In vitro and in vivo properties differ among liquid intravenous immunoglobulin preparations.

OBJECTIVE: To compare in vitro and in vivo biological and biochemical properties of five liquid intravenous immunoglobulin (IVIg) preparations licensed for therapeutic use in Europe. METHODS: ClairYg(®) was compared in a blinded manner to four other liquid IVIg preparations licensed in Europe (Octagam(®) , Kiovig(®) , Gamunex(®) , Privigen(®) ). Three batches of each preparation were tested, except for the IgG repertoires and the animal model. RESULTS: Levels of anti-A and anti-B antibodies were lower in ClairYg(®) (0·11/0·11) relative to a positive EDQM standard and Octagam(®) (0·11/0·08) than in other preparations (0·33-0·69/0·42-0·46). IgG in ClairYg(®) recognized 365 and 416 protein spots in HEp-2 cell and Escherichia coli protein extracts vs. 230-330 and 402-842 protein spots, respectively, for IgG in other preparations. IgA content (301 vs. 165-820 ng/mg of IgG), Factor XI and Factor XII antigen (0·46 vs. 0·85-2·40 mU/mg of IgG and 7·8 vs. 20·0-46·2 lU/mg of IgG) C1q binding (0·42 vs. 0·67-1·89 arbitrary units) and C5a uptake (0·41 vs. 0·45-0·66% of activation) were lower in ClairYg(®) than in other preparations. Finally, intravenous infusion of ClairYg(®) , Gamunex(®) and Privigen(®) had no major effect on arterial blood pressure in spontaneously hypertensive rats. CONCLUSIONS: Our results evidence some differences in the biological and biochemical properties among licensed liquid IVIg preparations.

Mechanisms mediating pituitary adenylate cyclase-activating polypeptide depolarization of rat sympathetic neurons.

The direct effects of pituitary adenylate cyclase-activating polypeptides (PACAP) on sympathetic neurons were investigated using rat superior cervical ganglion neurons. Electrophysiological and pharmacological analyses were used to evaluate PACAP modulation of sympathetic neuron membrane potentials and to investigate potential ionic and intracellular signaling mechanisms mediating the responses. More than 90% of the sympathetic neurons were depolarized by the PACAP peptides even when stimulated release was blocked, indicating that the PACAP peptides elicited primary responses in the postganglionic neurons. The response profile was consistent for activation of PACAP-selective PAC(1) receptors: nanomolar concentrations of PACAP27 and PACAP38 were required to stimulate depolarization, whereas vasoactive intestinal peptide failed to evoke any response. Furthermore, depolarizations elicited by PACAP27 were reduced by the PAC(1) receptor antagonist PACAP(6-38). Both sodium influx and inhibition of a potassium current contributed to the peptide-induced depolarizations. Activation of neither pertussis toxin- nor cholera toxin-sensitive G-proteins was required for generation of the depolarizations. cAMP and diacylglycerol production and activation of protein kinase A or protein kinase C also were not requisite for the responses. By contrast, phospholipase C (PLC)-dependent inositol 1,4,5-triphosphate (IP(3)) synthesis was crucial to the PACAP-mediated depolarizations. Although calcium release from IP(3)-sensitive stores was not required for the PACAP-induced responses, inhibition of IP(3) receptors reduced the depolarizations. Thus, among the many signal transduction pathways coupled to the PAC(1) receptor, the PACAP-induced depolarization of sympathetic neurons appears to require activation of PLC and subsequent generation of IP(3).

Age-associated risks of prophylactic anticoagulation in the setting of hip fracture.

