Are homeopathics able to replace antibiotics in the therapy of bovine mastitis? A placebo controlled randomized double-blind trial

To evaluate the effects of homeopathics on clinical mastitis cows and herd udder health this investigation was conducted in a Brandenburg bio-dyn herd of about 300 cows in two phases using a randomized doubleblind control trial design. After the first part in July 2002 the results preliminarily were evaluated and then the whole concept due to unsatisfying results was adapted. In Phase 1 a number of 121 clinical mastitis cases with 137 affected quarters matched the including criteria, in Phase 2 the number was 126 cows with 148 quarters. These animals were allocated to a code number which classified the case to Verum (n=65 and n=60) or placebo group (n=56 and n=66). In case of clinical mastitis cows were treated either by the oral dilution contending the required combined homeopathics or placebo. Animals were treated twice a day for 5 to 14 days (Phase 2: 1 to 7 days) depending on development of disease. In case of therapy failure in Phase 1 all animals were treated by an not coded homeopathic preparation and in Phase 2 by antibiotics according to bacteriological findings. Milk samples (double samples) for bacteriological and cell count investigation were taken before treatment (M1), 4 to 5 weeks after treatment termination (M2) and 7 to 8 weeks after treatment termination (M3). To evaluate the herd situation additional samples were taken after calving and before dry off. Healing criteria on the cow level was the clinical cure without secondary therapy and release to production. On quarter level the cure was determined by bacterial findings (BCR) and additional by cytological findings. A quarter was determined as „completely cured“, if no bacteria were found AND the cell count was below 100.000/ml. To assess the reduction of antibiotics within the concept it was hypothetically assumed that the mastitis cows had an average milk yield of 20,5 kg per day, was treated under conventional conditions by antibiotics over 3 days with a mean withdrawal time of 5 days (organic conditions x2). Afterwards, these theoretical values were compared to the extrapolated antibiotics input within our concept. Results While there is no difference between the cows in phase 1, on quarter level the verum group showed a significant higher complete cure rate than placebo group in Phase 2. These results are balanced by additional antibiotics treatment in case of therapy failure in the placebo group. The complete cure rate in the verum group after 8 weeks was 32% compared to 13% in placebo group (p<0.05). The limited cure results in single cows did not lead to an udder health depression of the herd. During the study the mean of somatic cell count could decreased by 100.000 cells/ml while the milk yield increased slightly by 250 kg/cow to 6.500 kg/cow/year. The number of actual antibiotic treatments during observation time compared to the number of mastitis cases which would be treated by antibiotics under conventionel conditions showed a reduction by 75%. The extrapolated reduction of milk loss by withdrawal was 25.000kg and the reduction of contaminated milk during treatment time was 13.100 kg per year for the herd. Discussion and Conclusions The increasing cure rates in the second part of the study are influenced by the enhancement of environmental preconditions in combination with the simplified therapy scheme. The therapists seemed to be more familiar with the fixed combinations of homeopathics so that positive effects of the homeopathics can be seen in this phase. After additional antibiotic treatments in case of therapy failure in specific infections (i.e. streptococci and staph. aureus) the cure rates could be elevated to a satisfying level. This fact shows that the limited and controlled use of antibiotics in organic herds can be helpful in the mastitis control. Regardless the conceptual modification to an antibiotic emergency concept, the massive reduction of antibiotics in combination with an increase of herd udder health justifies the therapy protocol in the second phase of the study. Hypothetically, the self cure of the animals is higher than known. The interaction between farmer or therapist and the cow could be a crucial criterion for the positive development of disease. As a conclusion, the integrated system consisting of preventive herd measures and complementary therapy added by limited antibiotic therapy. The precondition for the success is the attendance to optimize environmental conditions. The therapy system should be transparent, simple and easy to use. However, it is necessary to reflect every single mastitis case as a special one

Metaplastic carcinoma of the breast : Prognosis and response to systemic treatment in metastatic disease

