Prevalence of and risk factors for self-reported menstrual changes following COVID-19 vaccination: a Danish cohort study.

STUDY QUESTION: Are there some characteristics that render individuals more susceptible to report menstrual changes following the Coronavirus disease 2019 (COVID-19) vaccination? SUMMARY ANSWER: We found that 30% of menstruating women reported menstrual changes following COVID-19 vaccination and several potential risk factors including stress, vaccine concerns, severe COVID-19 infection, and immediate vaccine symptoms were associated with these reports. WHAT IS KNOWN ALREADY: Studies suggest that COVID-19 vaccination might temporarily prolong menstrual cycle length by less than 1 day. Specific characteristics may trigger menstrual changes in temporal relation to the vaccination simply by chance or render women more vigilant to potential menstrual changes after being vaccinated. However, research investigating potential risk factors for reporting menstrual changes following COVID-19 vaccination is limited. STUDY DESIGN, SIZE, DURATION: A population-based Danish cohort study. Data were collected from May 2021 to December 2021 as a part of the BiCoVac Cohort with the aim of examining non-specific effects following COVID-19 vaccination. The main study population included 13 648 menstruating women aged 16-65 years who completed all surveys, received their first dose of a COVID-19 vaccine during the data collection period, and completed questions related to their menstrual cycle. PARTICIPANTS/MATERIALS, SETTING, METHODS: Potential risk factors included 14 biological, physical, or psychological measures. Information on most potential risk factors was self-reported and collected before the participants' first COVID-19 vaccination. Information about any menstrual change following COVID-19 vaccination was self-reported at the end of the data collection period. Logistic regression analyses were used to estimate crude and adjusted odds ratios (ORs) with 95% CIs for the association between each potential risk factor and reporting menstrual changes following COVID-19 vaccination. MAIN RESULTS AND THE ROLE OF CHANCE: Any menstrual change following COVID-19 vaccination was reported by 30% of menstruating women. Most of the potential risk factors were associated with reports of menstrual changes following COVID-19 vaccination. In particular, higher odds were found among women who reported ≥5 immediate vaccine symptoms; OR 1.67 [1.50-1.86], had had a prior severe COVID-19 infection; OR 2.17 [1.40-3.35], had a high-stress level at baseline; OR 1.67 [1.32-2.10], or were concerned about COVID-19 vaccines prior to vaccination; OR 1.92 [1.50-2.45]. Lower odds were found among women with regular menstrual cycles using hormonal contraception; OR 0.71 [0.65-0.78]. LIMITATIONS, REASONS FOR CAUTION: We were unable to address the causal effect of COVID-19 vaccination on the reported menstrual changes, as information about menstrual changes was not available among non-vaccinated women. WIDER IMPLICATIONS OF THE FINDINGS: The study identified several potential risk factors for reporting menstrual changes following COVID-19 vaccination. Further studies are needed to establish causal associations and the clinical impact of self-reported menstrual changes. STUDY FUNDING/COMPETING INTEREST(S): The BiCoVac data collection was funded by TrygFonden (id-number: 153678). No competing interests are declared. TRIAL REGISTRATION NUMBER: N/A.

Immediate adverse reactions following COVID-19 vaccination among 16-65-year-old Danish citizens.

INTRODUCTION: There is sparse knowledge of immediate adverse reactions following COVID-19 vaccination. OBJECTIVE: This study aimed to estimate the frequency and number of immediate adverse reactions following COVID-19 vaccination in a Danish population. METHODS: The study used data from the Danish population-based cohort study BiCoVac. The frequencies of 20 self-reported adverse reactions were estimated for each vaccine dose stratified by sex, age, and vaccine type. Also, the distributions of number of adverse reactions following each dose were estimated stratified by sex, age, vaccine type, and prior COVID-19 infection. RESULTS: A total of 889,503 citizens were invited and 171,008 (19 %) vaccinated individuals were included in the analysis. The most frequently reported adverse reaction following the first dose of COVID-19 vaccine was redness and/or pain at the injection site (20 %) while following the second and third dose, tiredness was the most frequently reported adverse reaction (22 % and 14 %, respectively). Individuals aged 26-35 years, females, and those with a prior COVID-19 infection were more likely to report adverse reactions compared with older individuals, males, and those with no prior COVID-19 infection, respectively. Following the first dose, individuals vaccinated with ChAdOx1-2 (AstraZeneca) reported more adverse reactions compared with individuals vaccinated with other vaccine types. Individuals vaccinated with mRNA-1273 (Moderna) reported more adverse reactions following the second and third dose compared with individuals vaccinated with BNT162b2 (Pfizer-BioNTech). CONCLUSION: The frequency of immediate adverse reactions was highest among females and younger persons, however, most of the Danish citizens did not experience immediate adverse reactions following COVID-19 vaccination.

