Renin Angiotensin system-modifying therapies are associated with improved pulmonary health.

BACKGROUND: Pulmonary diseases are often complicated and have diverse etiologies. One common factor is the lack of therapeutics available for these diseases. The goal of this study was to investigate the impact of Renin-Angiotensin System (RAS)-modifying medications on incidence and time to pulmonary complications. METHODS: A retrospective analysis was conducted using claims data from a US commercial insurance company (2007-2013). The study consisted of patients with an emerging hypertension (HTN) diagnosis. Cox analysis was used to look at the effect of angiotensin converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) in this population. The events included pneumonia and influenza (infectious), Chronic obstructive pulmonary disease (COPD) and allied conditions (inflammatory), and other diseases (structural). RESULTS: A total of 215,225 patients were followed in the study. These fell into three groups depending on the first prescribed anti-hypertension medication; ACE-Is (47.21%), ARBs (11.40%) and calcium channel blockers (CCBs)/Diuretics-Control (41.39%). The use of ACE-I as first treatment significantly reduced the incidence of infectious (Hazard Ratio (HR) 0.886, 95% Confidence Interval (95% CI) 0.859-0.886), inflammatory (HR 0.924, 95% CI 0.906-0.942) and structural outcomes (HR 0.865, 95% CI 0.847-0.885); it also increased the time (delayed) to diagnosis with prolonged treatment. Primary ARB use only significantly lowered the incidence of structural outcomes (HR 0.900, 95% CI 0.868-0.933); prolonged treatment did reduce incidence of all three diagnosis groups and significantly delayed disease onset. CONCLUSIONS: There is an association between the use of ACE-Is and ARBs and a delay in the progression of pulmonary complications in vulnerable populations. Research into the RAS may identify future therapies for patients with potential chronic pulmonary conditions.

Accuracy of single and parallax film and digital periapical radiographs in diagnosing apical periodontitis - a cadaver study.

AIM: To compare the accuracy of film and digital periapical radiography (PR) in detecting apical periodontitis (AP) using histopathological findings as a reference standard. METHODOLOGY: Jaw sections containing 67 teeth (86 roots) were collected from nine fresh, unclaimed bodies that were due for cremation. Imaging was carried out to detect AP lesions using film and digital PR with a centred view (FP and DP groups); film and digital PR combining central with 10˚ mesially and distally angled (parallax) views (FPS and DPS groups). All specimens underwent histopathological examination to confirm the diagnosis of AP. Sensitivity, specificity and predictive values of PR were analysed using rater mean (n = 5). Receiver operating characteristics (ROC) analysis was carried out. RESULTS: Sensitivity was 0.16, 0.37, 0.27 and 0.38 for FP, FPS, DP and DPS, respectively. Both FP and FPS had specificity and positive predictive values of 1.0, whilst DP and DPS had specificity and positive predictive values of 0.99. Negative predictive value was 0.36, 0.43, 0.39 and 0.44 for FP, FPS, DP and DPS, respectively. Area under the curve (AUC) for the various imaging methods was 0.562 (FP), 0.629 (DP), 0.685 (FPS), 0.6880 (DPS). CONCLUSIONS: The diagnostic accuracy of single digital periapical radiography was significantly better than single film periapical radiography. The inclusion of two additional horizontal (parallax) angulated periapical radiograph images (mesial and distal horizontal angulations) significantly improved detection of apical periodontitis.

Two cases of rheumatoid meningitis.

Central nervous system (CNS) involvement by rheumatoid arthritis (RA) in the form of rheumatoid meningitis (RM) is rare and most commonly occurs in the setting of longstanding severe RA. Due to a wide range of clinical presentations and nonspecific laboratory findings, it presents a diagnostic challenge often requiring brain biopsy. Only a few histopathologically confirmed cases have been described in the literature. Our aim is to describe two cases of RM and review the literature. The first case is of a previously healthy 37-year-old man who presented with severe headaches and focal neurologic deficits. Magnetic resonance imaging demonstrated abnormal leptomeningeal enhancement in the left frontal and parietal sulci. The second case is of a 62-year-old woman with a history of mild chronic joint pain who presented with confusion, personality changes and seizures. Both patients ultimately underwent brain biopsy which demonstrated RM on pathologic examination. Administration of corticosteroids resulted in significant clinical improvement in both cases. To our knowledge, our unusual case of RM in the young man is the fifth reported case of rheumatoid meningitis in a patient with no prior history of RA. Such an atypical presentation makes diagnosis even more difficult and highlights the need for awareness of this entity in the diagnostic consideration of a patient presenting with unexplained neurologic symptoms. Our literature review underscores the clinical and pathologic heterogeneity of CNS involvement in RA.