PURPOSE: Controversy exists as to whether patient age, either independently or as a marker of concomitant illness or medication use, is associated with the dose or complication rate of warfarin prophylaxis. The aim of this study was to assess this relationship in patients receiving warfarin prophylaxis after hip fracture repair. PATIENTS AND METHODS: We undertook a retrospective cohort study of 215 patients 55 years of age or greater who underwent surgery for a fractured hip between January 1, 1990, and December 31, 1991, and received warfarin prophylaxis. The mean age was 78.9 (SD 9.5) years. The average daily warfarin dose, the decrease in hemoglobin in the postoperative period, and the rate of bleeding complications were assessed. RESULTS: Elderly patients required a significantly lower average daily warfarin dose than younger patients. This effect persisted even after controlling for the number of medical conditions, number of medications on admission, proportion of time the international normalized ration (INR) was in therapeutic range, and gender. Postoperative hemoglobin decrease was associated with patient age as well as with the use of antibiotics postoperatively. Factors associated with bleeding complications included a history of alcohol abuse and a smaller proportion of time spent in the targeted anticoagulant range. CONCLUSIONS: Older age itself and not as a marker for polypharmacy or increased number of medical conditions is associated with lower requirements for warfarin and a greater hemoglobin decrease postoperatively even when the proportion of time the INR fell within the therapeutic range is controlled. Advanced patient age, in this study, was not associated with an increased incidence of bleeding complications.

Impact of radiation therapy fraction size on local control of early glottic carcinoma.

PURPOSE: Different radiotherapy fractionation schedules were used over a 10-year period to treat patients with early squamous cell carcinoma of the vocal cords at McGill University. A retrospective analysis was performed to study the effect of fraction size on local control in this group of patients. METHODS AND MATERIALS: A total of 126 previously untreated patients with T1 invasive squamous cell carcinoma of the true vocal cords were irradiated between January 1978 and December 1988 in the Department of Radiation Oncology at McGill University. All patients received megavoltage irradiation, 94 patients received daily fractions > 2 Gy (64 patients received 50 Gy with once-daily 2.5-Gy fractions, and 30 received 65.25 Gy in 29 fractions of 2.25 Gy each), and 32 patients were treated to a dose of 66 Gy in 33 fractions with 2 Gy/fraction. Patients' characteristics of prognostic importance were equally distributed between the two fractionation groups. RESULTS: At a median follow-up of 84 months, the 10-year disease-free survival and overall survival were 76% and 93%, respectively. Local control for patients treated with > 2 Gy fraction was 84%, compared to 65.6% for those treated with 2-Gy fractions (p = 0.026). Among the prognostic factors tested, such as gender, age, stage, anterior and posterior commissure involvement, smoking history, and fraction size, the latter was the only significant predictor of local control for the whole group of patients in univariate (p = 0.041) and multivariate (p = 0.023) analysis. There was no observed difference in the incidence of complications between the two fractionation groups. CONCLUSIONS: From the results of this retrospective review of patients treated with radiotherapy for T1 true vocal cord cancer, and within the range of total doses and overall treatment times used in our patients, it was found that fractionation schedules using daily fraction size > 2 Gy are associated with a better local control than schedules delivering 2 Gy/fraction, with no increase in toxicity.

Purification of functional T lymphocytes from splenocytes of the beluga whales (Delphinapterus leucas).

In an effort to gain knowledge on immune functions in beluga whales, Delphinapterus leucas, we have used two physical methods for the purification of T lymphocytes of spleen cells. Isolation by sheep red blood cells (SRBC) rosetting and by adherence on nylon wool columns were tested. SRBC-rosetting gave unreliable results in obtaining purified T cells. Therefore, the purification of T cells was done using nylon wool columns. Less than 3% of the IgM(+) B cells remained in effluent populations. In the later population, 45% gave positive staining with mouse anti-human CD4 allowing us to verify functionality of the cells. The study of calcium mobilization and tyrosine kinase activation, mediated by CD4 cross-linking permitted verification of the functionality of cells. We also showed that upon activation with mitogens, beluga T cells upregulate the density of MHC class II molecules on their surfaces. CD4 cross-linking with a specific antibody inhibited the proliferation response. Overall, the activation of beluga whales lymphocytes did not differ markedly from what is known in other species. This study can help in the groundwork for functional investigation of the beluga whale's immune system.

A two-year follow-up of geriatric consults in the emergency department.

