Failure Of Conventional Treatments Research Articles

Efficacy and safety of intracoronary epinephrine versus conventional treatments alone in STEMI patients with refractory coronary no-reflow during primary PCI: The RESTORE observational study.

We aimed to compare intracoronary (IC) epinephrine versus conventional treatments alone in patients with ST-elevation myocardial infarction and refractory coronary no-reflow during primary percutaneous coronary intervention (PPCI). Thirty consecutive patients with severe refractory coronary no-reflow (TIMI 0-1, MBG 0-1) during PPCI were prospectively included after initial failure of conventional treatments. Conventional treatments used in both groups included IC nitrates, thrombectomy. Glycoprotein IIb/IIIa inhibitors and adenosine. Patients received IC epinephrine or no epinephrine. Intracoronary administration of epinephrine yielded significantly better coronary flow patterns (28.6% TIMI 3, 64.3% TIMI 2, 7.1% TIMI 1, and 0% TIMI 0), compared to those after treatment with conventional agents alone (18.8% TIMI 3, 12.5% TIMI 2, 37.5% TIMI 1, and 31.3% TIMI 0) (p value between groups = .004). In the IC epinephrine vs. no epinephrine group there was a significant reduction of 30-day composite of death or heart failure (35.7% vs. 81.25%), improvement of ejection fraction (p = .01) and ST-segment resolution (p = .01). The findings of this proof-of-concept study suggest that as compared to use of conventional agents alone, IC epinephrine provides substantial improvement of coronary flow in STEMI patients with refractory no-reflow during PPCI that may result into improved prognosis.

Evolving nanotechnological trends in the management of mycotic keratitis

The alarming increase in global burden of various corneal diseases in general and mycotic keratitis in particular has raised up a major concern for its treatment. Mycotic keratitis is one of the most serious infections among the various ocular diseases. The proper diagnosis and effective treatment strategies remain a great challenge for ophthalmologists. The inefficacy and failure of conventional treatments have generated need to develop alternative approaches for the treatment of mycotic keratitis. Considering the promising applications of nanotechnology in biomedical area, it is believed that various nanomaterials can be effectively used in the management of mycotic keratitis. This review focuses on worldwide burden of various corneal diseases including mycotic keratitis and the role of nanotechnology in its treatment. In addition, safety and toxicological issues are also discussed.

Recours à la biothérapie dans la prise en charge de la maladie de Behçet dans un service de médecine interne

BackgroundBehçet's disease (BD) is a recurrent multisystemic disease responsible for occlusive vasculitis with arterial, venous and capillary involvement. The aim of this study was to determine the frequency and the features associated with the use of biotherapy in the management of patients followed in our department for BD. MethodsThis is a retrospective study of patients medical records followed for BD in a department of internal medicine from January 2005 to August 2018. ResultsA total of 41 patients were included with a mean age at diagnosis of 42.5±12.1 years (range 16 to 63) and a sex ratio men/women of 1.05. Oral and/or genital aphtosis was present in 70.7% of the patients. Other lesions were: ocular (78.0%), articular (46.3%), cutaneous (41.5%), central neurological (34.1%), vascular (26.8%), digestive (7.3%), pericardial (2.4%) and epididymal (2.4%). A biotherapy, interferon α and monoclonal antibodies, was used in 15 patients (36.6%), after failure of conventional treatments. The monoclonal antibodies were anti-TNFα (infliximab, adalimumab, certolizumab and golimumab) except in one patient for whom ustekinumab was used. Biotherapy was used in 46.9% of the patients with ocular involvement and never used in those patients without ocular involvement (P=0.01). ConclusionBiotherapy is effective and represents a solution to the failures of conventional treatments in severe forms of Behçet's disease with ocular involvement.

Melatonin Enhances Cisplatin and Radiation Cytotoxicity in Head and Neck Squamous Cell Carcinoma by Stimulating Mitochondrial ROS Generation, Apoptosis, and Autophagy.