Principal component analysis of cerebellar shape on MRI separates SCA types 2 and 6 into two archetypal modes of degeneration.

Although "cerebellar ataxia" is often used in reference to a disease process, presumably there are different underlying pathogenetic mechanisms for different subtypes. Indeed, spinocerebellar ataxia (SCA) types 2 and 6 demonstrate complementary phenotypes, thus predicting a different anatomic pattern of degeneration. Here, we show that an unsupervised classification method, based on principal component analysis (PCA) of cerebellar shape characteristics, can be used to separate SCA2 and SCA6 into two classes, which may represent disease-specific archetypes. Patients with SCA2 (n=11) and SCA6 (n=7) were compared against controls (n=15) using PCA to classify cerebellar anatomic shape characteristics. Within the first three principal components, SCA2 and SCA6 differed from controls and from each other. In a secondary analysis, we studied five additional subjects and found that these patients were consistent with the previously defined archetypal clusters of clinical and anatomical characteristics. Secondary analysis of five subjects with related diagnoses showed that disease groups that were clinically and pathophysiologically similar also shared similar anatomic characteristics. Specifically, Archetype #1 consisted of SCA3 (n=1) and SCA2, suggesting that cerebellar syndromes accompanied by atrophy of the pons may be associated with a characteristic pattern of cerebellar neurodegeneration. In comparison, Archetype #2 was comprised of disease groups with pure cerebellar atrophy (episodic ataxia type 2 (n=1), idiopathic late-onset cerebellar ataxias (n=3), and SCA6). This suggests that cerebellar shape analysis could aid in discriminating between different pathologies. Our findings further suggest that magnetic resonance imaging is a promising imaging biomarker that could aid in the diagnosis and therapeutic management in patients with cerebellar syndromes.

MRI shows a region-specific pattern of atrophy in spinocerebellar ataxia type 2.

In this study, we used manual delineation of high-resolution magnetic resonance imaging (MRI) to determine the spatial and temporal characteristics of the cerebellar atrophy in spinocerebellar ataxia type 2 (SCA2). Ten subjects with SCA2 were compared to ten controls. The volume of the pons, the total cerebellum, and the individual cerebellar lobules were calculated via manual delineation of structural MRI. SCA2 showed substantial global atrophy of the cerebellum. Furthermore, the degeneration was lobule specific, selectively affecting the anterior lobe, VI, Crus I, Crus II, VIII, uvula, corpus medullare, and pons, while sparing VIIB, tonsil/paraflocculus, flocculus, declive, tuber/folium, pyramis, and nodulus. The temporal characteristics differed in each cerebellar subregion: (1) duration of disease: Crus I, VIIB, VIII, uvula, corpus medullare, pons, and the total cerebellar volume correlated with the duration of disease; (2) age: VI, Crus II, and flocculus correlated with age in control subjects; and (3) clinical scores: VI, Crus I, VIIB, VIII, corpus medullare, pons, and the total cerebellar volume correlated with clinical scores in SCA2. No correlations were found with the age of onset. Our extrapolated volumes at the onset of symptoms suggest that neurodegeneration may be present even during the presymptomatic stages of disease. The spatial and temporal characteristics of the cerebellar degeneration in SCA2 are region specific. Furthermore, our findings suggest the presence of presymptomatic atrophy and a possible developmental component to the mechanisms of pathogenesis underlying SCA2. Our findings further suggest that volumetric analysis may aid in the development of a non-invasive, quantitative biomarker.

Sequential rupture of triceps and quadriceps tendons in a dialysis patient using hormone supplements.

