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Transport and storage of vaccines in Hungary: the first cold chain monitor study in Europe.

With assistance from WHO the Hungarian Ministry of Health organized two cold chain studies: the first in three counties in summer (1 July to 30 September 1987), the second in six counties (including the previous three) in winter (1 January to 31 March 1988). The counties were chosen according to their distance (50-300 km) from Budapest, individual districts and child health centres being selected randomly. All participants were trained before beginning the studies. The vaccines (DPT, measles and BCG) for immunization, with attached cold chain monitors, were transported from the manufacturers to the child health centres using the normal distribution systems in the country. The whole cold chain process was analysed with regard to (1) actual exposures to adverse temperatures and delays in distribution; (2) the places where such exposure or delay occurred; (3) the percentage of vaccines at risk of deterioration (actual and predicted) at the end of the study; and (4) the performance of refrigerators of different types. Evaluation of the results (using WHO's EPIC software) showed significant deviations from acceptable standards. This first cold chain study in a European country proves that even in a temperate climate and with a reasonably well-organized public health service there can be significant weaknesses in the transportation and storage of vaccines. Recommendations to overcome these deficiencies are given.

Drug Storage↗

Missed opportunities for immunization in children under 2 years attending an urban teaching hospital.

A cross-sectional survey was done to assess the missed opportunity for immunization (MOI) in children under two years of age attending Medical Outpatient, Newborn Follow-up Service and Immunization Clinic of Institute of Child Health and to evaluate interventions. Baseline survey phase-I was done and two interventions: (i) education and awareness of immunization among health personnel; and (ii) attaching immunization slip to the outpatient form were done. After each intervention phase-II and phase-III surveys were carried out. The data from the different phases were analyzed for the effect of interventions. The total number of children surveyed were 634; 423 from Medical Outpatients, 108 from Newborn Follow-up Service and 103 from immunization Clinic. MOI was 35.5%, 23.1% and 9.7% in the above health facilities, respectively. After intervention I, the MOI was 24.5% and 12.2% in Medical Outpatient and Newborn Follow-up Service and none in Immunization Clinic. After intervention-II there was an improvement in immunization of 18.4%, 30.4% and 16.0% in the three health facilities mentioned above. MOI was avoided because the medical officers advised immunization in the above children. The difference in the MOI among Medical Outpatient and Immunization Clinic between baseline, phase-I and phase-II were significant (p < 0.001). It is concluded that MOI can be brought down by creating awareness periodically and that attaching an immunization schedule to the outpatient forms is an effective method of reducing MOI.

Attitude of Health Personnel↗

Dynamics of carriage of Neisseria meningitidis in a group of military recruits: subtype stability and specificity of the immune response following colonization.

Meningococcal carriage and the immune response to colonization were studied in a group of military recruits undergoing basic training. Subtyping by determination of the class 1 protein sequence clearly differentiated between strains and demonstrated the dynamics of carriage and transmission. Expression of class 1 protein by each strain remained stable during prolonged carriage by different subjects. Following colonization, a marked increase in serum bactericidal response occurred, which was specific for the subtype of the acquired strain and was associated with an increase in reactivity by Western blot to the homologous class 1 protein. Subjects colonized by multiple strains showed evidence of a specific immune response to the class 1 protein of each strain acquired. The subtype specificity of the bactericidal response to meningococci and the stability of expression of the class 1 protein have important implications for the design of vaccines for prevention of serogroup B meningococcal disease.

Antibodies, Bacterial↗

Immune modulator studies in primates: the utility of flow cytometry and immunohistochemistry in the identification and characterization of immunotoxicity.

