Indiana University-Purdue University Indianapolis (IUPUI) / The cardiac voltage-gated sodium channel α subunit Nav1.5 generates the cardiac sodium current, which is essential for the initiation and propagation of the cardiac action potentials. Mutations of SCN5A, the gene that encodes Nav1.5, have been well documented to cause long-QT syndrome (LQTs) by disrupting channel inactivation and increasing late sodium current. Previous studies have revealed the importance of the intracellular loop region between transmembrane domain III and IV of sodium channel α subunit in regulating the fast inactivation. A recent clinical case study reported an infant patient with LQTs carrying a phenylalanine (F) deletion at amino acid 1486 of the Nav1.5 channel. This study reported that the patient showed severe cardiac arrhythmia reflected as LQTs and subsequent ventricular tachycardia, which was refractory to antiarrhythmic drug lidocaine treatment. Therefore, it was hypothesized that the deletion of F1486 on Nav1.5 would substantially alter electrophysiological properties of the channel and reduce the potency of lidocaine on sodium channel. Using HEK293 cells and neonatal rat cardiomyocytes, the F1486del channel was functionally characterized by whole-cell patch clamp techniques. Studies revealed that the deletion of F1486 causes a combination of changes including a loss-of-function alteration reflected as a substantial reduction of peak current density and a number of gain-of-function alterations including reduced channel inactivation, substantial augmentation of late sodium current, and an increase in ramp current. In addition, lidocaine sensitivity was dramatically reduced. By contrast, the voltage for half maximal activation (V1/2) and the time constant for channel deactivation for the F1486del channel were identical to the wild type channels. Using neonatal rat cardiomyocytes, we were able to study the functional consequence of F1484del on action potential duration (APD). Cardiomyocytes expressing F1486del channel have substantial APD prolongation and prominent spontaneous early afterdepolarizations, which likely underlie the subsequent LQTs in the patient. Taken together, despite the reduction in peak current density, the substantial gain-of-function changes are sufficient to cause the APD prolongation, which is a prominent characteristic of LQTs. These findings provide knowledge for understanding the relationships between sodium channel structure, pharmacology and the physiological consequence of sodium channel mutations that underlie LQT3.

The purpose of this study was to determine if patients with cancer receiving radiation therapy were satisfied with the nutrition counseling they were receiving and if they obtained any benefit. Radiation increases the risk for side effects such as taste changes, chewing/swallowing problems, constipation, diarrhea, nausea, and vomiting. When these side effects are present, a decrease in food and fluid intake occurs, which leads to weight loss, increased risk of morbidity and mortality, as well as decreased quality of life. Subjects were recruited from a regional cancer treatment facility and a survey was administered to those who met criteria. Subjects were found to manage some of their side effects better after counseling from the registered dietitian. A minimal amount of weight loss was observed. Therefore, registered dietitians, when effectively incorporated into a radiation treatment facility, can provide a nutrition program targeted at reducing weight loss and improving quality of life.

No description available.

Two subjects exhibiting drug-induced hand tremor received EMG feedback from electrode sites above the forearm extensor muscles . EMG feedback resulted in reductions in muscle potentials for both subjects. However, self-report measures of tremor severity showed only general improvement in Subject l and little or no improvement in Subject 2. Behavioral measures of hand steadiness taken immediately after each treatment session showed slight changes across treatment conditions for both subjects. As indicated by a rapid increase in EMG measures during reversal, treatment effects appear transitory.

As people age they are more likely to develop chronic conditions and will tend to be on multiple medications for long periods of time to manage those conditions. Some of these medications have side effects that are anticholinergic in nature. These side effects can impact different parts of the body including the central nervous system. As people enter their later years the permeability of the blood brain barrier increases, increasing their risk of these kinds of side effects.

