Incident depression in patients diagnosed with multiple sclerosis: a multi-database study.

BACKGROUND AND PURPOSE: Data on rates of newly diagnosed depression after multiple sclerosis (MS) diagnosis are sparse. Here, incident, treated depression in MS patients after diagnosis compared with matched non-MS patients is described. METHODS: A matched cohort study was conducted in two separate electronic medical databases: the US Department of Defense (US-DOD) military healthcare system and the UK's Clinical Practice Research Datalink GOLD (UK-CPRD). The study population included all patients with a first recorded diagnosis of MS and matched non-MS patients. Patients with a history of treated depression were excluded. Incidence rates and incidence rate ratios with 95% confidence intervals for treated depression after MS diagnosis/matched date were estimated. RESULTS: Incidence rate ratios of treated depression amongst MS patients compared with non-MS patients were 3.20 (95% confidence interval 3.05-3.35) in the US-DOD and 1.90 (95% confidence interval 1.74-2.06) in the UK-CPRD. Incidence rate ratios were elevated across age and sex. Rates were higher in females than males but, compared to non-MS patients, males with MS had a higher relative risk than females with MS. CONCLUSIONS: Multiple sclerosis patients in the UK and the USA have a two- to three-fold increased risk of new, treated depression compared to matched non-MS patients.

Infections in patients diagnosed with multiple sclerosis: A multi-database study.

BACKGROUND: Recent data on the rates of infections among patients with multiple sclerosis (MS) are sparse. The objective of this study was to quantify incidence of infections in patients with MS compared with a matched sample of patients without MS (non-MS). METHODS: This study was conducted in two separate electronic medical databases: the United States Department of Defense (US-DOD) military health care system and the United Kingdom's Clinical Practice Research Datalink GOLD (UK-CPRD). We identified patients with a first recorded diagnosis of MS between 2001 and 2016 (UK-CPRD) or 2004 and 2017 (US-DOD) and matched non-MS patients. We identified infections recorded after the MS diagnosis date (or the matched date in non-MS patients) and calculated incidence rates (IRs) and incidence rate ratios (IRRs) with 95% confidence intervals (CIs) by infection site and type. RESULTS: Relative to non-MS patients, MS patients had higher rates of any infection (US-DOD IRR 1.76; 95% CI 1.72-1.80 and UK-CPRD IRR 1.25; 95% CI 1.21-1.29) and a two-fold higher rate of hospitalized infections (US-DOD IRR 2.43; 95% CI 2.23-2.63 and UK-CPRD IRR 2.00; 95% CI 1.84-2.17). IRs of any infection were higher in females compared with males in both MS and non-MS patients, while IRs of hospitalized infections were similar between sexes in both MS and non-MS patients. The IR of first urinary tract or kidney infection was nearly two-fold higher in MS compared with non-MS patients (US-DOD IRR 1.88; 95% CI 1.81-1.95 and UK-CPRD IRR 1.97; 95% CI 1.86-2.09) with higher rates in females compared with males. IRs for any opportunistic infection, candidiasis and any herpes virus were increased between 20 and 52% among MS patients compared with non-MS patients. IRs of meningitis, tuberculosis, hepatitis B and C were all low. CONCLUSION: MS patients have an increased risk of infection, notably infections of the renal tract, and a two-fold increased risk of hospitalized infections compared with non-MS patients.

Registered Replication Report: Rand, Greene, and Nowak (2012).