Spontaneous rupture of tendons is rare, and typically occurs in large weight bearing tendons such as the quadriceps, Achilles and patellar tendon, in the context of various chronic diseases including end-stage renal disease. In general, tendon rupture in dialysis patients is associated with hyperparathyroidism, long duration of dialysis, steroid and quinolone use. We present a case of a young man on chronic dialysis who presented with sequential rupture of triceps and quadriceps tendons requiring surgical repair, several months after initiating use of multiple hormone supplements including human growth hormone and androgens. The supplements were obtained over the internet with the aim of improving his kidney function. Although this patient did have hyperparathyroidism, it is likely his PTH elevation was exacerbated by use of human growth hormone, and tendon rupture risk increased by concurrent use of an androgen supplement. This case highlights the fact that dialysis patients do utilize alternative remedies and that there may be unexpected, dialysis-specific complications associated with their use.

VSL#3 probiotic upregulates intestinal mucosal alkaline sphingomyelinase and reduces inflammation.

BACKGROUND: Alkaline sphingomyelinase, an enzyme found exclusively in bile and the intestinal brush border, hydrolyzes sphingomyelin into ceramide, sphingosine and sphingosine-1-phosphate, thereby inducing epithelial apoptosis. Reduced levels of alkaline sphingomyelinase have been found in premalignant and malignant intestinal epithelia and in ulcerative colitis tissue. Probiotic bacteria can be a source of sphingomyelinase. OBJECTIVE: To determine the effect of VSL#3 probiotic therapy on mucosal levels of alkaline sphingomyelinase, both in a mouse model of colitis and in patients with ulcerative colitis. METHODS: Interleukin-10 gene-deficient (IL10KO) and wild type control mice were treated with VSL#3 (10(9) colony-forming units per day) for three weeks, after which alkaline sphingomyelinase activity was measured in ileal and colonic tissue. As well, 15 patients with ulcerative colitis were treated with VSL#3 (900 billion bacteria two times per day for five weeks). Alkaline sphingomyelinase activity was measured through biopsies and comparison of ulcerative colitis disease activity index scores obtained before and after treatment. RESULTS: Lowered alkaline sphingomyelinase levels were seen in the colon (P=0.02) and ileum (P=0.04) of IL10KO mice, as compared with controls. Treatment of these mice with VSL#3 resulted in upregulation of mucosal alkaline sphingomyelinase activity in both the colon (P=0.04) and the ileum (P=0.01). VSL#3 treatment of human patients who had ulcerative colitis decreased mean (+/- SEM) ulcerative colitis disease activity index scores from 5.3+/-1.8946 to 0.70+/-0.34 (P=0.02) and increased mucosal alkaline sphingomyelinase activity. CONCLUSION: Mucosal alkaline sphingomyelinase activity is reduced in the intestine of IL10KO mice with colitis and in humans with ulcerative colitis. VSL#3 probiotic therapy upregulates mucosal alkaline sphingomyelinase activity.

Characterization of recombinant prolidase from Lactococcus lactis- changes in substrate specificity by metal cations, and allosteric behavior of the peptidase.

The Lactococcus lactis NRRL B-1821 prolidase gene was cloned and overexpressed in Escherichia coli. Under suboptimum growth conditions, recombinant soluble and active prolidase was produced; in contrast, inclusion bodies were formed under conditions preferred for cell growth. Recombinant prolidase retained more than half its full activity between 30 and 60 degrees C, and was completely inactivated after 30 min at 70 degrees C. CD analysis confirmed that prolidase was inactivated at 67 degrees C. The enzyme was active under weak alkali to weak acidic conditions, and showed maximum activity at pH 7.0. Although these characteristics are similar to those for other reported prolidases, this prolidase was distinctive for two kinetic characteristics. Firstly, different substrate specificity was observed for its two preferred metal cations, zinc and manganese: Leu-Pro was preferred with zinc, whereas Arg-Pro was preferred with manganese. Secondly, the enzyme showed an allosteric response to changes in substrate concentrations, with Hill constants of 1.53 for Leu-Pro and 1.57 for Arg-Pro. Molecular modeling of this prolidase suggests that these unique characteristics may be attributed to a loop structure near the active site.

Roles of plasma proteins in the formation of silicotic nodules in rats.

