Association between severe pandemic 2009 influenza A (H1N1) virus infection and immunoglobulin G(2) subclass deficiency.

BACKGROUND: . Severe pandemic 2009 influenza A virus (H1N1) infection is associated with risk factors that include pregnancy, obesity, and immunosuppression. After identification of immunoglobulin G(2) (IgG(2)) deficiency in 1 severe case, we assessed IgG subclass levels in a cohort of patients with H1N1 infection. METHODS: Patient features, including levels of serum IgG and IgG subclasses, were assessed in patients with acute severe H1N1 infection (defined as infection requiring respiratory support in an intensive care unit), patients with moderate H1N1 infection (defined as inpatients not hospitalized in an intensive care unit), and a random sample of healthy pregnant women. RESULTS: Among the 39 patients with H1N1 infection (19 with severe infection, 7 of whom were pregnant; 20 with moderate infection, 2 of whom were pregnant), hypoabuminemia (P < .001), anemia (P < .001), and low levels of total IgG (P= .01), IgG(1) (P= .022), and IgG(2) (15 of 19 vs 5 of 20; P= .001; mean value +/- standard deviation [SD], 1.8 +/- 1.7 g/L vs 3.4 +/- 1.4 g/L; P= .003) were all statistically significantly associated with severe H1N1 infection, but only hypoalbuminemia (P= .02) and low mean IgG(2) levels (P= .043) remained significant after multivariate analysis. Follow-up of 15 (79%) surviving IgG(2)-deficient patients at a mean (+/- SD) of 90 +/- 23 days (R, 38-126) after the initial acute specimen was obtained found that hypoalbuminemia had resolved in most cases, but 11 (73%) of 15 patients remained IgG(2) deficient. Among 17 healthy pregnant control subjects, mildly low IgG(1) and/or IgG(2) levels were noted in 10, but pregnant patients with H1N1 infection had significantly lower levels of IgG(2) (P= .001). CONCLUSIONS: Severe H1N1 infection is associated with IgG(2) deficiency, which appears to persist in a majority of patients. Pregnancy-related reductions in IgG(2) level may explain the increased severity of H1N1 infection in some but not all pregnant patients. The role of IgG(2) deficiency in the pathogenesis of H1N1 infection requires further investigation, because it may have therapeutic implications.

Outcomes of telemedicine intervention in a regional intensive care unit: a before and after study.

Telemedicine consultations in remote intensive care units (ICUs) overseas were found to be effective in reducing mortality and hospital length of stay (LOS). In Australia, there were anecdotal reports of these clinical outcomes. This retrospective before and after study assessed the improvement in patient outcomes with the implementation of a telemedicine program in a regional high dependency unit. Daily virtual consultations were conducted between the rural facility and the intensivists at the regional centre. A total of 525 patients received intensive care support between 2010 and 2015. Hospital and High Dependency Unit mortality showed no evidence of significant differences between the telemedicine group and the baseline (relative risk 1.02, 95% confidence interval [CI] 0.99-1.06, P=0.25 and relative risk 1.00, 95% CI 0.98-1.03, P=0.67 respectively). The hospital LOS was lower in the baseline group by 1.5 days. There was no significant difference in High Dependency Unit LOS. To adjust for the covariates in LOS, log linear regression analysis was performed. The telemedicine intervention, Acute Physiology and Chronic Health Evaluation II scores and inter-hospital transfers were found to contribute significantly to hospital LOS. The most important result of the study was that the proportion of inter-hospital transfers was lower in the telemedicine group (relative risk 0.88, 95% CI 0.80-0.98, P=0.03) compared to baseline. This means that critically ill patients in our regional centre can continue to receive specialist care remotely through tele-ICU consultations thus avoiding the need for patient transport. However, further study is needed to establish the benefits and risks of telemedicine intervention in ICUs in Australia.

Serum lipid response to dietary cholesterol in subjects fed a low-fat, high-fiber diet.