Head and neck cancer is the sixth leading cancer by incidence worldwide. Unfortunately, drug resistance and relapse are the principal limitations of clinical oncology for many patients, and the failure of conventional treatments is an extremely demoralizing experience. It is therefore crucial to find new therapeutic targets and drugs to enhance the cytotoxic effects of conventional treatments without potentiating or offsetting the adverse effects. Melatonin has oncostatic effects, although the mechanisms involved and doses required remain unclear. The purpose of this study is to determine the precise underlying mitochondrial mechanisms of melatonin, which increase the cytotoxicity of oncological treatments, and also to propose new melatonin treatments in order to alleviate and reverse radio- and chemoresistant processes. We analyzed the effects of melatonin on head and neck squamous cell carcinoma (HNSCC) cell lines (Cal-27 and SCC-9), which were treated with 0.1, 0.5, 1, and 1.5 mM melatonin combined with 8 Gy irradiation or 10 μM cisplatin. Clonogenic and MTT assays, as well as autophagy and apoptosis, involving flow cytometry and western blot, were performed in order to determine the cytotoxic effects of the treatments. Mitochondrial function was evaluated by measuring mitochondrial respiration, mtDNA content (RT-PCR), and mitochondrial mass (NAO). ROS production, antioxidant enzyme activity, and GSH/GSSG levels were analyzed using a fluorometric method. We show that high concentrations of melatonin potentiate the cytotoxic effects of radiotherapy and CDDP in HNSCC, which are associated with increased mitochondrial function in these cells. In HNSCC, melatonin induces intracellular ROS, whose accumulation plays an upstream role in mitochondria-mediated apoptosis and autophagy. Our findings indicate that melatonin, at high concentrations, combined with cisplatin and radiotherapy to improve its effectiveness, is a potential adjuvant agent.

Healing of resistant corneal neurotrophic ulcers using a matrix regenerating agent

To assess the success rate of a matrix regenerating agent (RGTA) in the treatment of chronic corneal ulcers resistant to conventional treatments. Uncontrolled prospective observational study in patients with corneal neurotrophic ulcer (Stage 2 or 3 of the Mackie classification), unresponsive to standard medical or surgical treatments and managed with RGTA as an adjunctive treatment. Corneal ulcers were evaluated using slit-lamp examination and optical coherence tomography after 2 weeks, 1 month, 2 months and 3 months. Success was defined as complete corneal healing. RGTA was administered to 20 patients (20 eyes) with chronic corneal ulcers of various causes, including keratoplasty (7 eyes, 35.0%), herpetic keratitis (5 eyes, 25.0%) and intracorneal ring (3 eyes, 15.0%). Total corneal healing was observed in 13/20 patients (65.0%) within 1 to 3 months. RGTA was discontinued due to partial healing/ulcer stagnation in 6 patients (30.0%), and aggravation of the ulcer in 1 patient (5.0%). Relapses were reported in 4 patients (20.0%) several months after cessation of RGTA treatment. No adverse reactions were noted. In the event of failure of conventional treatments, RGTA may be an alternative medical treatment for patients with chronic corneal ulcers, avoiding the need to resort to surgical treatment.

Early Intervention with a Multi-Ingredient Dietary Supplement Improves Mood and Spatial Memory in a Triple Transgenic Mouse Model of Alzheimer's Disease.

The increasing global burden of Alzheimer's disease (AD) and failure of conventional treatments to stop neurodegeneration necessitates an alternative approach. Evidence of inflammation, mitochondrial dysfunction, and oxidative stress prior to the accumulation of amyloid-β in the prodromal stage of AD (mild cognitive impairment; MCI) suggests that early interventions which counteract these features, such as dietary supplements, may ameliorate the onset of MCI-like behavioral symptoms. We administered a polyphenol-containing multiple ingredient dietary supplement (MDS), or vehicle, to both sexes of triple transgenic (3xTg-AD) mice and wildtype mice for 2 months from 2-4 months of age. We hypothesized that the MDS would preserve spatial learning, which is known to be impaired in untreated 3xTg-AD mice by 4 months of age. Behavioral phenotyping of animals was done at 1-2 and 3-4 months of age using a comprehensive battery of tests. As previously reported in males, both sexes of 3xTg-AD mice exhibited increased anxiety-like behavior at 1-2 months of age, prior to deficits in learning and memory, which did not appear until 3-4 months of age. The MDS did not reduce this anxiety or prevent impairments in novel object recognition (both sexes) or on the water maze probe trial (females only). Strikingly, the MDS specifically prevented 3xTg-AD mice (both sexes) from developing impairments (exhibited by untreated 3xTg-AD controls) in working memory and spatial learning. The MDS also increased sucrose preference, an indicator of hedonic tone. These data show that the MDS can prevent some, but not all, psychopathology in an AD model.

