Sequential vs. prolonged 14-day triple therapy for Helicobacter pylori eradication: the meta-analysis may be influenced by 'geographical weighting'.

BACKGROUND: Sequential therapy is a first-line regimen obtaining satisfactory Helicobacter pylori eradication. Triple therapy prolongation improves the success rate even if a recent meta-analysis showed satisfying results only for the 14-day regimen. Studies from Africa and North America were unavailable in previous meta-analyses. AIM: To perform a meta-analysis comparing sequential vs. prolonged 14-day triple therapy with regard to 'geographic weighting' by considering subgroups analysis according to metronidazole/clarithromycin low and high resistance areas. METHODS: Based on PRISMA recommendations, we considered all first-line clinical studies from 2003 to November 2014. Randomised clinical trials (RCTs) were included by a search on PubMed, MEDLINE, Science Direct, EMBASE. Data on eradication rates were expressed as ITT. Risk ratio (RR), pooled RR and 95% confidence intervals were calculated by the Mantel-Haenszel method. Data were entered into RevMan 5.2 software (Nordic Cochrane Centre) using a random-effects model. RESULTS: Databases identified 194 studies; seven met the inclusion criteria. Overall results showed a similar effectiveness of the two regimens considered (RR = 0.99; 95% CI = 0.94-1.05; p = 0.75). In areas with high resistance to clarithromycin, sequential was superior to 14-day triple therapy (RR = 0.95; 95% CI = 0.90-1.00; p = 0.03). In areas with high metronidazole resistance, sequential and 14-day triple therapy were equivalent (RR = 0.99; 95% CI = 0.91-1.08; p = 0.82). CONCLUSIONS: 'Geographic weighting' could be the main factor affecting the lack of differences between sequential and 14-day triple therapy outcomes.

Co-exposure to metals modulates CYP1A mRNA inducibility in Atlantic tomcod Microgadus tomcod from two populations.

Populations from urbanized and industrialized sites are often exposed to mixtures of chemical contaminants including aromatic hydrocarbons (AHs) and heavy metals. The effects of mixtures of these contaminants on these populations are largely unknown. The Hudson River Estuary is highly contaminated with a variety of AHs including, PCBs and PAHs, and metals, and its population of Atlantic tomcod Microgadus tomcod bioaccumulates those which are persistent. The Hudson River's tomcod population exhibits resistance to persistent AHs as exemplified by significantly decreased inducibility of hepatic cytochrome P4501A (CYP1A) mRNA. We used hepatic CYP1A mRNA inducibility in tomcod from the Hudson River and a sensitive population to investigate the effects of acute co-exposure to metals on aryl hydrocarbon receptor (AHR)-mediated gene expression. Adult tomcod from the Hudson River and the cleaner Miramichi River were i.p. injected with one dose of benzo[a]pyrene (B[a]P) or coplanar PCB77 and graded doses of four metals, As, Cd, Cr, and Ni, and levels of hepatic CYP1A mRNA and protein were assayed. We observed no effects of metals treatment on basal levels of hepatic CYP1A mRNA expression, but all four metals significantly reduced CYP1A mRNA inducibility in tomcod from one or both populations. The magnitude of the inhibition of CYP1A mRNA inducibility differed among the metals and fish from the two populations. Also, the profile of the metals modulation of induced CYP1A mRNA showed differences that depended on the time after treatment of sacrifice. Our results demonstrate that co-exposure to several metals can impact inducible, but not basal levels of CYP1A expression and perhaps other toxicities mediated by the AHR.

Induction of antibacterial activity by alpha-d-oligogalacturonides in Nephrolepis sp. (pteridophyta).

This paper presents data on the induction by alpha-d-oligogalacturonides (OG) of antibiotic activity in vitro by the fern Nephrolepis sp. The extracts from the fern grown aseptically, partly in a medium containing a mixture of OG and partly in a medium lacking OG, as control, were tested against several bacterial strains. The results show that the OG mixture promotes the production of antibiotic compounds. Comparing the present results with those on the antimicrobial properties of the same fern grown in a greenhouse, we discuss the hypothesis that the production of antibiotic substances can be elicited by different factors, such as products of synthesis or degradation of the biotic component of the soil or by OG (in axenic culture) that can mimic the effect of natural elicitors.