In an anonymous 4-person economic game, participants contributed more money to a common project (i.e., cooperated) when required to decide quickly than when forced to delay their decision (Rand, Greene & Nowak, 2012), a pattern consistent with the social heuristics hypothesis proposed by Rand and colleagues. The results of studies using time pressure have been mixed, with some replication attempts observing similar patterns (e.g., Rand et al., 2014) and others observing null effects (e.g., Tinghög et al., 2013; Verkoeijen & Bouwmeester, 2014). This Registered Replication Report (RRR) assessed the size and variability of the effect of time pressure on cooperative decisions by combining 21 separate, preregistered replications of the critical conditions from Study 7 of the original article (Rand et al., 2012). The primary planned analysis used data from all participants who were randomly assigned to conditions and who met the protocol inclusion criteria (an intent-to-treat approach that included the 65.9% of participants in the time-pressure condition and 7.5% in the forced-delay condition who did not adhere to the time constraints), and we observed a difference in contributions of -0.37 percentage points compared with an 8.6 percentage point difference calculated from the original data. Analyzing the data as the original article did, including data only for participants who complied with the time constraints, the RRR observed a 10.37 percentage point difference in contributions compared with a 15.31 percentage point difference in the original study. In combination, the results of the intent-to-treat analysis and the compliant-only analysis are consistent with the presence of selection biases and the absence of a causal effect of time pressure on cooperation.

Nanojunctions of the Sarcoplasmic Reticulum Deliver Site- and Function-Specific Calcium Signaling in Vascular Smooth Muscles.

Vasoactive agents may induce myocyte contraction, dilation, and the switch from a contractile to a migratory-proliferative phenotype(s), which requires changes in gene expression. These processes are directed, in part, by Ca2+ signals, but how different Ca2+ signals are generated to select each function is enigmatic. We have previously proposed that the strategic positioning of Ca2+ pumps and release channels at membrane-membrane junctions of the sarcoplasmic reticulum (SR) demarcates cytoplasmic nanodomains, within which site- and function-specific Ca2+ signals arise. This chapter will describe how nanojunctions of the SR may: (1) define cytoplasmic nanospaces about the plasma membrane, mitochondria, contractile myofilaments, lysosomes, and the nucleus; (2) provide for functional segregation by restricting passive diffusion and by coordinating active ion transfer within a given nanospace via resident Ca2+ pumps and release channels; (3) select for contraction, relaxation, and/or changes in gene expression; and (4) facilitate the switch in myocyte phenotype through junctional reorganization. This should serve to highlight the need for further exploration of cellular nanojunctions and the mechanisms by which they operate, that will undoubtedly open up new therapeutic horizons.

Hypoxia, AMPK activation and uterine artery vasoreactivity.

Genes near adenosine monophosphate-activated protein kinase-α1 (PRKAA1) have been implicated in the greater uterine artery (UtA) blood flow and relative protection from fetal growth restriction seen in altitude-adapted Andean populations. Adenosine monophosphate-activated protein kinase (AMPK) activation vasodilates multiple vessels but whether AMPK is present in UtA or placental tissue and influences UtA vasoreactivity during normal or hypoxic pregnancy remains unknown. We studied isolated UtA and placenta from near-term C57BL/6J mice housed in normoxia (n = 8) or hypoxia (10% oxygen, n = 7-9) from day 14 to day 19, and placentas from non-labouring sea level (n = 3) or 3100 m (n = 3) women. Hypoxia increased AMPK immunostaining in near-term murine UtA and placental tissue. RT-PCR products for AMPK-α1 and -α2 isoforms and liver kinase B1 (LKB1; the upstream kinase activating AMPK) were present in murine and human placenta, and hypoxia increased LKB1 and AMPK-α1 and -α2 expression in the high- compared with low-altitude human placentas. Pharmacological AMPK activation by A769662 caused phenylephrine pre-constricted UtA from normoxic or hypoxic pregnant mice to dilate and this dilatation was partially reversed by the NOS inhibitor l-NAME. Hypoxic pregnancy sufficient to restrict fetal growth markedly augmented the UtA vasodilator effect of AMPK activation in opposition to PE constriction as the result of both NO-dependent and NO-independent mechanisms. We conclude that AMPK is activated during hypoxic pregnancy and that AMPK activation vasodilates the UtA, especially in hypoxic pregnancy. AMPK activation may be playing an adaptive role by limiting cellular energy depletion and helping to maintain utero-placental blood flow in hypoxic pregnancy.

