Pharmacokinetics and pharmacodynamics of ropinirole in patients with prolactinomas.

AIMS: Treatment of prolactinomas with ergoline dopamine agonists can be complicated by intolerance and resistance. This study investigated the pharmacokinetics and pharmacodynamics of the nonergot dopamine agonist ropinirole, to assess its therapeutic potential as a novel therapy for prolactinomas. METHODS: Five female subjects with prolactinomas participated in this dose-response study. Subjects received up to three doses of ropinirole (0.5, 1.0 and 2.0 mg), each on separate occasions. Frequent blood samples for prolactin and ropinirole were collected for 24 h following drug administration. Data were analysed using noncompartmental and compartmental pharmacokinetic-pharmacodynamic (PKPD) techniques. RESULTS: Seven 24-h curves revealed increased systemic drug exposure with increasing ropinirole doses. Ropinirole concentrations peaked at 4.4 ± 2.7 h and exhibited a half-life of 5.8 ± 1.7 h. A dose-dependent prolactin nadir occurred 4.4 ± 1.2 h after drug intake and prolactin concentrations transiently normalized in two of five subjects. PKPD modelling revealed that single-dose PK of ropinirole is dose-independent and can be described with a one-compartment model with linear absorption and elimination. An indirect response model successfully captures the inhibitory effect of ropinirole on prolactin secretion and incorporates time-dependent receptor desensitization for three of five subjects whose prolactin concentrations nadired before ropinirole reached Cmax . CONCLUSIONS: This data-rich study has informed our understanding of the clinical pharmacokinetics and pharmacodynamics of ropinirole, which are successfully captured by the proposed semi-mechanistic PKPD model. This model can be used to further investigate the PKPD of ropinirole and may facilitate the identification of optimal dose regimens for the treatment of prolactinomas and the establishment of a new therapeutic option for patients impacted by this rare disease.

Advancing social research relationships in postnatal support settings.

Global trends in public health nursing (PHN) suggest the value of community-based social research. However, it is not always clear how social research relationships may be of benefit to PHN or how such skills can best be learned and applied. To advance this understanding, we present a qualitative analysis of the development of social research relationships in PHN. Using a background literature review as a foundation, our qualitative mixed method strategy involved a comparative case-study analysis based on the authors' participant observation in two distinct postnatal group settings. Our findings suggest that participant observation facilitates the advancement of social research relationships through practitioner-research management of role conflict. Reflexivity and reciprocity is an emergent relational process, which relies upon a de-professionalization of the traditional PHN role. Conversely, social research relationships help build PHN capacity for family health needs assessment. Thus, we contend that the application of participant observation enables the development of social research relationships, which advance the practice of PHN in postnatal support settings.

Social support within a mother and child group: An ethnographic study situated in the UK.

Social support has been associated with positive outcomes regarding the mothering experience, and professional interventions have therefore been developed in formal settings to promote this. An ethnographic approach was used to consider the subjective experiences of mothers attending a professionally-facilitated group for parents and children aged 0-4 years, focusing on relationships within the group and their importance within existing social networks. Qualitative data were collected from seven participants using interviews and participant observation. These were analyzed by the constant comparison method into codes, categories, and themes. Three themes emerged: past history, being a mother, and function of the group. To ensure mothers and children benefit from such groups, nurses who participate in developing and leading community interventions for mothers and their children need to be aware of the importance of maternal identity and the factors that can impact the relationships between mothers within group settings.

Reversible alopecia associated with high blood mercury levels and early menopause: a report of two cases.

