Genesis and pathogenesis of the 1918 pandemic H1N1 influenza A virus

The source, timing, and geographical origin of the 1918–1920 pandemic influenza A virus have remained tenaciously obscure for nearly a century, as have the reasons for its unusual severity among young adults. Here, we reconstruct the origins of the pandemic virus and the classic swine influenza and (postpandemic) seasonal H1N1 lineages using a host-specific molecular clock approach that is demonstrably more accurate than previous methods. Our results suggest that the 1918 pandemic virus originated shortly before 1918 when a human H1 virus, which we infer emerged before ∼1907, acquired avian N1 neuraminidase and internal protein genes. We find that the resulting pandemic virus jumped directly to swine but was likely displaced in humans by ∼1922 by a reassortant with an antigenically distinct H1 HA. Hence, although the swine lineage was a direct descendent of the pandemic virus, the post-1918 seasonal H1N1 lineage evidently was not, at least for HA. These findings help resolve several seemingly disparate observations from 20th century influenza epidemiology, seroarcheology, and immunology. The phylogenetic results, combined with these other lines of evidence, suggest that the highmortality in 1918 among adults aged ∼20 to ∼40 y may have been due primarily to their childhood exposure to a doubly heterosubtypic putative H3N8 virus, which we estimate circulated from ∼1889–1900. All other age groups (except immunologically naive infants) were likely partially protected by childhood exposure to N1 and/or H1-related antigens. Similar processes may underlie age-specific mortality differences between seasonal H1N1 vs. H3N2 and human H5N1 vs. H7N9 infections

Gender differences in local and systemic reactions to inactivated influenza vaccine, established by a meta-analysis of fourteen independent studies

In order to determine whether there is a difference between genders in reported adverse reactions to inactivated influenza vaccine, a computerized database of serological studies was investigated. A standardized questionnaire was used to evaluate vaccine reactogenicity. A total of 1,800 vaccinees in 14 studies were analyzed separately for two age groups ( or = 60 years of age). Females reported significantly more local reactions than males. The pooled odds ratio for the outcome measure "any local reaction" was 0.32 (95% confidence interval, 0.26-0.40, significant) and 0.54 (95% Cl, 0.41-0.70, significant) for young and elderly adults, respectively. Similar results were obtained for the outcome measure "any systemic reaction." Previous exposure to influenza or influenza vaccine had no influence on reactogenicity. There were no gender differences in sero-responses. In conclusion, gender should be regarded as a predictor of reported reactions to influenza vaccine in both young and elderly adults and should be addressed in future study designs

Humoral immune response and delayed type hypersensitivity to influenza vaccine in patients with diabetes mellitus

The antibody response and delayed type hypersensitivity reaction to commercially available trivalent influenza vaccine in 159 patients with diabetes mellitus was compared with response and reaction in 28 healthy volunteers. A correction for prevaccination titres was made. No differences were found between diabetic patients and control subjects with respect to antibody response to the three vaccine strains as measured by the difference between geometric mean titres of post- and prevaccination sera. In Type 1 (insulin-dependent) diabetic patients the incidence of non-responders to two vaccine components was significantly increased (p less than 0.05). The delayed type hypersensitivity reaction to influenza antigen was significantly decreased in patients with high concentrations of glycosylated haemoglobin (p less than 0.01). These findings suggest a role for impaired immune response in the increased influenza morbidity and mortality in patients with diabetes mellitus. Implications for therapy and vaccination strategy are discussed

Humoral immune response to influenza vaccination in patients with primary immunoglobulin A nephropathy. An analysis of isotype distribution and size of the influenza-specific antibodies.

Primary IgA nephropathy (IgAN) is characterized by mesangial deposits of IgA1, increased serum IgA1 levels, and circulating immune complexes containing predominantly IgA1. It has previously been found that patients with IgAN have a higher than normal IgA response to vaccination, but the IgA subclasses have not been studied. To investigate whether the IgA hyperresponsiveness is limited to the subclass IgA1, which is involved in the pathogenesis of IgAN, we compared the immune responses of 18 patients with 22 healthy controls after intramuscular vaccination with inactivated influenza virus. Antibody titers were significantly higher (P less than 0.0001) for the IgA1 subclass in patients versus controls, but not for the other isotypes. A substantial portion of the IgA and IgA1 antiinfluenza immune response comprised polymers in both patients and controls. There was no preferential response of polymers in patients. Patients produced significantly more monomeric IgA1 antibodies than controls. These results show that patients with IgAN have a hyperresponsiveness limited to the subclass IgA1 and mainly expressed by an excess of monomers

Interleukin-7 deficiency in rheumatoid arthritis: consequences for therapy-induced lymphopenia

