Involvement of Advanced Practice Nurse in the Management of Geriatric Conditions: Examples from Different Countries.

The increasing demand for healthcare services is placing great strain on healthcare systems throughout the world. Although the older population is increasing worldwide, there is a marked deficit in the number of persons trained in geriatrics. It is now recognized that early detection and treatment of geriatric conditions (e.g., frailty, sarcopenia, falls, anorexia of aging, and cognitive decline) will delay or avert the development of disability. At the same time, recent years have seen an increased interest and use of advanced practice nurses (APN). Models of best practices of supervision and collaboration have been promulgated by many organizations. APN's roles and scope of practice have been expanded in many countries and the quality and cost-effectiveness of healthcare systems have improved. Nevertheless, in older people, evidence of advanced practice roles remains scattered, and there is little synthesis of evidence, and therefore it is not easy to visualize the different practice models and their components. The aim of this paper is to explain the need for advanced practice nurses to manage geriatric conditions.

Quetiapine safety in older adults: a systematic literature review.

WHAT IS KNOWN AND OBJECTIVE: Quetiapine is a second-generation antipsychotic that is commonly prescribed for a range of approved and off-label indications in older adults. However, little is known about its safety in this population. The available evidence on quetiapine safety is based on studies on second-generation antipsychotics as a group, often in the general population and for approved indications. There are no systematic reviews on the safety of quetiapine in older adults, and therefore, there is a need for systematically assessing quetiapine safety in this group of patients to establish an appropriate safety profile for this vulnerable population. The aim of this paper was to review and describe adverse drug events associated with quetiapine use in older adults. METHODS: A systematic literature search was performed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Databases searched were CINAHL, PubMed, Medline, PsycInfo and the Cochrane Library. RESULTS AND DISCUSSION: Sixty-nine papers met the inclusion criteria. The majority of the studies (n = 36, 52%) were observational, and 11 (16%) were randomized controlled trials (RCTs). Most of the reported indications (75%) were off-label. The most commonly reported adverse events were somnolence (25-39%), dizziness (15-27%), headache (10-23%), postural hypotension (6-18%) and weight gain (11-30%). From the included RCTs, comparing quetiapine with placebo, quetiapine resulted in significantly greater cognitive impairment, higher rates of falls and injury and increased mortality in patients with parkinsonism, but not in patients with dementia. Compared with risperidone and olanzapine, quetiapine had significantly lower risk of mortality, reduced rate of cerebrovascular events, increased rate of falls and injury and less metabolic disorders compared with olanzapine, but higher metabolic disorders compared with risperidone. WHAT IS NEW AND CONCLUSION: This work provides full characterization of quetiapine safety in older people, which may help healthcare providers better anticipate, prevent and manage ADEs in this population.

Use of a think-aloud procedure to explore the relationship between clinical reasoning and solution-focused training in self-harm for emergency nurses.

Self-harm is a risk factor for further episodes of self-harm and suicide. The most common service used by self-injurers is the emergency department. However, very often, nurses have received no special training to identify and address the needs of these patients. In addition this care context is typically biomedical and without psychosocial skills, nurses can tend to feel unprepared and lacking in confidence, particularly on the issue of self-harm. In a study that aimed to improve understanding and teach solution-focused skills to emergency nurses so that they may be more helpful with patients who self-harm, several outcome measures were considered, including knowledge, professional identity and clinical reasoning. The think-aloud procedure was used as a way of exploring and improving the solution-focused nature of nurses' clinical reasoning in a range of self-harm scenarios. A total of 28 emergency nurses completed the activity. Data were audiotaped, transcribed and analysed. The results indicated that significant improvements were noted in nurses' ability to consider the patients' psychosocial needs following the intervention. Thus this study has shown that interactive education not only improves attitude and confidence but enlarges nurses' reasoning skills to include psychosocial needs. This is likely to improve the quality of care provided to patients with mental health problems who present to emergency settings, reducing stigma for patients and providing the important first steps to enduring change - acknowledgment and respect.

Working effectively with clients who self-injure using a solution focused approach.