Risk factors for Clostridium difficile infections in Baranya County, Southern Hungary.

In the past decade, Clostridium difficile infections (CDIs) have become a major public health challenge. Their epidemiology has radically changed with a significant rise in the number of cases and an increase in severe episodes. Recurrence and failure of conventional treatments are very common. Furthermore, a spread of CDI has emerged in general population without the usual risk factors (unexposed to antibiotic treatment, young people, etc.). The conventional treatments (metronidazole and vancomycin) are still effective and are the first-line antibiotics with new recommendations. New therapeutic strategies are now available. Recent studies show a better efficacy of vancomycin compared with metronidazole for severe episodes. Fidaxomicin is a novel antibiotic drug with an efficacy similar to vancomycin and a lower risk of recurrence. Finally, for relapsing forms, fecal microbiota transplantation (FMT) seems to be the best option. We determined risk factors for CDI among patients treated at the infectious diseases ward of our hospital in Pécs. The study included 886 patients with CDI from 2009 to 2014. The average number of recurrent episodes was 2.16 and the proportion of severe cases was 66%. Among our patients, 726 (82%) had taken antibiotics and 769 (86.8%) had been hospitalized in the prior 3months before developing CDI. We have found that prior statin use could be a significant risk factor of CDI (OR: 1.7765, 95% CI: 1.3966-2.2597, p < 0.0001). Finally, we present the comparative efficacy of different types of treatment (metronidazole, vancomycin, fidaxomicin, and FMT).

Concise Review: Mesenchymal Stromal/Stem Cells: A New Treatment for Sepsis and Septic Shock?

Sepsis and septic shock are the leading cause of admission and mortality in non-coronary intensive care units. Currently, however, no specific treatments are available for this syndrome. Due to the failure of conventional treatments in recent years, research is focusing on innovative therapeutic agents, including cell therapy. One particular type of cell, mesenchymal stromal/stem cells (MSCs), has raised hopes for the treatment of sepsis. Indeed, their immunomodulatory properties, antimicrobial activity and capacity of protection against organ failure confer MSCs with a major advantage to treat the immune and inflammatory dysfunctions associated with sepsis and septic shock. After a brief description of the pathophysiology of sepsis and septic shock, the latest advances in the use of MSCs to treat sepsis will be presented. Stem Cells 2017;35:2331-2339.

A Review of Demographic, Medical, and Treatment Variables Associated with Health-Related Quality of Life (HRQOL) in Survivors of Hematopoietic Stem Cell (HSCT) and Bone Marrow Transplantation (BMT) during Childhood.

Hematopoietic stem cell transplantation (HSCT) is a standard treatment after disease relapse and failure of conventional treatments for cancer in childhood or as a first line treatment for some high-risk cancers. Since hematopoietic stem cells can be found in the marrow (previously called a bone marrow transplantation) or periphery, we refer to HSCT as inclusive of HSCT regardless of the origin of the stem cells. HSCT is associated with adverse side effects, prolonged hospitalization, and isolation. Previous studies have shown that survivors of HSCT are at particularly high risk for developing late effects and medical complications, and thus, in addition to survival, quality of life in survivors of HSCT is an important outcome. This review summarizes and distills findings on the health-related quality of life (HRQOL) of long-term childhood cancer survivors of HSCT and examines significant sociodemographic, medical, disease and treatment correlates of HRQOL, as well as the methodology of the studies (instruments, type of studies, timing of assessment, type of transplantation). Because previous reviews covered the studies published before 2006, this review searched three databases published between January, 2006, and August, 2016. The search identified nine studies, including 2 prospective cohort studies and 7 cross-sectional studies. All studies reported a follow-up time of >5 years. The review found that HRQOL is significantly impacted over time following childhood HSCT, with salient correlates of HRQOL found to be presence of a severe chronic health or major medical condition, graft vs. host disease (GVHD), or pain. Continual evaluation of HRQOL must be integrated into long-term follow-up after childhood HSCT, and intervention should be offered for those survivors with poor HRQOL. Longitudinal studies should be emphasized in future research to allow for predictor models of resilience and poor HRQOL.

