Performance of GAP and ILD-GAP models in predicting lung transplant or death in interstitial pneumonia with autoimmune features.

OBJECTIVES: To assess the ability of two risk prediction models in interstitial lung disease (ILD) to predict death or lung transplantation in a cohort of patients with interstitial pneumonia with autoimmune features (IPAF). METHODS: We performed a retrospective cohort study of adults with IPAF at an academic medical center. The primary outcome was a composite of lung transplantation or death. We applied the patient data to the previously described GAP and ILD-GAP models to determine the ability of these models to predict the composite outcome. Model discrimination was assessed using the c-index, and model calibration was determined by comparing the incidence ratios of observed versus expected deaths. RESULTS: Ninety-four patients with IPAF were included. Mean (standard deviation) age was 58 (13.5) years and the majority were female (62%). The majority met serologic and morphologic criteria for IPAF (94% and 91%, respectively). The GAP model had a c-index of 0.664 (95% confidence interval [CI] 0.547-0.781), while the ILD-GAP model had a c-index of 0.569 (95% CI 0.440-0.697). In those with GAP stage 1 or GAP stage 2 disease, calibration of the GAP model was satisfactory at 2 and 3 years for the cumulative end point of lung transplantation or death. CONCLUSION: In patients with IPAF, the GAP model performed well as a predictor of lung transplantation or death at 2 years and 3 years from ILD diagnosis in patients with GAP stage 1 and GAP stage 2 disease.

Functional morphology of the hindlimb of fossilized pygmy hippopotamus from Ayia Napa (Cyprus).

We studied the functional morphology of the postcranial skeleton of the endemic hippopotamus Phanourios minor, derived from the Upper Pleistocene site of Ayia Napa. The deposit, which consists of a hard limestone substrate on which the species moved, has yielded a great abundance of hippopotamus material, making the Ayia Napa locality one of the most important paleontological sites in Cyprus. The immigration of the large-sized mainland Hippopotamus to Cyprus led to the emergence of a new insular species with its main characteristic being the extremely reduced body size. In this study, all the hindlimb elements of the Cypriot hippo are described in detail and compared with those of the modern species, with the extant Hippopotamus amphibius being considered similar to the possible ancestor of P. minor. In some cases, the morphological comparison is reinforced using bones of other extinct insular and mainland hippos. Additionally, we provided a functional analysis of the hindlimb joints, suggesting specific locomotor habits for the species. The anatomical examination reveals that the elements in P. minor are robust with marked muscular insertion areas resembling those found in Hippopotamus. However, there are also similarities with Choeropsis liberiensis in certain morphofunctional traits. P. minor adapted to slow but powerful locomotion with remarkable stabilization, particularly in the zeugopodium and the autopodium. The knee was less mobile in the craniocaudal direction compared with that in recent hippos, while the abduction-adduction movements of the thigh were advanced. The pes presented good mobility in the sagittal plane and limitation in transversal movements. Thus, P. minor displayed modifications to its limbs, influenced by the mountainous island environment and the body size reduction, resulting in specialized locomotion, which was different from that of extant hippopotamuses.

Morphofunctional examination of the carpal bones of pygmy hippopotamus from Ayia Napa, Cyprus.

This study provides a complete morphological description and functional analysis of the carpal bones of the endemic pygmy hippopotamus Phanourios minor, derived from the Upper Pleistocene site of Ayia Napa. From this deposit, numerous skeletal remains of this fossil hippo have been collected, making the locality one of the richest in Cyprus. The carpal bones were compared with those of extant hippopotamuses, to determine the changes that occurred in the fossil hippo. Examination of the elements showed that Phanourios presented some important features that were common among the endemic fossil ungulates of the Mediterranean islands. The carpal bones display a proximal-distal compression due to shortening of the distal part of the leg, due to the new ecological island conditions. However, they are robust with rough areas for strong muscular and ligament insertions, providing stability to the carpal joints, and low speed movement to the animal. The great flexor capabilities, and the limitation in ulnar deviation of the carpus, indicate that P. minor had increased agility in the sagittal plane and restricted transverse movements, while the suggestion of a more unguligrade stance for the species is ambiguous. Thus, the endemic Cypriot hippos developed specialized locomotion, suitable for walking on the rugged terrain of Cyprus, which seems to be different from that of its extant counterparts.