Background: Metaplastic breast carcinomas (MpBCs) are rare, aggressive breast cancers. Due to the scant literature of this disease most guidelines do not give recommendation for this entity. The aim of the study was to review the clinicopathologic features, treatment, and outcomes of the patients with MpBC treated at our institution. Material and methods: We searched databases for patients with histologically confirmed MpBC from 2002 to 2016. Results: A total of 78 patients with MpBC were included in the study. All histological material was reviewed by an experienced breast pathologist. Most tumors were grade 3 (83%) and triple negative (85%). Eighty-two percent were node negative. Sixty-four percent received adjuvant chemotherapy. The 5-year disease free survival was 63% and 5-year breast cancer specific overall survival was 61%. Tumor size and mixed metaplastic histology were associated with worse outcome in this patient group. One third of the patients (n = 28) had metastatic disease at initial presentation or developed metastases at follow-up. The lungs were the most common site of first distant recurrence. Half (n = 14) of these patients received palliative chemotherapy. Of those only 6% (n = 2) had partial response and 18% had stable disease as best response to treatment. The median overall survival time with metastatic disease was only 3.4 months. Conclusion: MpBC is an aggressive type of breast cancer with poor outcome despite low nodal involvement and aggressive local and systemic therapy. Tumor response to palliative systemic chemotherapy remains poor for MpBC patients.Peer reviewe

New Empirical Evidence on 'Economic Convergence'

This paper provides a mapping and sample of recently developed risk assessment techniques that are available for the distribution system operator. Three estimates on the value of more detailed risk analysis are desccribed. I.e. component reliability importance indices can be used to divversify the maintenance efforts, gaining better expected system performance at no cost. Furthermore, components that are assumed to be relatively harmless (based on average values) are identified as critical for longer interruptions. Finally it is shown that losses in a transformer are critical in the decision on transformer lifetime.QC 2011070

Conditional versus non-conditional incentives to maximise return of participant completed questionnaires in clinical trials: a cluster randomised study within a trial

Background High participant retention enhances the validity of clinical trials. A monetary incentive can increase retention, but it is not known if when it is provided and if it is conditional matters. We aimed to determine whether there was a difference in the number of follow-up trial questionnaires returned when a monetary (gift voucher) incentive was given to participants at recruitment (non-conditional), compared to informing participants at recruitment that the incentive would be given only once their 14-day daily diary (questionnaire) had been returned (conditional). Method A cluster randomised study within a trial embedded within the Antivirals for influenza-Like Illness, An rCt of Clinical and Cost effectiveness in primary CarE (ALIC4E) Trial. Matched site pairs (GP practices) were randomised using computer-generated random numbers, to either a non-conditional or conditional monetary voucher incentive (only once their 14-day daily diary (questionnaire) had been returned. Sites were matched on previous recruitment levels and practice list size. Analyses were conducted according to randomised groups irrespective of compliance with a two-sided 5% level statistical significance level. The main analysis of the primary outcome (site proportion of diaries returned) was linear regression accounting for site pair (using cluster-robust variance). Additional weighted, paired and non-parametric sensitivity analyses were conducted. Secondary outcomes were the site average number of completed pages, time to return diary, and cost related to the incentive (administration and postage). Results Of the 42 randomised sites (21 for each intervention), only 28 recruited at least one participant with only 10 practice pairs recruiting participants at both constituent sites. Raw diaries return proportions were 0.58 (127/220) and 0.73 (91/125) for non-conditional and conditional incentive groups. Regression analysis adjusted for site pair showed no significant difference in returns, − 0.09, (95% CI, − 0.29, 0.10, p = 0.34); when weighted, there was still no clear difference: 0.15 (95% CI, − 0.02, 0.31, p = 0.07). There was no clear statistical evidence of a difference in time taken to return questionnaires, nor the proportion of pages completed, by the intervention group in the main analyses (all p > 0.05). The conditional incentive was approximately £23 cheaper per diary returned based upon observed data. Conclusion There was no clear evidence of a statistically significant difference in the proportion of participant-completed diaries returned between conditional or non-conditional incentive groups. The time to questionnaire return and completeness of the returned questionnaires were similar in both groups. There was substantial statistical uncertainty in the findings. Some of the sensitivity analyses suggested that a meaningful benefit of a conditional incentive of a magnitude that would be meaningful was plausible. The conditional approach costs less in cash terms