Is There Any Benefit Adding Anticholinergics to Drug Regime of Patients with Benign Prostate Hyperplasia?

Aim: the efficacy and safety of combined therapy with anticholinergics and alpha blockers in comparison with alpha blockers monotherapy among patients with BPH. Methods: We conducted a single blinded RCT and 80 patients with BPH who referred to Ali-ebn-abitaleb, Zahedan were included. One group received 0.4 mg/d Tamsulosin in addition to Tolterodine and the other group received the same doses of Tamsulosin in addition to placebo. Both groups were evaluated before and 6 months after treatment with special attention to clinical symptoms, life quality improvement and treatment satisfaction. SPSS was applied for data analysis. Results: There is no significant difference between these two groups of patientsr demographics and basic indices such as PVR, PSA and the volume of prostate. IPSS was significantly improved among patients who received Toltrodine (p=0.0008) whereas both groups showed same score before treatment. Conclusion: It seems that combined therapy with anticholinergics and alpha blockers is a safe and efficient regimen among patients with BPH, either as primary or alternative treatment after the failure of conventional treatments.

Polymeric Micelles of PEG-PLA Copolymer as a Carrier for Salinomycin Against Gemcitabine-Resistant Pancreatic Cancer.

Resistance to gemcitabine in pancreatic cancer (PC) may account for the failure of conventional treatments. Recently, salinomycin (SAL) has been identified as selective inhibitor of cancer stem cells (CSCs). In our study, we aimed to deliver SAL to gemcitabine-resistant PC by the aid of poly ethylene glycol-b-poly lactic acid (PEG-b-PLA) polymeric micelles (PMs). SAL-loaded PMs were prepared and investigated in terms of pharmaceutical properties. MTT and Annexin V/PI assays were used to study cell proliferation and apoptosis in AsPC-1 cells in response to treatment with SAL micellar formulations. Alterations in CSC phenotype, invasion strength, and mRNA expression of epithelial mesenchymal transition (EMT) markers were also determined in the treated cells. In vivo antitumor study was performed in Balb/c AsPC-1 xenograft mice. PM formulations of SAL were prepared in suitable size and loading traits. In gemcitabine-resistant AsPC-1 cells, SAL was found to significantly increase cell mortality and apoptosis. It was also observed that SAL micellar formulations inhibited invasion and harnessed EMT in spite of induced expression of Snail. The in vivo antitumor experiment showed significant tumor eradication and the highest survival probability in mice treated with SAL PMs. The obtained results showed the efficacy of SAL nano-formulation against PC tumor cells.

Glioblastoma stem cells: radiobiological response to ionising radiations of different qualities.

Glioblastoma multiforme (GBM) is the most common and malignant primary brain tumour, with very poor prognosis. The high recurrence rate and failure of conventional treatments are expected to be related to the presence of radio-resistant cancer stem cells (CSCs) inside the tumour mass. CSCs can both self-renew and differentiate into the heterogeneous lineages of cancer cells. Recent evidence showed a higher effectiveness of C-ions and protons in inactivating CSCs, suggesting a potential advantage of Hadrontherapy compared with conventional radiotherapy for GBM treatment. To investigate the mechanisms involved in the molecular and cellular responses of CSCs to ionising radiations, two GBM stem cell (GSC) lines, named lines 1 and 83, which were derived from patients with different clinical outcomes and having different metabolic profiles (as shown by NMR spectroscopy), were irradiated with (137)Cs photons and with protons or C-ions of 62 MeV u(-1) in the dose range of 5-40 Gy. The biological effects investigated were: cell death, cell cycle progression, and DNA damage induction and repair. Preliminary results show a different response to ionising radiation between the two GSC lines for the different end points investigated. Further experiments are in progress to consolidate the data and to get more insights on the influence of radiation quality.

Whole-Genome Sequence of Clostridium botulinum A2B3 87, a Highly Virulent Strain Involved in a Fatal Case of Foodborne Botulism in Italy.