OBJECTIVE: The aim of this study was to report on two women in early menopause with alopecia and high mercury (Hg) levels which reversed with a decrease in toxic levels. METHODS: Retrospective chart review and case studies in a reproductive endocrinology practice. RESULTS: A 43-year-old woman initially evaluated for early menopause later experienced sudden circumscribed hair loss on the scalp. Blood tests indicated elevated Hg levels and further investigation revealed a diet high in tuna. Levels fell with elimination of dietary tuna. Another woman, 39 years old was complaining of severe hot flashes, night sweats, and menstrual irregularity also developed alopecia. Treated unsuccessfully for low testosterone, blood tests indicated high Hg levels and simultaneous hair loss was observed; recommendation to alter diet, including fish intake, was followed by a reversal of alopecia, along with a decrease in blood Hg levels. Literature searches were conducted with a focus on Hg toxicity or poisoning with symptom of alopecia. CONCLUSIONS: Women of reproductive age frequently seek treatment for what is thought to be hormone-related hair loss especially at menopause. Two women demonstrated a strong temporal correlation to high Hg levels associated with early menopause, which was reversible. The development of alopecia in the setting of mild Hg intoxication has not been reported in the medical literature despite its appearance in the popular press. Measurement of Hg levels should be considered in women with alopecia and its relationship to early menopause is unclear but bears further research.

How do parents perceive and utilize knowledge of their infant's mental health? A systematic review.

Infant mental health (IMH) is a growing area of practice for health, education and social care practitioners, as links are increasingly made between experiences in the early years and subsequent child development, mental health and well-being. It is unclear how parents perceive IMH and use knowledge relating to IMH with their children. We conducted a systematic review, the aim of which was to determine parents' perceptions of IMH and how they utilize this knowledge with their infants. We undertook a search of relevant databases and journals and from an initial list of 4147 potential papers, identified 16 for the review. Original data were extracted and presented in a table, and the content of all papers was analysed thematically and presented in narrative form. Three main themes emerged from the available research: knowledge and understanding of child development, influences of society and culture, and interpretation of emotions and expressions. Our results indicate that research is limited in terms of parental perspectives of IMH and how they obtain and use this knowledge. Further research is needed to investigate this topic to maximize mental well-being in infancy and later life.

Plasma Agouti-Related Protein and Cortisol Levels in Cushing Disease: Evidence for the Regulation of Agouti-Related Protein by Glucocorticoids in Humans.

Context: Glucocorticoids regulate energy balance, in part by stimulating the orexigenic neuropeptide agouti-related protein (AgRP). AgRP neurons express glucocorticoid receptors, and glucocorticoids have been shown to stimulate AgRP gene expression in rodents. Objective: We sought to determine whether there is a relationship between plasma AgRP and hypothalamic AgRP in rats and to evaluate the relationship between cortisol and plasma AgRP in humans. Methods: We retrospectively evaluated plasma AgRP levels prior to transsphenoidal surgery in 31 patients with Cushing disease (CD) vs 31 sex- and body mass index-matched controls from a separate study. We then prospectively measured plasma AgRP, before and 6 to 12 months after surgery, in a subgroup of 13 patients with CD. Plasma and hypothalamic AgRP were measured in adrenalectomized rats with and without corticosterone replacement. Results: Plasma AgRP was stimulated by corticosterone in rats and correlated with hypothalamic AgRP expression. Plasma AgRP levels were higher in patients with CD than in controls (139 ± 12.3 vs 54.2 ± 3.1 pg/mL; P < 0.0001). Among patients with CD, mean 24-hour urine free cortisol (UFC) levels were 257 ± 39 µg/24 hours. Strong positive correlations were observed between plasma AgRP and UFC (r = 0.76; P < 0.0001). In 11 of 13 patients demonstrating surgical cure, AgRP decreased from 126 ± 20.6 to 62.5 ± 8.0 pg/mL (P < 0.05) postoperatively, in parallel with a decline in UFC. Conclusions: Plasma AgRP levels are elevated in CD, are tightly correlated with cortisol concentrations, and decline with surgical cure. These data support the regulation of AgRP by glucocorticoids in humans. AgRP's role as a potential biomarker and as a mediator of the adverse metabolic consequences of CD deserves further study.

Modeling the decision to undergo colorectal cancer screening: insights on patient preventive decision making.