The contribution of plasma protein(s) to the stabilization of fibroids formed in rat lungs exposed to acute silica dust inhalation was examined. Antibodies against component proteins of the nodules remaining insoluble in 2% SDS, 10M urea and 40 mM sulfhydryl reagents under prolonged boiling conditions were raised in rabbits and used to capture plasma proteins, which were identified by 2D-gel electrophoresis and MALDI-TOF analysis. The silica particles were encapsulated with extracellular protein composites whose amino acid compositions showed high levels of alanine, i.e., above those of glycine and proline, a building block of collagen. Antibody-captured plasma proteins showed the dominant presences of fibrinogen, albumin, and prealbumin (transthyretin), and other minor proteins, which included alpha-1-protease inhibitor, contraspin-like protease inhibitor, cathepsin B, etc. The presence of the N(epsilon)-(gamma-glutamyl) lysine isopeptide bond in the nodules was evidenced by direct chemical methods and by immunoreactivity for anti-isopeptide bonds. Immunostaining of affected lung tissue and of the fibroid regions showed elevated levels of transglutaminase (TGase) E and plasma factor XIII (F-XIII), but showed no reactivity towards other TGases. These findings suggest that the silica encapsulated nodules are a mixture of extracellular proteins that include collagen type I, fibrin and transthyretin, which is stabilized by TGase catalyzed crosslinking between plasma and extracellular proteins during fibrosis to eventually form insoluble nodules.

Oral contraception and cyclic changes in premenstrual and menstrual experiences.

Despite the widespread use of oral contraceptives (OC) there is no consensus regarding their effect on menstrual cycle experiences. This study examines the cyclic changes of prospectively collected, daily menstrual cycle experiences of two groups of 'healthy women' using monophasic and triphasic OC compared with a group using non-hormonal contraception. A total of 119 'healthy women' using monophasic, triphasic or non-hormonal contraception for three months, made daily ratings over at least two complete menstrual cycles. Cyclic changes of ratings within and between the groups were analyzed. The three groups showed significant cyclic changes in abdominal fullness, abdominal discomfort, breast fullness, general 'premenstrual syndrome-like symptoms' and in at least two mood ratings. Maximal changes in ratings occurred during the late premenstrual and menstrual phases. There were no significant differences between the three groups in cyclic changes for any physical rating, but there were for tiredness or fatigue (non-OC users reported experiencing tiredness or fatigue more frequently than the OC users) and sadness or depression (non-OC users experienced sadness or depression less frequently than OC users during the early part of the cycle, followed by a sharp rise from early premenstrual to the menstrual phase). There were no significant cyclic differences in ratings between the monophasic and triphasic groups. In conclusion, 'healthy women' using OC experience premenstrual and menstrual changes. Any differences between OC formulations are subtle and not of clinical significance in 'healthy women' already established on monophasic or triphasic hormonal contraception.

Determination of N(pp)(gas) and N(pp)(D) for a plane-parallel chamber.

The purpose of this work is to investigate the consistency of determining N(pp)(gas) and N(pp)(D) by using three independent calibration methods from the AAPM TG 39 and IAEA TRS 381 protocols: 1) calibration with a high-energy electron beam in a phantom; 2) in-phantom calibration in a (60)Co beam; and 3) in-air calibration in a (60)Co beam. The plane-parallel chamber considered was the PTW-Markus and the comparisons were made against a calibrated PTW cylindrical Farmer-type chamber 30001. The phantom material used for the electron beam and (60)Co in-phantom methods was a solid water phantom (RW3). For the electron beam method, the nominal energies were 18 and 21 MeV. An acrylic buildup of 0.5 g/cm(2) thickness was used for the (60)Co in-air method. For each method, N(pp)(gas) and N(pp)(D) were obtained for the plane-parallel chamber as proposed by the AAPM TG 39 and IAEA TRS 381 protocols. The absorbed doses were measured along the central axis at a distance of 100 cm (SSD=100 cm) with 10 x 10 cm(2) field size at the depth of the maximum for each electron beam. The values of N(pp)(gas) by the three independent calibration methods agreed to within +/-0.6%. This meant that any of the methods would give a fairly good value. Similar results were obtained for N(pp)(D). In comparing the results for the electron beam method at energies of 18 and 21 MeV, the latter gave better agreement. The ratios of N(pp)(gas) and N(pp)(D) for the three methods were in agreement within 0.7%. The results for the absorbed dose intercomparison in the AAPM TG 39 and IAEA TRS 381 protocols showed that they agreed to within +/-0.7% which meant that any of the calibration methods and two different protocols would give an accurate result.