Evaluation of factors that act as barriers in conducting academic trials - An investigator's perception.

Background: Academic trials are essential in investigating health research questions relevant to the society. Only a few leading research institutions in India have been engaged in academic trials. Thus, there is a need to understand what factors dampen the spirit of the academician in conducting academic clinical trials. Aims and Objectives: The aim of the study is to evaluate the investigator's perception of obstacles to carrying out academic trials and to identify factors that will motivate investigators in conducting academic trials. Materials and Methods: We conducted a prospective observational study in a tertiary care hospital for 6 months. Faculty members working in academic institutes were selected. A structured questionnaire was designed for the study and administered using google forms. Responses were taken on a Likert scale. Validity and reliability assessments were carried out. Mann-Whitney test was applied to assess differences between demographic groups. P <0.05 was considered significant. Results: Most of the participants rated applying for research grants (76%), obtaining funding for the study and making arrangements for compensation for trial-related events (75%) as extremely challenging. We found that the degree of challenge is significantly lower in the faculty members who conducted clinical trials in the past as against those who did not (P = 0.00069). We also found that the degree of challenge is significantly higher in the faculty members with <10 years of experience than those with >10 years of experience (P = 0.00001). Conclusion: Thus, to conclude the challenges faced by investigators were at multiple levels, most common being applying for research grants and making arrangements for the funds for payment towards participation or study-related injury. Faculty members with exposure to conducting clinical trials and with experience of more than 10 years had perceived a reduced degree of challenges.

Risk factors for post-ERCP pancreatitis: it depends on the ERCP indication.

BACKGROUND AND AIMS: Endoscopic retrograde cholangiopancreatography (ERCP) is an invasive modality, and has a high risk of causing post-ERCP pancreatitis (PEP). Risk factors of PEP have been investigated and conflicting results are present for most risk factors. The aim of this study was to evaluate the risk factors for PEP and to determine whether the risk factors differ due to the ERCP indication. PATIENTS AND METHODS: A retrospective study was conducted which included 666 patients with 968 ERCP procedures. Some risk factors were evaluated for PEP, and they were also evaluated separately for patients with bile duct stones and patients who underwent ERCP for other reasons than bile duct stones. RESULTS: In patients with bile duct stones detected on ERCP ; female gender, lower diameter of the common bile duct, placing a biliary plastic stent and not having a cholecystectomy history were risk factors for PEP, whereas in patients without bile duct stones the only risk factor for PEP was not having a prior endoscopic sphincterotomy. CONCLUSIONS: Our study revealed that PEP risk factors depend on the indication of ERCP. To the best of our knowledge our study is the first study defining cholecystectomy as a protective factor for PEP in patients with bile duct stones and endoscopic sphincterotomy history as a protective factor for PEP in patients without bile duct stones. Our study also showed that female gender, lower diameter of the common bile duct and placing a plastic biliary stent were risk factors for PEP in patients with bile duct stones.

Fatal acute haemolysis and methaemoglobinaemia in a man with renal failure and Alkaptonuria - Is nitisinone the solution?

Haemolysis and methaemoglobinaemia (MetHb) are rare metabolic complications that can occur in Alkaptonuria (AKU), for which there is no curative treatment. Presented is a case of a man who had AKU, and serves as a reminder of life-threatening complications that can occur with haemolysis and MetHb. This case presents an opportunity to revisit important considerations relating to the investigation and treatment of haemolysis and MetHb with a view to raising awareness, and in doing so hopefully reducing the uniformly fatal outcome. Additionally it is proposed that treatment of haemolysis and MetHb with nitisinone is considered as a potentially lifesaving treatment as it is believed that reducing the concentration of circulating homogentisic acid will reduce oxidative stress.

Pleuroparenchymal fibroelastosis (PPFE) associated with giant cell arteritis: A coincidence or a novel phenotype?

