Efficacy of ultramicronised diclofenac in patients with osteoarthritis - systematic review with network meta-analysis.

OBJECTIVE: This systematic review with network meta-analysis was performed to compare the effectiveness of oral anti-inflammatory drugs used in Brazil for osteoarthritis. PATIENTS AND METHODS: Randomized clinical trials evaluating ultramicronised diclofenac, diclofenac, celecoxib, etodolac and placebo in patients with osteoarthritis were identified. A search was conducted in May 2021 through PubMed, Scopus and Web of Science databases. A network meta-analysis was developed for efficacy outcome related to analgesia measured by the pain subscale of the Western Ontario and McMaster Universities tool. In addition, surface under the cumulative ranking was performed to rank the drugs in relation to this outcome. RESULTS: Twelve randomized clinical trials were included. Overall, ultramicronised diclofenac 105 mg/day (UD105) was better than all the others, including ultramicronised diclofenac 70 mg/day (UD70). In addition, surface under the cumulative ranking resulted in the following order: 1) ultramicronised diclofenac 105 mg/day (100%), 2) ultramicronised diclofenac 70 mg/day (80%), 3) celecoxib 200 mg/day (49%), 4) diclofenac 100 mg/day (48%), 5) placebo (19%) and 6) diclofenac 150 mg/day (6%). CONCLUSIONS: Ultramicronised diclofenac demonstrated superior efficacy compared to other conventional anti-inflammatory drugs and placebo in relieving osteoarthritis pain.

Fixed-time post-cervical artificial insemination in weaned sows following buserelin use combined with/without eCG.

Fixed-time post-cervical artificial insemination (FTAI) drastically reduces labour requirements and increases the use of boars with higher genetic merit. This study evaluated the efficiency of eCG administration combined with/without the GnRH agonist buserelin for the induction and synchronization of ovulation in weaned sows submitted to FTAI. The sows were allocated into three groups. In the control group, the first artificial insemination was performed at the onset of oestrus and repeated every 24 hr. In the eCG+GnRH group, sows received 600 IU eCG at weaning and buserelin (10 µg) after 86-89 hr of eCG, and in the GnRH group, sows received only buserelin after 86-89 hr of weaning. The hormone-treated sows received a single FTAI after 30-33 hr of buserelin application. All the sows were inseminated with homospermic doses (1.5 × 109  sperm cells/50 ml). The interval between weaning and ovulation was shorter (p < .05) in the eCG+GnRH (133.3 hr) and GnRH (135.9 hr) groups than the control (141.5 hr) group. In the eCG+GnRH group, the sows ovulated earlier (p < .05) than those in the GnRH group (44.5 vs. 48.2 hr after buserelin administration). The reproductive performance of GnRH sows was not compromised when only sows exhibiting oestrus at the time of insemination were considered, but lower farrowing rate and smaller litter size were observed in eCG+GnRH sows. The reproductive performance of eCG+GnRH sows was primarily compromised because the insemination was performed outside the optimal time relative to ovulation; therefore, it is advisable to inseminate them before 116-122 hr after weaning.

Use of a modified Furlow Z-plasty as a secondary cleft palate repair procedure to reduce velopharyngeal insufficiency.

Cleft palate repair is done to allow for normal speech by separating the oral and nasal cavities and creating a functioning velopharyngeal valve. However, despite cleft palate repair, some patients demonstrate velopharyngeal insufficiency (VPI). An attempt was made to determine the effectiveness of a modified secondary Furlow Z-plasty in improving VPI. Fifty-five children aged between 12 and 15 years, with postoperative VPI following primary palatoplasty, were included in the study. These children underwent a modified Furlow Z-plasty. Nasometry was done to determine the change in velopharyngeal function due to the secondary Furlow Z-plasty by comparing the preoperative with the 1-year postoperative nasalance scores. A test-retest study was performed to determine the reliability of the nasometric measures. Reliability measurements of the nasometer passages revealed good reliability for 18 out of the 25 speech passages. There was a statistically significant reduction in VPI at 1 year postoperative in patients who were treated with the modified Furlow Z-plasty, with a P-value of <0.001 in all passages, except velar plosives, which had a P-value of 0.002. Patients with VPI after primary palatoplasty and treated using a modified Furlow Z-plasty had significantly lower nasalance scores at 1 year postoperative, indicating significantly improved velopharyngeal function.