BACKGROUND: Little is known about how patients decide whether or not to undergo colorectal cancer screening. Although low screening rates evidence the outcome of these decisions, the processes patients use to balance benefits, risks, and costs with their own values and preferences are unclear. To increase screening rates, and ultimately save lives, it is important for providers to be aware of how patients make screening decisions. OBJECTIVES: The purpose of this study was to identify patterns of patient colorectal cancer screening decisions that might be supported by health care providers. POPULATION: In this study, we focused on people from Central Kentucky--a region with historically low screening rates. METHOD: We interviewed patients using a semi-structured format. Three members of the research team independently analyzed each interview transcript for factors that influenced the decision, and a pictorial representation of each decision process, based on Kurt Lewin's theory of decision making, was constructed for each participant. The individual decision processes were compared with identify patterns. RESULTS: Seventeen women and 13 men made up the sample. We discerned 7 decision patterns. CONCLUSIONS: This research documents 7 patterns and identifies common driving and restraining forces.

Including the online feedback site, Patient Opinion, in the nursing curriculum: Exploratory study.

BACKGROUND: Globally, universities aim to involve people who use health services to enrich the nursing curriculum for students, but there can be barriers to this involvement. Many also want students to contribute to local communities. Online communication can help connect students to service users to achieve these aims. The online British patient feedback site, Patient Opinion, gathers comments from service users about services and encourages service responses to the comments. OBJECTIVES: To explore the feasibility and acceptability of five ways of including Patient Opinion in the undergraduate nursing curriculum. DESIGN: Five case studies using mixed data collection methods. SETTINGS: British University with nursing students across two campuses, accustomed to using webinars, video presentations and social media. PARTICIPANTS: Students from different years participated in the five approaches of making use of Patient Opinion in the curriculum; 18 students took part in an online forum to discuss Patient Opinion in the curriculum. METHODS: We trialled timetabled webinars, video-linked lectures, optional enhanced access for self-study, optional audit of service user comments for two local hospitals, and optional Twitter and Tweetchat. Students discussed the aims and approaches in an online forum. RESULTS: Of the five approaches trialled, webinars seemed effective in ensuring that all nursing students engaged with the topic. Video-linked lectures provided an alternative when timetabling did not allow webinars, but were less interactive. The three optional approaches (Tweetchats, audit exercise, self-directed study) provided opportunities for some students to enhance their learning but students needed guidance. Sending a summary of student reviews of patients' feedback to local hospitals illustrated how students might be agents of change in local health services. CONCLUSIONS: Experience from these case studies suggests that webinars followed by use of Patient Opinion preparing for placements may be a sustainable way of embedding feedback sites in the nursing curriculum.

A Cancer Research UK First Time in Human Phase I Trial of IMA950 (Novel Multipeptide Therapeutic Vaccine) in Patients with Newly Diagnosed Glioblastoma.

PURPOSE: To perform a two-cohort, phase I safety and immunogenicity study of IMA950 in addition to standard chemoradiotherapy and adjuvant temozolomide in patients with newly diagnosed glioblastoma. IMA950 is a novel glioblastoma-specific therapeutic vaccine containing 11 tumor-associated peptides (TUMAP), identified on human leukocyte antigen (HLA) surface receptors in primary human glioblastoma tissue. EXPERIMENTAL DESIGN: Patients were HLA-A*02-positive and had undergone tumor resection. Vaccination comprised 11 intradermal injections with IMA950 plus granulocyte macrophage colony-stimulating factor (GM-CSF) over a 24-week period, beginning 7 to 14 days prior to initiation of chemoradiotherapy (Cohort 1) or 7 days after chemoradiotherapy (Cohort 2). Safety was assessed according to NCI CTCAE Version 4.0 and TUMAP-specific T-cell immune responses determined. Secondary observations included progression-free survival (PFS), pretreatment regulatory T cell (Treg) levels, and the effect of steroids on T-cell responses. RESULTS: Forty-five patients were recruited. Related adverse events included minor injection site reactions, rash, pruritus, fatigue, neutropenia and single cases of allergic reaction, anemia and anaphylaxis. Two patients experienced grade 3 dose-limiting toxicity of fatigue and anaphylaxis. Of 40 evaluable patients, 36 were TUMAP responders and 20 were multi-TUMAP responders, with no important differences between cohorts. No effect of pretreatment Treg levels on IMA950 immunogenicity was observed, and steroids did not affect TUMAP responses. PFS rates were 74% at 6 months and 31% at 9 months. CONCLUSIONS: IMA950 plus GM-CSF was well-tolerated with the primary immunogenicity endpoint of observing multi-TUMAP responses in at least 30% of patients exceeded. Further development of IMA950 is encouraged. Clin Cancer Res; 22(19); 4776-85. ©2016 AACRSee related commentary by Lowenstein and Castro, p. 4760.