Pleuroparenchymal fibroelastosis (PPFE) is a rare interstitial lung disease characterized by the fibrotic thickening of subpleural and parenchymal areas of the upper lobes. It may be both idiopathic or secondary to infections, interstitial lung diseases and/or drug exposure. Often PPFE patients report recurrent lower respiratory tract infections, suggesting that repeated inflammatory alterations induced by pulmonary infections may contribute to the development/progression of PPFE. Here, we report for the first time the case of a patient affected by Giant cell Arteritis with histologically proven PPFE. The lung involvement in GCA is rare and interstitial lung diseases are usually reported as an uncommon clinical manifestation of GCA. Our patient is probably the first case presenting PPFE associated with GCA and we wonder if this is a real associative disease or a coincidence perhaps, secondary to drug effects.

Association between serum vitamin D and parathyroid hormone levels in Turkish patients with colonic polyps.

UNLABELLED: Epidemiological and investigational studies have proved that vitamin D is important in autoimmune processes and has anticancerogenic properties. But the interplay between serum vitamin D and parathyroid hormone (PTH) in colorectal polyps has been less clearly put forward. We evaluated serum vitamin D, PTH levels in Turkish people and tried to stratify colorectal polyps according to risk factors. Patients undergoing colonoscopy between January 2012 and March 2012 were considered to study serum vitamin D levels during winter. Study population comprised of 98 colorectal polyp and 197 normal colonoscopy patients. RESULTS: Serum vitamin D levels were not different between the groups (mean vitamin D level in polyp group 14.3 ± 11.1 vs. 12.7 ± 6.74 the normal group, p = 0.12). Likewise serum PTH levels were not different between the groups Patients with polyps were further classified as high and low risk polyps. When discriminant function analysis was conducted, the effects of vitamin D or PTH levels were not again significant. During the study period 16 colorectal carcinoma cases were detected. Serum vitamin D or PTH levels were not significantly different between colorectal cancer or overall study group patients. Finally serum vitamin D levels were stratified into quartiles. Likewise there was not any significant difference between the groups. The present study suggests that serum vitamin D and PTH levels were not different between colorectal polyp and control groups. And serum vitamin D levels were significantly low in both groups suggesting a significant vitamin D deficient state in Turkish patients.

Should the Functional Residual Capacity be Ignored?

AIM AND OBJECTIVES: The functional residual capacity was given the least importance than the other lung volume parameters. Studies have revealed the restrictive pattern of lung disease in patients with liver cirrhosis. We aimed to analyze the importance of the functional residual capacity and other lung volumes of cirrhotic patients. SUBJECTS AND METHODS: Forty (40) patients with cirrhosis (Child's-B) were enrolled in this study. The vital capacity was measured by an instrument called V02 Max 22. The other lung volumes which were measured were derived parameters. The functional residual capacity was measured by the nitrogen wash-out method. RESULTS: The measured value of the functional residual capacity was below normal as compared to the reference value. The total lung capacity and the vital capacity were positively correlated with the functional residual capacity. The residual volume was found to be increased in twelve out of forty cirrhotic patients. CONCLUSION: The functional residual capacity can be determined by the compliance of the lung and the chest wall. The patients with a reduced functional residual capacity may be suffering from dyspnoea, probably due to the restrictive pattern of the lung disease. Hence, the reduced lung volumes of the subjects may be due to the abnormalities in the mechanics of ventilation.

Comparison between Capsule Endoscopy and Magnetic Resonance Enterography for the Detection of Polyps of the Small Intestine in Patients with Familial Adenomatous Polyposis.

Objective. The objective of this study was to assess the utility of magnetic resonance enterography (MRE) compared with capsule endoscopy (CE) for the detection of small-bowel polyps in patients with familial adenomatous polyposis (FAP). Methods. Patients underwent MRE and CE. The polyps were classified according to size of polyp: <5 mm (small size), 5-10 mm (medium size), or >10 mm (large size). The location (jejunum or ileum) and the number of polyps (1-5, 6-20, >20) detected by CE were also assessed. MRE findings were compared with the results of CE. Results. Small-bowel polyps, were detected by CE in 4 of the 6 (66%) patients. Three patients had small-sized polyps and one patient had medium-sized polyps. CE detected polyps in four patients that, were not shown on MRE. Desmoid tumors were detected on anterior abdominal wall by MRE. Conclusion. In patients with FAP, CE can detect small-sized polyps in the small intestine not seen with MRE whereas MRE yields additional extraintestinal information.

Transient "sicca syndrome" during phenobarbital treatment.