Assessing predictors of rheumatoid arthritis-associated interstitial lung disease using quantitative lung densitometry.

OBJECTIVE: To assess predictors of subclinical RA-associated interstitial lung disease (RA-ILD) using quantitative lung densitometry (qLD). METHODS: RA patients underwent multi-detector row CT scanning at baseline and after an average of 39 months. Scans were analysed with qLD for the percentage of lung parenchyma with high attenuation areas (%HAA: the percentage of voxels of -600 to -250 Hounsfield units). Additionally, a pulmonary radiologist calculated an expert radiologist scoring (ERS) for RA-ILD features. Generalized linear models were used to identify indicators of baseline %HAA and predictors of %HAA change. RESULTS: Baseline %HAA was assessed in 193 RA patients and 106 had repeat qLD assessment. %HAA was correlated with ERS (Spearman's rho = 0.261; P < 0.001). Significant indicators of high baseline %HAA (>10% of lung parenchyma with high attenuation) included female sex, higher pack-years of smoking, higher BMI and anti-CCP ≥200 units, collectively contributing an area under the receiver operator curve of 0.88 (95% CI 0.81, 0.95). Predictors of %HAA increase, occurring in 49% with repeat qLD, included higher baseline %HAA, presence of mucin 5B (MUC5B) minor allele and absence of HLA-DRB1 shared epitope (area under the receiver operator curve = 0.69; 95% CI 0.58, 0.79). The association of the MUC5B minor allele with %HAA change was higher among men and those with higher cumulative smoking. Within the group with increased %HAA, anti-CCP level was significantly associated with a greater increase in %HAA. CONCLUSIONS: %HAA, assessed with qLD, was linked to several known risk factors for RA-ILD and may represent a more quantitative method to identify RA-ILD and track progression than expert radiologist interpretation.

Risk of progression of interstitial pneumonia with autoimmune features to a systemic autoimmune rheumatic disease.

OBJECTIVE: The aim of this study was to determine the risk of developing a systemic autoimmune rheumatic disease (ARD) after an initial diagnosis of interstitial pneumonia with autoimmune features (IPAF). METHODS: We performed a retrospective cohort study of patients with interstitial lung disease (ILD) who were evaluated at Columbia University Irving Medical Center from 2009 to 2017. We divided patients with idiopathic ILD into two groups: those who met IPAF criteria and those who did not meet IPAF criteria at initial ILD diagnosis. We examined the association between IPAF and diagnosis of ARD during the follow-up period using a multivariable-adjusted logistic regression model. RESULTS: Of the 697 patients with ILD who were screened, 174 met inclusion criteria (50 met IPAF criteria and 124 did not). During a median follow-up period of 5.2 years, 16% (8/50) of subjects with IPAF were diagnosed with an ARD compared with 1.6% (2/124) of subjects without IPAF (P = 0.001). Adjusting for age, sex, smoking status and use of immunosuppressive therapy, the odds of progressing to an ARD were 14 times higher in subjects with IPAF than in those without IPAF (odds ratio 14.18, 95% CI 1.44-138.95, P = 0.02). CONCLUSION: The presence of IPAF confers an increased risk of developing an ARD. Patients with IPAF should therefore be followed closely for the development of an ARD.

Implementing an Electronic Medical Record-Based Reminder for Cardiovascular Risk Screening in Rheumatoid Arthritis.

OBJECTIVE: Although cardiovascular disease (CVD) is the leading cause of death among individuals with rheumatoid arthritis (RA), CVD risks are not being assessed frequently and systematically in RA. We implemented an electronic medical record (EMR)-based reminder in a tertiary care center and assessed the effects of this intervention on CVD risk screening by rheumatologists and primary care providers. METHODS: The EMR reminder was implemented in December 2013 and included the most recent value and target ranges for body mass index, blood pressure (BP), and lipid profiles. It was displayed for every rheumatology and primary care visit for all patients with the International Classification of Diseases, Ninth Revision code for RA (714.0). Lipid screening rates, as well as changes in BP and obesity rates were compared pre- and postimplementation. Factors associated with lipid screening postimplementation were assessed using multivariate logistic regression. RESULTS: A total of 138 and 112 RA patients were seen in the outpatient clinics pre- and postimplementation, respectively. The demographic characteristics were similar in the pre- and postimplementation groups. Lipid screening rates were 50% preimplementation and 46% postimplementation (P = 0.58). There were no significant improvements in BP or obesity rates postimplementation. Factors associated with the higher odds of lipid screening included older age and history of diabetes mellitus. CONCLUSION: Implementing an EMR reminder did not improve CVD risk screening among RA patients. Future research is needed to identify and address barriers to CVD screening, and to educate patients and providers about RA-related risks.

