Dipeptidyl-peptidase-4 inhibitors and pancreatic cancer: a cohort study.

AIM: To compare pancreatic cancer incidence and diagnostic evaluation among patients initiating dipeptidyl-peptidase-4 (DPP-4) inhibitor treatment with those initiating sulfonylureas (SU) and thiazolidinediones (TZD). METHODS: Medicare claims data were examined in a new-user active-comparator cohort study. Patients >65 years with no prescriptions for DPP-4 inhibitors, SU or TZD at baseline were included if they had at least two claims for the same drug within 180 days. Using an as-treated approach and propensity score-adjusted Cox models, we estimated the hazard ratios (HRs) and 95% confidence intervals (CIs) for pancreatic cancer. Diagnostic evaluations were compared using risk ratios. RESULTS: In the DPP-4 inhibitor versus SU comparison, there were 18 179 patients who initiated treatment with DPP-4 inhibitors, of whom 26 developed pancreatic cancer (interquartile range follow-up 5-18 months). In the DPP-4 inhibitor versus TZD comparison there were 29 366 people initiating DPP-4 inhibitor treatment and 52 of these developed pancreatic cancer. The risk of pancreatic cancer with DPP-4 inhibitor treatment was lower relative to SU treatment (HR: 0.6, CI: 0.4-0.9) and similar to TZD treatment (HR: 1.0, 95% CI: 0.7-1.4). After the first 6 months of follow-up were excluded to reduce the potential for reverse causality, the results were not altered. The probability of diagnostic evaluation after commencing DPP-4 inhibitor treatment (79.3%) was similar to that for TZD (74.1%, risk ratio 1.06, 95% CI: 1.05-1.07) and SU (74.6%) (risk ratio 1.06, 95% CI: 1.05-1.07). The probability of diagnostic evaluation before the index date (date of initiating treatment) was ∼80% for all cohorts. CONCLUSION: Although the present study was limited by sample size and the observed duration of treatment in the USA, our well-controlled population-based study suggests there is no higher short-term pancreatic cancer risk with DPP-4 inhibitor treatment relative to SU or TZD treatment.

EUFOREA summit in Brussels 2023: inspiring the future of allergy & respiratory care.

In March 2023, the European Forum for Research and Education in Allergy and Airways diseases (EUFOREA) organized its bi-annual Summit in Brussels with expert panel members of EUFOREA, representatives of the EUFOREA patient advisory board, and the EUFOREA board and management teams. Its aim was to define the research, educational and advocacy initiatives to be developed by EUFOREA over the next 2 years until the 10th anniversary in 2025. EUFOREA is an international non-for-profit organization forming an alliance of all stakeholders dedicated to reducing the prevalence and burden of chronic allergic and respiratory diseases via research, education, and advocacy. Based on its medical scientific core competency, EUFOREA offers an evidence-supported platform to introduce innovation and education in healthcare leading to optimal patient care, bridging the gap between latest scientific evidence and daily practice. Aligned with the mission of improving health care, the expert panels of asthma, allergic rhinitis (AR), chronic rhinosinusitis (CRS) & European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS), allergen immunotherapy (AIT) and paediatrics have proposed and elaborated a variety of activities that correspond to major unmet needs in the allergy and respiratory field. The current report provides a concise overview of the achievements, ambitions, and action plan of EUFOREA for the future, allowing all stakeholders in the allergy and respiratory field to be up-dated and inspired to join forces in Europe and beyond.

The use of disinfection tunnels or disinfectant spraying of humans as a measure to reduce the spread of the SARS-CoV-2 virus.

In endeavouring to mitigate the spread of the SARS-CoV-2 virus, a concerning practice of spraying individuals with disinfectant via so-called 'disinfection tunnels' has come to light. The Allergy Society of South Africa supports the World Health Organization in strongly condemning all human spraying, owing to lack of efficacy and potential dangers, especially to patients with coexisting allergic conditions.

Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors.

TRAIL (also called Apo2L) belongs to the tumor necrosis factor family, activates rapid apoptosis in tumor cells, and binds to the death-signaling receptor DR4. Two additional TRAIL receptors were identified. The receptor designated death receptor 5 (DR5) contained a cytoplasmic death domain and induced apoptosis much like DR4. The receptor designated decoy receptor 1 (DcR1) displayed properties of a glycophospholipid-anchored cell surface protein. DcR1 acted as a decoy receptor that inhibited TRAIL signaling. Thus, a cell surface mechanism exists for the regulation of cellular responsiveness to pro-apoptotic stimuli.

Acquisition of tolerance to egg and peanut in African food-allergic children with atopic dermatitis.