Exposure to natural environmental products, biopharmaceuticals, or investigational adjuvants has the potential to negatively impact the immune system, resulting in either up- or downregulation of immune function (immunomodulation). Many current protocols for primate toxicologic testing call for the evaluation of changes in immune cell number (peripheral blood or tissue), alterations in the weights of immune system organs (lymph nodes, spleen, thymus), and/or increases in the overall incidence of infections or neoplasms; these data are relied upon to suggest altered immune function. However, these are informative only when clear differences in frequency and/or severity of effects can be distinguished across control and dosed groups. In the absence of such distinct morphologic or clinical pathologic changes, the identification of potential immunomodulatory effects can present a much greater challenge. Additional evaluations may be needed to detect altered immune system integrity; these are based on in vivo assessments in primates of cellular or humoral responsiveness. Immunomodulatory effects can be characterized by in vitro or in vivo immune function tests: these tests require prestudy planning to integrate assessments into ongoing toxicology programs. These methods also involve specialized training and equipment, particularly if the intent is to evaluate parameters in a GLP laboratory setting. In primate toxicology, the added costs required to perform a complete functional analysis of the immune system can be substantial, but may be warranted depending on the clinical development plans. Two analytical methods that are easily incorporated into the standard toxicology profile in primates are flow cytometry and immunohistochemistry. Flow cytometry (FC) is used to assess changes in the relative distribution of immune cell marker expression, and where marker expression is known to fluctuate with the state of cell activation, can also provide information on functional attributes of immune cells. Immunohistochemistry (IHC) provides a means to evaluate similar characteristics of immune cells within tissue sections. Used together, FC and IHC can aid in the identification of changes in immune system that may not be apparent by traditional testing procedures (such as H&E staining), thus aiding in the characterization of immune system alterations. This presentation focused on the utility of flow cytometry and immunohistochemistry in a standard primate toxicology evaluation, with representative examples showing the benefits of these technologies in the diagnosis of potential immunomodulatory effects.

Adjuvants, Immunologic↗

Introducing auto-disable syringes to the national immunization programme in Madagascar.

OBJECTIVE: To evaluate the safety and coverage benefits of auto-disable (AD) syringes, weighed against the financial and logis- tical costs, and to create appropriate health policies in Madagascar. METHODS: Fifteen clinics in Madagascar, trained to use AD syringes, were randomized to implement an AD syringe only, mixed (AD syringes used only on non-routine immunization days), or sterilizable syringe only (control) programme. During a five-week period, data on administered vaccinations were collected, interviews were conducted, and observations were recorded. FINDINGS: The use of AD syringes improved coverage rates by significantly increasing the percentage of vaccines administered on non-routine immunization days (AD-only 4.3%, mixed 5.7%, control 1.1% (P<0.05)). AD-only clinics eliminated sterilization sessions for vaccinations, whereas mixed clinics reduced the number of sterilization sessions by 64%. AD syringes were five times more expensive than sterilizable syringes, which increased AD-only and mixed clinics' projected annual injection costs by 365% and 22%, respectively. However, introducing AD syringes for all vaccinations would only increase the national immunization budget by 2%. CONCLUSION: The use of AD syringes improved vaccination coverage rates by providing ready-to-use sterile syringes on non-routine immunization days and decreasing the number of sterilization sessions, thereby improving injection safety. The mixed programme was the most beneficial approach to phasing in AD syringes and diminishing logistical complications, and it had minimal costs. AD syringes, although more expensive, can feasibly be introduced into a developing country's immunization programme to improve vaccination safety and coverage.

Child, Preschool↗

Role of IFIT1 and IFIT3 in systemic lupus erythematosus: modeling a diagnosis and exploring immune regulation.

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder characterized by multi-organ involvement and a protracted clinical course. Current diagnostic strategies, which rely heavily on clinical symptoms and serology, are often insufficient for early detection. Therefore, highly accurate diagnostic biomarkers are urgently needed to facilitate early intervention and optimize personalized treatment strategies. D atasets GSE61635 and GSE135779 were integrated to identify differentially expressed genes. Weighted gene co-expression network analysis (WGCNA) was performed to isolate the module with the strongest clinical relevance. Mendelian randomization and single&#x2011;cell RNA&#x2011;seq were used to identify key disease&#x2011;relevant genes. A diagnostic model was then constructed, and gene set variation analysis (GSVA), along with gene set enrichment analysis (GSEA), was conducted to elucidate the underlying molecular pathways. IFIT1 and IFIT3 were identified as 2 core genes highly expressed in monocytes and T cells of SLE patients. Functional enrichment analysis revealed that these genes were enriched in immune-related pathways, metabolic pathways related to inflammation and genomic stability. The diagnostic model showed good accuracy, with an area under the curve (AUC) of 0.974 on the training set and 0.912 on the validation set. IFIT1 and IFIT3 represent promising biomarkers for diagnosing SLE and appear to mediate key immune and metabolic disturbances. Furthermore, the developed model serves as an accurate and reliable instrument for early diagnosis and personalized therapy. Large-scale clinical studies are warranted to further validate these findings and evaluate their clinical application.