A Cochrane review of the evidence for non-surgical interventions for flexible pediatric flat feet.

The pediatric flat foot is a frequent presentation in clinical practice, a common concern to parents and continues to be debated within professional ranks. As an entity, it is confused by varied classifications, the notion of well-intended prevention and unsubstantiated, if common, treatment. The available prevalence estimates are all limited by variable sampling, assessment measures and age groups and hence result in disparate findings (0.6-77.9%). Consistently, flat foot has been found to normally reduce with age. The normal findings of flat foot versus children's age estimates that approximately 45% of preschool children, and 15% of older children (average age 10 years) have flat feet. Few flexible flat feet have been found to be symptomatic. Joint hypermobility and increased weight or obesity may increase flat foot prevalence, independently of age. Most attempts at classification of flat foot morphology include the arch, heel position and foot flexibility. Usual assessment methods are footprint measures, X-rays and visual (scaled) observations. There is no standardized framework from which to evaluate the pediatric flat foot. The pediatric flat foot is often unnecessarily treated, being ill-defined and of uncertain prognosis. Contemporary management of the pediatric flat foot is directed algorithmically within this review, according to pain, age, flexibility; considering gender, weight, and joint hypermobility. When foot orthoses are indicated, inexpensive generic appliances will usually suffice. Customised foot orthoses should be reserved for children with foot pain and arthritis, for unusual morphology, or unresponsive cases. Surgery is rarely indicated for pediatric flat foot (unless rigid) and only at the failure of thorough conservative management. The assessment of the pediatric flatfoot needs to be considered with reference to the epidemiological findings, where there is consensus that pediatric flexible flat foot reduces with age and that most children are asymptomatic. Globally, there is need for a standard by which the pediatric flat foot is assessed classified and managed. Until then, assessment should utilize the available evidence-based management model, the p-FFP Future research needs to evaluate the pediatric flat foot from representative samples, of healthy and known disease-group children prospectively, and using validated assessment instruments. The preliminary findings of the benefits of foot exercises, and discrete investigation into the effects of shoes and footwear use are also warranted.

Long-chain acylcarnitine deficiency in patients with chronic fatigue syndrome. Potential involvement of altered carnitine palmitoyltransferase-I activity.

OBJECTIVE: The underlying aetiology of chronic fatigue syndrome is currently unknown; however, in the light of carnitine's critical role in mitochondrial energy production, it has been suggested that chronic fatigue syndrome may be associated with altered carnitine homeostasis. This study was conducted to comparatively examine full endogenous carnitine profiles in patients with chronic fatigue syndrome and healthy controls. DESIGN: A cross-sectional, observational study. SETTING AND SUBJECTS: Forty-four patients with chronic fatigue syndrome and 49 age- and gender-matched healthy controls were recruited from the community and studied at the School of Pharmacy & Medical Sciences, University of South Australia. MAIN OUTCOME MEASURES: All participants completed a fatigue severity scale questionnaire and had a single fasting blood sample collected which was analysed for l-carnitine and 35 individual acylcarnitine concentrations in plasma by LC-MS/MS. RESULTS: Patients with chronic fatigue syndrome exhibited significantly altered concentrations of C8:1, C12DC, C14, C16:1, C18, C18:1, C18:2 and C18:1-OH acylcarnitines; of particular note, oleyl-L-carnitine (C18:1) and linoleyl-L-carnitine (C18:2) were, on average, 30-40% lower in patients than controls (P < 0.0001). Significant correlations between acylcarnitine concentrations and clinical symptomology were also demonstrated. CONCLUSIONS: It is proposed that this disturbance in carnitine homeostasis is reflective of a reduction in carnitine palmitoyltransferase-I (CPT-I) activity, possibly a result of the accumulation of omega-6 fatty acids previously observed in this patient population. It is hypothesized that the administration of omega-3 fatty acids in combination with l-carnitine would increase CPT-I activity and improve chronic fatigue syndrome symptomology.