CPAP compliance: video education may help!

BACKGROUND: CPAP remains the treatment of choice for Obstructive Sleep Apnea Hypopnea Syndrome (OSAHS), but compliance with CPAP is poor. Of many interventions tried to improve CPAP compliance, only education and humidification have been shown to be of benefit. Our purpose was to develop and pilot test a video to enhance patient understanding of obstructive sleep apnea and of the purpose, logistics, and benefits of CPAP use in patients newly diagnosed with OSAHS. A patient's CPAP compliance in the first few weeks after starting its use is predictive of long-term compliance with CPAP treatment. It is imperative that patients grasp at the outset both the severity of OSAHS and the effectiveness of CPAP therapy. METHODS: An educational video script was written based on recommendations for patient educational video materials and covering identified misconceptions about OSAHS and perceived barriers to CPAP use. The videotape is 15 min in length and features two middle-aged males, one African-American and one Euro-American, discussing OSAHS and CPAP in a factory break room. RESULTS: In a randomized two-group design with a control group, patients with newly diagnosed OSAHS, and who viewed the CPAP educational video on their first clinic, were significantly more likely to use their machine and to return for a 1-month clinic visit than were those in the control group. CONCLUSION: Viewing of a patient education video at the initial visit was found to significantly improve the rate of return for the follow-up visit.

"Do we really need all that equipment?": factors influencing colorectal cancer screening decisions.

The lifetime risk of developing colorectal cancer is 2.5 to 5% in the general population. Colorectal screening can prevent mortality, and there are a number of screening methods, ranging from noninvasive to highly invasive. Although recommendations have been widely disseminated in the media and scientific journals, screening usage is low. In this project, the authors examine the factors that influence individuals' decisions regarding colorectal screening. They conducted semistructured interviews with 30 people (13 men and 17 women) selected to provide a maximum variation sample. They categorized factors into the following themes: concern for one's personal well-being, competing demands, preparing for the procedure, the screening process, gender concerns, fear of having cancer, feeling healthy, cost, the experiences of others, and turning 50 years old.

Unraveling the mysteries of timing: women's perceptions about time to treatment for cardiac symptoms.

Women in the USA are at disproportionate risk of dying from a myocardial infarction (MI), of suffering disabilities following an MI, and of reinfarcting and dying within a year of their initial MI. Various explanations, including women's older age at clinical manifestation of coronary heart disease (CHD) and higher likelihood of co-morbidities, have been offered for women's heightened risk of poor outcomes. Less frequently, research has focused on examining women's prolonged time elapse between symptom onset and biomedical treatment, a phenomenon that renders women less likely to undergo lifesaving reperfusion strategies. [1] To explore factors and circumstances that may shape CHD time to treatment, 40 middle age and older women living in Kentucky, USA, half with diagnosed CHD and half with chronic conditions considered to be risk factors for CHD, participated in a series of in-depth interviews. While much of the existing CHD literature implicates individual responsibility as the determining feature in time to treatment, these women's narratives suggested that treatment decisions inextricably are linked to broader social and structural constraints. Such supra-individual forces that shape the CHD experiences of women include the social construction of "standard" cardiac symptoms based on male norms that ultimately confuse symptom detection, women's negative encounters with health care providers who discount their knowledge, the competing social demands women face when threatened by a serious illness, and structural barriers delimiting women's health care choices.

Phase I clinical and pharmacokinetic evaluation of the vascular-disrupting agent OXi4503 in patients with advanced solid tumors.

