Utilization of Complementary Alternative Medicine, Diet, and Exercise Among Women at High Risk for Developing Breast Cancer.

Background: Women diagnosed as having a high risk for breast cancer (HR-BC) often seek different health behaviors (HBs) such as complementary and alternative medicine (CAM), diet, and exercise to improve their health and cancer outcome. Methods: Women already enrolled in a multimodality screening study for patients at HR-BC (gene mutation carrier or >20% cumulative lifetime risk) were given a questionnaire to evaluate their use of CAM therapies, diet, and exercise before and after a diagnosis of HR-BC. Patients were also asked to complete the Short-Form 36, State-Trait Anxiety Inventory, and Beck Depression Inventory. Results: A total of 134 (67%) subjects completed the survey from the original cohort. General characteristics included a median age of 46 years (range = 24-73 years), majority were White (91%), BRCA1/2 gene mutation carrier (49%), and prior diagnosis of breast and/or ovarian cancer (30%). Almost all of the patients reported a lifetime prevalence of any HB (97%) and CAM utilization (91%). Subjects also had a high lifetime utilization of exercise (83%), herbs and supplements(72%), and diet programs (58%). All of these HBs declined in utilization after diagnosis of HR-BC by as much as 30%. After diagnosis of a HR-BC, a personal history of breast and/or ovarian cancer was significantly correlated with increased use of CAM (odds ratio [OR] = 5.9, P < .01), herbs and supplements (OR = 4.3, P < .01), and diet program (OR = 4.4, P < .01) in multivariate analysis. Conclusions: HBs such as CAM, diet, and exercise are highly prevalent among women with HR-BC, and the utilization of HB decreases significantly after diagnosis of HR-BC.

Microbiological Analysis from a Phase 2 Randomized Study in Adults Evaluating Single Oral Doses of Gepotidacin in the Treatment of Uncomplicated Urogenital Gonorrhea Caused by Neisseria gonorrhoeae.

We evaluated microbiological correlates for the successful treatment of Neisseria gonorrhoeae isolates from a phase 2 study of gepotidacin, a novel triazaacenaphthylene antibacterial, for therapy of uncomplicated urogenital gonorrhea. Culture, susceptibility testing, genotypic characterization, and frequency of resistance (FoR) were performed for selected isolates. Microbiological success was defined as culture-confirmed eradication of N. gonorrhoeae Against 69 baseline urogenital isolates, gepotidacin MICs ranged from ≤0.06 to 1 µg/ml (MIC90 = 0.5 µg/ml). For gepotidacin, the ratio of the area under the free-drug concentration-time curve to the MIC (fAUC/MIC) was associated with therapeutic success. Success was 100% (61/61) at fAUC/MICs of ≥48 and decreased to 63% (5/8) for fAUC/MICs of ≤25. All 3 isolates from microbiological failures were ciprofloxacin resistant, had a baseline gepotidacin MIC of 1 µg/ml, and carried a preexisting ParC D86N mutation, a critical residue for gepotidacin binding. In a test-of-cure analysis, the resistance to gepotidacin emerged in 2 isolates (MICs increased ≥32-fold) with additional GyrA A92T mutations, also implicated in gepotidacin binding. Test-of-cure isolates had the same sequence type as the corresponding baseline isolates. For 5 selected baseline isolates, all carrying a ParC D86N mutation, the in vitro FoR to gepotidacin was low (10-9 to 10-10); the resistant mutants had the same A92T mutation as the 2 isolates in which resistance emerged. Five participants with isolates harboring the ParC D86N mutation were treatment successes. In summary, fAUC/MICs of ≥48 predicted 100% microbiological success, including 3 isolates with the ParC D86N mutation (fAUC/MICs ≥ 97). Pharmacokinetic/pharmacodynamic determinations may help to evaluate new therapies for gonorrhea; further study of gepotidacin is warranted. (This study has been registered at ClinicalTrials.gov under identifier NCT02294682.).

Access, delivery and perceived efficacy of physiotherapy and use of complementary and alternative therapies by people with progressive multiple sclerosis in the United Kingdom: An online survey.