To determine whether hyperresponse to dietary cholesterol occurs in individuals consuming a low-fat diet, a study was performed on 58 subjects whose plasma cholesterol had changed by greater than or equal to 5% when intakes of two and seven eggs per week were compared in a previous study. Here, the effect of eating nine, zero, and nine eggs per week was studied over 3 consecutive months. Plasma total, LDL, and HDL cholesterol did not differ significantly. There was no correlation between individuals' lipoprotein changes in this and the previous study. Consistent hyperresponse to moderate cholesterol intake is not apparent in people eating a low-fat, high-fiber diet. Reduction in dietary cholesterol below 400 mg/d produces no further substantial cholesterol lowering.

The effect of aging on the immune response: influence of phosphatidylcholine-containing lipid on IgD-receptor expression and antibody formation.

It was reported previously that IgD-receptors (IgD-R) are expressed on both CD4+ and CD8+ human T cells and CD4+ murine T cells after exposure to oligomeric IgD, certain cytokines, or various pharmacological agents, as shown by rosetting with IgD-coated erythrocytes. Enhancement of antibody production is observed in mice after injection of oligomeric IgD and is mediated by these IgD-R+ T cells, while injection of monomeric IgD inhibits both IgD-R upregulation and augmentation of antibody responses induced by simultaneously injected oligomeric IgD. The effects of oligomeric IgD on IgD-R upregulation are lacking in aged mice. However, the oligomeric IgD induced enhanced antibody production can be transferred to aged mice with IgD-R+ T cells from young donors suggesting that the environment of the aged mouse supports the effector function of IgD-R+ T cells. We now report, in addition, that exposure to phosphatidylcholine (PC) and a PC-containing lipid mixture, AL721, is effective in causing IgD-R upregulation on T cells from both young and aged mice, and young humans. This effect can also be demonstrated in mice in vivo after administration of AL721. Moreover, this agent causes a two-fold enhancement of antibody production, as measured by PFC/spleen, to 4-hydroxy-5-iodo-3-nitrophenyl(acetyl)-Brucella abortus (NIP-BA) and NIP-horse red blood cells (RBC) in young and aged mice. There is no difference in the baseline membrane fluidity of lymphocytes from aged and young mice. Although PC causes an increase in membrane fluidity of lymphocytes from both young and old mice, and from humans, this effect on fluidity is not prevented by a protein kinase inhibitor, while PC's effect on IgD-R upregulation is prevented by the inhibitor. Moreover, no correlation was observed between IgD-R upregulation and membrane fluidity changes induced by AL721 administered in vivo. To evaluate the role of IgD-R induction in the augmentation of antibody production by phospholipids, the effect of monomeric IgD was investigated. The augmenting effect of AL721 on antibody production was prevented by a single injection of monomeric IgD at the time of antigen administration. We conclude that (1) PC-containing lipid mixtures are effective in enhancing antibody production in aged mice, (2) induction of IgD-R is responsible for the augmenting effects of AL721 on antibody production, and (3) monomeric IgD not only blocks the upregulation of IgD-R, as shown previously, but also the augmenting effect of previously upregulated IgD-R on T cells by preventing their interaction with surface IgD+ B cells.

Detection of chromosome aberrations by FISH as a function of cell division cycle (harlequin-FISH).

Chromosome aberrations are a sensitive indicator of genetic change, and the measurement of chromosome aberration frequency in peripheral blood lymphocytes is often used as a biological dosimeter of exposure (1,4). The length of time that cells are maintained in culture before cytogenetic analysis is probably the most important in vitro factor that influences both the frequency and types of aberrations that are seen following exposure to mutagens. Therefore, for accurate cytogenetic measurements of genetic damage, cells must be analyzed in their first mitosis following exposure. As cells progress through subsequent mitotic division cycles, cells with unstable types of aberrations, e.g., dicentrics and acentric fragments, are eliminated (1,3,4). Even the use of synchronized populations of cells does not guarantee that all cells analyzed will be in their first division following treatment. Small variations in growth rate after irradiation can lead to large variations in the proportion of cells that are in their first vs. a subsequent mitosis. For example, 48 h after G0 lymphocytes are stimulated to enter the cell cycle (the standard sampling time for cytogenetic analysis), up to 50% of the cells in mitosis can be in their second division cycle (10). While there are methods available to distinguish cells in different division cycles (see Introduction), they are not easily adapted for use with standard fluorescence in situ hybridization (FISH) procedures. The goal of this study was to develop a simple approach to detect aberrations by FISH whereby cells in different division cycles could be distinguished.