Humans↗

Immune response to heavy exertion.

Epidemiological data suggest that endurance athletes are at increased risk for upper respiratory tract infection during periods of heavy training and the 1- to 2-wk period following race events. There is growing evidence that, for several hours subsequent to heavy exertion, several components of both the innate (e.g., natural killer cell activity and neutrophil oxidative burst activity) and adaptive (e.g., T and B cell function) immune system exhibit suppressed function. At the same time, plasma pro- and anti-inflammatory cytokines are elevated, in particular interleukin-6- and interleukin-1-receptor antagonist. Various mechanisms explaining the altered immunity have been explored, including hormone-induced trafficking of immune cells and the direct influence of stress hormones, prostaglandin-E2, cytokines, and other factors. The immune response to heavy exertion is transient, and further research on the mechanisms underlying the immune response to prolonged and intensive endurance exercise is necessary before meaningful clinical applications can be drawn. Some attempts have been made through chemical or nutritional means (e.g., indomethacin, glutamine, vitamin C, and carbohydrate supplementation) to attenuate immune changes following intensive exercise.

Humans↗

Physician credentials and practices associated with childhood immunization rates: private practice pediatricians serving poor children in New York City.

Private practice physicians in New York City's poorest neighborhoods are typically foreign trained, have generally substandard clinical practices, and have been accused of rushing Medicaid patients through to turn a profit. However, they also represent a sizable share of physician capacity in medically underserved neighborhoods. This article documents the level of credentials, systems, and immunization-related procedures among these physicians. Furthermore, it assesses the relationship between such characteristics and childhood immunization rates. The analysis utilizes a cross-sectional comparison of immunization rates in 60 private practices that submitted 2,500 or more Medicaid claims for children. Immunization data were gathered from medical records for 2,948 randomly selected children under 3 years of age. Half of sampled physicians were board certified (55%), and half were accepted by the Medicaid Preferred Physicians and Children (PPAC) program (51.7%). Of physicians, 43% saw patients only on a walk-in basis, while only 17% scheduled the next appointment while the patient was still in the office. There were 75% of the physicians who reported usually immunizing at acute care visits. Immunization rates were higher among PPAC physicians compared to others (41% vs. 29% up to date for diphtheria and tetanus toxoids and pertussis [DTP]/Haemophilus influenzae type b [Hib], polio, and measles-mumps-rubella [MMR], P = .01), and board-certified physicians showed a trend toward better immunization rates (39% vs. 30%, P =.07). Physicians who reported usually immunizing at acute care visits also had higher rates than those who did not (38% vs. 27%, P = .05). Scheduling a date and time for the next immunization showed a trend toward association with immunization coverage (37% vs. 28%, P= .10). Private practice physicians who provide high volumes of care reimbursed by Medicaid have improved their credentials and affiliations over time, thereby expanding reimbursement options. Credentials and affiliations were at least as effective in distinguishing relatively high- and low-performing physicians, as were immunization-related practices, suggesting that they are useful markers for higher quality care. The relative success of the PPAC program should inform efforts to improve the capacity and quality of primary care for vulnerable children. Appointment and reminder systems that effectively manage the flow of children back into the office for immunizations and the vigilant use of acute care visits for immunizations go hand in hand. Opportunity exists for payers and plans to encourage and support these actions.

Certification↗

Stress management and psychoneuroimmunology in HIV infection.

Does stress management affect psychological and immune functioning in persons with human immunodeficiency virus infections? Stress-management techniques, such as relaxation training and imagery, cognitive restructuring, coping-skills training, and interpersonal-skills training, may reduce anxiety, depression, and social isolation in HIV-infected persons by lowering physical tension and increasing a sense of control and self-efficacy. A psychoneuroimmunologic model is proposed wherein these psychological changes are hypothesized to be accompanied by an improved ability to regulate neuroendocrine functioning, which in turn may be associated with a partial normalization of immune system functions such as lymphocyte proliferation and cytotoxicity, providing more efficient surveillance of latent viruses that may contribute directly to increased HIV replication and generate opportunistic infections or cancer if left unchecked. Such a normalization of stress-associated immune system decrements are hypothesized to forestall or minimize increases in viral load and expression of clinical symptoms. This model is useful for testing the factors contributing to the health effects of stress-management interventions in HIV-infected persons. In this context, one general research strategy for testing the effects of stress-management interventions is to target them toward the more prevalent psychosocial challenges that HIV-infected people face at various points in the disease process; enroll an HIV-infected population (eg, HIV-positive homosexual and bisexual men) into a randomized trial; and monitor changes in cognitive, affective, behavioral, and social factors in parallel with hormonal, immunologic, viral, and clinical changes over the course of time. This article will review the major psychoneuroimmunologic findings that have emerged using this paradigm and suggest future research directions and clinical applications.