INTRODUCTION: All people with progressive MS in the United Kingdom should have access to physiotherapy through the National Health Service (NHS). However levels of access and delivery are unknown. Furthermore there is no research on perceived efficacy of physiotherapy or the use of complementary and alternative medicine in people with progressive MS in the United Kingdom. METHODS: An online survey was carried out via the UK MS Register. Inclusion criteria were diagnosis of progressive MS, a member of UK MS Register and 18 years or older. The survey asked participants regarding access and delivery of physiotherapy; perceived efficacy of physiotherapy and interventions received; barriers to accessing physiotherapy and use of complementary and alternative medicine. The following additional data were supplied from the UK MS Register: demographics, EQ5D, MSIS-29 physical and psychological sub-scales and geographical data. RESULTS: Total number of respondents was 1,298 from an identified 2,538 potential registrants: 87% could access physiotherapy services, 77% received physiotherapy from the NHS and 32% were currently receiving physiotherapy. The most common interventions received were home exercise programme (86%), exercises with a physiotherapist (74%) and advice/education (67%). 40% had recently used complementary and alternative medicine. Perceived efficacy of physiotherapy was high with 70% reporting it to be either 'beneficial' or 'very beneficial'. Main barriers to accessing physiotherapy were mobility, fatigue, continence, transport issues, requiring someone to go with them and pain. DISCUSSION: Access to physiotherapy was high with most people reporting it as beneficial. However 13% reported not having access indicating a gap in accessibility. Considering some of the barriers reported may allow physiotherapy services to address this gap in accessibility.

Functional Electrical Stimulation for Foot Drop in Multiple Sclerosis: A Systematic Review and Meta-Analysis of the Effect on Gait Speed.

OBJECTIVE: To review the efficacy of functional electrical stimulation (FES) used for foot drop in people with multiple sclerosis (pwMS) on gait speed in short and long walking performance tests. DATA SOURCES: Five databases (Cochrane Library, CINAHL, Embase, MEDLINE, and PubMed) and reference lists were searched. STUDY SELECTION: Studies of both observational and experimental design where gait speed data in pwMS could be extracted were included. DATA EXTRACTION: Data were independently extracted and recorded. Methodologic quality was assessed using the Effective Public Health Practice Project tool. DATA SYNTHESIS: Nineteen studies (described in 20 articles) recruiting 490 pwMS were identified and rated as moderate or weak, with none gaining a strong rating. All studies rated weak for blinding. Initial and ongoing orthotic and therapeutic effects were assessed regarding the effect of FES on gait speed in short and long walking tests. Meta-analyses of the short walk tests revealed a significant initial orthotic effect (t=2.14, P=.016), with a mean increase in gait speed of .05m/s, and ongoing orthotic effect (t=2.81, P=.003), with a mean increase of .08m/s. There were no initial or ongoing effects on gait speed in long walk tests and no therapeutic effect on gait speed in either short or long walk tests. CONCLUSIONS: FES used for foot drop has a positive initial and ongoing effect on gait speed in short walking tests. Further fully powered randomized controlled trials comparing FES with alternative treatments are required.

Physiotherapy Rehabilitation for People With Progressive Multiple Sclerosis: A Systematic Review.

OBJECTIVE: To assess the efficacy of physiotherapy interventions, including exercise therapy, for the rehabilitation of people with progressive multiple sclerosis. DATA SOURCES: Five databases (Cochrane Library, Physiotherapy Evidence Database [PEDro], Web of Science Core Collections, MEDLINE, Embase) and reference lists of relevant articles were searched. STUDY SELECTION: Randomized experimental trials, including participants with progressive multiple sclerosis and investigating a physiotherapy intervention or an intervention containing a physiotherapy element, were included. DATA EXTRACTION: Data were independently extracted using a standardized form, and methodologic quality was assessed using the PEDro scale. DATA SYNTHESIS: Thirteen studies (described by 15 articles) were identified and scored between 5 and 9 out of 10 on the PEDro scale. Eight interventions were assessed: exercise therapy, multidisciplinary rehabilitation, functional electrical stimulation, botulinum toxin type A injections and manual stretches, inspiratory muscle training, therapeutic standing, acupuncture, and body weight-supported treadmill training. All studies, apart from 1, produced positive results in at least 1 outcome measure; however, only 1 article used a power calculation to determine the sample size and because of dropouts the results were subsequently underpowered. CONCLUSIONS: This review suggests that physiotherapy may be effective for the rehabilitation of people with progressive multiple sclerosis. However, further appropriately powered studies are required.

Prevalence and correlates of postdiagnosis initiation of complementary and alternative medicine among patients at a comprehensive cancer center.

PURPOSE: Patients with cancer increasingly use complementary and alternative medicine (CAM) in conjunction with conventional oncology treatments. Previous studies have not investigated postdiagnosis initiation of CAM therapies or independent correlates of use of individual CAM modalities. The purpose of this study was to determine the prevalence and correlates of individual CAM modalities initiated after cancer diagnosis. METHODS: A cross-sectional survey was conducted of a random sample of adults with a cancer diagnosis (N = 1,228) seeking care at a National Cancer Institute-designated comprehensive cancer center within a 12-month period. RESULTS: The majority of patients were female (64.7%), white (86.9%), and married (72.8%).Three-quarters (75.2%) used at least one CAM modality, and 57.6% of those using CAM initiated use after cancer diagnosis. For all CAM therapies combined, women were 1.7 times more likely than men to initiate any CAM therapy after cancer diagnosis. However, when CAM modalities were differentiated by type, men and women were equally likely to initiate all therapies except for psychotherapy and mind-body approaches. Postdiagnosis initiation of every CAM modality, except mind-body therapies, differed by cancer type. CONCLUSION: A significant proportion of patients initiated CAM use after diagnosis. However, specific type of CAM initiated varied by demographics and cancer type, suggesting there is not a "typology" of CAM user. Optimal comprehensive cancer treatment, palliation, and survivorship care will require patient and provider education regarding CAM use by modality type; improved provider-patient communication regarding potential benefits, limitations, and risks; and institutional policies to support integrated conventional and CAM treatment.