Relationship between humoral immunoaugmenting properties of DHEAS and IgD-receptor expression in young and aged mice.

IgD-receptors are associated with augmented antibody production in vivo and are induced on CD4+ T cells by aggregated IgD in young but not in aged mice. In the current study orally or intraperitoneally administered DHEAS was found to enhance antibody production, as measured in a plaque-forming cell assay, and also to cause an increased expression of IgD-R on T cells in both young and aged mice. IgD-R+ T cells are enumerated by rosette cell formation with IgD-coated SRBC. Since, as shown previously, the immunoaugmenting effect of IgD-R+ T cells is blocked by injection of monomeric IgD, the effect of monomeric IgD was also examined in DHEAS-pretreated mice. The inhibitory effect obtained with monomeric IgD in these studies indicates that upregulation of IgD-R by DHEAS plays an important role in the immunoenhancing effect of this hormone. In addition, no significant effect of DHEAS was obtained on contact hypersensitivity to DNCB or on proliferative responses of T cells from young or aged mice. Aged but not young mice showed increases in the numbers of Ia+ epidermal Langerhans cells after DHEAS treatment.

Prevalence of malnutrition in patients in general practice.

The objective of this study was to determine the prevalence and correlates of malnutrition in patients living at home with cancer and chronic diseases. Patients (213) with cancer and 228 patients with chronic diseases were randomly selected from general practice registers. Nutritional status was determined from body mass index (BMI in kg/metre2), triceps skinfold thickness (TST), mid-arm muscle circumference (MAMC) and population centiles. Patients were classified as mildly malnourished if they had a BMI < 20 and TST or MAMC < 15th centile, moderately malnourished if they had a BMI < 18 and TST or MAMC < 5th centile, and severely malnourished if they had a BMI < 16 and TST or MAMC < 5th centile. Using these criteria, nearly 10% of patients were malnourished: 24 (5.4%) mildly, 12 (2.7%) moderately and 4 (0.01%) severely. Malnutrition was more common in patients in social classes 3.2, 4 and 5 than in social classes 1, 2 and 3.1 (P = 0.003), and in patients receiving district nurse care (P < 0.001). Malnutrition was more prevalent in cancer patients who complained of chronic or severe pain (32% vs 12%, P = 0.021) and in patients with chronic disorders who experienced mental apathy (22% vs 5%, P = 0.014). Clinicians need to be aware that malnutrition is common in patients living at home. In this study BMI proved to be a fairly good indicator of malnutrition and routine measurement of BMI would be one simple way of detecting patients who are at risk.

Effect of nutritional status on use of health care resources by patients with chronic disease living in the community.

The prevalence of malnutrition in patients with chronic disease living in the community in the UK is around 8%. Whether such patients experience greater morbidity and mortality or make increased use of health care resources is unknown. The aim of this study was to investigate how the use of health care resources by patients with chronic disorders of the respiratory, gastrointestinal and neurological systems varied by nutritional status. We used longitudinal data, collected since 1987, which formed part of the General Practice Research Database in the UK. Subjects were 11 357 men and women aged 18 years or over. Main outcomes were consultation rates in general practice, prescription rates, hospital referral rates, hospital admission rates and mortality. Consultation and prescription rates were lowest amongst patients whose body mass index (BMI) was between 20 and 25. Rates were higher in patients whose BMI was below 20, or 25 and above. There was no statistically significant relation between rate of hospital outpatient referral and nutritional status, but both hospital admission rate and mortality were greatest in those people whose BMIs were below 20 and declined as BMIs increased. In patients with differential use of health care resources in both primary care and hospital practice, and with differences in mortality.