Modulation of O(2) sensitive K (+) channels by AMP-activated protein kinase.

Hypoxic inhibition of K(+) channels in type I cells is believed to be of central importance in carotid body chemotransduction. We have recently suggested that hypoxic channel inhibition is mediated by AMP-activated protein kinase (AMPK). Here, we have further explored the modulation by AMPK of recombinant K(+) channels (expressed in HEK293 cells) whose native counterparts are considered O(2)-sensitive in the rat carotid body. Inhibition of maxiK channels by AMPK activation with AICAR was found to be independent of [Ca(2+)](i) and occurred regardless of whether the alpha subunit was co-expressed with an auxiliary beta subunit. All effects of AICAR were fully reversed by the AMPK inhibitor compound C. MaxiK channels were also inhibited by the novel AMPK activator A-769662 and by intracellular dialysis with the constitutively active, truncated AMPK mutant, T172D. The molecular identity of the O(2)-sensitive leak K(+) conductance in rat type I cells remains unclear, but shares similarities with TASK-1 and TASK-3. Recombinant TASK-1 was insensitive to AICAR. However, TASK-3 was inhibited by either AICAR or A-769662 in a manner which was reversed by compound C. These data highlight a role for AMPK in the modulation of two proposed O(2) sensitive K(+) channels found in the carotid body.

Isosteviol reduces plasma glucose levels in the intravenous glucose tolerance test in Zucker diabetic fatty rats.

AIM: The aim of this study was to test the effect of isosteviol on blood glucose and insulin levels during the intravenous glucose tolerance test (IVGTT) in Wistar and Zucker diabetic fatty (ZDF) rats. METHODS: ZDF rats were divided into a control and three isosteviol treatment (1, 5 and 10 mg/kg) groups. Wistar rats were divided into a control group and an isosteviol treatment group (10 mg/kg). The rats were fasted for 12 h prior to infusion of isosteviol and glucose (1.0 g/kg). Blood samples were taken at 0, 5, 15, 30, 60, 90 and 120 min after the injection of glucose. Glucose concentrations were determined by the glucose oxidase method, and plasma insulin was analysed by radioimmunoassay. The area under the curve (AUC) of the net change in plasma glucose concentration was used to compare the isosteviol treatment and control groups. RESULTS: In ZDF rats, isosteviol at 5 and 10 mg/kg caused a significant (p < 0.05) reduction in the AUC of glucose during the IVGTT. However, isosteviol did not increase plasma insulin concentrations in ZDF rats. In Wistar rats, isosteviol did not significantly affect plasma glucose or insulin levels during the IVGTT. CONCLUSION: Isosteviol exerts an antihyperglycaemic effect during IVGTT in ZDF rats but not in Wistar rats. Isosteviol has no significant effect on plasma insulin concentrations. The glucose-lowering effect of isosteviol may be due to changes in the sensitivity of peripheral tissues to insulin.

Transference in the nurse-patient relationship.

The therapeutic relationship has been considered foundational to psychiatric nursing practice since at least the mid-20th century. However, this does not, in itself, guarantee either its continuity or relevance to current practice. Concepts such as the therapeutic relationship require sustained attention, both in theory and in practice, to illustrate ongoing relevance to the discipline. This paper addresses the therapeutic relationship in psychiatric nursing via aspects of psychoanalytic theory, particularly the notion of transference, as theorized by both Freud and Lacan. Two case fragments provide practice material, through which transference in the nurse-patient relationship is explored. The nurse, in the context of his/her relationship with the patient, a sick stranger, offers both a listening and the potential development of transference. This transference can be experienced, in part, as a form of attachment to the nurse, one that is not regarded pejoratively as dependency. There is the potential, within the nurse-patient relationship, for a psychical holding to develop, one from within which both the patient can speak and transference might arise. It is argued that listening to the patient has the potential to assist the patient and, with the development of transference, can provide the context for important work.