Functional somatic symptoms in youths in general practice: A cross-sectional study on prevalence, clinical management and perceived burden.

OBJECTIVE: Functional somatic symptoms (FSS) may progress into a functional disorder if poorly managed, which may have serious implications. This cross-sectional study describes the management of youths compared to adults in general practice and estimates the prevalence of FSS in youths in this setting by comparing consultation-related aspects between youths with FSS and 1) youths with a specific diagnosis and 2) adults with FSS. METHODS: We used data from a Danish survey (2008-2009), including 3295 face-to-face consultations between GPs and patients aged 15-64 years. Patients were divided into youths (15-24 years) and adults (25-64 years) and then into subgroups according to the GPs' classifications: 1) specific diagnosis, 2) resolving symptom and 3) FSS. Logistic regression analysis was used for all comparisons, and estimates were adjusted for gender, concomitant chronic disorder and GP cluster. RESULTS: The GPs more frequently ensured continuity of care in adults (AOR:0.75, 95%CI:0.61-0.92, p < 0.01) and perceived youths as less time consuming (AOR:0.58, 95%CI: 0.43-0.77, p < 0.01) and less burdensome (AOR:0.60; 95%CI: 0.45-0.81, p < 0.01) compared to adults. FSS prevalence was 4.4% in youths and 9.0% in adults. However, GPs perceived youths with FSS as more burdensome (AOR:7.77, 95%CI:2.93-20.04, p < 0.01) and more time consuming (AOR:3.98, 95%CI:1.42-11.12, p < 0.01) than youths with a specific diagnosis. No significant differences were found between youths and adults with FSS, respectively, in regards to perceived burden and consultation time. CONCLUSION: The results indicate age-related variations in the prevalence and clinical management of FSS in general practice. The GPs perceived both youths and adults with FSS time consuming, which underlines a need for supportive management strategies.

Attachment and symptom reporting in adolescents and young adults after a concussion.

BACKGROUND: The incidence of hospital-treated concussion is 100-300/100,000 person years. Reporting of long-lasting post-concussion symptoms (PCS) is estimated at 5-15%. Attachment insecurity is a potential vulnerability factor for physical illness and poorer disease outcomes in general. This study aimed to explore associations between attachment insecurity and PCS in young people sustaining a concussion. METHODS: This cross-sectional study was embedded in a cohort of 15-30-year-old patients (n = 3080) 3 months after sustaining a concussion. Data were obtained from a database and questionnaires. PCS were measured by the Rivermead Post-Concussion Symptoms Questionnaire and attachment dimensions (anxiety and avoidance) by the Experiences in Close Relationships-Relationship Structures Questionnaire. Multiple linear regression models were performed to investigate the association between the attachment dimensions and PCS with adjustment for demographic, injury-related and psychological factors and with additional testing for interaction between the attachment dimensions. RESULTS: In the final study sample, comprising 973 patients (31.6%), we found an interaction between the attachment dimensions. Hence, the effect of attachment anxiety on PCS was statistically insignificant at low avoidance (25th percentile) but significant at high avoidance (75th percentile, ß = 0.64 (95%CI: 0.02; 1.26)), whereas the effect of attachment avoidance was significant regardless of level of attachment anxiety (25th percentile, ß = 1.09 (95%CI: 0.18; 2.01); 75th percentile, ß = 2.71 (95%CI: 1.80; 3.61)). CONCLUSION: Attachment insecurity, especially characterised by high avoidance in combination with high anxiety, also called fearful attachment, is associated with PCS. Considering the attachment perspective can potentially improve health care for this patient group.

Self-help interventions for young people with persistent physical symptoms: A systematic review.