Mer receptor tyrosine kinase mediates both tethering and phagocytosis of apoptotic cells.

Billions of inflammatory leukocytes die and are phagocytically cleared each day. This regular renewal facilitates the normal termination of inflammatory responses, suppressing pro-inflammatory mediators and inducing their anti-inflammatory counterparts. Here we investigate the role of the receptor tyrosine kinase (RTK) Mer and its ligands Protein S and Gas6 in the initial recognition and capture of apoptotic cells (ACs) by macrophages. We demonstrate extremely rapid binding kinetics of both ligands to phosphatidylserine (PtdSer)-displaying ACs, and show that ACs can be co-opsonized with multiple PtdSer opsonins. We further show that macrophage phagocytosis of ACs opsonized with Mer ligands can occur independently of a requirement for αV integrins. Finally, we demonstrate a novel role for Mer in the tethering of ACs to the macrophage surface, and show that Mer-mediated tethering and subsequent AC engulfment can be distinguished by their requirement for Mer kinase activity. Our results identify Mer as a receptor uniquely capable of both tethering ACs to the macrophage surface and driving their subsequent internalization.

Molasses as an efficient low-cost carbon source for biological Cr(VI) removal.

In the present study, indigenous microorganisms from industrial sludge were used to reduce the activity of Cr(VI). Molasses, a by-product of sugar processing, was selected as the carbon source (instead of sugar used in a previous work) as it is a low-cost energy source for bioprocesses. Initially, experiments were carried out in suspended growth batch reactors for Cr(VI) concentrations of 1.5-110 mg/L. The time required for complete Cr(VI) reduction increased with initial Cr(VI) concentration. Initial molasses concentration was also found to influence the Cr(VI) reduction rate. The optimal concentration for all initial Cr(VI) concentrations tested was 0.8 gC/L. Experiments were also carried out in packed-bed reactors. Three different operating modes were used to investigate the optimal performance and efficiency of the filter, i.e. batch, continuous and SBR with recirculation. The latter mode with a recirculation rate of 0.5L/min lead to significantly high Cr(VI) reduction rates (up to 135 g/m(2)d). The results of this work were compared with those of a similar work using sugar as the carbon source and indicate that molasses could prove a feasible technological solution to a serious environmental problem.

Integrated Cr(VI) removal using constructed wetlands and composting.

The present work was conducted to study integrated chromium removal from aqueous solutions in horizontal subsurface (HSF) constructed wetlands. Two pilot-scale HSF constructed wetlands (CWs) units were built and operated. One unit was planted with common reeds (Phragmites australis) and one was kept unplanted. Influent concentrations of Cr(VI) ranged from 0.5 to 10mg/L. The effect of temperature and hydraulic residence time (8-0.5 days) on Cr(VI) removal were studied. Temperature was proved to affect Cr(VI) removal in both units. In the planted unit maximum Cr(VI) removal efficiencies of 100% were recorded at HRT's of 1 day with Cr(VI) concentrations of 5, 2.5 and 1mg/L, while a significantly lower removal rate was recorded in the unplanted unit. Harvested reed biomass from the CWs was co-composted with olive mill wastes. The final product had excellent physicochemical characteristics (C/N: 14.1-14.7, germination index (GI): 145-157%, Cr: 8-10mg/kg dry mass), fulfills EU requirements and can be used as a fertilizer in organic farming.

Biological Cr(VI) removal using bio-filters and constructed wetlands.