Multivariate analyses for determining the association of field porcine fertility with sperm motion traits analysed by computer-assisted semen analysis and with sperm morphology.

This study investigates the association of semen traits with boar fertility. The fertility outcome (farrowing rate - FR and total piglets born - TB) of 14 boars was obtained from a field trial conducted during 10 week of breeding period on a commercial farm using multiparous sows (n = 948) through single-sire mating with 2 × 10(9) motile sperm cells per artificial insemination (AI) dose. Sperm motion parameters, evaluated with computer-assisted semen analysis system in raw and stored semen at 17°C for 240 h, in addition to morphological sperm defects, measured on the collection day, were included in the analysis to determine which semen traits were important to discriminate the fertility potential of ejaculates from these boars. The data underwent multivariate cluster, canonical and discriminant analyses. Four clusters of boars were formed based on fertility outcome. One boar, with the lowest FR and TB values (89.7% and 11.98), and two boars, with the highest FR and TB values (97.8% and 14.16), were placed in different clusters. The other boars were separated in two distinct clusters (four and seven boars), including boars with intermediate TB (12.64 and 13.22) but divergent values for FR (95.9% vs 91.8%). Semen traits with higher discriminatory power included total motility, progressive motility, amplitude of lateral head displacement and cytoplasmatic droplets. Through multivariate discriminant analysis, more than 80% of the 140 ejaculates were correctly classified into their own group, showing that this analysis may be an efficient statistical tool to improve the discrimination of potential fertility of boars. Nevertheless, the validation of the relationship between fertility and semen traits using this statistical approach needs to be performed on a larger number of farms and with a greater number of boars.

Evaluation of fatigue in Parkinson's disease using the Brazilian version of Parkinson's Fatigue Scale.

OBJECTIVE: Fatigue is common in Parkinson's disease (PD). However, factors associated with fatigue in PD are still controversial. This study aimed to translate the Parkinson's Fatigue Scale (PFS) into Brazilian-Portuguese, to test its psychometric properties, and to assess the severity of fatigue in PD as well as its relation to demographic and clinical features, depression, anxiety, excessive daytime sleepiness and cognitive performance. METHODS: We translated and assessed the internal consistency of the Brazilian version of the PFS. After, we assessed 87 PD patients with several neurological and psychopathological instruments. RESULTS: The Brazilian version of PFS had good internal consistency (Cronbach's alpha = 0.939). Clinical significant fatigue was present in 36 patients (41.4%). A logistic regression analysis showed that fatigue was better explained by dysthymia (P = 0.006), more severe symptoms of depression as assessed by the Hamilton Depression Rating Scale (P = 0.027), daytime sleepiness (P = 0.022) and female gender (P = 0.031). CONCLUSIONS: Fatigue is a common non-motor symptom in PD and seems to be associated with female gender, dysthymia, severity of depression and daily somnolence.

Zinc accumulation in N-methyl-N-nitrosourea-induced rat mammary tumors is accompanied by an altered expression of ZnT-1 and metallothionein.

