary medicine clinics in the UK in 2008. Data were aggregated by region and clinic, allowing practice to be compared between regions, as well as to national averages and against national Guidelines. In this paper the case-notes of 4121 patients were audited. A high proportion of the case-notes were deemed to be completely legible. In other respects there is considerable inter-regional variation in the adherence to national Guidelines. Interventions are especially required to improve documentation of practice in discussing condom use, HIV risk assessment, offer of a chaperone and assessment for hepatitis B vaccination and hepatitis C testing, and issues concerning sexual contacts.

UK National Audit of Sexual History-taking: clinic policies audit.

Provision of a confidential, private environment for sexual history-taking was provided in almost all clinics. However, less than half of the clinics had a policy displayed about their confidentiality policy in waiting areas, although more had this available by other means. About two-thirds of clinic information/advertising literature included information about the need to take a sexual history. Sixty percent of clinics assessed clinician communication skills as part of service quality. Most clinics had policies relating to patients whose first language is not English, but only around half of clinics had policies for hearing difficulties and learning difficulties. Policies are also lacking in some clinics for documentation of the offer of chaperones and assessment of the competency of under-16-year-olds to consent to history-taking and examination.

Utilization of HIV point-of-care testing clinics in general practice and genitourinary medicine services in south-east London.

We compared the utilization of HIV point-of-care testing (POCT) clinics in a general practice and a genitourinary (GU) medicine service. Retrospective case-note review of patients attending the general practice HIV POCT clinic from February 2005 to July 2007 was undertaken. Those attending the GU medicine service over the same period were used as a comparator group. HIV POCT clinics in general practice when compared with GU medicine services were significantly more likely to be utilized by those of Black ethnicity (Black African 61/370 [16.5%] vs. 107/1231 [8.7%], P < 0.001; Black Caribbean 19/370 [5.1%] vs. 11/1231 [0.9%], P < 0.001 and Black Other 20/370 [5.4%] vs. 26/1231 [2.1%], P = 0.001, respectively). Fewer men who have sex with men attended for HIV POCT in general practice than in GU medicine; 82/238 (34.5%) vs. 337/816 (41.3%), P = 0.058. We have demonstrated that HIV POCT clinics in primary care and GU medicine attract different 'at-risk' groups and provide increased opportunity for testing.

Serological and molecular detection of Mycoplasma pneumoniae in children with community-acquired lower respiratory tract infections.

This study was designed to evaluate the incidence of Mycoplasma pneumoniae infection in children with community-acquired lower respiratory tract infections (LRTIs). A total of 245 patients 6 months to 12 years of age were investigated for M. pneumoniae employing serological tests, polymerase chain reaction (PCR), nested PCR, and reverse transcription PCR (RT-PCR) on throat swab samples. Forty five (59.2%) children <5 years and 31 (40.7%) children ≥5 years age group were positive for M. pneumoniae infection, and this difference was statistically significant (P ≤ 0.01).Clinical and radiological findings across M.pneumoniae-positive and -negative cases were comparable. Serology, PCR, nested PCR, and RT-PCR together detected M. pneumoniae infection in 76 (31%) patients. Sensitivity, specificity, and positive and negative predictive values of PCR were 16.18%, 95.48%, 57.89%, and 74.78%, respectively, and those of serology were 57.89%, 74.78%, 16.18%, and 95.48%, respectively. Serological and molecular detection in combination is useful for rapid and reliable diagnosis of M. pneumoniae infections in children with LRTIs.

Mycoplasma pneumoniae infection and asthma in children.

A clinical association between exacerbation of asthma symptoms and Mycoplasma pneumoniae ( M. pneumoniae) infection has long been suspected. We studied 80 children aged 5-15 years; 50 with asthma (Group 1) and 30 without an acute exacerbation of asthma (Group 2) for detection of M. pneumoniae by serology and polymerase chain reaction (PCR) on nasopharyngeal aspirates. Our study confirms that lower respiratory tract infections with M. pneumoniae are frequently associated with exacerbations of asthma in children.