Patterns of prescribing of nutritional supplements in the United Kingdom.

BACKGROUND AND AIMS: A large number of prescriptions are issued for nutritional supplements under British National Formulary classifications 9.4.1 (foods for special diets) and 9.4.2 (enteral feeds), but little is known about the characteristics of the patients who receive them. We used the General Practice Research Database to examine patterns of prescribing of these supplements. METHODS: We selected patients who had been prescribed supplements under classifications 9.4.1 and 9.4.2 during 1996-1997. Descriptive statistics were used to examine how prescribing varied. RESULTS: 28644 patients received prescriptions during 1996-1997. Among the 27413 (96%) patients prescribed supplements for oral use, 14750 received supplements for enteral nutrition alone, 8122 received supplements for special diets alone and 4541 had both types of supplement. 51% of patients receiving supplements for special diets were <18 years. The commonest diagnoses among such children were milk intolerance (24%) and malnutrition (17%). 94% of patients receiving supplements for enteral nutrition were adult, 52% of whom had cancer or cardiovascular disease. Only 4% of patients had weight and height recorded prior to first prescription. CONCLUSIONS: The GPRD provides valuable information on the characteristics of patients prescribed nutritional supplements. But because only limited data are available on their nutritional status prior to supplementation, it is hard to assess whether general practitioners are prescribing these supplements appropriately.

A prospective randomised controlled trial of nutritional supplementation in malnourished elderly in the community: clinical and health economic outcomes.

BACKGROUND & AIMS: Malnutrition is common in sick elderly people on admission to hospital and in the community. We conducted a randomised controlled trial to determine if nutritional supplementation after discharge from hospital improved nutritional status and functional outcomes, or reduced health-care costs. METHODS: Elderly malnourished subjects were randomised to 8 weeks of supplementation or no supplementation post discharge, and followed up for 24 weeks. Weight, body mass index, anthropometrics, handgrip strength, quality of life and requirements for health-care professionals' services and social services were measured throughout the study. RESULTS: Nutritional status improved significantly from baseline to week 24 in the intervention group (P<0.05), but not in the control group. There was no significant difference in nutritional status between groups at week 24. Handgrip strength improved significantly in the intervention group during supplementation, and was significantly different from that of the control group at week 8, but decreased thereafter. There was no significant difference in quality of life or health economic outcomes between groups at week 24. CONCLUSIONS: In already malnourished elderly subjects, it may be too late to expect to improve function or quality of life or to reduce health-care costs simply by providing nutritional supplements after hospitalisation. Prevention is key. All elderly patients should be nutritionally assessed as part of their routine care, and appropriate intervention initiated early.

Prevalence of malnutrition on admission to four hospitals in England. The Malnutrition Prevalence Group.

AIMS: The primary objective was to estimate prevalence of malnutrition on admission to four hospitals. Secondary objectives included assessing the relationship between nutritional status and length of hospital stay, numbers of new prescriptions, new infections and disease severity. METHODS: We entered eligible patients according to predefined quotas for elective and emergency admissions to 23 specialties. We measured height, weight, Body Mass Index and anthropometrics, and recorded history of unintentional weight loss. Patients who had lost > or = 10% of their body weight, had a Body Mass Index <20, or had a Body Mass Index <20 with one anthropometric measurement <15th centile were considered malnourished. RESULTS: Of 1611 eligible patients, 761 did not participate; 269 were too ill; 256 could not be weighed; and 236 refused consent. Eight hundred and fifty were subsequently evaluated. Prevalence of malnutrition on admission was 20%. Length of stay, new prescriptions and infections and disease severity were significantly higher in the malnourished. CONCLUSIONS: One patient in every five admitted to hospital is malnourished. Although this figure is unacceptably high, it may underestimate true prevalence. Malnutrition was associated with increased length of stay, new prescriptions and infections. Malnutrition may also have contributed to disease severity.