Zinc is essential for cell proliferation. Several human studies have shown that in breast cancer tissues, zinc concentration expressed on a per tissue weight basis is higher than that in normal breast tissues. However, the mechanisms involved are unknown. N-methyl-N-nitrosourea (MNU)-induced rat mammary tumorigenesis is one of the most widely used rodent mammary tumorigenesis models for studying human breast cancer due to their similarities in hormone dependency, pathogenesis, histological classification, and immunocytochemical markers. This study was to establish if there was an accumulation of zinc in MNU-induced rat mammary tumors and, if there was, to explore the possible mechanisms involved. Sprague-Dawley rats were sham-treated or MNU-treated (50 mg/kg; n = 12) for 100 days. In MNU-induced mammary tumors (mammary tumors), zinc concentration expressed on a per dry weight basis was 12 times of that in normal mammary glands. Moreover, the mRNA level of ZnT-1 (a transporter involved in zinc efflux) in mammary tumors was reduced by 55% as compared with that in normal mammary glands. The mRNA level of Nramp2 (a divalent cation importer) and ZnT-4 (another transporter involved in zinc efflux) was unaffected by MNU-induced mammary tumorigenesis. The mRNA and protein levels of metallothionein (a putative zinc storage protein) in mammary tumors were 1.3 and 3.5 times of that in normal mammary glands, respectively. Collectively, our observations showed that zinc is accumulated in MNU-induced rat mammary tumors and this accumulation is accompanied by an altered expression of ZnT-1 and metallothionein, suggesting that zinc homeostasis might be altered in MNU-induced rat mammary tumorigenesis. Because zinc is essential to cell proliferation and cell proliferation is increased in mammary tumors, zinc accumulation is likely a part of an integrated effort to ensure sufficient zinc supply to sustain tumor growth.

Des(1-3)IGF-1 treatment normalizes type 1 IGF receptor and phospho-Akt (Thr 308) immunoreactivity in predegenerative retina of diabetic rats.

Little is known about interventions that may prevent predegenerative changes in the diabetic retina. This study tested the hypothesis that immediate, systemic treatment with an insulin-like growth factor (IGF)-1 analog can prevent abnormal accumulations of type 1 IGF receptor, and phospho-Akt (Thr 308) immunoreactivity in predegenerative retinas of streptozotocin (STZ) diabetic rats. Type 1 IGF receptor immunoreactivity increased approximately 3-fold in both inner nuclear layer (INL) and ganglion cell layer (GCL) in retinas from STZ rats versus nondiabetic controls. Phospho-Akt (Thr 308) immunoreactivity increased 5-fold in GCL and 8-fold in INL of STZ rat retinas. In all cases, immunoreactive cells were significantly reduced in STZ des(1-3)IGF-1-treated versus STZ rats. Preliminary results suggested that vascular endothelial growth factor (VEGF) levels may also be reduced. Hyperglycemia/failure of weight gain in diabetic rats continued despite systemic des(1-3)IGF-1. These data show that an IGF-1 analog can prevent early retinal biochemical abnormalities implicated in the progression of diabetic retinopathy, despite ongoing hyperglycemia.

Smart single-chip gas sensor microsystem.

Research activity in chemical gas sensing is currently directed towards the search for highly selective (bio)chemical layer materials, and to the design of arrays consisting of different partially selective sensors that permit subsequent pattern recognition and multi-component analysis. Simultaneous use of various transduction platforms has been demonstrated, and the rapid development of integrated-circuit technology has facilitated the fabrication of planar chemical sensors and sensors based on three-dimensional microelectromechanical systems. Complementary metal-oxide silicon processes have previously been used to develop gas sensors based on metal oxides and acoustic-wave-based sensor devices. Here we combine several of these developments to fabricate a smart single-chip chemical microsensor system that incorporates three different transducers (mass-sensitive, capacitive and calorimetric), all of which rely on sensitive polymeric layers to detect airborne volatile organic compounds. Full integration of the microelectronic and micromechanical components on one chip permits control and monitoring of the sensor functions, and enables on-chip signal amplification and conditioning that notably improves the overall sensor performance. The circuitry also includes analog-to-digital converters, and an on-chip interface to transmit the data to off-chip recording units. We expect that our approach will provide a basis for the further development and optimization of gas microsystems.

Analysis of iceA genotypes in South African Helicobacter pylori strains and relationship to clinically significant disease.