Expression of markers of stem cell characteristics, epithelial-mesenchymal transition, basal-like phenotype, proliferation, and androgen receptor in metaplastic breast cancer and their prognostic impact

Background Metaplastic breast cancer (MpBC) is a heterogeneous subtype of invasive mammary carcinoma associated with epithelial-mesenchymal transition (EMT) and cancer stem cell characteristics. Data regarding prognostic markers and potentially actionable targets for therapy are still limited. The present study aimed to characterize the immunohistochemical landscape of this rare malignancy and to identify potential prognostic factors and targets for therapy. Material and methods A total of 75 patients diagnosed with MpBC over a 15-year period were included in the study. We performed immunohistochemical analyses for Ki-67 (MIB-1), epidermal growth factor receptor (EGFR), cytokeratin 5/6, vimentin, CD44, and androgen receptor (AR) and correlated their expression with clinicopathologic features and clinical outcomes. The p-values for survival analyses were corrected for multiple testing (threshold 0.01). Results Most tumors expressed CK5/6 (73%), EGFR (59%), CD44 (81%), and vimentin (87%). Eighty-nine percent had a high Ki-67 index. Eighty-four percent were classified as basal-like (CK 5/6 or EGFR positive). AR was expressed in 21% of the tumors. The basal-like phenotype was significantly (p = 0.009) associated with inferior disease-free (DFS) and breast-cancer-specific overall survival (BCOS) with borderline significance (p = 0.01). In addition, a low Ki-67 index was associated with improved DFS (p = 0.033) and BCOS (p = 0.03). Conclusion Most MpBCs express basal markers (CK5/6, EGFR), epithelial-mesenchymal transition marker vimentin, and the stem cell marker CD44. Expression of basal-like markers was significantly related to inferior DFS. All the 11 patients with a lack of expression of basal markers survived without relapse.Peer reviewe

Comparing Responsiveness of Six Common Patient-Reported Outcomes to Changes Following Autologous Chondrocyte Implantation: A Systematic Review and Meta-Analysis of Prospective Studies

Objective: To compare the responsiveness of six common patient-reported outcomes (PROs) following autologous chondrocyte implantation (ACI). Design: A systematic search was conducted to identify reports of PROs following ACI. Study quality was evaluated using the modified Coleman Methodology Score (mCMS). For each outcome score, pre- to postoperative paired Hedge\u27s g effect sizes were calculated with 95% confidence intervals (CIs). Random effects meta-analyses were performed to provide a summary response for each PRO at time points (TP) I (\u3c1 year), II (1 year to \u3c2 years), III (2 years to \u3c4 years), IV (\u3e= 4 years), and overall. Results: The mean mCMS for the 42 articles included was 50.9 +/- 9.2. For all evaluated instruments, none of the mean effect size CIs encompassed zero. The International Knee Documentation Committee Subjective Knee Form (IKDC) had increasing responsiveness over time with TP-IV, demonstrating greater mean effect size [confidence interval] (1.78 [1.33, 2.24]) than TP-I (0.88 [0.69, 1.07]). The Knee Injury and Osteoarthritis Outcome Score-Sports and recreation subscale (KOOS-Sports) was more responsive at TP-III (1.76 [0.87, 2.64]) and TP-IV (0.98 [0.81, 1.15]) than TP-I (0.61 [0.44, 0.78]). Overall, the Medical Outcomes Study 36-Item Short Form Health Survey Physical Component Scale (0.60 [0.46, 0.74]) was least responsive. Both the Lysholm Scale (1.42 [1.14, 1.72]) and the IKDC (1.37 [1.13, 1.62]) appear more responsive than the KOOS-Sports (0.90 [0.73, 1.07]). All other KOOS subscales had overall effect sizes ranging from 0.90 (0.74, 1.22) (Symptoms) to 1.15 (0.76, 1.54) (Quality of Life). Conclusions: All instruments were responsive to improvements in function following ACI. The Lysholm and IKDC were the most responsive instruments across time. IKDC and KOOS-Sports may be more responsive to long-term outcomes, especially among active individuals

Fortification and health: challenges and opportunities.