Adaptation, Psychological↗

Developing a national system for dealing with adverse events following immunization.

Although vaccines are among the safest of pharmaceuticals, the occasional severe adverse event or cluster of adverse events associated with their use may rapidly become a serious threat to public health. It is essential that national monitoring and reporting systems for vaccine safety are efficient and adequately coordinated with those that conventionally deal with non-vaccine pharmaceuticals. Equally important is the need for an enlightened and informed national system to be in place to deal with public concerns and rapid evaluation of the risk to public safety when adverse events occur. Described in this article is the outcome of efforts by the WHO Global Training Network to describe a simple national system for dealing with vaccine safety and with emergencies as they arise. The goals of a training programme designed to help develop such a system are also outlined.

Adverse Drug Reaction Reporting Systems↗

Physiological implications of altitude training for endurance performance at sea level: a review.

Acclimatisation to environmental hypoxia initiates a series of metabolic and musculocardio-respiratory adaptations that influence oxygen transport and utilisation, or better still, being born and raised at altitude, is necessary to achieve optimal physical performance at altitude, scientific evidence to support the potentiating effects after return to sea level is at present equivocal. Despite this, elite athletes continue to spend considerable time and resources training at altitude, misled by subjective coaching opinion and the inconclusive findings of a large number of uncontrolled studies. Scientific investigation has focused on the optimisation of the theoretically beneficial aspects of altitude acclimatisation, which include increases in blood haemoglobin concentration, elevated buffering capacity, and improvements in the structural and biochemical properties of skeletal muscle. However, not all aspects of altitude acclimatisation are beneficial; cardiac output and blood flow to skeletal muscles decrease, and preliminary evidence has shown that hypoxia in itself is responsible for a depression of immune function and increased tissue damage mediated by oxidative stress. Future research needs to focus on these less beneficial aspects of altitude training, the implications of which pose a threat to both the fitness and the health of the elite competitor. Paul Bert was the first investigator to show that acclimatisation to a chronically reduced inspiratory partial pressure of oxygen (P1O2) invoked a series of central and peripheral adaptations that served to maintain adequate tissue oxygenation in healthy skeletal muscle, physiological adaptations that have been subsequently implicated in the improvement in exercise performance during altitude acclimatisation. However, it was not until half a century later that scientists suggested that the additive stimulus of environmental hypoxia could potentially compound the normal physiological adaptations to endurance training and accelerate performance improvements after return to sea level. This has stimulated an exponential increase in scientific research, and, since 1984, 22 major reviews have summarised the physiological implications of altitude training for both aerobic and anaerobic performance at altitude and after return to sea level. Of these reviews, only eight have specifically focused on physical performance changes after return to sea level, the most comprehensive of which was recently written by Wolski et al. Few reviews have considered the potentially less favourable physiological responses to moderate altitude exposure, which include decreases in absolute training intensity, decreased plasma volume, depression of haemopoiesis and increased haemolysis, increases in sympathetically mediated glycogen depletion at altitude, and increased respiratory muscle work after return to sea level. In addition, there is a risk of developing more serious medical complications at altitude, which include acute mountain sickness, pulmonary oedema, cardiac arrhythmias, and cerebral hypoxia. The possible implications of changes in immune function at altitude have also been largely ignored, despite accumulating evidence of hypoxia mediated immunosuppression. In general, altitude training has been shown to improve performance at altitude, whereas no unequivocal evidence exists to support the claim that performance at sea level is improved. Table 1 summarises the theoretical advantages and disadvantages of altitude training for sea level performance. This review summarises the physiological rationale for altitude training as a means of enhancing endurance performance after return to sea level. Factors that have been shown to affect the acclimatisation process and the subsequent implications for exercise performance at sea level will also be discussed. Studies were located using five major database searches, which included Medline, Embase, Science Citation Index, Sports Discus, and Sport, in

Acclimatization↗

Influence of carbohydrate on immune function following 2 h cycling.