BACKGROUND: South African Helicobacter pylori isolates are characterised by the universal presence of cagA but have differences in vacuolating cytotoxin gene (vacA) alleles which correlate with clinically significant disease. However, the candidate virulence marker gene iceA has not been investigated. AIM: To characterise the genetic organisation and heterogeneity of iceA genotypes in different South African clinical isolates. PATIENTS AND METHODS: We studied H pylori strains isolated from 86 dyspeptic patients (30 with peptic ulcer disease (PUD), 19 with distal gastric adenocarcinoma (GC), and 37 with non-erosive gastritis) for the presence of iceA1 or iceA2 genes, and for differences in the genetic organisation of iceA2 by polymerase chain reaction, Southern hybridisation analysis, and sequencing. RESULTS: Genetic analysis of iceA1 demonstrated significant homology (92-95%) with the USA type strain 26695 and probably functions as a transcriptional regulator, while a novel variant (iceA2D') of iceA2 and marked differences in predicted protein secondary structure of the iceA2 protein were defined. iceA1 was detected in 68% and iceA2 in 80% of all clinical isolates. Although approximately 40% of patients had both strains, a higher prevalence (p< 0.01) of GC patients were infected with iceA1 isolates which were invariably vacA s1/iceA1 (p< 0.005 v gastritis). Isolates from PUD patients were distinguished by the structurally altered iceA2D variant (53%; p<0.03 v gastritis) while the iceA2C variant distinguished isolates from patients with gastritis alone (67%; p< 0.005 v PUD). CONCLUSION: In this study, an association between iceA1 and GC was noted while differences in variants of iceA2 differentiated between PUD and gastritis alone. Combination analyses of iceA genotypes and vacA alleles supported these associations.

T cell infiltration and MHC I and II expression in the presence of tumor antigens: An immunohistochemical study in patients with serous epithelial ovarian cancer.

OBJECTIVES: Ovarian cancer is a frequent cause of death among women with gynaecologic malignancies despite the introduction of combination chemotherapy. There is therefore a need for new therapeutic strategies for patients with ovarian cancer, such as cellular immunotherapy. In this immunohistochemical study we analysed the expression of three tumor antigens, p53, HER-2/neu and MUC-1 in relation to the expression of major histocompatibility complex (MHC) class I and II on tumor cells, and we searched for the presence of (activated) immune effector cells at the tumor site. STUDY DESIGN: The study was carried out retrospectively in tumor tissue from 29 patients with serous ovarian cancer. Material used had been formalin fixed and paraffin embedded. Material had been obtained from 15 patients at staging laparotomy and from 14 patients during second look or intervention laparotomy. RESULTS: A positive staining for p53 was found in 19/29 (66%) of the tumors, with a high positivity in 13/29 (45%). HER-2/neu and MUC-1 staining was positive in 8/29 (28%) and 21/28 (75%), respectively. Downregulation of MHC class I on tumor cells was found in a minority of the patients, beta-2-microglobin (beta2m) was expressed on tumor cells in all patients. High staining for CD45RO correlated with a high positive staining for granzyme-B (R=0.40, P=0.04) and TIA-1 (R=0.39, P=0.04). A statistically significant better survival in the group with lower stage of disease was found. CONCLUSIONS: As only three out of 29 patients were negative for the tumor antigens p53, HER-2/neu and MUC-1, immunotherapy aiming at all three could serve almost all patients with ovarian cancer. We found that granzyme-B, TIA-1 and CD45RO+ T cells are present in the tumor biopsies, increasing this number by immunotherapy may be beneficial. The immune escape mechanism by MHC class I and beta2m downregulation seems to be of minor importance. Our data support the view that immunotherapy may offer new possibilities with high specificity in ovarian cancer.

The relationship between Helicobacter pylori infection, the virulence genotypes of the infecting strain and gastric cancer in the African setting.