Bakgrund: Läkemedelsbehandling är den vanligaste medicinska behandlingsformen för äldre personer och det är viktigt att sjuksköterskor har kunskap om den äldres känslighet för läkemedel för att kunna identifiera läkemedelsbiverkningar. Multisjuka sköra äldre och polyfarmaci är en utmaning för den kommunala hälso- och sjukvårdens sjuksköterskor som ska bedöma om dess symtom beror på sjukdom eller biverkningar. Syfte: Att beskriva sjuksköterskor erfarenheter av att identifiera läkemedelsbiverkan hos multisjuka sköra äldre inom kommunal hälso- och sjukvård. Metod: En kvalitativ induktiv ansats användes. Datainsamlingen gjordes genom semistrukturerad intervju och en manifest analys utfördes. Resultat: Ett övergripande tema, kompetens och säkerhet framkom med tre underkategorier, sjuksköterskans kunskap samverkan med andra professioner samt att arbeta säkert med tydliga rutiner. Sjuksköterskans erfarenheter, engagemang och kunskap var viktiga faktorer för att kunna identifiera läkemedelsbiverkningar. Samverkan i team med andra professioner ansågs som viktigt för att kunna arbeta säkert med läkemedel, under förutsättning att samarbetet var välfungerande. Tydliga läkemedelsrutiner saknades, men man hade goda kunskaper om den årliga läkemedelsgenomgången. Slutsats: För att kunna identifiera läkemedelsbiverkningar krävs goda kunskaper och erfarenheter hos sjuksköterskor, men det behövs även ett bra samarbete med andra professioner och läkemedelsrutiner behöver synliggöras för en säkrare läkemedelshantering inom den kommunal hälso- och sjukvården. / Background: Drug treatment is the most common form of medical treatment for older adults and it is important that nurses have knowledge of the older adults’ sensitivity to drugs in order to identify drug side effects. Multimorbid frail older patients and polypharmacy are a challenge for the municipal health care nurses who must assess whether the symptoms are due to illness or side effects. Purpose: To describe nurses’ experiences of identifying drug sides effects in frail multimorbid older adults in municipal health. Method: A qualitative inductive approach was used. Data collection was done through semi-structured interviews and a manifest analysis was performed. Results: An overarching theme, competence and safety emerged with three subcategories, the nurse´s knowledge and collaboration with other professions and working with clear routines. The nurse´s experience, commitment and knowledge were impotent factors in being able to identify drug side effects. Cooperation in teams with other professions was considered impotent to be able to work safely with medicines, but this was something that did not always work. Clear medication routines were missing, but there was good knowledge of the annual medication review. Conclusion: In order to be able to identify drug side effects, good knowledge and experience is required on the part of nurses, but a good collaboration with other professions is also needed and drugs routines need to be made visible for safer drug handling within the municipal healthcare system.

No description available.

Cancer is a generic term for a large group of diseases where cells of the body lose their normal mechanisms for growth so that they grow in an uncontrolled way. One of the most common treatments of cancer is chemotherapy that aims to kill abnormal proliferating cells; however normal cells and other organs of the patients are also adversely affected. In practice, it¿s often difficult to maintain optimum chemotherapy doses that can maximise the abnormal cell killing as well as reducing side effects. The most chemotherapy drugs used in cancer treatment are toxic agents and usually have narrow therapeutic indices, dose levels in which these drugs significantly kill the cancerous cells are close to the levels which sometime cause harmful toxic side effects. To make the chemotherapeutic treatment effective, optimum drug scheduling is required to balance between the beneficial and toxic side effects of the cancer drugs. Conventional clinical methods very often fail to find drug doses that balance between these two due to their inherent conflicting nature. In this investigation, mathematical models for cancer chemotherapy are used to predict the number of tumour cells and control the tumour growth during treatment. A feedback control method is used so as to maintain certain level of drug concentrations at the tumour sites. Multi-objective Genetic Algorithm (MOGA) is then employed to find suitable solutions where drug resistances and drug concentrations are incorporated with cancer cell killing and toxic effects as design objectives. Several constraints and specific goal values were set for different design objectives in the optimisation process and a wide range of acceptable solutions were obtained trading off among different conflicting objectives. Abstract v In order to develop a multi-objective optimal control model, this study used proportional, integral and derivative (PID) and I-PD (modified PID with Integrator used as series) controllers based on Martin¿s growth model for optimum drug concentration to treat cancer. To the best of our knowledge, this is the first PID/I-PD based optimal chemotherapy control model used to investigate the cancer treatment. It has been observed that some solutions can reduce the cancer cells up to nearly 100% with much lower side effects and drug resistance during the whole period of treatment. The proposed strategy has been extended for more drugs and more design constraints and objectives. / Libyan Ministry of Higher Education