Effects of postmenopausal hypoestrogenism on skin collagen.

OBJECTIVE: The aim of our study was to evaluate the effect of aging and postmenopausal hypoestrogenism on skin collagen content. METHODS: Thirty-two women (mean age 48.78 +/- 9.86; year +/- S.D., range 28-68), 14 in premenopause and 18 in postmenopause, underwent skin biopsies performed during laparotomic operation. The amount of collagen type I, III and type III/type I ratio was evaluated by immunohistochemistry and computerised image analysis, and was related to age and years of postmenopause. RESULTS: In the postmenopausal patients, a significant (P < 0.01) decrease of percentage of skin collagen type I, type III and type III/type I ratio was observed in comparison to premenopausal women. The percentages of collagen type I, type III and type III/I ratio of all patients studied was significantly (P < 0.01) correlated with chronological age (r = 0.88, 0.89 and 0.61, respectively). Considering only postmenopausal subjects, the correlation with chronological age was significant (P < 0.01) for collagen type I and type III of postmenopausal women (r = 0.59, r = 0.64, respectively), but not for the type III/I ratio (r = 0.37, P = 0.131). The percentages of collagen type I, type III and type III/I ratio of postmenopausal women showed a significant (P < 0.01) inverse correlation with years of postmenopause (r = 0.76, 0.73 and 0.73, respectively). CONCLUSIONS: Our data suggest that the decrease of skin collagen is an estrogen-related phenomenon.

B[a]P-DNA binding in early life-stages of Atlantic tomcod: population differences and chromium modulation.

Atlantic tomcod (Microgadus tomcod) from the Hudson River (HR) are resistant at the molecular and organismic levels to the effects of exposure to dioxin-like aromatic hydrocarbon (AH) compounds, but much less so to benzo[a]pyrene (B[a]P). The aims of this study were to determine in early life-stages of tomcod exposed to B[a]P: (1) if DNA binding levels differed between fish from the HR and Miramichi River (MR), and (2) if co-exposure to chromium could modulate this genotoxic effect. After exposure to [(3)H]B[a]P alone, DNA-bound radioactivity was 5-10-fold higher in embryos and larvae of MR than HR descent. Co-exposure to chromium modulated DNA binding levels in offspring of both populations. In MR embryos, co-exposure to chromium inhibited B[a]P uptake. These results demonstrated resistance to the genotoxic effects of B[a]P in early life stages of HR tomcod at an ecologically important endpoint and suggest the ability of chromium to modulate AH-induced genotoxicity.

[Postmenopausal osteoporosis: therapeutic approaches]. / Osteoporosi postmenopausale. Approcci terapeutici.

The preventive and therapeutical measures to be implemented the post-menopausal osteoporosis are varied, although there is no clear, single protocol of intervention. ESTROGENS AND PROGESTOGENS: It si verify that the administration of estrogens and/or progestogens prevents bone loss with an action on mineral components of bone and on collagenic metabolism. BIPHOSPONATES: Operate inhibiting mineralization and, particularly, bone reabsorption. At present its use, in low dosages, is reserved to "fast bone loser" patients. CALCITONIN: It increases bone mass and significantly reduces the frequency of fractures in comparison with only calcium, but its use is limited by high costs. IPRIFLAVONE: Anti-reabsorption effects has on bone and stimulates osteoblastic activity; besides, it seems to developed the effect of estrogens on the bone. FLUORIDES: Fluorides also operate on both components of bone turnover, with a most important action on bone formation. An interesting approach is the association of low doses of monofluorophosphate with calcium. However, further confirmation of the "quality" of neoformed bone is necessary. CALCIUM: Calcium supplementation is obligatory where the alimentary supply of calcium is lower then 1 g/die or where an osteomalacic component coexists; only dosages higher than 15 g/die can produce/pharmacological effects on bone turnover. CALCITRIOL: The use is still disputed. The calcitriol-calcium association seems convincing haveved. ORG: OD 14. The efficacy of this synthetic steroid to prevent bone loss is probably superimposable on the efficacy of classic estrogen therapy.

[Effect of hormone replacement therapy on postmenopausal ocular function]. / Effetti della terapia ormonale sostitutiva sulla funzionalità oculare in postmenopausa.