OBJECTIVE: To characterize the population and provide a 2-year follow-up for those patients for whom a geriatric consult was requested in the emergency department (ED) of an acute care hospital. BACKGROUND: Older people tend to use health services, including the ED, disproportionately. This phenomenon has implications for medical services as the number of older people continues to increase. To our knowledge, long-term follow-up of patients for whom ED geriatric consultation was requested has not been described. SETTING: The emergency department of a 628-bed tertiary care university hospital in Montreal, Canada. SUBJECTS: 326 older patients examined in the ED by a geriatric consult team (GCT). METHODS: The records kept by the GCT during a 12-month period were reviewed retrospectively, and the patient cohort was followed for 2 years by telephone or review of hospital charts. Mortality, rate of revisit to ED, readmission to hospital, and final disposition were examined. RESULTS: The study revealed a particularly high hospital admission rate (63.5%) among those older people consulted by the GCT. The high prevalence rates for the classic geriatric syndromes of falls, incontinence, iatrogenic events, and confusional states suggest a need to address these problems early in their presentation, preferably beginning in the ED. A 2-year follow-up exhibited high mortality rates (33.7%) as well as a long-term institutionalization rate of 52%. CONCLUSION: The older patients seen in the ED of the acute care hospital for whom multidisciplinary geriatric consult is requested constitute a high-risk population. Within 2 years after initial consultation, many are dead and more than half have been institutionalized. The results of our follow-up imply the need for multidisciplinary intervention early on in the course of an older patient's ED visit as well as close follow-up after hospital discharge.

Mechanisms of pituitary adenylate cyclase activating polypeptide (PACAP)-induced depolarization of sympathetic superior cervical ganglion (SCG) neurons.

Our understanding of PACAP expression and regulation of sympathetic neuronal function has been augmented considerably over the last few years. Among the three major VIP/PACAP receptor subtypes, the SCG appears to express preferentially one particular variant of the PACAP-selective PACAP1 receptor coupled to multiple intracellular signaling cascades. The in situ histochemical hybridization and immunocytochemical studies of PACAP1 receptor mRNA and protein are in good agreement; nearly all of the SCG neurons express the PACAP-selective receptor, suggesting that most of the sympathetic neurons are under PACAP neuromodulation. In accord with that possibility, several independent studies have now demonstrated PACAP peptide expression in the IML sympathetic preganglionic neurons and fibers, including those projecting to the SCG, further emphasizing the significance of PACAP peptides as a preganglionic noncholinergic mediator of sympathetic function. Given the high potency of PACAP on any of a number of cellular responses, the functional relevance of PACAP peptides on SCG neurons is considerable. We have previously demonstrated the potency and efficacy of both PACAP27 and PACAP38 on sympathetic neuron neurotransmitter/neuropeptide production and secretion; the ability of these peptides to stimulate neuronal second messenger activation was also in the nanomolar range. These results are congruous with our current electrophysiological studies, which were driven to further define the dynamic sympathetic responses to PACAP. In line with the morphological studies, for example, more than 90% of the sympathetic neurons responded to PACAP. In agreement with previous neuropharmacological data, the PACAP-induced depolarizations were elicited at physiologically relevant peptide concentrations at high affinity PACAP-selective receptors. The effects were direct and the alterations in postganglionic neuronal membrane properties appeared to be mediated by several ionic mechanisms. If these studies were analogous to pieces in a puzzle to understand the effects of PACAP in sympathetic development and function, the picture of late has been more completely assembled. But several important challenges still remain. What are the signal transduction mechanisms that mediate the PACAP-induced changes in sympathetic membrane properties? How do the resulting alterations impact the acute and more long-term responses of sympathetic neurons? Does the coupling of PACAP1 receptors to intracellular signaling pathways differ during development, resulting in a transition from the neurotrophic properties of PACAP in neuroblasts to neuromodulatory roles of the peptides in postmitotic neurons? By looking at these issues in one distinct neuronal system, we enlarge our understanding and appreciation of peptides, and PACAP in particular, in the molecular and cellular events guiding neuronal development, function, and plasticity.

The impact of ibuprofen on the efficacy of antihypertensive treatment with hydrochlorothiazide in elderly persons.