Characterization of the G alpha(s) regulator cysteine string protein.

Cysteine string protein (CSP) is an abundant regulated secretory vesicle protein that is composed of a string of cysteine residues, a linker domain, and an N-terminal J domain characteristic of the DnaJ/Hsp40 co-chaperone family. We have shown previously that CSP associates with heterotrimeric GTP-binding proteins (G proteins) and promotes G protein inhibition of N-type Ca2+ channels. To elucidate the mechanisms by which CSP modulates G protein signaling, we examined the effects of CSP(1-198) (full-length), CSP(1-112), and CSP(1-82) on the kinetics of guanine nucleotide exchange and GTP hydrolysis. In this report, we demonstrate that CSP selectively interacts with G alpha(s) and increases steady-state GTP hydrolysis. CSP(1-198) modulation of G alpha(s) was dependent on Hsc70 (70-kDa heat shock cognate protein) and SGT (small glutamine-rich tetratricopeptide repeat domain protein), whereas modulation by CSP(1-112) was Hsc70-SGT-independent. CSP(1-112) preferentially associated with the inactive GDP-bound conformation of G alpha(s). Consistent with the stimulation of GTP hydrolysis, CSP(1-112) increased guanine nucleotide exchange of G alpha(s). The interaction of native G alpha(s) and CSP was confirmed by coimmunoprecipitation and showed that G alpha(s) associates with CSP. Furthermore, transient expression of CSP in HEK cells increased cellular cAMP levels in the presence of the beta2 adrenergic agonist isoproterenol. Together, these results demonstrate that CSP modulates G protein function by preferentially targeting the inactive GDP-bound form of G alpha(s) and promoting GDP/GTP exchange. Our results show that the guanine nucleotide exchange activity of full-length CSP is, in turn, regulated by Hsc70-SGT.

Molecular determinants of cysteine string protein modulation of N-type calcium channels.

Cysteine string proteins (CSPs) are secretory vesicle chaperones that are important for neurotransmitter release. We have previously reported an interaction of CSP with both heterotrimeric GTP-binding proteins (G proteins) and N-type calcium channels that results in a tonic G protein inhibition of the channels. In this report we directly demonstrate that two separate regions of CSP associate with G proteins. The N-terminal binding site of CSP, which includes the J domain, binds Galpha subunits but not Galphabeta subunits whereas the C terminal binding site of CSP associates with either free Galphabeta subunits or Galphabeta in complex with Galpha. The interaction of either binding site of CSP (CSP1-82 or CSP83-198) with G proteins elicits robust tonic inhibition of N-type calcium channel activity. However, CSP1-82 inhibition and CSP83-198 inhibition of calcium channels occur through distinct mechanisms. Calcium channel inhibition by CSP83-198 (but not CSP1-82) is completely blocked by co-expression of the synaptic protein interaction site (synprint) of the N-type channel, indicating that CSP83-198 inhibition is dependent on a physical interaction with the calcium channel. These results suggest that distinct binding sites of CSP can play a role in modulating G protein function and G protein inhibition of calcium channels.

A review of the antimicrobial activity of clavulanate.

Clavulanate is a broad-spectrum beta-lactamase inhibitor, with activity against many of the chromosomally and plasmid-mediated beta-lactamases of both Gram-positive and Gram-negative bacteria. Although clavulanate has minimal antibacterial activity in vitro, accumulating evidence suggests that it may have an effect on pathogenic bacteria regardless of beta-lactamase production. Like other beta-lactams, clavulanate has been shown to bind to penicillin-binding proteins (PBPs) in Gram-positive and Gram-negative bacteria. It was found to bind selectively to PBP3 in Streptococcus pneumoniae. It has been suggested that complementary binding to different PBPs and subsequent effects on autolysis contribute to the enhancement of the activity of other beta-lactams by clavulanate. In addition, co-amoxiclav has been shown to enhance the intracellular killing functions of human polymorphonuclear cells (PMNs) in studies undertaken with beta-lactamase-producing and non-beta-lactamase-producing strains of bacteria. These data from in vitro and cell culture systems have been reflected in vivo, where clavulanate enhanced the activity of amoxicillin against non-beta-lactamase-producing organisms. Further studies are required to determine whether the effects seen within in vitro and in vivo animal studies have clinical significance.