Bowel function of long-term tube-fed patients consuming formulae with and without dietary fiber.

Diarrhea, constipation and subsequent laxative use are chronic problems in long-term enterally fed patients. We have conducted a double-blind randomized crossover study to evaluate the effects of two enteral formulae (Enrich, 12.8 g of dietary fiber per 1000 kcal and Ensure, fiber-free) on stool frequency, fecal weight, laxative use, gastrointestinal tolerance and bowel function in chronic care tube-fed patients. Twenty-eight subjects (24 male, 4 female) completed the study. Mean daily number of stools and mean daily fecal wet weight in Enrich-fed patients were not significantly different from those of patients receiving Ensure. Ensure-fed patients required significantly more laxatives (p = 0.02) than those receiving Enrich. There were 26 reports of diarrhea in the Ensure-fed group as compared to 6 in the Enrich-fed group, and this difference was significant (p = 0.006). Reporting rates for constipation were not significantly different in the two groups. At the end of the study, the bowel function of 57.1% of patients receiving Enrich was improved when compared with that of 14.3% of Ensure-fed patients, and this difference was significant (p = 0.005). These results suggest that the addition of dietary fiber to enteral formulae improves gastrointestinal tolerance and bowel function, and reduces laxative use in long-term enterally fed patients.

Setting standards using integrated care pathways.

An integrated care pathway is a tool that can help to deliver clinical governance objectives if implemented well. Key factors of successful implementation are: effective project management; communication and training; and top-down and bottom-up support for the process.

Problems of nutritional assessment in the community.

The present paper explores the problems associated with assessment of nutritional status in the community and reviews the literature related to this subject. The first problem is one of terminology, since a logical first step before assessment is screening, which identifies characteristics known to be associated with dietary or nutritional problems. Its purpose is to differentiate individuals who are at high nutritional risk or have poor nutritional status. There are certain factors which should alert the primary health care team to the fact that nutritional intake may be reduced and that risk of malnutrition is increased. These include disease condition, functional disabilities, inadequate or inappropriate food intake, poor dentition or difficulty swallowing, polypharmacy, alcoholism, depression, poor social circumstances or recent discharge from hospital. Patients suffering from these factors need to be identified so that screening becomes a routine part of their medical treatment. At-risk groups include the elderly, the chronically ill, those with cancer and neurological disorders, post-surgical patients and children with developmental disabilities. In the community, practice and community nurses see the majority of at-risk patients and should carry out screening. A number of screening tools have been developed for community use. Most are aimed at the elderly population, but there are others designed to assess nutritional risk in children with developmental disabilities and the general population. These are reviewed and problems of content and validity identified. Some problems associated with nutritional assessment are also reviewed.

A wolf in wolf's clothing--the abdominal compartment syndrome.

Four patients are described in whom massive abdominal distension after laparotomy led to increased airway and central venous pressure and severely reduced urine output. All cases were associated with massive fluid resuscitation and operative findings were a grossly oedematous bowel with free fluid under pressure in the abdomen. These findings are consistent with the diagnosis of intra-abdominal compartment syndrome. In 1 case trauma was remote from the abdomen indicating that abdominal surgery or trauma may not be a prerequisite for the development of the condition. Recognition of the features of the condition is essential as it can only be treated by decompression of the abdominal contents.

The Emu-bcl-2 transgene enhances antigen-induced germinal center formation in both BALB/c and SJL mice but causes age-dependent germinal center hyperplasia only in the lymphoma-prone SJL strain.