BACKGROUND: Nonsteroidal antiinflammatory drugs (NSAIDs) may alter blood pressure through their inhibitory effects on prostaglandin biosynthesis. Such potential hypertensive effects of NSAIDs have not been adequately examined in the elderly, who are the largest group of NSAID users. METHODS: We performed a randomized, double-blind, two-period crossover trial of ibuprofen (1800 mg per day) vs placebo treatment in patients older than 60 years of age with hypertension controlled with hydrochlorothiazide. While continuing their usual thiazide dosage, subjects were randomized to a 4-week treatment period (ibuprofen or placebo) followed by a 2-week placebo wash-out period and a second 4-week treatment period with the alternative therapy. Supine and standing systolic and diastolic blood pressures were measured weekly. RESULTS: Of 25 randomized subjects, 22 completed the study protocol (mean age = 73 +/- 6.7 years). Supine systolic blood pressure and standing systolic blood pressure were increased significantly with ibuprofen treatment, compared with placebo. Mean supine systolic blood pressures were 143.8 +/- 21.0 and 139.6 +/- 15.9 mmHg on ibuprofen and placebo, respectively (p = .004). Mean standing systolic blood pressures were 148.1 +/- 19.9 and 143.4 +/- 17.9 mmHg on ibuprofen and placebo, respectively (p = .002). CONCLUSION: We conclude that 1800 mg per day of ibuprofen does induce a significant increase in systolic blood pressure in older hypertensive patients treated with hydrochlorothiazide. NSAID therapy may negatively impact the control of hypertension in elderly patients.

Emergency department use and misuse.

We conducted a 14-day survey of the emergency department (ED) at a university tertiary care teaching hospital to examine appropriate and inappropriate use of the ED. The results are based on a convenience sample of 849 patients, selected to represent a 1-week period. Three categories (CAT) of patients were defined. CAT I: patients had a medical condition that could only be assessed in the ED. CAT II: patients had a medical condition that required evaluation either in the ED or elsewhere within 6 hours of triage. CAT III: patients could wait to be evaluated 6 or more hours from time of triage. Patients in CAT II were matched with outpatient facilities (OPF), based on the time of presentation, the presenting complaint, investigative tests, and treatments required. Overall, it was found that 69% of the patients were appropriate users and could have been seen only in the ED. Fifteen percent of the patients were classified as inappropriate users and should have been seen at an OPF. The remaining 15.8% represented "gray zone" cases. An interview conducted on a subset of ambulatory patients revealed the main reasons for choosing to visit the ED were lack of awareness of other facilities, perceived seriousness of condition, trust in the ED staff, or proximity of the ED. It was concluded that misusers represent a small portion of our ED caseload.

Depression.

According to the 1994-95 National Population Health Survey, close to 6% of Canadians aged 18 and over had experienced a major depressive episode in the previous 12 months. Univariate analysis shows that the prevalence of depression was higher among women than among men, but tended to decline at older ages both sexes. The prevalence of depression was also related to a number of socioeconomic characteristics such as marital status, education, and household income, and to several measures of stress, psychological resources and social support. However, multivariate analysis shows that not all of these variables were significantly associated with the odds of experiencing depression. In some instances, factors that increased the risk differed for men and women. For both sexes, chronic strain, recent negative events, lack of closeness, and low self-esteem increased the odds of depression. Traumatic events in childhood or young adulthood and a low sense of mastery were associated with a higher risk of depression for women, but not men. For men, being single and having moderate self-esteem heightened the risk of depression. A substantial proportion of both men and women who had suffered depression reported using drugs. As well, a notable share of people who had been depressed sought professional health care for emotional or mental problems.

Changes in social support in relation to seniors' use of home care.