Gamma Radiation-Induced Disruption of Cellular Junctions in HUVECs Is Mediated through Affecting MAPK/NF-κB Inflammatory Pathways.

Ionizing radiation-induced cardiovascular diseases (CVDs) have been well documented. However, the mechanisms of CVD genesis are still not fully understood. In this study, human umbilical vein endothelial cells (HUVECs) were exposed to gamma irradiation at different doses ranging from 0.2 Gy to 5 Gy. Cell viability, migration ability, permeability, oxidative and nitrosative stresses, inflammation, and nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) pathway activation were evaluated postirradiation. It was found that gamma irradiation at doses ranging from 0.5 Gy to 5 Gy inhibited the migration ability of HUVECs without any significant effects on cell viability at 6 h and 24 h postirradiation. The decreased transendothelial electrical resistance (TEER), increased permeability, and disruption of cellular junctions were observed in HUVECs after gamma irradiation accompanied by the lower levels of junction-related proteins such as ZO-1, occludin, vascular endothelial- (VE-) cadherin, and connexin 40. The enhanced oxidative and nitrosative stresses, e.g., ROS and NO2 - levels and inflammatory cytokines IL-6 and TNF-α were demonstrated in HUVECs after gamma irradiation. Western blot results showed that protein levels of mitogen-activated protein kinase (MAPK) pathway molecules p38, p53, p21, and p27 increased after gamma irradiation, which further induced the activation of the NF-κB pathway. BAY 11-7085, an inhibitor of NF-κB activation, was demonstrated to partially block the effects of gamma radiation in HUVECs examined by TEER and FITC-dextran permeability assay. We therefore concluded that the gamma irradiation-induced disruption of cellular junctions in HUVECs was through the inflammatory MAPK/NF-κB signaling pathway.

Concomitant back pain as a predictor of outcome after single level lumbar micro-decompressive surgery - A study of 995 patients.

OBJECTIVE: To determine if preoperative leg pain and low back pain severity affected postoperative outcome. METHOD: Prospectively collected Spine-Tango data was analysed for 995 consecutive patients who underwent a primary, single level, lumbar micro-decompression/microdiscectomy at a single tertiary spinal centre. RESULT: At 3 months, 72% of patients were satisfied with the outcome of surgery. Pre-operative low back pain was a significant predictor of poor outcome (P < 0.01). CONCLUSION: Our study has shown that patients with a low back pain VAS of 6 or more have a significantly greater chance of a poor outcome following primary lumbar microdecompressive/microdiscectomy surgery.

Black and minority ethnic men who have sex with men: a London genitourinary medicine clinic experience.

The aim was to examine sexual behaviour and rates of sexually transmitted infections (STIs) in black and minority ethnic (BME) men who have sex with men (MSM) attending a London genitourinary medicine clinic. A case-note review of BME MSM (n = 203) attending our service between 1 April 2005 and 31 March 2006 was carried out. BME MSM were those who self-identified as being of Black (Caribbean, African or Other), South Asian (Indian, Pakistani, Bangladeshi or Sri Lankan) and Chinese/South-East Asian (Malaysian, Thai, Filipino, Japanese) ethnicities. Consecutively attending self-identified white British (WB) MSM (n = 203) were used as a comparative group. BME MSM were significantly more likely to report unprotected anal intercourse with casual male partners in the preceding three months (P = 0.0016) and were more likely to report female sexual partners (P = 0.0018). Rectal gonorrhoea was more common in WB MSM (P = 0.02). Numbers of other bacterial STIs and HIV infection were similar in both groups. The higher reported rates of risk behaviour in BME MSM are of concern and support the need for focussed sexual health promotion.

Comparison of PCR, culture & serological tests for the diagnosis of Mycoplasma pneumoniae in community-acquired lower respiratory tract infections in children.