The bioreduction of hexavalent chromium from aqueous solution was carried out using suspended growth and packed-bed reactors under a draw-fill operating mode, and horizontal subsurface constructed wetlands. Reactors were inoculated with industrial sludge from the Hellenic Aerospace Industry using sugar as substrate. In the suspended growth reactors, the maximum Cr(VI) reduction rate (about 2 mg/L h) was achieved for an initial concentration of 12.85 mg/L, while in the attached growth reactors, a similar reduction rate was achieved even with high initial concentrations (109 mg/L), thus confirming the advantage of these systems. Two horizontal subsurface constructed wetlands (CWs) pilot-scale units were also built and operated. The units contained fine gravel. One unit was planted with common reeds and one was kept unplanted. The mean influent concentrations of Cr(VI) were 5.61 and 5.47 mg/L for the planted and unplanted units, respectively. The performance of the planted CW units was very effective as mean Cr(VI) removal efficiency was 85% and efficiency maximum reached 100%. On the contrary, the unplanted CW achieved very low Cr(VI) removal with a mean value of 26%. Both attached growth reactors and CWs proved efficient and viable means for Cr(VI) reduction.

Serum and ascites chromogranin-A in patients with metastatic neuroendocrine tumors.

OBJECTIVES: Ascites secondary to neuroendocrine tumor metastases may arise from a variety of mechanisms. Our aim was to measure serum and ascitic chromogranin-A (CgA) to help determine whether ascites resulted from intraperitoneal/retroperitoneal disease burden or from other carcinoid complications such as congestive heart failure or portal hypertension. METHODS: Patients with metastatic neuroendocrine tumors and ascites were identified. Chromogranin-A was obtained and measured from both serum and ascites. The causes of carcinoid ascites was categorized into 2 groups: high intraperitoneal or retroperitoneal disease burden (ie, peritoneal metastases and/or lymphatic obstruction; n = 12, group 1) or other organ-specific carcinoid complications such as CHF or portal hypertension (n = 12, group 2). RESULTS: An ascites CgA/serum CgA ratio greater than 1 was more likely to be found in group 1 (P = 0.01). This ratio produced 100% sensitivity and 75% specificity for ascites secondary to peritoneal metastases and/or lymphatic obstruction. CONCLUSIONS: An ascites CgA/serum CgA ratio greater than 1 produces excellent accuracy in predicting peritoneal metastases and/or retroperitoneal disease as the cause of ascites in the setting of metastatic carcinoid. This test may play a role in the earlier identification of those patients who may be well served by aggressive management.

Development and validation of a liquid chromatographic method for the determination of hydroxymethylfurfural and alpha-ketoglutaric acid in human plasma.

Hydroxymethylfurfural (HMF) and alpha-ketoglutaric acid (KG) have been recently investigated as potential cancer cell damaging agents. We herein report for the first time a validated quantitative assay for their simultaneous determination in human plasma which is amenable to be applied in the future screening of the target compounds in human probands in order to properly design a targeted chemotherapeutic regimen for certain types of malignant tumors. A simple liquid chromatographic method in conjunction to derivatization after a two-step optimized solid phase clean-up procedure is described. The method is based on the reaction of HMF and KG with 2-nitrophenylhydrazine or 2,4-dinitrophenylhydrazine in an aqueous environment. Reaction conditions were studied with respect to pH, reagent volume, reaction temperature and time. Exact testing of such parameters beside careful selection of the mobile phase composition rendered feasible the quantification of the chemically significantly differing analytes along a single chromatographic run. The formed derivatives could be separated isocratically by reversed-phase LC on a C(8)-column. Detection in the UV and in the visible range is possible. Results showed good recovery and reproducibility with detection limits (S/N=3) down to 2 picomoles analyte on column. Resolution of the syn and anti geometric isomers of the HMF and KG derivatives is possible. The isomeric ratio in relation to the reaction pH is discussed.

Hydroxymethylfurfural: an enemy or a friendly xenobiotic? A bioanalytical approach.