In Australia, the most common service used by self-injurers is the emergency department. Even though nurses are the key clinician available to such patients, nurses have usually received no special training to identify and address the needs of these clients. Building on the knowledge that emergency nurses feel ill-prepared, lack clear frameworks for practice and are thus vulnerable to subtle discourse tensions such as managing versus caring, and diagnosing versus understanding, an intervention was conducted and evaluated to enhance understanding and build proactive nursing skills. It was centred on a nursing philosophy known as solution focused nursing (SFN) - a model of care developed by author to orient care away from a deficit model. Deficit models tend to be reactive and centred on presenting problems. SFN is designed to move nurses' perspective towards a proactive, strengths orientation, the aim of which is to assist them to instill hope in the client and motivate him/her to take the next steps needed for change and recovery. Nurses in two Australian emergency departments completed questionnaires before and after participating in SFN training focused on working with complex clients who self-harm. A comparison group of nurses also completed questionnaires. Results indicated some benefits of the intervention; there were improvements in participants' perception that nursing is strengths oriented and in nurses' satisfaction with their skills. Yet, there were no significant improvement in nurses' reports of their professional self-concept. There is merit in: broadening access to the intervention, so that more nurses in other contexts can learn a strengths model of care and apply it to their practice; and extending the research to measure sustained learning outcomes and improvements to practice.

Alternatively folded choriogonadotropin analogs. Implications for hormone folding and biological activity.

Most heterodimeric proteins are stabilized by intersubunit contacts or disulfide bonds. In contrast, human chorionic gonadotropin (hCG) and other glycoprotein hormones are secured by a strand of their beta-subunits that is wrapped around alpha-subunit loop 2 "like a seatbelt." During studies of hCG synthesis in COS-7 cells, we found that, when the seatbelt was prevented from forming the disulfide that normally "latches" it to the beta-subunit, its carboxyl-terminal end can "scan" the surface of the heterodimer and become latched by a disulfide to cysteines substituted for residues in the alpha-subunit. Analogs in which the seatbelt was latched to residues 35, 37, 41-43, and 56 of alpha-subunit loop 2 had similar lutropin activities to those of hCG; that in which it was latched to residue 92 at the carboxyl terminus had 10-20% the activity of hCG. Attachment of the seatbelt to alpha-subunit residues 45-51, 86, 88, 90, and 91 reduced lutropin activity substantially. These findings show that the heterodimer can form before the beta-subunit has folded completely and support the notions that the carboxyl-terminal end of the seatbelt, portions of alpha-subunit loop 2, and the end of the alpha-subunit carboxyl terminus do not participate in lutropin receptor interactions. They suggest also that several different architectures could have been sampled without disrupting hormone activity as the glycoprotein hormones diverged from other cysteine knot proteins.

Partial restoration of lutropin activity by an intersubunit disulfide bond: implications for structure/function studies.

Gonadal function is controlled by lutropins and follitropins, heterodimeric cystine knot proteins that have nearly identical alpha-subunits. These heterodimeric proteins are stabilized by a portion of the hormone-specific beta-subunit termed the "seatbelt" that is wrapped around alpha-subunit loop 2 (alpha 2). Here we show that replacing human chorionic gonadotropin (hCG) alpha 2 residue Lys51 with cysteine or alanine nearly abolished its lutropin activity, an observation that implies that alpha Lys51 has a key role in hormone activity. The activity of the heterodimer containing alpha K51C, but not that containing alpha K51A, was increased substantially when beta-subunit seatbelt residue beta Asp99 was converted to cysteine. As had been reported by others, heterodimers containing alpha K51C and beta D99C were crosslinked by a disulfide. The finding that an intersubunit disulfide restored some of the activity lost by replacing alpha Lys51 suggests that this residue is not crucial for receptor binding or signaling and also that hCG and related hormones may be particularly sensitive to mutations that alter interactions between their subunits. We propose the unique structures of hCG and related family members may permit some subunit movement in the heterodimer, making it difficult to deduce key residues involved in receptor contacts simply by correlating the activities of hormone analogs with their amino acid sequences.

Threading of a glycosylated protein loop through a protein hole: implications for combination of human chorionic gonadotropin subunits.

Chorionic gonadotropin (hCG) is a heterodimeric placental glycoprotein hormone essential for human reproduction. Twenty hCG beta-subunit residues, termed the seatbelt, are wrapped around alpha-subunit loop 2 (alpha 2) and their positions "latched" by a disulfide formed by cysteines at the end of the seatbelt (Cys 110) and in the beta-subunit core (Cys 26). This unique arrangement explains the stability of the heterodimer but raises questions as to how the two subunits combine. The seatbelt is latched in the free beta-subunit. If the seatbelt remained latched during the process of subunit combination, formation of the heterodimer would require alpha 2 and its attached oligosaccharide to be threaded through a small beta-subunit hole. The subunits are known to combine during oxidizing conditions in vitro, and studies described here tested the idea that this requires transient disruption of the latch disulfide, possibly as a consequence of the thioredoxin activity reported in hCG. We observed that alkylating agents did not modify either cysteine in the latch disulfide (Cys 26 or Cys 110) during heterodimer formation in several oxidizing conditions and had minimal influence on these cysteines during combination in the presence of mild reductants (1--3 mM beta-mercaptoethanol). Reducing agents appeared to accelerate subunit combination by disrupting a disulfide (Cys 93--Cys 100) that forms a loop within the seatbelt, thereby increasing the size of the beta-subunit hole. We propose a mechanism for hCG assembly in vitro that depends on movements of alpha 2 and the seatbelt and suggest that the process of glycoprotein hormone subunit combination may be useful for studying the movements of loops during protein folding.