BACKGROUND & OBJECTIVE: Mycoplasma pneumoniae is known to be a major cause of lower respiratory tract infections in children. A specific diagnosis is important to institute the appropriate treatment. Information on diagnostic methods used for M. pneumoniae in Indian paediatric population is scarce. The study was thus conducted to compare polymerase chain reaction (PCR), culture and serology for the diagnosis of M. pneumoniae in community-acquired lower respiratory tract infections in children. METHODS: Seventy five children aged 6 months to 12 yr with signs of community-acquired lower respiratory tract infections were selected for the study. Culture of nasopharyngeal aspirates was done. The serum samples were analyzed for the detection of IgM and IgG antibodies to M. pneumoniae. A 543 base pairs (bp) region of P1 gene of M. pneumoniae was selected for amplification in PCR assay applied to nasopharyngeal aspirates. RESULTS: M. pneumoniae was isolated in culture from 4 (5.33%) children. Serological evidence of M. pneumoniae infection was observed in 16(21.3%) children. All culture positive patients were also positive by serology. Overall, PCR for M. pneumoniae was positive in 13 (17.3%) patients. All four culture positive patients were also positive by PCR. In 11 out of 13 (84.62%) PCR positive patients, serological evidence was there. Culture and/or serology and/or PCR positive results diagnosed M. pneumoniae infection in 18 (24%) of 75 patients. INTERPRETATION & CONCLUSION: A combination of culture, serology and PCR may provide diagnostic information on the aetiology of M. pneumoniae community-acquired lower respiratory tract infections in paediatric population.

Sexual health services for South Asians in London, UK: a case-control study.

National guidance on sexual health in England recommends service development to meet the specific needs of ethnic minority populations. Our aim was to evaluate mode of referral, number of sexually transmitted infections (STIs) diagnosed, and the offering and uptake of HIV testing in patients of South Asian ethnicity. A retrospective case-control study was undertaken in two London genito-urinary (GU) medicine clinics. There were 250 case-control pairs with approximately equal numbers of men and women. South Asians were less likely to have an STI (Odds ratio [OR] 0.66, 95% confidence interval [CI] 0.45, 0.97) or to report risk factors for HIV (OR 0.45, 95% CI 0.28, 0.71). Offering and uptake of HIV antibody testing were high in both South Asian and non-South Asian groups (OR 0.62, 95% CI 0.27, 1.51). South Asians were significantly more likely than controls to have been referred by other medical services rather than self-referred (OR 2.00, 95% CI 1.32, 3.01), which is in keeping with poorer access to GU medicine services in London.

Renal Transplantation - An Experience of 500 Patients.

BACKGROUND: Renal transplantation is the treatment modality of choice for patients with end stage kidney failure. We present our experience of graft and patient survival of initial 500 renal transplants performed between May 1991 and July 2006, at Army Hospital (R&R). MATERIAL AND METHODS: All patients received triple drug immunosuppression with cyclosporine/tacrolimus, azathioprine/ mycophenolate mofetil and steroids. Patients in high risk group received induction therapy with IL-2 receptor blockers/anti-thymocyte globulin. RESULTS: Majority of the recipients (79%) were males, whereas majority of the donors (59.4%) were females. In the donor profile, 385 (77%) transplants were live related, 108 (21.6 %) were spousal and 7 (1.4%) were cadaveric transplants. Mean age of the donors and recipients was 42.11 ± 11.53 years (range 19-72 years) and 33 ± 9.39 years (range 5-60 years) respectively. Eighty two patients (16.4%) were lost to follow up and the present data on rejections, patients and graft survival pertains to 418 patients. These patients have been followed up for a mean period of 2.63 years (SE, 0.122; median 1.8 years; range 0-13.36 years). Acute rejection episodes occurred in 115 (27.3%) patients and 95% of these could be reversed with steroids/ATG. Sixty eight patients (16%) have died on follow-up. Our one-year, 5 year and 10 year estimated graft survival is 95.4% (SE, 0.01), 80.5% (SE, 0.03) and 53.1% (SE, 0.09) respectively and patient survival at one year is 93.2% (SE, 0.01). The estimated graft and patient survival in our series is 9.83 (95% CI, 8.92-10.73) and 9.80 (8.93-10.67) years respectively. CONCLUSION: This centre's short-term graft survival of 95.4% is comparable to the best centres of the world.