Prediction of drug absorption based on immobilized artificial membrane (IAM) chromatography separation and calculated molecular descriptors.

The aim of this study was to evaluate the usefulness of IAM chromatography in building a model that would allow prediction of drug absorption in humans. The human intestinal absorption values (%HIA) for 52 drugs with low to high intestinal absorption were collected from the literature. The retention (capacity factor, k') of each drug was measured by reverse-phase HPLC using an IAM.PC.DD2 column (prepared with phosphatidylcholine analogs, 12 microM, 300A, 15 cm x 4.6 mm) with an eluent of acetonitrile-0.1M phosphate buffer at pH 5.4. In addition, 76 molecular descriptors and solubility parameters for each drug were calculated using ChemSW from the 3D-molecular structures. Stepwise regression was employed to develop a regression equation that would correlate %HIA with molecular descriptors and k'. Human intestinal absorption was reciprocally correlated to the negative value of the capacity factor (-1/k') (R=0.64). The correlation was further improved with the addition of molecular descriptors representing molecular size and shape (molecular width, length and depth) solubility (solubility parameter, HLB, hydrophilic surface area) and polarity (dipole, polar surface area) (R=0.83). Experimentally measured IAM chromatography retention values and calculated molecular descriptors and solubility parameters can be used to predict intestinal absorption of drugs in humans. Developed QSAR can be used as a screening method in the designing of drugs with appropriate IA and for the selection of drug candidates in the early stage of drug discovery process.

The quantification of paracetamol, paracetamol glucuronide and paracetamol sulphate in plasma and urine using a single high-performance liquid chromatography assay.

A range of analytical methods exist for the determination of paracetamol in biological fluids. However, to understand the fate of paracetamol and the effect of other drugs on its disposition in vivo, the major metabolites require quantification in urine and plasma. A method to simultaneously quantify paracetamol, paracetamol glucuronide (PG) and paracetamol sulphate (PS) in plasma and urine with superior sensitivity is therefore desired, especially if the volume of plasma available is low. A simple isocratic reverse phase high-performance liquid chromatography (HPLC) assay with spectrophotometric detection has been developed. The method, requiring only 100 microl of plasma and 50 microl of urine, utilizes a reversed-phase C18 column, a wavelength of 254 nm for detection and a mobile phase composed of potassium dihydrogen orthophosphate (0.1 M)-isopropanol-tetrahydrofuran (THF) (100:1.5:0.1, v/v/v) adjusted to pH 3.7 with phosphoric acid. The method is sensitive and linear in plasma within a concentration range from 0.4 to 200 microM for paracetamol, PG and PS. For PG and PS in urine, the method is sensitive and linear within a concentration range from 100 to 20,000 microM. Over these ranges, accuracy and precision were less than 12%. The assay has been used to measure concentrations of paracetamol and the two metabolites in plasma collected by finger-prick sampling and of the metabolites in urine from healthy volunteers administered a single oral dose of 1000 mg of paracetamol.

Effect of ketoprofen and its enantiomers on the renal disposition of methotrexate in the isolated perfused rat kidney.

Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to inhibit the renal tubular secretion of methotrexate. However, the relative contribution of the active S- and inactive R-enantiomers is unknown. This study examined the effect of racemic ketoprofen and its enantiomers on the renal disposition of methotrexate in the isolated perfused rat kidney (IPK). Nineteen kidneys were divided between a control and three treatment groups. Controls were perfused with methotrexate alone (25 micrograms mL-1, n = 5) over three 30-min periods. Treatment groups were perfused with methotrexate (25 micrograms m-1) for the first period, followed by a second period of methotrexate (25 micrograms mL-1) plus R- (n = 5), S- (n = 5) or RS-ketoprofen (n = 4) at 25 micrograms mL-1, and a third period of methotrexate (25 micrograms mL-1) plus R-, S- or RS-ketoprofen (50 micrograms mL-1). Perfusate and urine were collected over 10-min intervals. Methotrexate was measured by HPLC and its binding in perfusate by ultrafiltration. The clearance ratio (CR) for methotrexate was obtained by dividing the renal clearance by the product of its fraction unbound and the glomerular filtration rate. During control experiments, there was no significant change in the CR over 90 min. R-, S- and RS-ketoprofen at 50 micrograms mL-1 reduced the CR of methotrexate significantly, but there was no difference between the three groups. While the enantiomers of ketoprofen reduced the renal excretion of methotrexate, the interaction was not enantioselective.