Trillions of microbes line the gastrointestinal tract to form the gut microbiome, a symbiotic organ whose supportive functions include energy production, immune homeostasis, and defense against pathogens. Disturbances to gut microbial composition, in turn, drive the pathogenesis of various metabolic, inflammatory, and carcinogenic diseases. Much effort has been dedicated to elucidating environmental triggers of gut dysbiosis, not the least of which is the consumption of medications. Antibiotics eradicate keystone commensals and enhance pathogenic behaviors of persisting pathobionts, whose resistance mechanisms can have off-target effects on human physiology and treatment response. Recent evidence indicates that the spectrum of antimicrobial compounds that disturb the gut microbiome extends far beyond traditional antibiotics, and includes commonly prescribed cardiovascular, neuropsychiatric, metabolic, and cancer medications. Although the capacity of non-antibiotic pharmaceuticals to induce gut dysbiosis is well appreciated, their impact on gut microbial function has not been studied systematically. Bacterial multi-omic profiling offers a cost-effective, high-throughput approach to understanding bacterial genetic responses to chemical perturbations, and how these functional changes might reciprocally impact relevant human phenotypes. Our laboratory, which houses a personal strain biobank of over 30,000 gut bacterial isolates spanning over 400 taxa, has established scalable pipelines for bacterial genomic and transcriptomic profiling that are readily applicable to diverse non-model gut microbes. We applied these methodologies to healthy fecal samples and bacterial isolates to elucidate strain-level responses to common pharmaceuticals with known gut microbiome associations. We first performed a gut microbiota transcriptomic screen of 19 representative fecal isolates against 20 top-prescribed orally delivered medications. Computational analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG) revealed induction of pathways associated with metabolism and multidrug resistance, including upregulation of efflux machinery by lipid-lowering drugs, antidepressants and cardiovascular medications. We discovered many bacterial responses with clinical significance, which we computationally validated using clinical metagenomic datasets. Most importantly, we showed that statin-mediated overexpression of the AcrAB-TolC efflux pump generates collateral toxicity in dietary retinol and secondary bile acids, resulting in depletion of pump-containing Bacteroidales species from patient microbiomes. We next performed the first comprehensive screen for antimicrobial activity in cancer drugs by exposing three healthy fecal samples to a panel of 41 first-line cancer therapeutics. Using 16S-genomic profiling, we identified several members of the targeted kinase inhibitor (TKI) class that induced gut dysbiosis, including first-line hepatocellular carcinoma (HCC) treatment sorafenib. We profiled natural bacterial isolates exposed to different TKI HCC treatments, and again observed transcriptional induction of conserved multidrug efflux pumps. Adaptive evolution assays identified Resistance-Nodulation-Division (RND) efflux pumps as effectors of TKI resistance. Remarkably, we demonstrated that acquired TKI resistance in evolved Bacteroidales lineages generated strain-specific cross-resistances and collateral sensitivities to several unrelated antibiotics. Collectively, our work demonstrates the importance of profiling xenobiotic impacts on the gut microbial resistome, as bacterial adaptations to pharmaceutical toxicities can feed back onto microbiome communities and the human host to affect health outcomes.

According to existing literature, there is a suggested correlation between certain vaccinations and oral cavity symptoms. Studies have shown that the Diphtheria, Tetanus, Acellular Pertusis, as well as Polio Vaccinations have an association with presented symptoms of bleeding gums, sores, ulcers, white spots in the mouth or on lips, and unpleasant breath odor. Although these symptoms may not occur simultaneously or directly after administration of the immunization, there has been supported evidence of correlation. Given the relevance of an association between vaccinations and orally manifested side effects, an investigation on the presence of such association with the widely administered flu vaccine was conducted. Data for this work was collected from a population including undergraduate students studying at the University of Central Florida. A brief voluntary online survey requesting demographic information regarding administration of the vaccine as well as any experienced side effects was used. The study was cohort in nature as it tracked subjects with known exposure to the flu shot in the past six months to understand the outcome of interest. Results from the survey were used to determine that there is no correlation between orally manifested side effects and administration of the flu vaccine.