Unexpected role of anticoagulant protein C in controlling epithelial barrier integrity and intestinal inflammation

The protein C (PC) pathway is a well-characterized coagulation system. Endothelial PC receptors and thrombomodulin mediate the conversion of PC to its activated form, a potent anticoagulant and anti-inflammatory molecule. Here we show that the PC pathway is expressed on intestinal epithelial cells. The epithelial expression of PC and endothelial PC receptor is down-regulated In patients with inflammatory bowel disease. PC(-/-)/PC(Tg) mice, expressing only 3% of WT PC, developed spontaneous intestinal inflammation and were prone to severe experimental colitis. These mice also demonstrated spontaneous elevated production of inflammatory cytokines and increased intestinal permeability. Structural analysis of epithelial tight junction molecules revealed that lack of PC leads to decreased JAM-A and claudin-3 expression and an altered pattern of ZO-1 expression. In vitro, treatment of epithelial cells with activated PC led to protection of tight junction disruption induced by TNF-α, and in vivo, topical treatment with activated PC led to mucosal healing and amelioration of colitis. Taken together, these findings demonstrate that the PC pathway is a unique system involved in controlling intestinal homeostasis and inflammation by regulating epithelial barrier function.     

Prognostic Role of Hypothyroidism in Heart Failure: A Meta-Analysis

Hypothyroidism is a risk factor of heart failure (HF) in the general population. However, the relationship between hypothyroidism and clinical outcomes in patients with established HF is still inconclusive.We conducted a systematic review and meta-analysis to clarify the association of hypothyroidism and all-cause mortality as well as cardiac death and/or hospitalization in patients with HF. We searched MEDLINE via PubMed, EMBASE, and Scopus databases for studies of hypothyroidism and clinical outcomes in patients with HF published up to the end of January 2015. Random-effects models were used to estimate summary relative risk (RR) statistics. We included 13 articles that reported RR estimates and 95% confidence intervals (95% CIs) for hypothyroidism with outcomes in patients with HF. For the association of hypothyroidism with all-cause mortality and with cardiac death and/or hospitalization, the pooled RR was 1.44 (95% CI: 1.29–1.61) and 1.37 (95% CI: 1.22–1.55), respectively. However, the association disappeared on adjustment for B-type natriuretic protein level (RR 1.17, 95% CI: 0.90–1.52) and in studies of patients with mean age <65 years (RR 1.23, 95% CI: 0.88–1.76).We found hypothyroidism associated with increased all-cause mortality as well as cardiac death and/or hospitalization in patients with HF. Further diagnostic and therapeutic procedures for hypothyroidism may be needed for patients with HF.     

Local host specialization,host-switching,and dispersal shape the regional distributions of avian haemosporidian parasites