Women's experience of early miscarriage: a phenomenological study.

This paper describes the experience of three women who had experienced early miscarriage within the previous 12 months. Three major themes of loss emerged: the loss of a baby, the loss of the role of motherhood and the loss of the hopes and dreams the women possessed for their baby. These losses were complicated by the women's negative thoughts about the care they received while in hospital, their perceptions of health professional's negative attitudes, the lack of information given to them, and the lack of understanding shown by family and friends about their situation. The authors recommend a number of changes to practice including the need for an increased sensitivity towards women following early miscarriage.

Breastfeeding duration of Thai women.

This quantitative study aimed to determine Thai working women's planned intention to breastfeed and to identify why the mothers chose to breastfeed their infants, how long they initially planned to breastfeed and how long they actually breastfeed. Ninety-nine Thai working mothers who had breastfed within the last 18 months, or who were still breastfeeding their infants and who used the services at three clinics in Ubon Ratchathani Province, Northeast Thailand were asked to participate in the study. The study findings show a strong correlation between the women's planned duration of breastfeeding and between the length of time she actually breastfed. The authors recommend that breastfeeding educational programs include partners and that the work environment provides support facilities to encourage and support the continuation of breastfeeding.

The surface of alpha-subunit loop 1 distant from the subunit interface is exposed in the hCG lutropin receptor complex.

Interactions of the placental glycoprotein hormone human choriogonadotropin (hCG) with lutropin receptors (LHR) are required for maintenance of early pregnancy. Knowledge of how hCG interacts with LHR is useful for understanding the mechanism of receptor function, an issue of considerable debate. A large surface of hCG remains exposed after the hormone binds the LHR and can be readily detected with monoclonal antibodies. Here we show that the surface of hCG alpha-subunit loop 1 furthest from the beta-subunit interface can also be recognized by a monoclonal antibody when hCG is bound to the LHR. This extends the area of hCG known to be exposed in the hormone receptor complex, an observation that further restricts models of hCG-LHR interaction.

Cultural beliefs and breastfeeding duration of Thai working women.

Breastfeeding's crucial role in infant health is universally recognised and yet there are a number of influences on the duration of breastfeeding. This quantitative study undertaken in Thailand explored whether personal beliefs and values influenced Thai working women's duration of breastfeeding. Ninety-nine Thai working mothers were asked to complete a questionnaire to explore the relationship between their cultural beliefs and their breastfeeding practices. Although the majority of the women undertook techniques based on their cultural beliefs, which they believed would encourage breastfeeding practice, the findings demonstrate that the women's cultural beliefs had no significant effect on the duration of their breastfeeding.

Bifunctional hCG analogs adopt different conformations in LH and FSH receptor complexes.

Human reproduction requires specific interactions between follitropin (hFSH) and its receptor (FSHR) and between lutropin (hLH) or choriogonadotropin (hCG) and the lutropin receptor (LHR). Substitution of hFSH residues between hCG beta-subunit cysteines 11-12 creates a bifunctional analog that binds both receptors. To understand the basis of this observation, we used antibody probes to compare the conformations of bifunctional analogs before and after they were complexed with each receptor. Introduction of hFSH residues between cysteines 11-12 changed a distant conformation-sensitive region created by the juxtaposition of the subunit aminotermini. This region, found not to contact either receptor, was altered further when bifunctional ligands bound FSHR. All other surfaces, detected in LHR complexes, were also recognized in FSHR complexes, an indication that bifunctional ligands bind both receptors in similar orientations. These observations suggest that unlike hCG or hFSH, bifunctional gonadotropins can acquire "lutropin" and "follitropin" conformations, a phenomenon accentuated by receptor contacts.

Deglycosylation of a bifunctional lutropin-follitropin agonist reduced its follitropin activity more than its lutropin activity.