Emu-bcl-2 transgenic and littermate control BALB/c and SJL mice were immunized in the front footpads with trinitrophenylated Brucella abortus and the germinal center (GC) response in draining brachial lymph nodes was studied by staining with peanut agglutinin peroxidase and methyl green. Although the GCs induced were not larger in transgenic than in control young mice, there was a significant increase in the percentage of B cell follicles exhibiting GCs 7 to 8 days after primary and secondary antigen injections in the transgenic mice of both strains. In addition, glucocorticosteroid injected on day 7 after the primary injection caused a marked decrease in GCs in littermate controls but had no effect in the bcl-2 transgenic SJL mice. Antibody production to B. abortus was only slightly higher in transgenic than in control mice, but anti-TNP immunoglobulin M and G titers were significantly enhanced in the transgenic mice. The bcl-2 transgenic SJL mice, older than 6 months, showed the spontaneous appearance of large numbers of peanut agglutinin-binding GCs that greatly varied in size and were located without regard for the normal lymph node structure or follicle localization. This GC hyperplasia was seen in a large percent of the older transgenic SJL mice and never in similarly aged normal SJL or BALB/c mice with and without the bcl-2 transgene. Frank lymphomatous transformation of peanut agglutinin-binding germinal center-like areas was seen in lymph nodes and Peyer's patches of some of the older bcl-2 transgenic SJL mice. These results suggest that the tendency of SJL mice to develop GC-derived lymphomas synergizes with the presence of the bcl-2 transgene to cause the development of GC hyperplasia.

Proliferative and cytotoxic immune functions in aging mice. IV. Effects of suppressor cell populations from aged and young mice.

The changes with age in three splenic suppressor cell populations were studied in C57BL/6 mice. Allospecific Ts cells and nonspecific non-T suppressor cells were both generated in vitro in allogeneic MLC. The presence of "pre-existing" suppressor cells in fresh spleen cells from normal mice was examined. Suppressor cell activities were assayed for their ability to suppress proliferation in a fresh allogeneic MLC after treatment to prevent their own proliferation. The ability to generate both specific and nonspecific suppressor cells decreased with age, whereas pre-existing suppressor cells were detected in spleens from the majority of the aged animals but not in spleens from young animals. The decrease in suppressor cell activity was not due to any requirement for age matching between donors of suppressor and target cells. The specific and nonspecific MLC-generated suppressor cells inhibited both the proliferative response in the assay MLC and the generation of cytotoxic cells. The pre-existing suppressor cells only suppressed the proliferative response and not the generation of cytotoxic cells. The changes seen with age in these suppressor cell populations suggest that the ability to generate suppression (both allospecific and nonspecific) to newly encountered Ag declines with age, whereas a resident splenic suppressor cell population accumulates over the lifetime of the animals.

The p53MH algorithm and its application in detecting p53-responsive genes.

A computer algorithm, p53MH, was developed, which identifies putative p53 transcription factor DNA-binding sites on a genomewide scale with high power and versatility. With the sequences from the human and mouse genomes, putative p53 DNA-binding elements were identified in a scan of 2,583 human genes and 1,713 mouse orthologs based on the experimental data of el-Deiry et al. [el-Deiry, W. S., Kern, S. E., Pietenpol, J. A., Kinzler, K. W. & Vogelstein, B. (1992) Nat. Genet. 1, 45-49] and Funk et al. [Funk, W. D., Pak, D. T., Karas, R. H., Wright, W. E. & Shay, J. W. (1992) Mol. Cell. Biol. 12, 2866-2871] (http://linkage.rockefeller.edu/p53). The p53 DNA-binding motif consists of a 10-bp palindrome and most commonly a second related palindrome linked by a spacer region. By scanning from the 5' to 3' end of each gene with an additional 10-kb nucleotide sequence appended at each end (most regulatory DNA elements characterized in the literature are in these regions), p53MH computes the binding likelihood for each site under a discrete discriminant model and then outputs ordered scores, corresponding site positions, sequences, and related information. About 300 genes receiving scores greater than a theoretical cut-off value were identified as potential p53 targets. Semiquantitative reverse transcription-PCR experiments were performed in 2 cell lines on 16 genes that were previously unknown regarding their functional relationship to p53 and were found to have high scores in either proximal promoter or possible distal enhancer regions. Ten (approximately 63%) of these genes responded to the presence of p53.