OBJECTIVE: Determination of the effects of hormonal replacement therapy (HRT) on various ocular parameters and symptoms in postmenopausal women. DESIGN: Prospective study. SETTING: Department of Obstetrics and Gynecology, University "Federico II" of Naples. PATIENTS: 14 healthy women treated orally with equine conjugated estrogen in continuous (0,625 mg/daily) and acetate-medroxyprogesteron (10 mg/daily) from 17th to 28th day for three months. MEASURES: Ocular symptomatology, intraocular pressure (IOP), lacrimal secretion, reflected and basal and corneal thickness. RESULTS: After 3 months of HRT the IOP was reduced of 10.8% (p < 0.005), the lacrimal secretion, reflected and basal, increased of 19% and 48%, respectively and the corneal thickness increased of 16.6%. CONCLUSION: The HRT has a positive effect on ocular physiology.

Absence of IL-12Rß2 in CD33(+)CD38(+) pediatric acute myeloid leukemia cells favours progression in NOD/SCID/IL2RγC-deficient mice.

Childhood acute myeloid leukemia (AML) is a hematological malignancy in which tumor burden is continuously replenished by leukemic-initiating cells (ICs), which proliferate slowly and are refractory to chemotherapeutic agents. We investigated whether interleukin (IL)-12, an immuno-modulatory cytokine with anti-tumor activity, may target AML blasts (CD45(+)CD33(+)) and populations known to contain leukemia ICs (that is, CD34(+)CD38(-), CD33(+)CD38(+) and CD44(+)CD38(-) cells). We demonstrate for the first time that: i) AML blasts and their CD34(+)CD38(-), CD33(+)CD38(+), CD44(+)CD38(-) subsets express the heterodimeric IL-12 receptor (IL-12R), ii) AML cells injected subcutaneously into NOD/SCID/Il2rg(-/-) (NSG) mice developed a localized tumor mass containing leukemic ICs and blasts that were virtually eliminated by IL-12 treatment, iii) AML cells injected intravenously into NSG mice engrafted within the first month in the spleen, but not in bone marrow or peripheral blood. At this time, IL-12 dramatically dampened AML CD45(+)CD33(+), CD34(+)CD38(-), CD33(+)CD38(+) and CD44(+)CD38(-) populations, only sparing residual CD33(+)CD38(+) cells that did not express IL-12Rß2. From 30 to 60 days after the initial inoculum, these IL-12-unresponsive cells expanded and metastasized in both control and IL-12-treated NSG mice. Our data indicate that the absence of IL-12Rß2 in pediatric AML cells favours leukemia progression in NOD/SCID/IL2Rγc-deficient mice.

Interleukin-27 inhibits pediatric B-acute lymphoblastic leukemia cell spreading in a preclinical model.

B-acute lymphoblastic leukemia (B-ALL) represents the most common pediatric hematological tumor that derives from the aberrant proliferation of early B lymphocytes in the bone marrow. Although most of the B-ALL children take advantage from current therapeutic protocols, some patients relapse and need alternative therapies. With this background, we investigated whether interleukin (IL)-27, an immunomodulatory cytokine with antitumor properties, may function as an antitumor agent against pediatric B-ALL cells. Here we show for the first time that pediatric B-ALL cells functional IL-27R and that IL-27 dampens directly tumor growth in vivo and in vitro through mechanisms elucidated in this study. The novelty of these results deals with the first demonstration that (1) B-ALL cells from pediatric patients injected intravenously (i.v.) into NOD/SCID/Il2rg(-/-) (NSG) mice gave rise to leukemic spreading that was severely hampered by IL-27; (2) IL-27-treated mice, compared with controls, showed significant reduction of putative B-ALL-initiating cells and blasts in the peripheral blood (PB), bone marrow (BM) and spleen; and that (3) IL-27 reduced in vitro B-ALL cell proliferation and angiogenesis, induced apoptosis and downregulated miR-155. Our results strongly encourage the development of future clinical trials to evaluate the toxicity and efficacy of IL-27 in childhood B-ALL patients.

Quilty effect has the features of lymphoid neogenesis and shares CXCL13-CXCR5 pathway with recurrent acute cardiac rejections.