OBJECTIVES: This article examines seniors' entry into government-supported home care in relation to changes in levels of social support and in living arrangements. DATA SOURCE: The analysis is based on longitudinal data from the household component of the first two cycles of the National Population Health Survey, conducted by Statistics Canada in 1994/95 and 1996/97. Data from a sample of 2,044 people aged 65 or older who were followed prospectively were weighted to represent 2.7 million household-dwelling seniors. ANALYTICAL TECHNIQUES: Descriptive data were produced using bivariate frequencies. A multiple logistic regression model was used to examine associations between home care entry and changes in levels of social support and in living arrangements, while controlling for demographic and health-related factors. MAIN RESULTS: Among people aged 65 or older who did not receive government-supported home care in 1994/95, an estimated 7% (192,000) were receiving these services in 1996/97. Changes in social support and in living arrangements between 1994/95 and 1996/97 were significantly associated with home care entry.

The health of lone mothers.

OBJECTIVES: This article focuses on differences in the health status and health care utilization patterns of mothers in two-parent families, women who recently became lone parents, and women who had been lone parents for a longer period. Changes in the health of these women and their health care use over time are also explored. DATA SOURCE: The findings are based on the longitudinal component of the first two cycles (1994/95 and 1996/97) of the National Population Health Survey (NPHS). The sample analyzed consisted of 1,805 women in the 10 provinces who had at least one child younger than 18 at home. ANALYTICAL TECHNIQUES: Measures of self-reported health status and health care use for the three types of mothers were compared, using unadjusted and adjusted means. Multiple regression models were used to determine if lone motherhood was significantly associated with measures of health status and health care utilization after accounting for selected factors. MAIN RESULTS: Lone mothers generally had poorer health status than mothers in two-parent families, as measured by self-reported health, happiness, and distress scores. Between the first two cycles of the NPHS, the health status of longer-term lone mothers did not improve significantly. No differences were found on measures of health care utilization.

Environmental predictors of well-being for at-risk older adults in a mid-sized city.

The influence of the physical and social environment on the well-being of a sample of 224 community-residing elderly adults is the focus of this study. Environmental predictors of well-being included house type, neighborhood quality, crime rate, age concentration at the block and census tract levels, distance to services and to city center, and social status of the neighborhood. These predictors were entered into five separate multiple linear regression analyses to determine the extent to which they explained the variance in five indicators of well-being: life satisfaction, activity level, social contacts, neighbor interaction, and neighborhood satisfaction. Personal characteristics of the respondents (sex, age, health, and social class) were controlled in these analyses. Well-being for this sample is associated with living in well-maintained neighborhoods that are primarily residential in character and that are located outside the center of the city.

Work stress and health.

OBJECTIVES: This article describes work stress experienced by the employed population. It examines associations between job strain, job insecurity, physical demands, low co-worker support and low supervisor support, and four health outcomes: migraine, work injury, high blood pressure and psychological distress. DATA SOURCE: The data are from the household component of the 1994/95 National Population Health Survey conducted by Statistics Canada. Results are based on a sample of 9,023 employed Canadians aged 18 to 64. ANALYTICAL TECHNIQUES: Multivariate analyses were used to estimate associations between work stress and health problems, while controlling for other potential stressors. MAIN RESULTS: Among men, job strain was associated with migraine and psychological distress, and among women, with work injury. Job insecurity was associated with migraine among women. High physical demands were related to work injury in both sexes. Low co-worker support was related to migraine among men, and to work injury and psychological distress among women.

Reversed dynamic slings: results of use in the treatment of post-traumatic flexion contractures of the elbow.

We report our experience with reversed dynamic slings used in the treatment of post-traumatic flexion contractures of the elbow. There were 21 patients treated for deformities ranging from 35 degrees to 70 degrees (average 55 degrees). The flexion deformity after treatment varied from 25 degrees to 45 degrees (average 34.8 degrees), giving an average increase in range of movement of 39.1 per cent.

Mutational analysis of the CYP2B2 phenobarbital response unit and inhibitory effect of the constitutive androstane receptor on phenobarbital responsiveness.