Hydroxymethylfurfural (HMF), a well-known heterocyclic Maillard reaction product, has often been studied for its potential toxic, mutagenic, and carcinogenic effects. Recent clinical studies, however, have strongly suggested that HMF might have exciting antitumor potential. We report on the development and validation of a bioanalytical assay for HMF that could be suitable as a basis for pharmacokinetic models in cancer patients. Two strategies were tested, i.e., direct and indirect methodologies. A direct isocratic LC determination at 283 nm was designed. Two indirect attempts involved derivatization coupled to HPLC-UV. It was possible to resolve the stereoisomers of the HMF derivative, and factors influencing their equilibrium ratio are discussed. HMF was extracted from the biomatrix by solid-phase extraction using different cartridges. A comparative study was made of the implemented methods as well as the extraction protocols. Both indirect assays proved to be more sensitive and were used to assess HMF quantitatively in human plasma. However, the newly introduced derivatization conditions led to the highest sensitivity with a LOD (S/N ratio = 3) of at least 2 pmol analyte on column. The assay selectivity was satisfactory in pre- and post-dose real samples. The mean recoveries of the assays were 79% and 89%, with acceptable accuracies and reproducibilities. Figure Schematic representation of hydroxymethylfurfural (HMF) in human plasma.

Lymphoscintigraphy and triangulated body marking for morbidity reduction during sentinel node biopsy in breast cancer.

Current trends in patient care include the desire for minimizing invasiveness of procedures and interventions. This aim is reflected in the increasing utilization of sentinel lymph node biopsy, which results in a lower level of morbidity in breast cancer staging, in comparison to extensive conventional axillary dissection. Optimized lymphoscintigraphy with triangulated body marking is a clinical option that can further reduce morbidity, more than when a hand held gamma probe alone is utilized. Unfortunately it is often either overlooked or not fully understood, and thus not utilized. This results in the unnecessary loss of an opportunity to further reduce morbidity. Optimized lymphoscintigraphy and triangulated body marking provides a detailed 3 dimensional map of the number and location of the sentinel nodes, available before the first incision is made. The number, location, relevance based on time/sequence of appearance of the nodes, all can influence 1) where the incision is made, 2) how extensive the dissection is, and 3) how many nodes are removed. In addition, complex patterns can arise from injections. These include prominent lymphatic channels, pseudo-sentinel nodes, echelon and reverse echelon nodes and even contamination, which are much more difficult to access with the probe only. With the detailed information provided by optimized lymphoscintigraphy and triangulated body marking, the surgeon can approach the axilla in a more enlightened fashion, in contrast to when the less informed probe only method is used. This allows for better planning, resulting in the best cosmetic effect and less trauma to the tissues, further reducing morbidity while maintaining adequate sampling of the sentinel node(s).

Using the intraoperative hand held probe without lymphoscintigraphy or using only dye correlates with higher sensory morbidity following sentinel lymph node biopsy in breast cancer: a review of the literature.

BACKGROUND: There are no studies that have directly investigated the incremental reduction in sensory morbidity that lymphoscintigraphy images (LS) and triangulated body marking or other skin marking techniques provide during sentinel lymph node biopsy (SLNB) compared to using only the probe without LS and skin marking or using only dye. However, an indirect assessment of this potential for additional sensory morbidity reduction is possible by extracting morbidity data from studies comparing the morbidity of SLNB to that of axillary lymph node dissection. METHODS: A literature search yielded 13 articles that had data on sensory morbidity at specific time points on pain, numbness or paresthesia from SLNB that used radiotracer and probe or used only dye as a primary method of finding the sentinel node (SN). Of these, 10 utilized LS, while 3 did not utilize LS. By matching the data in studies not employing LS to the studies that did, comparisons regarding the percentage of patients experiencing pain, numbness/paresthesia after SLNB could be reasonably attempted at a cutoff of 9 months. RESULTS: In the 7 studies reporting on pain after 9 months (> 9 months) that used LS (1347 patients), 13.8% of patients reported these symptoms, while in the one study that did not use LS (143 patients), 28.7% of patients reported these symptoms at > 9 months (P < 0.0001). In the 6 studies reporting on numbness and/or paresthesia at > 9 months that used LS (601 patients), 12.5% of patients reported these symptoms, while in the 3 studies that did not use LS (229 patients), 23.1% of patients reported these symptoms at > 9 months (P = 0.0002). Similar trends were also noted for all these symptoms at < or = 9 months. CONCLUSION: Because of variations in techniques and time of assessing morbidity, direct comparisons between studies are difficult. Nevertheless at a minimum, a clear trend is present: having the LS images and skin markings to assist during SLNB appears to yield more favorable morbidity outcomes for the patients compared to performing SLNB with only the probe or performing SLNB with dye alone. These results are extremely pertinent, as the main reason for performing SLNB itself in the first place is to achieve reduced morbidity.