The influence of carbohydrate compared with placebo ingestion on changes in immune cell counts and functions following 2 h intensive cycling was studied in 12 trained cyclists who functioned as their own controls. The subjects performed two tests 2 weeks apart where they cycled for 2 h at approximately 64% Watts(max) while receiving 4 mL x kg(-1) x 15 min(-1) carbohydrate (6%) (Cho) or placebo (Pla) beverages. Blood samples were collected 30 min preexercise, and immediately and 1 h postexercise. The samples were assayed for plasma cortisol and epinephrine, blood leukocyte subset counts, PHA-induced lymphocyte proliferation, and natural killer cell activity (NKCA). Compared with Pla ingestion, Cho attenuated exercise-induced changes in plasma cortisol, blood neutrophil, and monocyte counts, but not in total blood lymphocyte, T cell, and NK cell counts, PHA-induced lymphocyte proliferation, and NKCA. Thus despite a strong attenuating influence of carbohydrate ingestion on exercise-induced changes in plasma cortisol and blood neutrophil and monocyte counts, other immune measures related to lymphocyte subset counts, and function were unaffected.

Adult↗

Physical effort-induced changes in immune parameters.

Physical stress induces changes in immune system parameters; these changes depend on effort schedule and are influenced by customary training. The mechanisms whereby they take place are not fully elucidated: sympathetic activation-mediated mobilization of cells of lymphoid organs, including the spleen, has been suggested. We studied exercise-induced changes (20' of cycloergometer test conducted up to 80% of maximal expected heart rate) in white blood cells (WBC), lymphocyte subsets, plasma catecholamine and cortisol levels in three groups of subjects: swimmers, untrained controls and splenectomized individuals. Physical exercise induced increase of WBC and significant changes in the percentage of most investigated lymphocyte subsets (NK, CD3+, CD4+, CD8+ and CD4/CD8 ratio), except for DR+ cells. No changes occurred in the percentage of CD14+ cells. Norepinephrine (NE) levels increased after effort, while epinephrine (E) and cortisol levels were unchanged. Splenectomized patients displayed similar effort-induced changes in investigated parameters as controls and swimmers. The results support the interactions between physical work and immune response and minimize the role of the spleen in this context.

Adult↗

Exercise restores immune cell function in energy-restricted rats.

OBJECTIVE: To evaluate the effect of chronic moderate-intensity exercise upon the alterations of immune system cell function induced by energy restriction. METHODS: Forty male Wistar rats were randomly assigned to the following groups: sedentary animals fed ad libitum (SF, N = 10) or submitted to energy restriction (SER, N = 10, receiving 50% of the mean amount of chow consumed by SF); and trained animals fed ad libitum (TF, N = 10) or submitted to energy restriction (TER, N = 10), who exercised on a treadmill (at 60-65%VO(2max) 5 d.wk(-1) for 10 wk(-1), after 30 d under the restriction protocol. The incorporation of [2-(14)C]-thymidine by lymphocytes obtained from the spleen and mesenteric lymph nodes, plasma glucose and glutamine concentration, and cytokine production by cells cultivated in the presence of glutamine were measured in all groups, 24 h after the last exercise session. Two-way ANOVA and Tukey's posttest were employed for the statistical analysis. RESULTS: Training induced an increase in the proliferative response and in the production of gamma-interferon and interleukin-1 (P < 0.05) in cells from the spleen and lymph nodes of SER, in which these parameters were diminished when compared with SF (P < 0.05). SER spleen and lymph node cells produced more TNF (26 and 42%, respectively) and IL-2 (49 and 42%, respectively) than SF. The Th1-like diversion of the immune response observed in SER persisted after training. Partial recovery of the decreased SER plasma glutamine concentration and muscle glutamine synthase mRNA was observed. CONCLUSIONS: Training induced the recovery of the proliferative capacity of lymphocytes from SER, probably due to the partial restoration of plasma glutamine levels, but did not interfere with the diversion towards a Th1-type immune response induced by food restriction.