The drivers of regional parasite distributions are poorly understood, especially in comparison with those of free-living species. For vector-transmitted parasites, in particular, distributions might be influenced by host-switching and by parasite dispersal with primary hosts and vectors. We surveyed haemosporidian blood parasites (Plasmodium and Haemoproteus) of small land birds in eastern North America to characterize a regional parasite community. Distributions of parasite populations generally reflected distributions of their hosts across the region. However, when the interdependence between hosts and parasites was controlled statistically, local host assemblages were related to regional climatic gradients, but parasite assemblages were not. Moreover, because parasite assemblage similarity does not decrease with distance when controlling for host assemblages and climate, parasites evidently disperse readily within the distributions of their hosts. The degree of specialization on hosts varied in some parasite lineages over short periods and small geographic distances independently of the diversity of available hosts and potentially competing parasite lineages. Nonrandom spatial turnover was apparent in parasite lineages infecting one host species that was well-sampled within a single year across its range, plausibly reflecting localized adaptations of hosts and parasites. Overall, populations of avian hosts generally determine the geographic distributions of haemosporidian parasites. However, parasites are not dispersal-limited within their host distributions, and they may switch hosts readily.A regional community can be thought of as a set of species whose distributions partially overlap within a large geographic area (1, 2). The structure of the regional community (i.e., the relative abundances of species across space and the degree to which populations cooccur) is governed by local (e.g., interspecific competition) and regional (e.g., species diversification and dispersal) processes (3). Although regional communities include all species, parasites and pathogens are rarely considered integral community members (4). Indeed, impacts of parasites on community structure are frequently associated with epidemics—often following introductions to nonnative regions—that have driven naïve hosts to extinction or near extinction (5–7). However, parasites likely play a critical role in shaping regional community structure. Parasites can comprise a large proportion of the community biomass (8), form the majority of links in a community food web (9), and influence regional diversity by variously accelerating (10) or slowing (11) host diversification.Nevertheless, few studies have investigated the processes influencing the regional community structure of both parasites and their hosts. Parasite populations are integrated into community studies with difficulty, partly because these populations are distributed across multiple dimensions—space, host species, and host individuals (12)—and also because parasites are difficult to sample. Moreover, although parasites tend to specialize on one or a few host species, host-breadth may vary across a parasite’s range (13).Regional studies of birds and their dipteran-vectored haemosporidian (“malaria”) blood parasites (14–19) have shown that many parasites are heterogeneously distributed across space despite the availability of suitable hosts. Specialized associations between specific parasites and vectors (20–22) may drive such heterogeneity, although a recent analysis suggests that parasite–host compatibility is also important (23), and local coevolutionary relationships between parasites and their hosts likely influence geographic distributions of both host and parasite populations (11, 14, 15). However, most regional studies of these parasites have focused on individual host species (24–30).Here, we investigate the regional community structure of avian hosts and their haemosporidian parasites with respect to abiotic and biotic drivers of both host and parasite distributions. We surveyed local assemblages of avian haemosporidian parasites across eastern North America and related the distributions of individual parasite lineages to regional climate variation and to the distributions and abundances of their avian hosts. Community dissimilarities between sampling locations based on host assemblage structure (i.e., the relative abundances of potential host species) were positively correlated with those based on parasite assemblage structure, suggesting interdependence of host and parasite population distributions. However, when controlling statistically for that interdependence, local host assemblages responded strongly to environmental gradients and differed more with increasing geographic separation, whereas parasite assemblages did not. This finding suggests that haemosporidian parasites disperse readily across the distributions of their host populations in eastern North America, independently of difference in climate and geographic distance. The degree to which some parasite lineages specialized on particular hosts varied across years and locations, and the nonrandom parasite lineage turnover across the distribution of one well-sampled host species suggested that adaptations of hosts and parasites may also shape regional community structure. Despite evidence of pathogenicity of haemosporidian parasites in birds (31), correlations between host abundances and parasite relative abundances across the region were statistically indistinguishable from random. Taken together, these results suggest that the distributions of parasite populations largely follow the distributions of their hosts but that parasites readily switch hosts and may replace each other across the ranges of individual hosts, resulting in a complex and dynamic regional community.     

Subclinical Thyroid Dysfunction and the Risk of Heart Failure Events: An Individual Participant Data Analysis From 6 Prospective Cohorts