OBJECTIVE: Persistent physical symptoms are frequent among young people causing considerable social, psychological, and economic consequences. Easily accessible interventions adapted to non-specialized settings are needed. We aimed to systematically review randomized controlled trials on self-help interventions for young people with persistent physical symptoms compared to active or passive control groups. Our purpose was to 1) describe applied therapeutic approaches and content and 2) examine potential effects on symptom burden and psychosocial outcomes. METHODS: We included randomized controlled trials on minimal contact self-help interventions for young people with persistent physical symptoms. Systematic literature searches in PubMed, Cochrane Central, Embase, and PsycINFO were conducted. Study selection, data extraction and quality assessment were performed independently by two reviewers. A narrative synthesis of the effects was performed. RESULTS: We identified 11 studies on self-help interventions for young people. The methodological quality of the studies was generally low. Participants suffered from impairing fatigue, headache, abdominal pain, and musculoskeletal or multi-site pain. Applied therapeutic approaches were cognitive behavioral therapy, relaxation training, hypnotherapy, and written self-disclosure. Outcomes were diverse and mainly related to symptom burden, whereas psychosocial outcomes were only sporadically examined. Overall, evidence of effectiveness of self-help interventions in alleviating symptom burden was weak, and potential effects could not be linked to one specific theoretical approach. CONCLUSION: Few self-help interventions of diverse content exist for young people with persistent physical symptoms. Rigorously designed studies that include recommended outcome domains assessed by aligned measures are needed to determine and compare the clinical value of such interventions.

"Understand your illness and your needs": Assessment-informed patient education for people with multiple functional somatic syndromes.

OBJECTIVES: Patients suffering from multiple functional somatic syndromes (FSS) such as fibromyalgia, chronic fatigue syndrome, or irritable bowel syndrome, often lack both a clear diagnosis and tangible illness explanations, which is a barrier for treatment engagement. We tested a short-term intervention taking the unifying concept of Bodily Distress Syndrome (BDS) as a point of departure. The intervention consisted of a clinical assessment, group-based patient education, and one follow-up consultation. METHODS: 174 patients were included and received questionnaires at baseline, after clinical assessment, after patient education, and median 19 weeks after baseline. Data were analyzed using random effects models and simple t-tests. Qualitative data were thematically analyzed. RESULTS: We found small reductions in symptom levels, considerable reductions in illness worry, and improvement of illness perceptions and illness-related behaviors. Overall, patients evaluated the intervention positively and expressed high expectations for further treatment. Qualitative results mainly supported these findings. CONCLUSION: Targeting illness perceptions through patient education is crucial to obtain patient engagement in self-help management or further treatment. This may lead to improved outcomes. PRACTICAL IMPLICATIONS: Physicians in primary and secondary care should strive to give patients with multiple FSS a clear understanding that their various FSS diagnoses are related and provide tangible illness explanations.

Introducing the White Noise task in childhood: associations between speech illusions and psychosis vulnerability.

BACKGROUND: Auditory verbal hallucinations (AVH) are common during development and may arise due to dysregulation in top-down processing of sensory input. This study was designed to examine the frequency and correlates of speech illusions measured using the White Noise (WN) task in children from the general population. Associations between speech illusions and putative risk factors for psychotic disorder and negative affect were examined. METHOD: A total of 1486 children aged 11-12 years of the Copenhagen Child Cohort 2000 were examined with the WN task. Psychotic experiences and negative affect were determined using the Kiddie-SADS-PL. Register data described family history of mental disorders. Exaggerated Theory of Mind functioning (hyper-ToM) was measured by the ToM Storybook Frederik. RESULTS: A total of 145 (10%) children experienced speech illusions (hearing speech in the absence of speech stimuli), of which 102 (70%) experienced illusions perceived by the child as positive or negative (affectively salient). Experiencing hallucinations during the last month was associated with affectively salient speech illusions in the WN task [general cognitive ability: adjusted odds ratio (aOR) 2.01, 95% confidence interval (CI) 1.03-3.93]. Negative affect, both last month and lifetime, was also associated with affectively salient speech illusions (aOR 2.01, 95% CI 1.05-3.83 and aOR 1.79, 95% CI 1.11-2.89, respectively). Speech illusions were not associated with delusions, hyper-ToM or family history of mental disorders. CONCLUSIONS: Speech illusions were elicited in typically developing children in a WN-test paradigm, and point to an affective pathway to AVH mediated by dysregulation in top-down processing of sensory input.