OBJECTIVE: To design a drug that blocks the gonadal actions of lutropins and follitropins. DESIGN: Controlled in vitro study. SETTING: Academic laboratory. PATIENT(S): None. INTERVENTION(S): We removed three glycosylation signals from an hCG-hFSH chimera known to have high affinity for LH and FSH receptors, expecting this would create a bifunctional antagonist (dgCFC). To offset the inhibition of subunit combination caused by deglycosylation of alpha-subunit loop 2, we prepared dgCFC as a single-chain fusion protein containing the alpha-subunit downstream of the chimeric beta-subunit. MAIN OUTCOME MEASURE(S): Receptor binding, cyclic adenosine monophosphate accumulation. RESULT(S): dgCFC bound LH or FSH receptors similar to hCG or hFSH. It was a partial agonist and had one tenth the efficacy of hFSH and two thirds the efficacy of hCG. CONCLUSION(S): The surprising high residual lutropin activity of dgCFC indicated that its FSH residues offset the effects of deglycosylation, suggesting this approach to preparing a bifunctional antagonist is unlikely to lead to a useful drug. The increased lutropin efficacy of dgCFC relative to deglycosylated hCG supports the idea that oligosaccharides modulate glycoprotein hormone efficacy through an influence on hormone conformation.

Desensitization and resensitization of lutropin receptors expressed in transfected Y-1 adrenal cells.

Stimulation of gonadal cells by lutropins such as human chorionic gonadotropin (hCG) is often transient and followed by down-regulation and/or desensitization of lutropin receptors (LHR). Here we describe desensitization/resensitization of LHR in Y-1 adrenal cell lines (termed Y-1L) expressing a rat cDNA lacking most 5' and 3' LHR untranslated regions under the control of a metallothionein promoter. Using a simple morphological assay in which stimulated cells are round and unstimulated cells are flat, we identified clones that rounded and remained round and others that became insensitive to lutropin stimulation and reverted to their flat appearance within 2-4 h. Flattened cells were insensitive to further hormonal stimulation but rounded after treatments with cholera toxin, forskolin, or cyclic AMP, showing that loss of responsiveness was associated with an early step in signal transduction, not loss of rounding potential. Removing the lutropin stimulus for at least 90-120 min reversed hormone insensitivity, even in the presence of the protein synthesis inhibitor puromycin. The number of surface bound receptors did not change during a cycle of rounding/flattening and hCG bound to rounded or flattened cells was replaced equally by radioiodinated hCG during incubations at 4 degrees C. Thus, desensitization/resensitization of LHR in Y-1L cells occurred in the absence of new receptor synthesis, receptor degradation, or receptor recycling. These observations suggest that LHR desensitization/resensitization in Y-1L cells was closely coupled to receptor occupancy and that this cell line may be useful for identifying factors that modulate the activities of occupied receptors.

Addition of an N-terminal dimerization domain promotes assembly of hCG analogs: implications for subunit combination and structure-function analysis.

Human chorionic gonadotropin (hCG) is a heterodimeric placental glycoprotein hormone that acts through ovarian lutropin receptors (LHR) to maintain early pregnancy. Its ability to distinguish LHR and follitropin receptors (FSHR) is controlled by 20 beta-subunit 'seatbelt' residues that surround alpha-subunit loop 2. Positively charged amino acids between residues 93-100, a small loop within the seatbelt, have been postulated to make essential LH receptor contacts. Previous studies showed that analogs containing negatively charged amino acids in this small loop had 5-10% the activity of hCG and 1-10% the lutropin activities of hCG/hFSH chimeric analogs capable of binding LHR and FSHR. These effects might be due to the influence of these residues on receptor contacts or on hormone conformation. During efforts to distinguish these possibilities, we increased and decreased the number of residues in this loop, mutations we anticipated would distort its conformation. Consistent with this supposition, these changes inhibited dimer formation, precluding assessment of these mutations on hormone activity. Addition of Fos and Jun dimerization domains to the N-termini of hCGalpha- and hCG/hFSHbeta-subunit chimeras overcame the effects of the seatbelt mutations on subunit combination and enabled preparation of heterodimers containing six, seven, or nine residues in their seatbelt loops. These had 0.1-10% the lutropin and 3-60% the follitropin activities of bifunctional chimeras containing 8 residues derived from hCG in the seatbelt loop. The abilities of N-terminal dimerization domains to promote subunit combination may permit structure/function analysis of other residues that influence heterodimer formation.

Lutropins appear to contact two independent sites in the extracellular domain of their receptors.