BACKGROUND: American College of Cardiology/American Heart Association guidelines for the diagnosis and management of heart failure recommend investigating exacerbating conditions such as thyroid dysfunction, but without specifying the impact of different thyroid-stimulation hormone (TSH) levels. Limited prospective data exist on the association between subclinical thyroid dysfunction and heart failure events. METHODS AND RESULTS: We performed a pooled analysis of individual participant data using all available prospective cohorts with thyroid function tests and subsequent follow-up of heart failure events. Individual data on 25 390 participants with 216 248 person-years of follow-up were supplied from 6 prospective cohorts in the United States and Europe. Euthyroidism was defined as TSH of 0.45 to 4.49 mIU/L, subclinical hypothyroidism as TSH of 4.5 to 19.9 mIU/L, and subclinical hyperthyroidism as TSH <0.45 mIU/L, the last two with normal free thyroxine levels. Among 25 390 participants, 2068 (8.1%) had subclinical hypothyroidism and 648 (2.6%) had subclinical hyperthyroidism. In age- and sex-adjusted analyses, risks of heart failure events were increased with both higher and lower TSH levels (P for quadratic pattern <0.01); the hazard ratio was 1.01 (95% confidence interval, 0.81-1.26) for TSH of 4.5 to 6.9 mIU/L, 1.65 (95% confidence interval, 0.84-3.23) for TSH of 7.0 to 9.9 mIU/L, 1.86 (95% confidence interval, 1.27-2.72) for TSH of 10.0 to 19.9 mIU/L (P for trend <0.01) and 1.31 (95% confidence interval, 0.88-1.95) for TSH of 0.10 to 0.44 mIU/L and 1.94 (95% confidence interval, 1.01-3.72) for TSH <0.10 mIU/L (P for trend=0.047). Risks remained similar after adjustment for cardiovascular risk factors. CONCLUSION: Risks of heart failure events were increased with both higher and lower TSH levels, particularly for TSH ≥10 and <0.10 mIU/L.     

Spindle cell lipoma-like tumor, solitary fibrous tumor and myofibroblastoma of the breast: a clinico-pathological analysis of 13 cases in favor of a unifying histogenetic concept

We reviewed the clinico-pathological features of a series of 13 cases of benign spindle stromal tumors (BSSTs) of the breast relating to a basic common theme consisting of a well-circumscribed proliferation of vimentin+/CD34+/BCL-2+/CD99+ spindly to oval-epithelioid cells, variably arranged in haphazard to short fascicular growth pattern, with interspersed thick or thin collagen bands. Morphological variations included atypical mono- or multi-nucleated cells in five cases and a mature lipomatous tumor component, varying from focal to prominent, in eight cases. Based on morphological and immunophenotypical features, a distinction was made between two main subtypes of these tumors--fibroblastic and myofibroblastic. The former subtype included two cases respectively represented by a typical solitary fibrous tumor (SFT) and a neoplasm labeled "spindle-cell lipoma (SCL)-like tumor", closely reminiscent of soft tissue SCL. Both tumors had cells with fibroblastic-like appearance, haphazardly arranged and immunoreactive for vimentin, CD34, BCL-2, and CD99. The latter subtype, comprised nine cases exhibiting evidence of myofibroblastic differentiation (desmin and alpha-smooth muscle actin) which were classified as myofibroblastomas (MFBs). The remaining two cases were defined as "mixed BSSTs", having typical features of diverse neoplasms, respectively represented by a case of MFB with focal SFT and pleomorphic/SCL-like areas, and SFT with focal MFB-like component. The common basic morpho-immunophenotypical features, the possibility that both fibroblastic and myofibroblastic tumors may contain an additional mature lipomatous component, and the existence of hybrid stages (mixed BSSTs) strongly support the view that such tumors belong to the same category of lesions. We postulate that the precursor of all these neoplasms is the vimentin+/CD34+ cells of the mammary stroma, the well-known inherent plasticity of which to differentiate toward several mesenchymal lines, provides the explanation for the phenotypic heterogeneity of these neoplasms. Accordingly, the encompassing term "benign spindle stromal tumors of the breast" is advocated for such tumors.     

Is proliferative colonic disease presentation changing?