The interleukin-33 receptor ST2 is important for the development of peripheral airway hyperresponsiveness and inflammation in a house dust mite mouse model of asthma.

BACKGROUND: Several clinical and experimental studies have implicated IL-33 and its receptor ST2 in the development of asthma. However, the effect of IL-33/ST2 signalling on airway responses and inflammation in allergic asthma is not well established. OBJECTIVE: To investigate the role of IL-33/ST2 signalling in promoting allergen-induced airway hyperresponsiveness (AHR), airway inflammation, antigen-specific IgE production and mast cell activity in a mouse model of asthma. METHODS: ST2-deficient (ST2(-/-)) mice and control BALB/c mice were given house dust mite (HDM) extract over a 6-week period. Forty-eight hours after the final HDM administration, lung function and airway inflammation were evaluated. Airway responsiveness was determined in the central airways and peripheral lung. Cellular infiltration and mast cell protease mMCP-1 levels were quantified in bronchoalveolar lavage fluid (BALF). Recruitment of inflammatory cells and inflammatory cytokine profiles were assessed in pulmonary tissue, and HDM-specific IgE was measured in serum. RESULTS: ST2 deficiency diminished HDM-induced AHR in the peripheral lung, while AHR in the central airways was unaffected. Inflammatory responses to HDM were also reduced in ST2(-/-) mice as reflected by the lower induction of HDM-specific serum IgE, inhibition of HDM-induced eosinophilia and reduced macrophage count in BALF, and a diminished influx of inflammatory cells and reduced goblet cell hyperplasia around the peripheral airways. Furthermore, the levels of the inflammatory cytokines IL-1ß, IL-5, IL-13, IL-33, GM-CSF, thymic stromal lymphopoietin and mast cell protease mMCP-1 were reduced in HDM-treated ST2(-/-) mice compared with wild-type controls. CONCLUSIONS: In addition to promoting Th2 inflammation, we now suggest a role for the IL-33/ST2 pathway for the induction of peripheral inflammation and mucus production that causes AHR in the peripheral lung. This mechanism for inducing AHR at distal parts of the lung may be of specific importance as asthma is considered as a small airway disease.

Psychotic experiences and hyper-theory-of-mind in preadolescence--a birth cohort study.

BACKGROUND: Knowledge on the risk mechanisms of psychotic experiences (PE) is still limited. The aim of this population-based study was to explore developmental markers of PE with a particular focus on the specificity of hyper-theory-of-mind (HyperToM) as correlate of PE as opposed to correlate of any mental disorder. METHOD: We assessed 1630 children from the Copenhagen Child Cohort 2000 regarding PE and HyperToM at the follow-up at 11-12 years. Mental disorders were diagnosed by clinical ratings based on standardized parent-, teacher- and self-reported psychopathology. Logistic regression analyses were performed to test the correlates of PE and HyperToM, and the specificity of correlates of PE v. correlates of any Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) mental disorder. RESULTS: Univariate analyses showed the following correlates of PE: familial psychiatric liability; parental mental illness during early child development; change in family composition; low family income; regulatory problems in infancy; onset of puberty; bullying; concurrent mental disorder; and HyperToM. When estimating the adjusted effects, only low family income, concurrent mental disorder, bullying and HyperToM remained significantly associated with PE. Further analyses of the specificity of these correlates with regard to outcome revealed that HyperToM was the only variable specifically associated with PE without concurrent mental disorder. Finally, HyperToM did not share any of the investigated precursors with PE. CONCLUSIONS: HyperToM may have a specific role in the risk trajectories of PE, being specifically associated with PE in preadolescent children, independently of other family and child risk factors associated with PE and overall psychopathology at this age.

Differential effect on cell-mediated immunity in human volunteers after intake of different lactobacilli.