Here, we report the genome sequence of a rare bivalent strain of Clostridium botulinum, A2B3 87. The strain was isolated from a foodborne botulism case that occurred in Italy in 1995. The case was characterized by rapid evolution of the illness and failure of conventional treatments.

Actualités épidémiologiques et thérapeutiques des infections à Clostridium difficile

During the past 10years, Clostridium difficile infections (CDI) have become a major public health challenge. Their epidemiology has changed with a rise in the number of cases and an increase in severe episodes. Recurrence and failure of conventional treatments have become more common. Furthermore, a spread of CDI has been observed in the general population-involving subjects without the usual risk factors (unexposed to antibiotic treatment, young people, pregnant women, etc.). All these change are partially due to the emergence of the hypervirulent and hyperepidemic clone NAP1/B1/027. New therapeutic strategies (antimicrobial treatment, immunoglobulins, toxin chelation, fecal microbiota transplantation) are now available and conventional treatments (metronidazole and vancomycin) have been reevaluated with new recommendations. Recent studies show a better efficacy of vancomycin compared to metronidazole for severe episodes. Fidaxomicin is a novel antibiotic drug with interesting features, including an efficacy not inferior to vancomycin and a lower risk of recurrence. Finally, for multi-recurrent forms, fecal microbiota transplantation seems to be the best option. We present the available data in this review.

(1) H NMR spectroscopy of glioblastoma stem-like cells identifies alpha-aminoadipate as a marker of tumor aggressiveness.

Patients suffering from glioblastoma multiforme (GBM) face a poor prognosis with median survival of about 14 months. High recurrence rate and failure of conventional treatments are attributed to the presence of GBM cells with stem-like properties (GSCs). Metabolite profiles of 42 GSC lines established from the tumor tissue of adult GBM patients were screened with (1) H NMR spectroscopy and compared with human neural progenitor cells from human adult olfactory bulb (OB-NPCs) and from the developing human brain (HNPCs). A first subset (n=12) of GSCs exhibited a dramatic accumulation of the metabolite α-aminoadipate (αAAD), product of the oxidation of α-aminoadipic semialdehyde catalyzed by the ALDH7A1 aldehyde dehydrogenase (ALDH) family in lysine catabolism. αAAD was low/not detectable in a second GSC subset (n=13) with the same neural metabolic profile as well as in a third GSC subset (n=17) characterized by intense lipid signals. Likewise, αAAD was not detected in the spectra of OB-NPCs or HNPCs. Inhibition of mitochondrial ATP synthase by oligomycin treatment revealed that the lysine degradative pathway leading to αAAD formation proceeds through saccharopine, as usually observed in developing brain. Survival curves indicated that high αAAD levels in GSCs significantly correlated with poor patient survival, similarly to prostate and non-small-cell-lung cancers, where activity of ALDH7A1 correlates with tumor aggressiveness.

A polyphenol-rich cranberry extract protects from diet-induced obesity, insulin resistance and intestinal inflammation in association with increased Akkermansia spp. population in the gut microbiota of mice

ObjectiveThe increasing prevalence of obesity and type 2 diabetes (T2D) demonstrates the failure of conventional treatments to curb these diseases. The gut microbiota has been put forward as a key...

Dietary Assumption of Plant Polyphenols and Prevention of Allergy

Recent evidence has brought to the spotlight plant-derived polyphenols as a promising tool to prevent allergy. The worldwide increase of allergic disease, probably relying on many factors including immune response to stressors and its loss in complexity, environmental pressure by pollutants and chemical allergens, changes in lifestyle and lifespan, failure of conventional treatments to prevent and treat allergy, has strongly suggested people to refer to healthy promising nature-derived compounds, most of which contained in fruits and vegetables, e.g. in daily diet. Phenolic acids and polyphenols, such as flavonoids, are the best studied natural substances known to possess an anti-inflammatory and anti-allergic potential. Used as nutraceuticals, these compounds are thought to dampen the onset of allergic inflammation, by acting on several immune cells, but concerns still remain about their real employment by the organism who assumes polyphenols through diet, because of their bioavailability, gut transformation and pharmacokinetics. Other issues deal with the wide panoply of actions played by these compounds within cells, which has hampered a clear comprehension of their action on cell molecular signaling and function. In this review, special emphasis is placed on the effects of dietary polyphenols on allergy prevention, the possible mechanism of action of polyphenols-containing food and future perspectives for pharmacology design.