Specific proliferative T cell responses and antibodies elicited by vaccination with simian immunodeficiency virus Nef do not confer protection against virus challenge.

The efficacy of immunizing with a combination of simian immunodeficiency virus (SIV) Nef vaccines was evaluated. Four vaccinates received three intradermal immunizations with recombinant vaccinia virus that expressed SIV Nef, followed by three intramuscular immunizations with rDNA also expressing SIV Nef. Finally, the four vaccinates received two subcutaneous boosts with recombinant SIV Nef protein. This immunization protocol elicited anti-Nef antibodies in all of the vaccinates as well as specific proliferative responses. However, specific cytotoxic T cell responses were not detected before virus challenge. All vaccinates were challenged intravenously with 10 MID(50) of SIVmacJ5 along with four controls. All eight subjects became infected after SIV challenge and there were no group-specific differences in virus load as measured by virus titration and vRNA analysis. The results of this study support indirectly the report from Gallimore and colleagues (Nat Med 1995;1:1667) suggesting that CD8(+) T lymphocyte responses are required for Nef-based vaccines to restrict SIV infection. If Nef-based vaccines are to be beneficial in controlling infection with immunodeficiency viruses, then it will be necessary to develop more effective immunization protocols that elicit potent CD8(+) cell responses reproducibly.

Selection of high-level oxacillin resistance in heteroresistant Staphylococcus aureus by fluoroquinolone exposure.

To study the effect of fluoroquinolone exposure on the expression of mec(A)-encoded oxacillin resistance, population analysis profiling was performed on four strains of fluoroquinolone-susceptible, mec(A)-positive, heteroresistant Staphylococcus aureus. Growth in the presence of 0.5 x MIC of a fluoroquinolone resulted in >10-fold increase in the proportion of the population that grew on agar containing oxacillin 128 mg/L. Ciprofloxacin exhibited a greater effect than moxifloxacin, levofloxacin and gatifloxacin (average 3400-, 220-, 170- and 49-fold increase in oxacillin-resistant colonies versus the control, respectively). The increase was directly proportional to the fluoroquinolone concentration and could be detected as early as 8 h after exposure to the fluoroquinolone. At 8 h, the absolute number of colonies that grew on oxacillin 128 mg/L was similar whether or not the isolate was exposed to the fluoroquinolone, but the total cfu on non-selective media decreased. The resultant oxacillin-resistant colonies also showed a 1.5- to 3-fold increase in fluoroquinolone MIC. No oxacillin resistance was observed on two similarly treated fluoroquinolone-susceptible, mec(A)-negative strains. It appears that fluoroquinolones influence oxacillin resistance by selective inhibition or killing of the more susceptible subpopulations in heteroresistant S. aureus. The surviving populations are more resistant to both oxacillin and fluoroquinolone. The mechanisms of resistance to the two agents may be unrelated but tend to be associated. This could explain in part the observed increases in fluoroquinolone-resistant MRSA.

Cyclic ADP-ribose is the primary trigger for hypoxic pulmonary vasoconstriction in the rat lung in situ.