Animals↗

The effects of acute and chronic exercise of immunoglobulins.

The effects of acute exercise (both graded-maximal and submaximal) and exercise training on resting immunoglobulin levels and immunoglobulin production are reviewed. Brief graded-maximal or intensive short term submaximal exercise tends to be associated with increases in serum immunoglobulins, the pattern of which does not vary between athletes and nonathletes. Plasma volume changes appear to largely explain these acute increases. Acute moderate exercise, such as a 45-minute bout of walking, on the other hand, has been associated with a transient rise in serum immunoglobulin levels despite no change in plasma volume. This increase is probably the result of contributions from extravascular protein pools and an increased lymph flow. Total serum immunoglobulin changes following less than 40 km of running are minor and/or statistically insignificant, although the concentration of IgG is observed to be at its lowest by 1.5 hours after exercise. The greatest effect of acute submaximal exercise appears to be on serum IgM levels which tend to increase, although results are somewhat inconsistent. Various mechanisms of stimulation have been proposed to explain the exercise-induced effect on IgM, which is the first antibody class produced in an immune response. These mechanisms include nonspecific noradrenergic sympathetic neural interactions with the immune system and the possibility of antigen stimulation through greater-than-normal quantities of microorganisms entering the body through both increased ventilation rates and breakdown of natural mucosal immunity by drying of airway secretions. When athletes run 45 to 75 km at high intensities, serum immunoglobulin levels have been reported to be depressed for up to 2 days. Thus intense ultramarathon running may lead to greater and longer lasting decreases in serum immunoglobulin levels than following exercise of shorter duration. IgA and IgG, immunoglobulins commonly found in airway and alveolar space secretions, may have diffused from the serum during recovery from prolonged endurance exercise nonspecifically and/or in response to microbial agents and antigens introduced into the airways during the exercise bout. It has been well established that prolonged endurance exercise is associated with muscle cell damage and local inflammation. It has been hypothesised that natural (IgM) autoantibodies may be used to assist macrophages in disposal of muscle cell breakdown products. This could occur either by IgM binding to breakdown products present in the blood, followed by their clearance from the circulation, or it is possible that these antibodies may leave the circulation to carry out this same function in tissues.(ABSTRACT TRUNCATED AT 400 WORDS)

Exercise↗

The enhancing effect of exercise on the production of antibody to Salmonella typhi in mice.

The effect of long-term regular and moderate exercise on antibody production has been studied in mice. Healthy mice were trained to run for 10 min twice a day, and antibody levels following immunization were compared with those of healthy sedentary control mice. The antibody levels of the running mice were significantly higher than those of the sedentary animals at all times tested, from 1 to 13 wk post immunization. Overall, the antibody titres of the runners were 2.76 times that of the controls. The significance of these findings is discussed.

Animals↗

Discrimination of MHC-derived odors by untrained mice is consistent with divergence in peptide-binding region residues.

Genes of the major histocompatibility complex (MHC) play a central role in immune recognition, yet they also influence the odor of individuals. Mice can be trained to distinguish odors mediated by classical MHC loci; however, training can introduce confounding behavioral artifacts. This study demonstrates that mice can distinguish some, but not all, naturally occurring allelic variants at classical MHC loci without prior training. This result suggests that MHC-disassortative mating preferences might operate by means of small MHC-based odor differences, and could therefore contribute to diversifying selection acting on MHC loci. Here we show that odors of two MHC mutant mouse strains (bm1 and bm3) can be distinguished, even after genetic background is controlled by intercrossing strains. These two strains differ by five amino acids, three of which are predicted to chemically contact peptides bound to the peptide-binding region (PBR), the site of antigen presentation for T cell recognition. However, the odors of neither bm1 nor bm3 were distinguished from their parental B6 haplotype after randomizing genomic background, despite discrimination of pure-bred B6 and bm1 strain odors. These combined results suggest that (i) there may be an MHC odor discrimination threshold based on divergence in PBR residues, providing a more logical pattern of MHC-based odor discrimination than found in previous training studies, where discrimination ability was not correlated with PBR divergence; and (ii) additional (non-MHC) mutations that influence odor have accumulated in these strains during the 100 generations of divergence between pure B6 and bm1 strains.

Alleles↗