A 163-base pair enhancer in the CYP2B2 5' flank confers phenobarbital (PB) inducibility and constitutes a PB response unit (PBRU). By transfection of primary hepatocytes, we analyzed the function of elements comprising the PBRU and evaluated the role of the constitutive androstane receptor (CAR) in PB responsiveness. A 51-base pair PB-responsive enhancer module (PBREM) within the PBRU confers near-maximal PB response when fused to a tk promoter. However, replacing the PBRU with the PBREM in the CYP2B2 5' flank in the natural sequence context reduced PB responsiveness by approximately 4-fold. Mutational analysis also demonstrated that PBRU sequence elements outside the PBREM are essential for maximal PB responsiveness. The PBRU contains two putative nuclear receptor binding sites, NR1 and NR2. CAR binds to retinoic acid beta2 response elements (betaRARE) and to the NR1 and NR2 sites of the PBRU and activates transcription of reporter genes in cell lines. However, conversion of NR1 into betaRARE was the equivalent of an inactivating mutation, indicating that CAR does not activate PB-dependent transcription via NR1 in the natural sequence context. A betaRAREx2-tk reporter construct was inducible by all-trans-retinoic acid (at-RA) as expected and also responded to PB. The latter can be attributed to nuclear accumulation of CAR after PB exposure. Exogenous CAR increased both the basal and PB-induced response of betaRAREx2-tk but reduced PBRU-dependent PB response. Furthermore, exogenous CAR also reduced the at-RA response of the betaRAREx2-tk construct. Thus, CAR acts negatively on PB responsiveness mediated by the CYP2B2 PBRU just as it prevents maximal at-RA responsiveness mediated by betaRARE.

A healthy outlook.

The sense of coherence-a healthy outlook-can be thought of as a measure of positive health, that is, a factor promoting resilience which enables an individual to remain healthy. Based on National Population Health Survey (NPHS) data, three health measures were analyzed in relation to sense of coherence. The sense of coherence accounted for a substantial proportion of the total variance for two of the three measures. Theoretically, people with a healthy outlook are more able to cope successfully with trauma and stress. According to NPHS data, on average, those who reported at least one traumatic event had a lower sense of coherence than those who did not. For people who experienced trauma during childhood and young adulthood, yet had a strong sense of coherence, the impact of that trauma on their health was diminished.

Pituitary adenylate cyclase activating polypeptide (PACAP) expression in sympathetic preganglionic projection neurons to the superior cervical ganglion.

Pituitary adenylate cyclase activating polypeptides (PACAP27 and PACAP38) are members of the VIP/secretin/glucagon family of peptides and have diverse neuroregulatory effects in sympathoadrenal cell development and function. PACAP peptides regulate rat superior cervical ganglion (SCG) neuron catecholamine and neuropeptide Y content and secretion, and promote sympathoneuroblast survival through activation of specific PACAP1 receptor isoforms. In examining the potential sources of PACAP regulating the SCG, PACAP expression was identified in rat preganglionic neurons in the intermediolateral cell column (IML) of the thoracic spinal cord which provide primary afferent projections to this sympathetic ganglion. Thoracic spinal cord segments (T1-4) contained approximately 17 pmol PACAP38 immunoreactivity/g tissue wet weight. Reverse-transcription polymerase chain reaction of cDNA from microdissected thoracic spinal cord using primers specific for rat neuronal proPACAP identified proPACAP mRNA expression in the IML; the results correlated with neurons labeled for proPACAP mRNA by in situ hybridization histochemistry and implicated PACAP biosynthesis in IML neurons. To demonstrate directly proPACAP transcript expression in preganglionic projection neurons to the SCG, the ganglion was decentralized and the sympathetic trunk immersed in fluorogold to identify sympathetic preganglionic neurons by retrograde labeling. Cryosections of spinal cord segments containing preganglionic neuron fluorogold labeled neurons were processed subsequently for in situ hybridization histochemical localization of proPACAP mRNA using a digoxigenin-labeled riboprobe; IML neurons were examined for fluorogold and digoxigenin/alkaline phosphatase product dual labeling. More than half of the preganglionic projection neurons to the SCG expressed PACAP mRNA, consistent with the postulate that PACAP peptides released from a subpopulation of thoracic IML preganglionic neurons may be physiological anterograde modulators of sympathetic SCG function.