AIM: To compare the site, age and gender of cases of colorectal cancer (CRC) and polyps in a single referral center in Rome, Italy, during two periods.METHODS: CRC data were collected from surgery/pathology registers, and polyp data from colonoscopy reports. Patients who met the criteria for familial adenomatous polyposis, hereditary non-polyposis colorectal cancer syndrome or inflammatory bowel disease were excluded from the study. Overlap of patients between the two groups (cancers and polyps) was carefully avoided. The χ² statistical test and a regression analysis were performed.RESULTS: Data from a total of 768 patients (352 and 416 patients, respectively, in periods A and B) who underwent surgery for cancer were collected. During the same time periods, a total of 1693 polyps were analyzed from 978 patients with complete colonoscopies (428 polyps from 273 patients during period A and 1265 polyps from 705 patients during period B). A proximal shift in cancer occurred during the latter years for both sexes, but particularly in males. Proximal cancer increased > 3-fold in period B compared to period A in males [odds ratio (OR) 3.31, 95%CI: 2.00-5.47; P < 0.0001). A similar proximal shift was observed for polyps, particularly in males (OR 1.87, 95%CI: 1.23-2.87; P < 0.0038), but also in females (OR 1.62, 95%CI: 0.96-2.73; P < 0.07).CONCLUSION: The prevalence of proximal proliferative colonic lesions seems to have increased over the last decade, particularly in males.     

Achilles tendon problems: Not just an orthopaedic issue

Purpose. To review the current concepts on Achilles tendon involvement in various pathological conditions.

Method. A literature search was conducted to trace relevant literature on Achilles tendon problems in general pathologies.

Results. The Achilles tendon can be involved in inflammatory and autoimmune conditions, genetically determined collagen abnormalities, infectious diseases, tumours, and neurological conditions which are not of a primary surgical nature.

Conclusions. Although Achilles tendon problems are classically considered frequent in active individuals from overuse or a single acute episode, problems in the Achilles tendon can be a consequence of several conditions.     

Circadian pattern of emergency calls: implications for ED organization

A circadian variation has been shown in the onset of acute medical diseases and we postulate that there is a circadian variation in emergency calls. We reviewed the 20,858 emergency calls addressed to the Emergency Coordinating Unit of the Hospital of Ferrara, Italy, from January 1 to December 31, 1998. Precise determination of the time of calls was available from the recordings. Total calls and subgroups by different diseases were categorized into 24 one-hour increments and analyzed for circadian rhythmicity by applying a partial Fourier series. A circadian variation was found for all subgroups, except for alcoholic intoxication. There was a peak frequency of calls in the morning hours for cardiologic, respiratory, and neurologic disease. There was a peak frequency of calls in the afternoon for trauma, neoplastic diseases, and acute poisoning. Organization of quantity and quality of Emergency Department (ED) staff should take into account the increased demand of specific facilities during certain hours of the day.     

Evaluation of patient skin breakdown and comfort with a new face mask for non-invasive ventilation: a multi-center study

OBJECTIVE: To evaluate patient comfort, skin breakdown and eye irritation when comparing a prototype face mask (PM) and conventional face masks (CMs) during non-invasive ventilation. SETTING AND DESIGN: Eight centers (intensive or intermediate care units). Multicenter randomized study. POPULATIONS: Patients with acute respiratory failure of different etiologies. INTERVENTIONS: Patients were randomized to CMs or PM when ventilation was expected to last at least 12 consecutive hours a day for two consecutive days. Patient comfort, skin breakdown and eye irritation, assessed by means of standardized scoring systems, were measured after 24 and 48 h and before discontinuing ventilation. RESULTS: Hundred ninety-four patients were randomized. Forty-seven patients were finally enrolled: PM (24) and CMs (23). Ventilator settings were similar in the two groups at the beginning of the treatment and after 24 and 48 h. Skin breakdown was significantly higher in the CMs group over the study period ( p<0.001). Patient comfort was higher in the PM group after 24 and 48 h ( p=0.008 and p<0.001, respectively). Eye irritation was absent in both groups after 24 h and did not differ significantly after 48 h (p=0.539). Before ventilation was discontinued skin breakdown and patient comfort were significantly higher in the CMs group, when compared to the PM group ( p<0.001 and p=0.003, respectively). Eye irritation was slightly higher in the PM versus CMs group ( p=0.21). The time on ventilation was not significantly different between the two groups ( p=0.830). CONCLUSION: The PM significantly reduced skin breakdown while improving patient comfort, compared to the CMs.