We previously demonstrated prolonged, profound CD4+ T-lymphopenia in rheumatoid arthritis (RA) patients following lymphocyte-depleting therapy. Poor reconstitution could result either from reduced de novo T-cell production through the thymus or from poor peripheral expansion of residual T-cells. Interleukin-7 (IL-7) is known to stimulate the thymus to produce new T-cells and to allow circulating mature T-cells to expand, thereby playing a critical role in T-cell homeostasis. In the present study we demonstrated reduced levels of circulating IL-7 in a cross-section of RA patients. IL-7 production by bone marrow stromal cell cultures was also compromised in RA. To investigate whether such an IL-7 deficiency could account for the prolonged lymphopenia observed in RA following therapeutic lymphodepletion, we compared RA patients and patients with solid cancers treated with high-dose chemotherapy and autologous progenitor cell rescue. Chemotherapy rendered all patients similarly lymphopenic, but this was sustained in RA patients at 12 months, as compared with the reconstitution that occurred in cancer patients by 3–4 months. Both cohorts produced naïve T-cells containing T-cell receptor excision circles. The main distinguishing feature between the groups was a failure to expand peripheral T-cells in RA, particularly memory cells during the first 3 months after treatment. Most importantly, there was no increase in serum IL-7 levels in RA, as compared with a fourfold rise in non-RA control individuals at the time of lymphopenia. Our data therefore suggest that RA patients are relatively IL-7 deficient and that this deficiency is likely to be an important contributing factor to poor early T-cell reconstitution in RA following therapeutic lymphodepletion. Furthermore, in RA patients with stable, well controlled disease, IL-7 levels were positively correlated with the T-cell receptor excision circle content of CD4+ T-cells, demonstrating a direct effect of IL-7 on thymic activity in this cohort

Nocturnal hypoglycaemia in type 1 diabetic patients, assessed with continuous glucose monitoring: frequency, duration and associations

WSTĘP. W niniejszej pracy określono ilościowo częstość występowania i czas trwania epizodów nocnej hipoglikemii u chorych na cukrzycę typu 1, leczonych ciągłym podskórnym wlewem insuliny (CSII) lub za pomocą wielokrotnych wstrzyknięć insuliny (MIT), wykorzystując ciągły podskórny pomiar glukozy z zastosowaniem czujnika. METODY. Czujnik mikrodializacyjny był noszony w warunkach domowych przez 24 pacjentów leczonych CSII (średnie stężenie HbA1c 7,8 ± 0,9%) oraz przez 33 pacjentów, u których stosowano MIT (średnie stężenie HbA1c 8,7 ± 1,3%) przez 48 godzin. Oceniano częstość występowania i czas trwania epizodów hipoglikemii oraz związek między stężeniem HbA1c, czasem trwania cukrzycy, sposobem jej leczenia (CSII vs. MIT), wartościami glikemii na czczo oraz przed spoczynkiem nocnym, całkowitą dobową dawką insuliny, a także średnimi wartościami glikemii w nocy a częstością występowania i czasem trwania epizodów hipoglikemii. WYNIKI. Epizody nocnej hipoglikemii z wartościami glikemii ≤ 3,9 mmol/l wystąpiły u 33,3% pacjentów w obu grupach - zarówno w grupie leczonej CSII (8/24), jak i stosującej MIT (11/33). średni czas trwania hipoglikemii (± SD; mediana, przedział międzykwartylowy) wynosił 78 min na noc (± 76; 57, 23-120) u chorych poddanych CSII oraz 98 min na noc (± 80; 81, 32-158) u pacjentów stosujących MIT. W analizie metodą regresji wieloczynnikowej wykazano, że glikemia przed spoczynkiem nocnym najsilniej wiąże się z częstoœcią (p = 0,026) oraz czasem trwania (p = 0,032) epizodów nocnej hipoglikemii. WNIOSKI. Ciągłe monitorowanie glikemii z wykorzystaniem metody mikrodializy umożliwiło bardziej precyzyjne określenie ilościowe częstoœci występowania i czasu trwania epizodów nocnej hipoglikemii u chorych na cukrzycę typu 1. Parametry te wiążą się głównie z wartościami glikemii przed spoczynkiem nocnym.AIMS. We quantified the occurrence and duration of nocturnal hypoglycaemia in individuals with type 1 diabetes treated with continuous subcutaneous insulin infusion (CSII) or multiple-injection therapy (MIT) using a continuous subcutaneous glucose sensor. METHODS. A microdialysis sensor was worn at home by 24 patients on CSII (mean HbA1c 7.8 ± 0.9%) and 33 patients on MIT (HbA1c 8.7 ± 1.3%) for 48 h. Occurrence and duration of nocturnal hypoglycaemia were assessed and using multivariate regression analysis, the association between HbA1c, diabetes duration, treatment type (CSII vs. MIT), fasting and bedtime blood glucose values, total daily insulin dose and mean nocturnal glucose concentrations, and hypoglycaemia occurrence and duration was investigated. RESULTS. Nocturnal hypoglycaemia ≤ 3.9 mmol/l occurred in 33.3% of both the CSII- (8/24) and MITtreated patients (11/33). Mean (± SD; median, interquartile range) duration of hypoglycaemia ≤ 3.9 mmol/l was 78 (± 76; 57, 23-120) min per night for the CSII- and 98 (± 80; 81, 32-158) min per night for the MIT-treated group. Multivariate regression analysis showed that bedtime glucose value had the strongest association with the occurrence (p = 0.026) and duration (p = 0.032) of nocturnal hypoglycaemia. CONCLUSIONS. Microdialysis continuous glucose monitoring has enabled more precise quantification of nocturnal hypoglycaemia occurrence and duration in type 1 diabetic patients. Occurrence and duration of nocturnal hypoglycaemia were mainly associated with bedtime glucose value