Quilty effect (QE) is a frequent, yet enigmatic feature of cardiac allograft, since it is apparently devoid of clinical significance, though its association with acute (A) rejection (R) is strongly suspected. It was observed in 126/379 biopsies from 22 patients during the first posttransplant year. Most grade (G)2R biopsies displayed a concomitant QE. The following features typical of QE were identified: (a) focal angiogenesis and lymphangiogenesis associated with bFGF, VEGF-C and VEGF-A expression, (b) marked infiltrate of CD4(+)T and CD20(+)B followed by CD8(+)T lymphocytes arranged around PNAd(+)HEV-like vessels. Most QE appear as distinct B-T-cell-specific areas with lymphoid follicles sometimes endowed with germinal center-like structures containing VCAM-1(+)CD21(+)FDC and CD68(+)macrophages, which frequently expressed CXCL13. These cells were also found in mantle-like zones, where small lymphocytes expressed CXCR5, otherwise in the whole area of not clustered lymphoid aggregates. CXCL13 was also expressed, in association with CD20(+)B lymphocyte recruitment, in G2R biopsies obtained from patients with recurrent AR. QE has features of a tertiary lymphoid tissue suggesting an attempt, by the heart allograft, to mount a local response to a persistent alloantigen stimulation resulting in aberrant CXCL13 production, as also occurs in recurrent AR. CXCL13-CXCR5 emerge as a common molecular pathway for QE and recurrent episodes of AR.

Endomyocardial infiltration by B and NK cells foreshadows the recurrence of cardiac allograft rejection.

Heart allograft outcome is unpredictable and acute rejection episodes still occur despite the improvement of immunosuppressive regimens. We therefore investigated whether the immunopathological profile of endomyocardial biopsies might underlie the variations in the clinical course of a graft. Biopsies from transplanted patients were analysed by histology, immunohistochemistry (associated with digital image analysis), confocal and electron microscopy to determine the type and the functional state of leukocytes infiltrating the myocardium, together with their ultrastructural features and those of the graft itself. In comparison with biopsies with grade 0R or grade 1R rejection, those from patients with grade 2R rejection displayed significant infiltration of macrophages, T lymphocytes, and CD83+ and DC-SIGN+ dendritic cells. Fifty-seven per cent were invaded by CD20+B lymphocytes, most of which expressed CD69 activation marker and cooperated in interleukin-12 production, and by CD69+CD94+NK cells expressing interferon-gamma. Ultrastructural signs of myocyte degeneration and microvessel rupture by NK cells were frequent. These patients developed recurrent episodes of acute allograft rejection. Endomyocardial B and NK infiltrates are involved in the dynamics of allograft rejection and are associated with a high risk of its recurrence. Immunopathological assessment of endomyocardial biopsies may thus serve to forecast the probable outcome of a heart allograft.

Prostanoid production in the presence of platelet activation in hypoxic cocaine-treated rats.

To extend our previous in vitro data, we investigated the effects of cocaine on thromboxane A2 (TXA2) and prostacyclin (PGI2) production in vivo in the rat. To obtain the slight platelet activation that our in vitro experiments showed useful to highlight the effect of cocaine, we infused cocaine in rats in the presence of platelet-activating factors (circulation of blood through a perspex vascular device or by infusion of sodium arachidonate) and in various respiratory conditions. Experiments were conducted in rats breathing atmospheric air (normoxic conditions) and in rats breathing an oxygen-poor mixture (hypoxic conditions). In rats under hypoxic conditions cocaine invariably increased TXA2 plasma levels, whereas in normoxic conditions it increased TXA2 only in the presence of platelet-activating factors. Cocaine significantly increased PGI2 plasma levels in arachidonate-treated rats in hypoxic respiratory conditions; in normoxic conditions cocaine left PGI2 levels unchanged. These results support the hypothesis that in cocaine users who have concomitant pathological conditions able to activate platelets, such as atherosclerosis, coronary vasospasm or ischaemia, or both, cocaine may contribute to the onset of thrombotic phenomena by interfering with the prostaglandin system.

Regulation of alpha2-macroglobulin expression in rat Sertoli cells and hepatocytes by germ cells in vitro.