Probiotics are live microorganisms which have beneficial effects on the host when ingested in adequate amounts. Probiotic bacteria may stimulate immune effector functions in a strain-specific manner. In this blind placebo-controlled trial, we investigated the effects on the immune system following daily intake of six different strains of lactobacilli or the Gram-negative bacterium Pseudomonas lundensis for 2 or 5 weeks. Blood lymphocyte subsets were quantified by fluorescence activated cell sorter and the expression of activation and memory markers was determined. The bacterial strains were also examined for their capacity to adhere to human intestinal cells and to be phagocytosed by human peripheral blood mononuclear cells. Intake of Lactobacillus plantarum strain 299v increased the expression of the activation marker CD25 (P = 0·01) on CD8(+) T cells and the memory cell marker CD45RO on CD4(+) T cells (P = 0·03), whereas intake of L. paracasei tended to expand the natural killer T (NK T) cell population (P = 0·06). The phagocytic activity of granulocytes was increased following intake of L. plantarum 299v, L. plantarum HEAL, L. paracasei or L. fermentum. In contrast, ingestion of L. rhamnosus decreased the expression of CD25 and CD45RO significantly within the CD4(+) cell population. The observed immune effects after in-vivo administration of the probiotic bacteria could not be predicted by either their adherence capacity or the in-vitro-induced cytokine production. The stimulation of CD8(+) T cells and NK T cells suggests that intake of probiotic bacteria may enhance the immune defence against, e.g. viral infections or tumours.

An alternative allergen:adjuvant formulation potentiates the immunogenicity and reduces allergenicity of a novel subcutaneous immunotherapy product for treatment of grass-pollen allergy.

BACKGROUND: Subcutaneous specific immunotherapy (SCIT) has proven sustained clinical efficacy against allergy. The recommended regimen for SCIT is a gradual updosing over a period of weeks. Commonly, in commercial products for SCIT, the specific allergen is formulated with an adjuvant, most often in the form of aluminium hydroxide (AlOH). It has been shown that allergen-specific IgG antibodies are induced as a result of successful SIT. OBJECTIVE: To investigate the possibility of optimizing the formulation of AlOH-based grass-pollen allergy vaccines for SCIT in a way that allows for shorter updosing regimens while maintaining the immunogenicity of the vaccine. METHODS: Mice were immunized with various concentrations of Phleum pratense (Phl p) allergen extract and AlOH or a fixed dilution of the maintenance doses of one conventional and one alternatively formulated vaccine. The kinetics of Phl p-specific IgG antibody responses in serum and spleen T cell responses were determined. Allergenicity, measured as the ability of the formulations to activate human basophils, was also determined. In addition, human T cell responses and the expression of dendritic cell surface markers after vaccine challenge in vitro were analysed. RESULTS: Specific IgG antibody responses were shown to depend on the AlOH concentration, but not on the allergen concentrations. The immunogenicity of the conventional formulation and the alternative formulation was shown to be similar with regard to the in vivo-induced IgG and T cell responses. In contrast, the allergenicity of the alternative formulation was significantly reduced compared with the conventional formulation. CONCLUSION: The optimization of the formulation allows for administration of a lower dose of allergen while maintaining the immunogenicity of the product and at the same time reducing allergenicity. CLINICAL RELEVANCE: This study indicates that the optimization of the allergen and the adjuvant formulation could benefit the safety/efficacy profile and allow for shorter updosing.

Shorter dosing intervals of sublingual immunotherapy lead to more efficacious treatment in a mouse model of allergic inflammation.

Current day practice of sublingual immunotherapy (SLIT) includes varying modalities of treatment that differ with regard to formulation, dosing and administration regimens. The aim of this study was to explore the importance of the dosing intervals in SLIT. The immunological effect of increased SLIT dosing frequency was tested in a mouse model of allergic inflammation. Mice sensitized to Phleum pratense (Phl p) were SLIT-treated with the same weekly cumulative dose administered with different administration frequencies. A SLIT sham-treated group was also included. All mice were challenged intra-nasally with Phl p extract following SLIT. Local and systemic cytokine production, eosinophil infiltration into airways and the development of Phl p-specific antibody responses were determined. Higher frequency of sublingual administration of allergen extract has a profound positive impact on the effect of SLIT, measured as induction of IgG and IgA antibodies. The once daily SLIT was the only treatment regimen being able to reduce all systemic Th2 cytokines and systemic IgE antibody responses when compared to sham-treated mice after the intra-nasal challenge period. The group receiving SLIT with the highest frequency of administration had the most pronounced effect of the treatment. In the same group, there was also a higher degree of protection against increase in IgE antibody levels after intra-nasal challenge with the allergen, our data demonstrate that a once daily regimen is more efficacious than regimens where SLIT, with the same weekly cumulative allergen dose, is administered with longer intervals but higher doses.

Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP panel: clinical trial design.

The International Campaign for Cures of Spinal Cord Injury Paralysis established a panel tasked with reviewing the methodology for clinical trials for spinal cord injury (SCI), and making recommendations on the conduct of future trials. This is the fourth of four papers. Here, we examine the phases of a clinical trial program, the elements, types, and protocols for valid clinical trial design. The most rigorous and valid SCI clinical trial would be a prospective double-blind randomized control trial utilizing appropriate placebo control subjects. However, in specific situations, it is recognized that other trial procedures may have to be considered. We review the strengths and limitations of the various types of clinical trials with specific reference to SCI. It is imperative that the design and conduct of SCI clinical trials should meet appropriate standards of scientific inquiry to insure that meaningful conclusions about efficacy and safety can be achieved and that the interests of trial subjects are protected. We propose these clinical trials guidelines for use by the SCI clinical research community.

Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP Panel: clinical trial inclusion/exclusion criteria and ethics.

The International Campaign for Cures of Spinal Cord Injury Paralysis established a panel tasked with reviewing the methodology for clinical trials for spinal cord injury (SCI), and making recommendations on the conduct of future trials. This is the third of four papers. It examines inclusion and exclusion criteria that can influence the design and analysis of clinical trials in SCI, together with confounding variables and ethical considerations. Inclusion and exclusion criteria for clinical trials should consider several factors. Among these are (1) the enrollment of subjects at appropriate stages after SCI, where there is supporting data from animal models or previous human studies; (2) the severity, level, type, or size of the cord injury, which can influence spontaneous recovery rate and likelihood that an experimental treatment will clinically benefit the subject; and (3) the confounding effects of various independent variables such as pre-existing or concomitant medical conditions, other medications, surgical interventions, and rehabilitation regimens. An issue of substantial importance in the design of clinical trials for SCI is the inclusion of blinded assessments and sham surgery controls: every effort should be made to address these major issues prospectively and carefully, if clear and objective information is to be gained from a clinical trial. The highest ethical standards must be respected in the performance of clinical trials, including the adequacy and clarity of informed consent.

A full flora, but not monocolonization by Escherichia coli or lactobacilli, supports tolerogenic processing of a fed antigen.

Fed protein undergoes processing and coupling to major histocompatibility complex (MHC) II molecules during passage through the intestinal epithelium, generating a tolerogenic form of the antigen in serum. Transfer of this factor to naïve animals induces tolerance in the recipient. In this study, we investigate what impact colonization with Gram-positive (Lactobacillus plantarum) or Gram-negative (Escherichia coli) bacteria has on tolerogenic processing in the gut. Germ-free (GF), monocolonized or conventional mice were fed ovalbumin (OVA), and their serum was collected and transferred to naïve conventional recipients that were tested for delayed-type hypersensitivity against OVA after parenteral immunization. A transferable tolerogenic factor was produced by conventional mice, but not by mice that were germ free or monocolonized with either E. coli or L. plantarum. Conventional, but neither GF nor monocolonized mice showed upregulation of MHCII expression in the epithelium of small intestine. The results suggest that a complex intestinal microflora is needed to support oral tolerance development.

Prolonged oral treatment with low doses of allergen conjugated to cholera toxin B subunit suppresses immunoglobulin E antibody responses in sensitized mice.