Swine Influenza A Outbreak, Fort Dix, New Jersey, 1976

Published literature and events surrounding the outbreak are reviewed

Search for the best indicators for the presence of a VPS13B gene mutation and confirmation of diagnostic criteria in a series of 34 patients genotyped for suspected Cohen syndrome

BACKGROUND: Cohen syndrome is a rare autosomal recessive inherited disorder that results from mutations of the VPS13B gene. Clinical features consist of a combination of mental retardation, facial dysmorphism, postnatal microcephaly, truncal obesity, slender extremities, joint hyperextensibility, myopia, progressive chorioretinal dystrophy, and intermittent neutropenia.PATIENTS AND METHODS: The aim of the study was to determine which of the above clinical features were the best indicators for the presence of VPS13B gene mutations in a series of 34 patients with suspected Cohen syndrome referred for molecular analysis of VPS13B. RESULTS: 14 VPS13B gene mutations were identified in 12 patients, and no mutation was found in 22 patients. The presence of chorioretinal dystrophy (92% vs 32%, p=0.0023), intermittent neutropenia (92% vs 5%, p<0.001), and postnatal microcephaly (100% vs 48%, p=0.0045) was significantly higher in the group of patients with a VPS13B gene mutation compared to the group of patients without a mutation. All patients with VPS13B mutations had chorioretinal dystrophy and/or intermittent neutropenia. The Kolehmainen diagnostic criteria provided 100% sensibility and 77% specificity when applied to this series. CONCLUSION: From this study and a review of more than 160 genotyped cases from the literature, it is concluded that, given the large size of the gene, VPS13B screening is not indicated in the absence of chorioretinal dystrophy or neutropenia in patients aged over 5 years. The follow-up of young patients could be a satisfactory alternative unless there are some reproductive issues

Antibody landscapes after influenza virus infection or vaccination.

We introduce the antibody landscape, a method for the quantitative analysis of antibody-mediated immunity to antigenically variable pathogens, achieved by accounting for antigenic variation among pathogen strains. We generated antibody landscapes to study immune profiles covering 43 years of influenza A/H3N2 virus evolution for 69 individuals monitored for infection over 6 years and for 225 individuals pre- and postvaccination. Upon infection and vaccination, titers increased broadly, including previously encountered viruses far beyond the extent of cross-reactivity observed after a primary infection. We explored implications for vaccination and found that the use of an antigenically advanced virus had the dual benefit of inducing antibodies against both advanced and previous antigenic clusters. These results indicate that preemptive vaccine updates may improve influenza vaccine efficacy in previously exposed individuals.This is the author’s version of the work. It will be under embargo for 6 months following publication. It is posted here by permission of the AAAS for personal use, not for redistribution. The final version is available from AAAS in Science at http://www.sciencemag.org/content/346/6212/996.long

Policy drivers of international entrepreneurship in Europe

The diversity of countries and cultures in Europe necessitates an international outlook for most businesses. This paper examines the internationalisation of business in Europe through a literature review on international entrepreneurship theory. The role of the individual business owner and of business and interorganisational activity in facilitating the internationalisation of businesses in Europe is discussed by utilising the theoretical framework of international entrepreneurship and by putting forward three main propositions. The main aim and intent of this paper is to understand how the policies of individual governments and institutions such as the European Union help businesses in Europe to internationalise, with particular emphasis on businesses in the Baltic region. The paper discusses policy implications and suggestions for future research, which highlight the importance for firms in Europe of focussing on international markets.<br /