Even after the introduction of new antiepileptic drugs, phenobarbital continues to be largely used in the treatment of epilepsy. We report the case of a 59-year-old woman with focal seizures with secondary generalization, treated with phenobarbital with normal serum levels. After thirty days she showed Sjogren-like symptoms, which resolved after the replaced of phenobarbital with oxcarbazepine. Although many antiepileptic drugs are known to induce autoimmune disorders, a "Sicca Syndrome" has never been reported as an adverse effect of phenobarbital. We think this case report leads to take into consideration the possibility of a drug-induced disorder whenever patients treated with barbiturates develop symptoms suggestive of Sjogren's Syndrome.

Inhibitory effect of synthetic cannabinoids on cytokine production in rheumatoid fibroblast-like synoviocytes.

OBJECTIVE: To verify whether synthetic cannabinoids (CP55,940 and WIN55,212-2) are able to exert an anti-inflammatory effect on rheumatoid fibroblast-like synoviocytes (FLS) by down-regulating cytokine production, and determine whether this effect could be mediated by CB1/CB2 cannabinoid receptors. METHODS: Interleukin-6 (IL-6) and interleukin-8 (IL-8) were assayed in the supernatant from cultured FLS by ELISA method before and after 3 hours of incubation with CP55,940 (10 microM) and WIN55,212-2 (10 microM). Co-stimulation of cells with the cannabinoid receptor antagonists was performed to evaluate receptor involvement in cytokine modulation. All the experiments were conducted in basal conditions and after 1 hour pre-incubation with 0.1 ng/ml IL-1beta. FLS expression of CB1 and CB2 receptor was studied by Western Blot analyses. RESULTS: Both CP55,940 and WIN55,212-2 induced a potent and significant reduction in IL-6 and IL-8 secretion from IL-1beta. stimulated FLS. Although FLS express CB1 and CB2 receptor, cannabinoid receptor antagonists did not significantly modify the inhibition of cytokines secretion induced by CP55,940 and WIN55,212-2. CONCLUSIONS: In vitro, CP55,940 and WIN55,212-2 exert a potent anti-inflammatory effect on rheumatoid FLS via a non-CB1/CB2 receptor mediated mechanism.

Simvastatin inhibits cytokine production and nuclear factor-kB activation in interleukin 1beta-stimulated synoviocytes from rheumatoid arthritis patients.

OBJECTIVES: Recent studies demonstrated in vivo the effectiveness of statins in reducing the inflammatory response in rheumatic diseases, and still more recently, simvastatin has been reported to inhibit in vitro IL-6 and IL-8 production by unstimulated fibroblast-like-synoviocytes (FLS) from rheumatoid arthritis (RA) patients. However, no data are available on the effect of statins on the production of these cytokines induced by IL-1, which plays a crucial role in joint inflammation in the course of active RA in vivo. METHODS: In 12 RA patients, synovial tissue specimens were taken to obtain cultures of FLS. Cultures were incubated with IL-1 +/- simvastatin (5-50 micromol/l), and IL-6 and IL-8 production was evaluated (ELISA), also following the addition of mevalonate and its isoprenoid derivatives. Moreover, nuclear factor-kB (NF-kB) activation (immunocytochemistry and Western Blot analysis) were also evaluated. RESULTS: Culture incubation with IL-1 produced a dramatic increase (up to 40-fold) in cytokine production with respect to unstimulated cells. Simvastatin significantly inhibited (about 20%) IL-6 and IL-8 production from IL-1-stimulated FLS. This effect was completely reverted by the concomitant incubation with mevalonate or geranylgeraniol (but not farnesol or squalene). Moreover, simvastatin produced a clear-cut inhibition of IL-1-induced NF-kB activation. CONCLUSION: Simvastatin significantly inhibits the production of IL-6 and IL-8 also in IL-1-stimulated FLS, even though to a lesser extent than in unstimulated cells, via a HMG-CoA-reductase block with an interference in prenylation process and NF-kB activation. Our results further support the rationale for the use of statins in the treatment of rheumatoid synovitis.

Hyperhomocysteinemia: a cardiovascular risk factor in autoimmune diseases?