BACKGROUND: Oral tolerance is a long recognized method for inducing systemic immunological tolerance. However, large doses of antigen and frequent administrations are often required. By linking the antigen to the nontoxic mucosa-binding B subunit of cholera toxin (CTB), the required amount can be dramatically reduced. We have previously shown that mucosal administration of small amounts of antigens coupled to CTB can suppress peripheral Th1 cell-reactivity and associated inflammatory immunopathology in both naive and systemically-immunized animals. Induction of oral tolerance by repeated feeding of relatively small doses of antigen has, in some cases been shown to involve the generation of regulatory Th2-like CD4+ T cells, and hence could promote rather than suppress type I immunoglobulin (Ig) E-mediated allergic responses. OBJECTIVES: We examined whether oral prophylactic or therapeutic administration of a model allergen coupled to CTB would modulate allergen-specific IgE responses in high IgE responder Balb/c mice. METHODS: Ovalbumin (OVA) was used as a model allergen. Mice were treated perorally with free or CTB-coupled OVA before or after systemic priming with alum-adsorbed OVA. Allergen-specific IgE levels in serum were measured with the passive cutaneous anaphylaxis test at various time-points. RESULTS: Oral administration of a single low dose of CTB-linked OVA, prior to systemic sensitization and challenge with OVA, suppressed allergen-specific serum IgE antibody responses. Treatment with comparable doses of free OVA was much less effective. Most importantly, oral treatment with CTB-OVA conjugate could also suppress an already initiated IgE antibody response, but to achieve such a 'therapeutic effect', administration of multiple low doses of conjugate over a long time was required. Oral treatment with CTB-OVA conjugate could also effectively suppress antigen-specific Th1-mediated delayed-type hypersensitivity. Thus treatment with a CTB-conjugated model allergen can affect a broad range of T-cell-driven immune responses, even in antigen-experienced animals. CONCLUSION: These results may impact on the development of therapeutic vaccines against type I allergies.

A phase II trial of nerve growth factor for sensory neuropathy associated with HIV infection. AIDS Clinical Trials Group Team 291.

OBJECTIVE: To evaluate the safety and efficacy of recombinant human nerve growth factor (rhNGF) in HIV-associated sensory neuropathy (SN) within a multicenter, placebo-controlled, randomized trial (ACTG 291). BACKGROUND: SN affects 30% of individuals with AIDS, is worsened by neurotoxic antiretrovirals, and its treatment is often ineffective. NGF is trophic for small sensory neurons and stimulates the regeneration of damaged nerve fibers. METHODS: A total of 270 patients with HIV-associated SN were randomized to receive placebo, 0.1 microg/kg rhNGF, or 0.3 microg/kg rhNGF by double-blinded subcutaneous injection twice weekly for 18 weeks. The primary outcome was change in self-reported neuropathic pain intensity (Gracely Pain Scale). Secondary outcomes included an assessment of global improvement in neuropathy by patients and investigators, neurologic examination, use of prescription analgesics, and quantitative sensory testing. In a subset, epidermal nerve fiber densities were determined in punch skin biopsies. RESULTS: Both doses of NGF produced significant improvements in average and maximum daily pain compared with placebo. Positive treatment effects were also observed for global pain assessments (p = 0.001) and for pin sensitivity (p = 0.019). No treatment differences were found with respect to mood, analgesic use, or epidermal nerve fiber densities. Injection site pain was the most frequent adverse event, and resulted in unblinding in 39% of subjects. Severe transient myalgic pain occurred in eight patients, usually from accidental overdosing. There were no changes in HIV RNA levels or other laboratory indices. CONCLUSIONS: We found a positive effect of recombinant human nerve growth factor on neuropathic pain and pin sensitivity in HIV-associated sensory neuropathy. rhNGF was safe and well tolerated, but injection site pain was frequent.

[Invasive aspergillosis in hematological patients]. / Invasiv aspergillose hos haematologiske patienter.

An increasing incidence of invasive aspergillosis over the last decades is well documented in patients with haematological malignancies and is the most significant fungal infection in patients undergoing bone marrow transplantation and in aplastic anaemia. The diagnosis is difficult as clinical signs and symptoms usually are non-specific, but can be supported by frequent radiological examinations of the chest and sinuses and successive demonstrations of Aspergillus antigen in serum. The prognosis depends on the course of the underlying disease. A regeneration of the neutrophil granulocyte number is a condition for successful treatment. Early antifungal therapy is often necessary in neutropenic patients with fever and a lung infiltrate that does not remit following broad spectrum antibacterial treatment. Because of the risk of relapse after successful treatment these patients should receive prophylactic antifungal treatment during subsequent neutropenic episodes.