Colonization of mice by Candida albicans is promoted by chemically induced colitis and augments inflammatory responses through galectin-3

BACKGROUND: Little is known about the relationship between colonic inflammation and Candida albicans colonization. Galectin-3 (Gal-3) is an intestinal lectin that binds to specific C. albicans glycans and is involved in inflammation. METHODS: Colitis was experimentally induced in wild-type and Gal3(-/-) mice using dextran sulfate sodium (DSS) before oral administration of C. albicans. Yeast recovered from stools was quantified. The presence of yeast and inflammation were evaluated in sections of colon by histologic examination, quantification of myeloperoxidase (MPO) activity, and by gene expression for cytokines and innate immune receptors. Serum from mice was collected for determination of anti-yeast mannan antibodies, including anti-Saccharomyces cerevisiae antibodies (ASCA), which are biomarkers of an inflammatory bowel disease. RESULTS: Inflammation strongly promoted C. albicans colonization. Conversely, C. albicans augmented inflammation induced by DSS, as assessed by histologic scores, MPO activity, and tumor necrosis factor (TNF)-alpha and Toll-like receptor (TLR)-2 expression. C. albicans colonization generated ASCA. The absence of Gal-3 reduced DSS inflammation and abolished the response of TLR-2 and TNF-alpha to C. albicans colonization. CONCLUSIONS: DSS-induced colitis provides a model for establishing C. albicans colonization in mice. This model reveals that C. albicans augments inflammation and confirms the role of Gal-3 in both inflammation and the control of host responses to C. albicans.     

Thalidomide for previously untreated elderly patients with multiple myeloma: meta-analysis of 1685 individual patient data from 6 randomized clinical trials

The role of thalidomide for previously untreated elderly patients with multiple myeloma remains unclear. Six randomized controlled trials, launched in or after 2000, compared melphalan and prednisone alone (MP) and with thalidomide (MPT). The effect on overall survival (OS) varied across trials. We carried out a meta-analysis of the 1685 individual patients in these trials. The primary endpoint was OS, and progression-free survival (PFS) and 1-year response rates were secondary endpoints. There was a highly significant benefit to OS from adding thalidomide to MP (hazard ratio = 0.83; 95% confidence interval 0.73-0.94, P = .004), representing increased median OS time of 6.6 months, from 32.7 months (MP) to 39.3 months (MPT). The thalidomide regimen was also associated with superior PFS (hazard ratio = 0.68, 95% confidence interval 0.61-0.76, P < .0001) and better 1-year response rates (partial response or better was 59% on MPT and 37% on MP). Although the trials differed in terms of patient baseline characteristics and thalidomide regimens, there was no evidence that treatment affected OS differently according to levels of the prognostic factors. We conclude that thalidomide added to MP improves OS and PFS in previously untreated elderly patients with multiple myeloma, extending the median survival time by on average 20%.     

Case seminar: a young female with acute hyponatremia and a sellar mass

In familial cases of combined pituitary hormone deficiency the most common mutations are that of Prophet of Pit 1 (PROP1) gene. PROP1 mutations are associated with deficiencies of growth hormone, thyrotropin, prolactin, and gonadotropins (follicle-stimulating hormone and luteinizing hormone), with evolving adrenocorticotropin (ACTH) deficiency in some cases. On imaging in most patients the pituitary gland is hypoplastic, but occasionally transient pituitary enlargement is found. We report a 22-year-old female initially diagnosed at age 12 with familial hypopituitarism due to PROP1 mutation, who presented with coma and respiratory arrest (acute hyponatremia). She was urgently treated in Intensive Care Unit of Emergency Center with hypertonic saline and stress doses of hydrocortisone, which resulted in the fast increase of plasma osmolality resulting in the osmotic demyelination syndrome. Simultaneously and incidentally on computed tomography scan a large sellar and suprasellar mass were reported as possible Rathke's cleft cyst or craniopharyngioma. Once the patient was stable, ACTH deficiency was documented. She remained replaced with hydrocortisone and subsequently underwent transphenoidal surgery. The removed sellar content revealed no pituitary adenoma or pituitary cells, but only an eosinophilic, colloid-like mass, and necrotic acellular debris. Her sister with hypopituitarism had an empty sella. Genetic testing in both sisters revealed the same homozygous c.150delA mutation in PROP1 gene. Here we report two sisters with the same PROP1 mutation who presented in adulthood with different pituitary morphology, one of them with a large sellar and suprasellar mass, in which transphenoidal surgery provided an extremely rare opportunity for a histopathological analysis of the sellar content. Due to the lack of endocrine care during the transition period hypocortisolism which evolved, a consequence of PROP1 mutation, was not recognized. Empirical use of hydrocortisone in the Intensive Care in our patient with life-threatening acute hyponatremia was appropriate but because glucocorticoid therapy on its own corrects hyponatremia even after stopping hypertonic saline infusion, the risk for over-correction of hyponatremia in ACTH deficiency is high.     