Germ cells isolated from rat testes by trypsinization have been shown to yield unwanted artifacts in biological assays, since conditioned media derived from these germ cells (germ cell-conditioned media [GCCM]) can modulate Sertoli cell secretory function because of the presence of residual trypsin. To determine whether germ cells themselves can modulate Sertoli cell function, we isolated germ cells from tubules by a mechanical procedure and assessed the effect of these cells on Sertoli cell alpha2-macroglobulin (alpha2-MG) steady-state mRNA level. It was found that germ cells indeed could stimulate Sertoli cell alpha2-MG expression. This effect is probably mediated by a soluble factor(s) released from germ cells, since GCCM fractionated by HPLC contained multiple fractions that can stimulate Sertoli cell alpha2-MG expression dose-dependently. These results illustrate that germ cells play a role in regulating testicular alpha2-MG expression. Since Sertoli cells synthesize and secrete many of the serum proteins behind the blood-testis barrier that are also produced by hepatocytes, we sought to ascertain whether germ cells can affect hepatic alpha2-MG expression. When germ cells were cocultured with hepatocytes isolated from adult rats, the hepatocyte alpha2-MG steady-state mRNA level was shown to be stimulated by germ cells dose-dependently. Using different pools of fractions derived from GCCM after their fractionation by a preparative anion-exchange HPLC column, GCCM was found to contain a factor(s) that stimulated hepatocyte alpha2-MG expression dose-dependently. More importantly, the fractions that stimulated hepatocyte alpha2-MG expression had a retention time different from that of the factor(s) that affected Sertoli cell alpha2-MG expression. These data illustrate that germ cells secrete multiple biological factors capable of regulating alpha2-MG expression in the testis and the liver. In summary, this study reveals a possible physiological link between the testis and the liver in that germ cells may release a factor(s) capable of modulating alpha2-MG expression in both organs.

Just-in-time coding of the problem list in a clinical environment.

Clinically useful problem lists are essential to the CPR. Providing a terminology that is standardized and understood by all clinicians is a major challenge. UNMC has developed a lexicon to support their problem list. Using a just-in-time coding strategy, the lexicon is maintained and extended prospectively in a dynamic clinical environment. The terms in the lexicon are mapped to ICD-9-CM, NANDA, and SNOMED International classification schemes. Currently, the lexicon contains 12,000 terms. This process of development and maintenance of the lexicon is described.

Effects of thyroxine therapy on bone metabolism in postmenopausal women with hypothyroidism.

OBJECTIVE: To evaluate whether thyroid stimulating hormone-suppressive thyroxine replacement therapy increases bone loss in postmenopausal women. MATERIALS AND METHOD: The study had a cross-sectional design. Fifty-four postmenopausal women on long-term treatment with thyroxine for primary hypothyroidism, who showed suppressed thyroid stimulating hormone levels were enrolled in our study. In these patients and in a control group of 54 healthy postmenopausal women we evaluated bone mineral density at distal radius and the main biochemical parameters of bone turnover. Student's t test, Wilcoxon signed rank-test, Chi-square test and the univariate linear regression in the statistical analysis of the data were employed. RESULTS: Bone mineral density values, expressed as z-scores, in the treated group were significantly decreased in comparison with the control group (p < 0.01). We did not detect a significant relationship between different L-thyroxine doses administered and bone mineral density z-scores. On the contrary, an inverse correlation was detected between length of treatment and bone mineral density z-scores. Treated patients showed a significantly higher concentration of serum alkaline phosphatase, osteocalcin, urinary calcium/creatinine and hydroxyproline/creatinine in comparison with the controls. CONCLUSIONS: Our study suggests that thyroxine replacement therapy in patients with suppressed thyroid stimulating hormone levels increases postmenopausal bone loss.

Ultrasonographic measurement of endometrial thickness during hormonal replacement therapy in postmenopausal women.