PURPOSE: Preclinical studies show that OXi4503 (combretastatin A1 diphosphate, CA1P) is more potent than other clinically evaluated vascular-disrupting agents. EXPERIMENTAL DESIGN: Escalating doses of OXi4503 were given intravenously over 10 minutes on days 1, 8, and 15 every 28 days to patients with advanced solid tumors. RESULTS: Doses were escalated in single-patient cohorts from 0.06 to 1.92 mg/m(2), then expanded cohorts to 15.4 mg/m(2) in 43 patients. Common adverse drug reactions were hypertension, tumor pain, anemia, lymphopenia, and easily controllable nausea/vomiting and fatigue. Five patients experienced different drug-related dose-limiting toxicities, atrial fibrillation, increased troponin, blurred vision, diplopia, and tumor lysis. Prophylactic amlodipine failed to prevent adverse events. Pharmacokinetics showed dose-dependent linear increases in peak plasma concentrations and area under the curve value of OXi4503. One partial response was seen in a heavily pretreated patient with ovarian cancer. Dynamic contrast-enhanced MRI confirmed a dose effect and showed significant antivascular effects in 10 of 13 patients treated at doses of 11 mg/m(2) or higher. CONCLUSIONS: The maximum tolerated dose was 8.5 mg/m(2) but escalation to 14 mg/m(2) was possible with only temporary reversible cerebrovascular toxicity by excluding hypertensive patients. As a tumor response was seen at 14 mg/m(2) and maximum tumor perfusion reductions were seen at doses of 11 mg/m(2) or higher, the recommended phase II dose is from 11 to 14 mg/m(2).

The ribbon of hydrogen bonds in globular proteins. IV. The example of the papain family.

A study of the role of the hydrogen-bonding side chains in the ribbon of hydrogen bonds in globular proteins, using the papain family as an example, suggests that these side chains may be divided into three categories depending on their position in the molecule. In the first category, they form part of the local ribbon, in the second they form part of the ribbon at a site remote along the main chain, and in the third they play no role in the formation of the ribbon. The second case is particularly interesting because it provides a natural mechanism for the formation of the tertiary structure of the globular proteins. The results suggest that the robustness of the globular proteins towards mutations arises from the fact that many mutations that involve hydrogen-bonding side chains either leave the hydrogen bonding of the ribbon essentially unchanged or their hydrogen bonding plays no part in the formation of the ribbon in the first place. The results show that it is possible to obtain the ribbon of hydrogen bonds for a family of proteins whose data set's are of intermediate quality by studying the ribbons of several members of such a family and then taking an average over the different partial ribbons to create a standard ribbon of hydrogen bonds for the family as a whole. This method is used here to derive the standard ribbon for the papain family with papain itself, actinidin, and human liver cathepsin B as the representatives of the family. All three members of the family fit the standard ribbon with an accuracy of 85-91%. This result opens up the use of this technique for the study of a large number of globular proteins whose recorded data sets are of intermediate quality.

The ribbon of hydrogen bonds and the pseudomolecule in the three-dimensional structure of globular proteins. III. Bovine pancreatic ribonuclease A and bovine seminal ribonuclease.

The model of the three-dimensional structure of globular proteins, which is based on a ribbon of hydrogen bonds along the whole of the backbone, is now applied to the comparison between monomeric bovine pancreatic ribonuclease A and dimeric bovine seminal ribonuclease. Some waters are involved in the hydrogen bonding of the ribbon, and the protein molecule plus these waters forms a pseudomolecule. The conformations of the three backbones are essentially identical and the three ribbons of hydrogen bonds are conserved with greater than 90% accuracy. We suggest that the conservation of the backbone conformations of the two molecules is a consequence of the conservation of the ribbons of hydrogen bonds. There are 16 simple mutations between the two molecules, of which 15 involve only side-chain groups with no more than one hydrogen bond to the backbone. Such mutations are not sufficient to change the ribbon of hydrogen bonds and hence there is no change in the backbone conformation. Generalizing this result, we suggest that the conservation of the ribbon is the reason why single point mutations rarely change the conformation of the backbone of the globular proteins.