Tratamento homeopático de crianças com úlcera de córnea em escudo por ceratoconjuntivite primaveril: relato de casos e aspectos bioéticos

OBJETIVOS: apresentar um tratamento homeo-pático de úlcera de córnea por ceratoconjuntivite primaveril, considerando-o bioeticamente. MÉTODOS: foram usados nove casos, encami-nhados por insucesso terapêutico convencional. Escolheram-se os medicamentos de acordo com características singularizantes dos pacientes que incluíram o psiquismo. Levantaram-se os custos medicamentosos consultando-se três farmácias homeopáticas e três não-homeopáticas de Belo Horizonte. O tratamento convencional foi estimado a partir da medicação usada pelos enfermos antes do início dos cuidados homeopáticos. RESULTADOS: as cicatrizações ocorreram entre quinze e cento e oitenta dias, com custo medicamentoso médio de oito dólares, cerca de treze vezes menor do que a estimativa de custo direto de um mês da abordagem convencional. O manejo terapêutico da similitude pode minimizar preocupações bioéticas relativas à atenção à saúde de crianças com ceratoconjuntivite primaveril. CONCLUSÕES: a homeopatia pode colaborar para o tratamento desta enfermidade, aprimorando-o bioeticamente.

P-562 - Life experiences reported by brazilian women with weight regain after metabolic and bariatric surgery seen in a public service: a qualitative study

Introduction The high prevalence of obesity and the failure of conventional treatments have raised the number of weight loss surgeries worldwide. The problem of weight regain following metabolic and bariatric surgery (MBS) became an important clinical issue that concerns surgeons and other health professionals. Psychological and psychiatric factors are among the causes of weight regain. Objective To understand the emotional meanings of weight regain in women submitted to MBS and propose strategies to manage patients clinically. Method Qualitative study conducted with a purposive sample submitted to semi-directed interviews in-depth in a university general hospital, Sao Paulo, Brazil. Results With weight regain comes the loss of social insertion and self-esteem achieved after weight loss. Even losing some of the benefits derived from surgery, the memory of the positive experience stays with the patient, and they may even desire to repeat the surgical treatment. There is no regret for having been submitted to surgery, but a feeling of gratitude. The choice for the MBS is experienced as good. However, patients feel abandoned by the health team after weight regain, and tend to feel mistreated and not understood when they are criticized or considered as weak by others. Conclusions This clinical situation has a complex psychological constitution: there is gratitude, but a tendency to avoid the environment where the caregivers who have helped are. We suggest action programs to seek for patients with weight regain, aiming at psychosocial work. This search can provide incentive to treat this severe long-term complication of MBS.

Gef gene expression in MCF-7 breast cancer cells is associated with a better prognosis and induction of apoptosis by p53-mediated signaling pathway.

Breast cancer research has developed rapidly in the past few decades, leading to longer survival times for patients and opening up the possibility of developing curative treatments for advanced breast cancer. Our increasing knowledge of the biological pathways associated with the progression and development of breast cancer, alongside the failure of conventional treatments, has prompted us to explore gene therapy as an alternative therapeutic strategy. We previously reported that gef gene from E. coli has shown considerable cytotoxic effects in breast cancer cells. However, its action mechanism has not been elucidated. Indirect immunofluorescence technique using flow cytometry and immunocytochemical analysis were used to detect breast cancer markers: estrogen (ER) and progesterone (PR) hormonal receptors, human epidermal growth factor receptor-2 proto-oncogene (c-erbB-2), ki-67 antigen and p53 protein. gef gene induces an increase in ER and PR expressions and a decrease in ki-67 and c-erbB-2 gene expressions, indicating a better prognosis and response to treatment and a longer disease-free interval and survival. It also increased p53 expression, suggesting that gef-induced apoptosis is regulated by a p53-mediated signaling pathway. These findings support the hypothesis that the gef gene offers a new approach to gene therapy in breast cancer.