Histone deacetylase inhibitors impair antibacterial defenses of macrophages

Histone deacetylases (HDACs) control gene expression by deacetylating histones and nonhistone proteins. HDAC inhibitors (HDACi) are powerful anticancer drugs that exert anti-inflammatory and immunomodulatory activities. We recently reported a proof-of-concept study demonstrating that HDACi increase susceptibility to bacterial infections in vivo. Yet, still little is known about the effects of HDACi on antimicrobial innate immune defenses. Here we show that HDACi belonging to different chemical classes inhibit at multiple levels the response of macrophages to bacterial infection. HDACi reduce the phagocytosis and the killing of Escherichia coli and Staphylococcus aureus by macrophages. In line with these findings, HDACi decrease the expression of phagocytic receptors and inhibit bacteria-induced production of reactive oxygen and nitrogen species by macrophages. Consistently, HDACi impair the expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits and inducible nitric oxide synthase. These data indicate that HDACi have a strong impact on critical antimicrobial defense mechanisms in macrophages.     

Angiographic success and successful stent delivery for complex lesions using the GuideLiner™ five-in-six system- a case report

In this report, we describe two cases of transradial intervention of chronic total occlusions assisted by the GuideLiner catheter when the guide catheter support was suboptimal. This novel coaxial system can provide additional support for more complex lesions and, in our cases, allowed the procedure to be completed via the transradial approach rather than having to change to transfemoral access.     

Predictive factors of GI lesions in 241 women with iron deficiency anemia

OBJECTIVES: GI blood loss is the most common cause of iron deficiency anemia (IDA) in postmenopausal women and menstrual blood loss in premenopausal women. We aimed to evaluate the diagnostic yield of endoscopy in women with IDA and to define predictive factors of a GI lesion. METHOD: Clinical, biological, endoscopic, and histological data from patients with IDA were systematically collected on a computer. Multivariate analysis (logistic regression) was performed to determine whether these data were associated with a GI lesion. RESULTS: Between January, 1989 and June, 1999, 241 consecutive women had endoscopies for IDA (mean age = 52.3 +/- 21.8 yr). A substantial GI lesion was detected in 119 patients (49.4%). Ten patients (4%) had both upper and lower GI lesions. A source of IDA was revealed by upper endoscopy in 86 cases (35.6%) and by colonoscopy in 33 (13.7%). The most common upper lesions were peptic ulceration (42/241 [17.4%]), esophagitis (15/241 [6.2%]), and cancer (9/241 [3.7%]). Colonic cancer (15/241 [6.2%]) and polyps (10/241 [4.1%]) were the most frequent lesions detected by colonoscopy. Predictive factors (odds ratio, 95% CI) of GI lesions diagnosed by endoscopy were abdominal symptoms (8.3, 3.9-17.2), age > 50 yr (4.4, 2.1-9.2), and Hb < 9 g/dl (3, 1.5-6.1). Thirty-one women (13%) had none of these predictive factors; in this group only two lesions were identified (one esophagitis and one duodenal ulcer). The positive predictive value of these three independent predictors was 87%, and the negative predictive value was 93.5%. CONCLUSION: Endoscopy revealed a source of IDA in 49.4% of cases. Three predictive factors of GI lesion were identified. Endoscopic investigation should be avoided in women without these three predictive factors. Conversely, these factors are strongly associated with a GI lesion.     

Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis (AH): individual data analysis of the last three randomized placebo controlled double blind trials of corticosteroids in severe AH

BACKGROUND/AIMS: Controversy surrounding the efficacy of corticosteroids in severe alcoholic hepatitis (AH) persists. The aims of our study were: (a) to analyze individual data of patients with severe AH discriminant function (DF)> or =32 from the last three randomized controlled trials; and (b) to identify the independent prognostic factors associated with short-term survival. METHODS: Individual data were collected from the three principal investigators. Survival analysis was performed at 28 days using the Kaplan-Meier method and log-rank test. The independent prognostic values were assessed by the proportional hazards regression model. RESULTS: About 102 placebo and 113 corticosteroid patients with DF > or =32 were analyzed. At 28 days, corticosteroid patients had significantly higher survival: 84.6+/-3.4% vs. 65.1+/-4.8%, P=0.001. In univariate analysis, corticosteroid treatment, age, DF, albumin, creatinine and encephalopathy were prognostic factors. In multivariate analysis, age (P=0.0001), serum creatinine (P<0.002) and corticosteroid treatment (P=0.002) were independent prognostic variables. A more dramatic decrease of median serum bilirubin values (micromol/l) was observed at 7 and 14 days in corticosteroid patients (P<0.05) : -76.5 vs. -35 and -105 vs. -45. CONCLUSIONS: Corticosteroids improved short-term survival of patients with severe AH. Age and serum creatinine are independent prognostic factors. Corticosteroids are recommended for patients with severe AH.     

Incidence and predictors of atrioventricular conduction impairment after transcatheter aortic valve implantation

Atrioventricular (AV) conduction impairment is well described after surgical aortic valve replacement, but little is known in patients undergoing transcatheter aortic valve implantation (TAVI). We assessed AV conduction and need for a permanent pacemaker in patients undergoing TAVI with the Medtronic CoreValve Revalving System (MCRS) or the Edwards Sapien Valve (ESV). Sixty-seven patients without pre-existing permanent pacemaker were included in the study. Forty-one patients (61%) and 26 patients (39%) underwent successful TAVI with the MCRS and ESV, respectively. Complete AV block occurred in 15 patients (22%), second-degree AV block in 4 (6%), and new left bundle branch block in 15 (22%), respectively. A permanent pacemaker was implanted in 23 patients (34%). Overall PR interval and QRS width increased significantly after the procedure (p <0.001 for the 2 comparisons). Implantation of the MCRS compared to the ESV resulted in a trend toward a higher rate of new left bundle branch block and complete AV block (29% vs 12%, p = 0.09 for the 2 comparisons). During follow-up, complete AV block resolved in 64% of patients. In multivariable regression analysis pre-existing right bundle branch block was the only independent predictor of complete AV block after TAVI (relative risk 7.3, 95% confidence interval 2.4 to 22.2). In conclusion, TAVI is associated with impairment of AV conduction in a considerable portion of patients, patients with pre-existing right bundle branch block are at increased risk of complete AV block, and complete AV block resolves over time in most patients.     

Prognosis Assessment of Cardiac Involvement in Systemic AL Amyloidosis by Magnetic Resonance Imaging

Background

Cardiac involvement is one of the most important prognostic factors in systemic AL amyloidosis. The aim of our study was to assess the role of cardiovascular magnetic resonance (CMR) imaging in prognosis evaluation in AL amyloidosis.

Methods

We retrospectively analyzed 29 consecutive patients with AL amyloidosis who had undergone CMR. Clinical, laboratory, echocardiographic, and CMR characteristics were compared between CMR-positive (ie, with CMR signs of cardiac localization of AL amyloidosis) and CMR-negative patients. Univariate and multivariate analyses were performed to assess the prognostic value of positive CMR in comparison with other prognostic factors.

Results

CMR was positive in 11 patients (38%). The overall survival rates for CMR-positive patients were 28%, 14%, and 14% versus 84%, 77%, and 45% at 1, 2, and 5 years, respectively, for CMR-negative patients (P = .002). Late gadolinium enhancement patterns, biventricular hypertrophy, and pericardial effusion on CMR were more frequent in nonsurvivors. Congestive heart failure, abnormal echocardiography, Eastern Cooperative Oncology Group grade >1, brain natriuretic peptide, and left ventricular ejection fraction <55% also were associated with a decreased survival. The presence of congestive heart failure was the only significant variable associated with survival on multivariate analysis.

Conclusion

We found that the presence of a positive CMR in AL amyloidosis was associated with a significantly increased risk of death, in particular of cardiac origin, but was not independent of clinical congestive heart failure.