Epidemiological studies conducted over the past 25 years have provided ample support for the association of mild hyperhomocysteinemia (HHcy) with an elevated risk of atherothrombosis. Since autoimmune disorders (AD) are frequently associated with relevant and early signs of atherothrombotic damage not adequately explained by the traditional risk factors involved in the onset of cardiovascular disease (CVD), a large interest has been shown to the putative role of mild HHcy in this setting. On the basis of such considerations, we focused the attention on the relationship between homocysteine (Hcy) and CVD in patients affected with autoimmune diseases, reviewing the most recent literature data and also providing our original experience. Although the large amount of available studies clearly shows that HHcy represents a common finding in patients affected with several autoimmune diseases, the actual role of Hcy in the development of CVD in the course of AD is not clear yet, perhaps, with the only exception of the systemic lupus erythematosus. In the other conditions, the role of Hcy in the pathogenesis of vascular complications is still a matter of debate, as the result of conflicting reports and/or lack of an adequate body of investigation.

Homocysteine enhances cytokine production in cultured synoviocytes from rheumatoid arthritis patients.

OBJECTIVE: Hyperhomocysteinemia is commonly observed in Rheumatoid Arthritis (RA) patients, thus putatively accounting in part for the high rate of cardiovascular events in these subjects. Homocysteine (Hcy) is known to exert a pro-inflammatory effect putatively contributing to the progression of atherosclerotic lesions by cytokine production from several vascular cell-types. In order to evaluate the possibility that Hcy may play a direct pro-inflammatory activity also in the joints of RA patients, we investigated: (i) the joint concentration of Hcy, and (ii) the effect of Hcy on cytokine production by unstimulated and IL-1beta-stimulated human RA cultured synoviocytes. METHODS: In 5 RA and 5 controls subjects, Hcy was measured in the blood and knee synovial fluid, and specimens of synovial tissue were taken to obtain cell cultures. Cultures were incubated with Hcy (10-100 micromol/l) +/- IL-1beta, and IL-6 and IL-8 concentrations were evaluated in the supernatants (ELISA) together with the activation of nuclear factor-kB (NF-kB) (immunocytochemistry). RESULTS: Hcy was present in synovial fluids, with a mean concentration significantly higher in RA patients than in controls (9.0 +/- 1.1 vs 5.9 +/- 1.2 micromol/l). Hcy enhanced IL-6 and IL-8 production in RA synoviocytes only (up to 35%). Moreover, Hcy produced a clear-cut activation of NF-kB in rheumatoid cells only. CONCLUSION: Hcy enhances IL-1-dependent cytokine production by rheumatoid synoviocytes at a concentration measurable in RA joints in vivo. Thus, in RA patients, Hcy may not only represent an important risk factor for the progression of cardiovascular diseases, but it may also contribute to the joint damage.

Expression of macrophage migration inhibitory factor in diffuse systemic sclerosis.

OBJECTIVE: To evaluate whether, in patients with the diffuse form of systemic sclerosis (dSSc), macrophage migration inhibitory factor (MIF) production is dysregulated. METHODS: 10 patients with dSSc and 10 healthy controls, matched for age and sex, were studied. MIF expression was evaluated by immunohistochemistry on formalin fixed skin biopsies of patients with dSSc and controls. MIF levels were assayed in the sera and in the supernatants of skin cultured fibroblasts by a colorimetric sandwich enzyme linked immunosorbent assay (ELISA). MIF concentrations in culture medium samples and in serum samples were compared by Student's two tailed t test for unpaired data. RESULTS: Anti-MIF antibody immunostained the basal and mainly suprabasal keratinocytes. Small perivascular clusters of infiltrating mononuclear cells were positive; scattered spindle fibroblast-like cells were immunostained in superficial and deep dermal layers. The serum concentrations of MIF in patients with dSSc (mean (SD) 10705.6 (9311) pg/ml) were significantly higher than in controls (2157.5 (1288.6) pg/ml; p=0.011); MIF levels from dSSc fibroblast cultures (mean (SD) 1.74 (0.16) ng/2 x 10(5) cells) were also significantly higher than in controls (0.6 (0.2) ng/2 x 10(5) cells; p=0.008). CONCLUSION: These results suggest that MIF may be involved in the amplifying proinflammatory loop leading to scleroderma tissue remodelling.