The objective of this study was to measure endometrial thickness by transvaginal ultrasonography during two regimens of hormonal replacement therapy (HRT) in postmenopausal women and to compare these data with endometrial histology. Transvaginal ultrasonographic evaluation of endometrial thickness and endometrial biopsy were performed in 80 postmenopausal women before and after 6 months of HRT (between the 24th and the 28th day of the cycle). The group was randomized so that 40 women (Group A) were treated with a continuous sequential regimen consisting of 5 micrograms/day of estradiol continuously and 5 mg/day of medrogestone from the 17th to the 28th day of the cycle; and 40 women (Group B) were given continuous administration of 50 micrograms/day estradiol and 5 mg/day medrogestone. Prior to therapy, there was no significant difference in mean endometrial thickness between the groups. After 6 months of therapy, endometrial thickness was significantly increased in comparison with basal values in both groups. The mean value was significantly higher (p < 0.001) in Group A (8.5 +/- 3.7 mm) than in Group B (3.6 +/- 1.3 mm). In Group A, endometrial thickness was < or = 4 mm in 16.7% of patients and < or = 8 mm in 69.5% of patients. In Group B, 91% of patients had an endometrium of < or = 4 mm. In both groups, the thickness of the atrophic endometrium was less than that of the other histological types of endometrium (4.1 +/- 0.3 mm for Group A and 3.5 +/- 1.2 mm for Group B). In Group A, the difference in mean endometrial thickness between the proliferative and secretory endometrium was not statistically significant. In both groups, the transvaginal ultrasonographic measurement of endometrial thickness of < or = 4 mm had a high sensitivity for detecting atrophic endometrium (83.3% for Group A and 93.7% for Group B).

Rat prostaglandin D2 synthetase: its tissue distribution, changes during maturation, and regulation in the testis and epididymis.

The changes in glutathione-independent prostaglandin D2 synthetase (PGD-S) during maturation in the rat were determined in selected organs by an RIA using PGD-S purified from rat cerebrospinal fluid and a monospecific anti-rat PGD-S polyclonal antibody. In a survey of its tissue distribution in various organ extracts and biological fluids, it was found that the concentration of PGD-S was highest in the epididymis-about 6- and 80-fold greater than that in the brain and testis, respectively. During maturation, PGD-S concentration increased steadily in the testis and epididymis; this is in contrast to the pattern of changes in the brain and liver, which showed a general trend of decline. Reverse transcription-polymerase chain reaction and Southern blotting were used to demonstrate the presence of PGD-S mRNA transcript in the testis and in Sertoli and germ cells. In the epididymis, the steady-state PGD-S mRNA level was highest in the caput, followed by the cauda and corpus. Orchiectomy induced a drastic reduction of PGD-S concentration in all three epididymal compartments. Administration of dihydrotestosterone (DHT) failed to restore the reduced epididymal PGD-S level except in the caput epididymis, where 4 days after DHT treatment the level of PGD-S was restored to about 50% of the pre-orchiectomized level; this suggests that the epididymal PGD-S level is not entirely regulated by androgen and that another yet to be identified testicular factor(s) is likely to be involved in its regulation. Germ cell-conditioned medium was also shown to stimulate PGD-S expression in the Sertoli cell. These results illustrate that PGD-S is an important molecule in testicular and epididymal function and that it is likely involved in spermatogenesis and sperm maturation.

Quantification of prostaglandin D synthetase in cerebrospinal fluid: a potential marker for brain tumor.

Prostaglandin D synthetase (PGD-S; prostaglandin-H2 D-isomerase, EC 5,3,99,2), a 30 kDa glycoprotein also known as beta-trace protein that catalyzes the formation of prostaglandin D2 (PGD2) from PGH2, was purified to apparent homogeneity from human cerebrospinal fluid (CSF) using a two-step procedure involving HPLC on a Vydac C8 reversed-phase column and high performance electrophoresis chromatography (HPEC) using a 10% T SDS-polyacrylamide gel. The purity of PGD-S isolated from CSF was confirmed by silver stained SDS-polyacrylamide gel and direct protein microsequencing (NH2-APEAQVSVQPNFQ). A highly specific polyclonal antibody was prepared against this protein for immunoassay development. Using an ELISA, it was found that the concentration of PGD-S in CSF did not alter significantly in different pathological conditions of the central nervous system (CNS). These include dementia (n = 9), hydrocephalus (n = 4), neuropathy (n = 11), optic neuritis (n = 4), multiple sclerosis (n = 11), and demyelinating syndrome (n = 11), when compared to normal individuals (n = 12); however, the level of PGD-S in the CSF obtained from patients with brain tumor (n = 11), was reduced by as much as 2-fold when compared to control samples (n = 12) illustrating PGD-S is a potentially useful marker for brain tumor.