Human chorionic gonadotropin (hCG) and bovine lutropin (bLH), a hormone chemically more similar to most mammalian lutropins than hCG, interact with the extracellular domains of their gonadal lutropin receptors (LHRs). These portions of the rat and human LHRs are 85% identical and both receptors bind hCG with high, albeit not identical, affinity. However, at least 1000-fold more bLH is required to inhibit binding of radiolabelled hCG to the human LHR than to the rat LHR, a phenomenon that proved useful for identifying regions of the extracellular domain that contact lutropins. Previous studies using truncated receptors and lutropin/follitropin receptor chimaeras localized most, if not all, high-affinity ligand contacts to the N-terminal three-fifths of the rat LHR extracellular domain. We report here that 10-fold more bLH was needed to inhibit binding of labelled hCG to rat/human LHR chimaeras containing the N-terminal three-fifths of the human LHR extracellular domain than to the rat LHR. Unexpectedly, 100-fold more bLH was required to inhibit binding of labelled hCG to chimaeras containing the C-terminal one-fifth of the human LHR extracellular domain than to the rat LHR. The ability of the C-terminal portion of the human LHR extracellular domain to inhibit bLH binding suggests this region of the receptor also contacts the ligand even though it is not needed for ligand binding. The extracellular domains of all the glycoprotein hormone receptors are thought to be horseshoe-shaped, a consequence of their leucine-rich repeat motifs. Portions of the ligand that become located within the cavity created by the concave surface of the horseshoe would have the opportunity to contact residues in the C-terminal portion of the extracellular domain. Changes to the ligand or receptor that influence this interaction would be expected to alter binding and confound efforts to identify residues in key ligand-receptor contacts.

Epitope-specific focusing of the immune response to a minimized human chorionic gonadotropin analog.

Minimized proteins have long been used to elicit an immune response to particular regions of a protein antigen. Most efforts to derive minimized proteins have employed synthetic peptide fragments. This approach works well for linear epitopes but poorly for conformational epitopes. Here we describe a homodimeric human chorionic gonadotropin (hCG) analog that retains the conformation of related parts of hCG and elicits high affinity specific antibodies. This novel immunogen displays the tertiary structure of selected loops of the protein but lacks structures that could elicit potentially undesirable antibodies.

Functional homodimeric glycoprotein hormones: implications for hormone action and evolution.

BACKGROUND: Human chorionic gonadotropin (hCG), lutropin, follitropin, and thyrotropin act as alpha beta heterodimers to control reproduction and thyroid function. The alpha and beta subunits of these proteins are divided into three loops (alpha 1,alpha 2,alpha 3; beta 1,beta 2,beta 3) by cysteine knots and the heterodimer is stabilized by 20 beta-subunit residues wrapped around alpha 2 like a seatbelt. Understanding how these hormones interact with their receptors, a matter of considerable dispute, would facilitate design of pro- and anti-fertility agents. RESULTS: By swapping alpha 2 for beta 2 and vice versa and, in some cases, adding an amino-terminal coiled-coil dimerization domain, we prepared homodimeric analogs that have the conformation found in each 'half' of hCG. Homodimers containing loops beta 1,alpha 2,beta 3 and none, part, or all of the seatbelt stimulated signal transduction to the same extent as hCG, albeit with lower potency. Those containing alpha 1,beta 2,alpha 3 were inactive. CONCLUSIONS: The activities of homodimers containing the beta 1,alpha 2,beta 3 groove exceed those of other minimized analogs more than 100-1000-fold, suggesting this portion of the hormone forms the major receptor contact. The discovery that glycoprotein hormone heterodimers can be converted to functional homodimers supports the proposal that this protein family evolved from an active homodimeric ancestor by gene duplication and acquisition of mutations to loop 2 that prevent homodimerization. This approach to protein minimization should be applicable to other proteins composed of architecturally related subunits, including those that might have arisen by gene duplication.

The problem of arriving at a phenomenological description of memory loss.

This paper discusses a methodological difficulty that arose when uncovering the conscious experience of being nurtured as an in-patient with depression on a psychiatric ward. It considers the problem of arriving at a phenomenological description of memory loss in a patient who had undergone electroconvulsive therapy (ECT). The paper begins by describing the prevalence of depression and its significance for nurses working in in-patient settings. Examples of empirical research into memory loss in depression are used to show what researchers must set aside if they are to arrive at a phenomenological description of memory loss. The choice of a phenomenological approach to the wider study from which the methodological problem discussed here arose is then justified. The phenomena of memory is introduced to show the methodological significance of attempting to arrive at a phenomenological description of the statement made by one of the participants, a woman being treated as an in-patient for major depression. A possible description of the phenomena of memory loss based on the existential phenomenology of Sartre is offered to call into question the ability of researchers to bracket their assumptions. The significance for nurses of the wider study from which our example is taken is then described. Finally it is argued that despite the methodological difficulty described, a phenomenological perspective based on the philosophy of Husserl can point nurses in the direction of meeting the human needs of their patients.