Hypoxic pulmonary vasoconstriction (HPV) is unique to pulmonary arteries, and it aids ventilation/perfusion matching. However, in diseases such as emphysema, HPV can promote hypoxic pulmonary hypertension. We recently showed that hypoxia constricts pulmonary arteries in part by increasing cyclic ADP-ribose (cADPR) accumulation in the smooth muscle and, thereby, Ca(2+) release by ryanodine receptors. We now report on the role of cADPR in HPV in isolated rat pulmonary arteries and in the rat lung in situ. In isolated pulmonary arteries, the membrane-permeant cADPR antagonist, 8-bromo-cADPR, blocked sustained HPV by blocking Ca(2+) release from smooth muscle ryanodine-sensitive stores in the sarcoplasmic reticulum. Most importantly, we showed that 8-bromo-cADPR blocks HPV induced by alveolar hypoxia in the ventilated rat lung in situ. Inhibition of HPV was achieved without affecting (1) constriction by membrane depolarization and voltage-gated Ca(2+) influx, (2) the release (by hypoxia) of an endothelium-derived vasoconstrictor, or (3) endothelium-dependent vasoconstriction. Our findings suggest that HPV is both triggered and maintained by cADPR in the rat lung in situ.

Hypoxic release of calcium from the sarcoplasmic reticulum of pulmonary artery smooth muscle.

The hypoxic constriction of isolated pulmonary vessels is composed of an initial transient phase (phase 1) followed by a slowly developing increase in tone (phase 2). We investigated the roles of the endothelium and of intracellular Ca2+ stores in both preconstricted and unpreconstricted intrapulmonary rabbit arteries when challenged with hypoxia (PO2 16-21 Torr). Removing the endothelium did not affect phase 1, but phase 2 appeared as a steady plateau. Removing extracellular Ca2+ had essentially the same effect as removing the endothelium. Depletion of sarcoplasmic reticulum Ca2+ stores with caffeine and ryanodine abolished the hypoxic response. Omitting preconstriction reduced the amplitude of the hypoxic response but did not qualitatively affect any of the above responses. We conclude that hypoxia releases intracellular Ca2+ from ryanodine-sensitive stores by a mechanism intrinsic to pulmonary vascular smooth muscle without the need for Ca2+ influx across the plasmalemma or an endothelial factor. Our results also suggest that extracellular Ca2+ is required for the release of an endothelium-derived vasoconstrictor.

Cloning and sequencing of cynomolgus macaque CCR3, GPR15, and STRL33: potential coreceptors for HIV type 1, HIV type 2, and SIV.

The characterization of several seven-transmembrane G protein-coupled receptors, which function as coreceptors for HIV-1, HIV-2, and/or SIV, has opened up a whole new area of AIDS research. Animal models that have played a central role in the understanding of lentivirus pathogenesis and the design of novel vaccine strategies may also be invaluable in studying the role of these secondary receptors in infection and disease progression. However, since it is known that minor species-specific sequence changes in CCR3 and STRL33 affect their ability to act as coreceptors for HIV-1, HIV-2, and/or SIV, it is important to ascertain whether the relevant receptors function as expected in the animal model of choice. Many studies have been performed on the function of rhesus macaque receptors, but not on the cynomolgus macaque equivalents. Both species are used as animal models for lentivirus pathogenesis, but since there are differences in their susceptibility to viral infection, we felt it was important for information to be available for both rhesus and cynomolgus macaque receptors. The sequence of three cynomolgus macaque receptors, CCR3, GPR15, and STRL33, are presented in this sequence note. These sequences are compared with already published human and rhesus macaque homologs. Functional studies are currently being performed on these three cynomolgus macaque receptors to determine their ability to function as coreceptors for HIV-2, SIV, and/or SHIV isolates.

Scope of practice issues in forensic nursing.

1. There is significant role variation, across the Western world, in relation to how forensic nurses practice. 2. The authors conducted a pilot survey of forensic nurses in Australia, New Zealand, the United States, and the United Kingdom to examine forensic nursing practice, role definition, and role boundaries. 3. Issues arising from the data include the visibility of forensic nurses, the client group, forensic-specific education, and role development.