BACKGROUND: The relationship between Helicobacter pylori infection and gastric carcinoma remains controversial, especially in the African setting where infection is common, while gastric cancer is perceived to be uncommon, the basis of the so called 'African enigma'. This discrepancy between infection and the development of disease is commonly attributed to differences in host, environment and bacterial factors. Interest in the bacterial factors has focused on heterogeneity in the so-called 'virulence genes'. AIM: The aim of this prospective, case-controlled study was to establish whether H. pylori infection is significantly associated with gastric cancer and to investigate whether gastric cancer is associated with genotypically distinct (as it relates to the candidate virulence genes) organisms in this population. METHODS: Patients with histologically confirmed gastric cancer were matched with nonulcer dyspeptic controls for age (within 5 years), gender and ethnicity. Helicobacter pylori status was determined by RUT, histology, culture and serology (locally validated and used as default determinant of H. pylori status). Tumors were classified according to the Lauren classification. The 'virulence genotype' of 17 paired culture samples was determined by previously described and validated molecular techniques (cagA presence, vacA alleles, structure of the cag pathogenicity island and analysis of the iceA alleles). Categorical variables were analysed by the chi2 test. RESULTS: Forty-eight patients (median age 59 years) could be adequately matched to controls. 39/48 (81%) cases and 43/48 (90%) controls were H. pylori positive (NS). Significant differences in the virulence genotypes of infecting strains were noted: vacAs2-controls 24%, cases 0%, p < .00001; vacAs1 present - cases 100%, controls 76%, p < .05; cagA-3'-length > 650 bp - cases 47%, controls 0%, p < .002; cag pathogenicity island intact - cases 82%, controls 43%, p < .04; iceA1 - cases 53%, controls 6%, p < .005. cagA was found in all subjects. CONCLUSION: This study indicates that, in this African population at least, there is no difference in the prevalence of H. pylori infection when comparing gastric cancer cases with matched controls. However, the findings suggest that gastric cancer may be associated with infection by organisms that are genotypically different from those not associated with disease.

Drug-induced apoptosis in lung cnacer cells is not mediated by the Fas/FasL (CD95/APO1) signaling pathway.

Anticancer drugs exert at least part of their cytotoxic effect by triggering apoptosis. We previously identified chemotherapy-induced apoptosis in lung cancer cells and suggested a role for p53 alternative or complementary pathways in this process. Recently, a role for the Fas/FasL (CD95/Apo1) signaling system in chemotherapy-induced apoptosis was proposed in some cell types. In the present work, the involvement of the Fas/FasL system in drug-induced apoptosis in lung cancer cells was investigated upon exposure to four cytotoxic drugs (cisplatin, gemcitabine, topotecan, and paclitaxel). We assessed the expression of Fas and FasL and the function of the Fas pathway in six lung cancer cell lines (H460, H322, GLC4, GLC4/ADR, H187, and N417). All lung cancer cell lines expressed Fas and FasL at RNA and protein levels, and apoptosis could be induced in four of six cell lines upon exposure to the Fas agonistic monoclonal antibody (mAb) CLB-CD95/15. Nevertheless, after drug exposure, no significant FasL up-regulation was observed, whereas the Fas expression was increased in the wild-type p53 cell line H460, but not in the other lines, proved to be mutant p53 by direct gene sequencing. Moreover, no correlation was observed in lung cancer cell lines between sensitivity to drugs and to a Fas agonistic mAb, and preincubation of cells with either the Fas-antagonistic mAb CLB-CD95/2 or a FasL-neutralizing mAb did not protect from drug-induced apoptosis. Taken together, these observations strongly argue against a role of the Fas/FasL signaling pathway in drug-induced apoptosis in lung cancer cells. Interestingly, caspase-8 activation was observed upon drug exposure, independently from Fas/FasL signaling.

[Toxic megacolon as a complication of Campylobacter jejuni enterocolitis]. / Toxisches Megakolon als Komplikation einer Campylobacter-jejuni-Enterokolitis.