Occurrence and impact of domestic violence and abuse in gay and bisexual men: A cross sectional survey.

This cross-sectional survey measured adult experience and perpetration of negative and potentially abusive behaviours with partners and its associations with mental and sexual health problems, drug and alcohol abuse in gay and bisexual men attending a UK sexual health service. Of 532 men, 33.9% (95% CI: 29.4-37.9) experienced and 16.3% (95% CI: 13.0-19.8) reported carrying out negative behaviour. Ever being frightened of a partner (aOR 2.5; 95% CI: 2.0-3.1) and having to ask a partner's permission (aOR 2.7; 95% CI: 1.6-4.7) were associated with increased odds of being anxious. There were increased odds of cannabis use in the last 12 months amongst men who reported ever being physically hurt (aOR 2.4; 95% CI: 1.7-3.6). Being frightened (aOR 2.2; 95% CI: 1.5-3.2), being physically hurt (aOR 2.3; 95% CI: 1.4-3.8), being forced to have sex (aOR 2.5; 95% CI: 1.3-4.9) and experiencing negative behaviour in the last 12 months (aOR 1.7; 95% CI: 1.2-2.5) were associated with increased odds of using a Class A drugs in the last 12 months. Sexual health practitioners should be trained with regards to the risk indicators associated with domestic violence and abuse, how to ask about domestic violence and abuse and refer to support.

TNF blockade: an inflammatory issue.

Tumor necrosis factor (TNF), initially discovered as a result of its antitumor activity, has now been shown to mediate tumor initiation, promotion, and metastasis. In addition, dysregulation of TNF has been implicated in a wide variety of inflammatory diseases including rheumatoid arthritis, Crohn's disease, multiple sclerosis, psoriasis, scleroderma, atopic dermatitis, systemic lupus erythematosus, type II diabetes, atherosclerosis, myocardial infarction, osteoporosis, and autoimmune deficiency disease. TNF, however, is a critical component of effective immune surveillance and is required for proper proliferation and function of NK cells, T cells, B cells, macrophages, and dendritic cells. TNF activity can be blocked, either by using antibodies (Remicade and Humira) or soluble TNF receptor (Enbrel), for the symptoms of arthritis and Crohn's disease to be alleviated, but at the same time, such treatment increases the risk of infections, certain type of cancers, and cardiotoxicity. Thus blockers of TNF that are safe and yet efficacious are urgently needed. Some evidence suggests that while the transmembrane form of TNF has beneficial effects, soluble TNF mediates toxicity. In most cells, TNF mediates its effects through activation of caspases, NF-kappaB, AP-1, c-jun N-terminal kinase, p38 MAPK, and p44/p42 MAPK. Agents that can differentially regulate TNF expression or TNF signaling can be pharmacologically safe and effective therapeutics. Our laboratory has identified numerous such agents from natural sources. These are discussed further in detail.

A Comparative Study of Laparoscopic with Conventional Open Donor Nephrectomy in Renal Transplantation.

BACKGROUND: Laparoscopic donor nephrectomy (LDN) has been gaining popularity among kidney donors. There have been concerns about the safety and efficacy of the procedure as compared to open donor nephrectomy (ODN). We compare our results on LDN with ODN. METHODS: We retrospectively analysed our data of LDN and ODN. Duration of surgery, blood loss, period of hospitalisation, per oral intake and analgesic requirements. RESULT: 22 LDNs were done, the operation time ranged from 220-300 minutes, and blood loss from 100-150ml. In the first 10 laparoscopic operations four cases required conversion to open surgical dissection. Only one case was converted to open surgery in the subsequent 12 laparoscopic cases. Oral intake was started on the first postoperative day. Analgesic requirement in laparoscopy cases was less. Patients were mobilised on the first day after surgery. Patients were discharged by seventh day. There was no significant difference in the functioning of the graft after revascularisation in the recipient. CONCLUSION: Laparoscopic donor nephrectomy is a safe and effective technique of donor nephrectomy.