Fortification is the process of adding nutrients or non-nutrient bioactive components to edible products (e.g., food, food constituents, or supplements). Fortification can be used to correct or prevent widespread nutrient intake shortfalls and associated deficiencies, to balance the total nutrient profile of a diet, to restore nutrients lost in processing, or to appeal to consumers looking to supplement their diet. Food fortification could be considered as a public health strategy to enhance nutrient intakes of a population. Over the past century, fortification has been effective at reducing the risk of nutrient deficiency diseases such as beriberi, goiter, pellagra, and rickets. However, the world today is very different from when fortification emerged in the 1920s. Although early fortification programs were designed to eliminate deficiency diseases, current fortification programs are based on low dietary intakes rather than a diagnosable condition. Moving forward, we must be diligent in our approach to achieving effective and responsible fortification practices and policies, including responsible marketing of fortified products. Fortification must be applied prudently, its effects monitored diligently, and the public informed effectively about its benefits through consumer education efforts. Clear lines of authority for establishing fortification guidelines should be developed and should take into account changing population demographics, changes in the food supply, and advances in technology. This article is a summary of a symposium presented at the ASN Scientific Sessions and Annual Meeting at Experimental Biology 2014 on current issues involving fortification focusing primarily on the United States and Canada and recommendations for the development of responsible fortification practices to ensure their safety and effectiveness

Differential Regulation of the Melanoma Proteome by eIF4A1 and eIF4E.

Small molecules and antisense oligonucleotides that inhibit the translation initiation factors eIF4A1 and eIF4E have been explored as broad-based therapeutic agents for cancer treatment, based on the frequent upregulation of these two subunits of the eIF4F cap-binding complex in many cancer cells. Here, we provide support for these therapeutic approaches with mechanistic studies of eIF4F-driven tumor progression in a preclinical model of melanoma. Silencing eIF4A1 or eIF4E decreases melanoma proliferation and invasion. There were common effects on the level of cell-cycle proteins that could explain the antiproliferative effects in vitro Using clinical specimens, we correlate the common cell-cycle targets of eIF4A1 and eIF4E with patient survival. Finally, comparative proteomic and transcriptomic analyses reveal extensive mechanistic divergence in response to eIF4A1 or eIF4E silencing. Current models indicate that eIF4A1 and eIF4E function together through the 5'UTR to increase translation of oncogenes. In contrast, our data demonstrate that the common effects of eIF4A1 and eIF4E on translation are mediated by the coding region and 3'UTR. Moreover, their divergent effects occur through the 5'UTR. Overall, our work shows that it will be important to evaluate subunit-specific inhibitors of eIF4F in different disease contexts to fully understand their anticancer actions. Cancer Res; 77(3); 613-22. ©2016 AACR

Screening of HELQ in breast and ovarian cancer families

Several high and moderate risk alleles have been identified for breast and ovarian cancer predisposition and most of them encode proteins that function in DNA repair. A prospective candidate for breast and ovarian cancer susceptibility is the HELQ helicase that has a role in the resolution of DNA interstrand cross-links. HELQ interacts with the RAD51 paralog complex BCDX2. Two components of the complex, RAD51C and RAD51D, increase the risk of ovarian cancer especially, and the other two, RAD51B and XRCC2 have been associated with breast cancer risk. To investigate the role of HELQ in cancer predisposition, we screened the gene for germline variation in 185 Finnish breast or ovarian cancer families and performed haplotype analyses for 1517 breast cancer cases, 308 ovarian cancer cases, and 1234 population controls using five common polymorphisms at the HELQ gene locus. No truncating mutations were identified among the families. One putatively pathogenic missense mutation c.1309A > G was identified but no additional carriers were observed in the subsequent genotyping of 332 familial breast or ovarian cancer patients. Furthermore, the haplotype distribution did not differ between breast or ovarian cancer cases and population controls. Our results indicate that HELQ is not a major breast and ovarian cancer susceptibility gene in the Finnish population. However, we cannot rule out rare risk-variants in the Finnish or other populations and larger datasets are needed to further assess the role of HELQ especially in ovarian cancer predisposition.Peer reviewe