We report the case of a previously healthy 53-year-old white male who developed an extraordinary complication of acute Campylobacter jejuni colitis. Toxic megacolon occurred while the patient was treated with a fluoroquinolone antibiotic and glucocorticoids, which were given for endoscopically suspected Crohn's colitis. During the course of the disease no cause of colitis was found other than C. jejuni. Despite the extreme dilatation, the patient was treated conservatively with parenteral nutrition and repeated decompression colonoscopies and made a full, though slow, and uneventful recovery. Follow-up colonoscopies for up to 4 years showed persistent scarring of the transverse colon, probably due to the extreme dilatation, and mild unspecific inflammation of the terminal ileum without histological evidence of inflammatory bowel disease. A comparison with the 6 previously published cases leads to the following conclusions: in most cases the transverse colon is most severely affected. Treatment with either antimotility agents or systemic glucocorticoids does not seem to promote colonic dilatation. The complication has affected patients of both sexes (4 women, 3 men), in the age range of 21 to 83 years, most of them without an underlying disease. The interval between the start of diarrhea and development of the megacolon ranged widely from 3 to 33 days, as did recovery time (2 days to several months). Three of the 7 patients underwent colectomy for imminent or actual colonic perforation. The delayed recovery of our patient was partly attributed to colonic damage caused by extreme dilatation, leading to ischaemia and subsequent scarring of the mucosa, which persisted. Histologically no Crohn's disease or ulcerative colitis could be found at any stage. A rapid increase in resistance of C. species against fluoroquinolone antibodies has been observed in recent years, due to use of the antibiotics in farming. Our patient's severe illness may partly have resulted from delayed effective antibiotic treatment due to resistance. Antibiotic resistance to common enteropathogens should be considered in the case of unusually prolonged or severe enterocolitis. The level of suspicion for either infection or inflammatory bowel disease should remain high as it may be impossible to distinguish between them on the basis of clinical or endoscopic criteria alone.

Application of an ELISA-elution assay as a screening tool for dissociation of yolk antibody-antigen complexes.

A modified enzyme-linked immunosorbent assay termed ELISA-elution assay was used as a screening tool to compare the efficiency of eluents for the dissociation of hen yolk immunoglobulin IgY bovine IgG complexes. The potential denaturing effects of the eluents were also monitored. Different buffers (pH 2.3-7.5), containing various types and concentrations of salts (NaCl, (NH4)2SO4 and MgCl2) as well as polyols (ethylene glycol (EG) and glycerol) were compared to the commonly reported glycine x HCl (pH 2.8) buffer and to a commercially available eluent, Actisep. Acidic pH buffers, Actisep and MgCl2 (3.5 M with EG or 4 M without EG) all successfully dissociated IgY from immobilized IgG. However, some denaturation was apparent using MgCl, and, to a lesser extent, Actisep. Furthermore, these same eluents demonstrated a diminished ability for liberating IgG from immobilized IgY(IgG). Information on eluent efficacy obtained by the ELISA-elution assays was applied to selectively isolate lower affinity antibodies for immunoaffinity column chromatography.

Extracellular granzymes A and B in humans: detection of native species during CTL responses in vitro and in vivo.

Activated CTLs and NK cells induce apoptosis via multiple mechanisms, including that termed granule exocytosis. The latter pathway consists of vectorial secretion of perforin and a family of granule-associated serine proteases (granzymes) to the target cell. To establish whether granzymes are released extracellularly during cytolytic reactions in vivo, ELISAs that measure the native enzymes were developed and were found to specifically detect granzyme A (GrA) and granzyme B (GrB) at picogram concentrations. Low levels of GrA and GrB were present in plasma of healthy individuals (GrA, 33.5 pg/ml (median); GrB, 11.5 pg/ml (median)), whereas significantly higher levels were present in patients with ongoing CTL response, i.e., patients suffering from infections by EBV or HIV type 1. Markedly elevated levels were also noted in synovial fluid of patients with active rheumatoid arthritis. The measurement of soluble granzymes should be useful to assess clinical disorders associated with activated CTL and NK cells. Furthermore, these results suggest that granzymes mediate biologic effects beyond their described role in apoptotic cell death.