BACKGROUND: There are no previous data on tolerance development in children with atopic dermatitis (AD) and concomitant food allergy in low- and middle-income settings. OBJECTIVES: To determine the rate of tolerance acquisition to egg and peanut 5 years after diagnosing food allergies in South African (SA) children with AD, and to explore factors influencing tolerance acquisition. METHODS: Five years after first diagnosing food allergy in 37 SA children with egg and/or peanut allergy, they were reassessed for their allergies by questionnaire, skin-prick tests (SPTs) and ImmunoCAP-specific IgE (sIgE) tests (Thermo Fisher Scientific/Phadia, Sweden) to egg white, ovomucoid, peanut and Arachis hypogaea allergen 2 (Ara h 2), and incremental food challenges. RESULTS: Eighteen of 25 originally egg-allergic patients and 19 of 24 originally peanut-allergic children were followed up at a median age of 8 years and 3 months and 9 years and 6 months, respectively. A high percentage of children (72.2%) outgrew their egg allergy, and 15.8% outgrew their peanut allergy. Allergic comorbidity remained high, with asthma increasing over time, and AD remaining moderate in severity in the cohort overall. At diagnosis, sIgE egg white ≤9.0 kU/L and sIgE ovomucoid ≤2.0 kU/L were associated with tolerance development to egg 5 years later. At follow-up, sIgE egg white ≤0.70 kU/L, sIgE ovomucoid ≤0.16 kU/L, SPT egg-white extract ≤1 mm and SPT fresh egg ≤5 mm were associated with tolerance. At diagnosis, sIgE Ara h 2 ≤1.7 kU/L and SPT peanut ≤10 mm were associated with tolerance development to peanut 5 years later. At follow-up, sIgE peanut ≤0.22 kU/L, sIgE Ara h 2 ≤0.18 kU/L and SPT peanut ≤5.5 mm were associated with tolerance. CONCLUSIONS: Egg allergy was outgrown in 72.2% and peanut allergy in 15.8% of SA children 5 years after diagnosis of AD. This is in keeping with findings derived from studies in higher socioeconomic settings, and can help to guide the counselling of patients with allergies to these foods of high nutritional value.

Apo-3, a new member of the tumor necrosis factor receptor family, contains a death domain and activates apoptosis and NF-kappa B.

BACKGROUND: Two receptors that contain the so-called "death domain' have been described to date: tumor necrosis factor receptor 1 (TNFR1) and Fas/Apo-1 (CD95); both belong to the TNFR gene family. The death domain of TNFR1 mediates the activation of programmed cell death (apoptosis) and of the transcription factor NF-kappa B, whereas the death domain of CD95 only appears to activate apoptosis. RESULTS: We have identified an additional member of the TNFR family, which we have named Apo-3. Apo-3 is a transmembrane protein of approximately 47 kDa that has similarity of members of the TNFR family in its extracellular, cysteine-rich domains. In addition, Apo-3 resembles TNFR1 and CD95 in that it contains a cytoplasmic death domain. The Apo-3 gene mapped to human chromosome 1p36.3, and Apo-3 mRNA was detected in several human tissues, including spleen, thymus, peripheral blood lymphocytes, small intestine and colon. Ectopic expression of Apo-3 in HEK293 or HeLa cells induced marked apoptosis. CrmA, a poxvirus inhibitor of Ced-3-like proteases which blocks death signaling by TNFR1 and CD95, inhibited Apo-3-induced apoptosis. Ectopic expression of Apo-3 also induced the activation of NF-kappa B. Apo-3 did not specifically bind to the Apo-2 ligand, suggesting the existence of a distinct ligand for Apo-3. CONCLUSIONS: These results identify Apo-3 as a third member of the TNFR family that activates apoptosis, and suggest that Apo-3, TNFR1 and CD95 engage a common apoptotic cell-death machinery. Apo-3 resembles TNFR1 because it can stimulate NF-kappa B activity and regulate apoptosis. Apo-3 mRNA is expressed in various tissues, consistent with the possibility that this receptor may regulate multiple signaling functions.

Respiratory comorbidity in South African children with atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is an early and important step in the propagation of the allergic march, enhancing food and respiratory allergies via epicutaneous sensitisation to allergens. OBJECTIVES: To determine the prevalence and patterns of aeroallergen sensitisation, asthma and allergic rhinitis in South African (SA) children with AD. METHODS: This was a prospective, observational study in a paediatric university hospital in Cape Town, SA. Children with moderate to severe AD, aged 6 months - 10 years, were recruited randomly and investigated for food sensitisation and allergy. They were assessed for sensitisation to aeroallergens by the immuno solid-phase allergen chip test. House-dust mite DerP and DerF, dust mite Eur m, Timothy grass, Bermuda grass, tree pollen, mould (Alternaria), cat and dog sensitisation patterns were analysed. Symptoms of asthma and allergic rhinitis were elicited using a questionnaire modified from the International Study of Asthma and Allergies in Childhood study questions. RESULTS: One hundred participants (59 black Africans and 41 of mixed ethnicity) were enrolled (median age 42 months). Of the participants, 39% had symptoms of asthma and 53% symptoms of allergic rhinitis; 89% tested positive to at least one aeroallergen, most commonly house-dust mite DerP or DerF (81%), dust mite Eur m (51%), Timothy grass (36%) and cat (35%). Asthma, allergic rhinitis and aeroallergen sensitisation all increased with increasing age, while food allergy decreased with age. Food allergy was not an independent risk factor for respiratory allergies. Children were sensitised to indoor allergens (house-dust mite, pets) from an early age, while pollen allergies increased with age. CONCLUSIONS: In this cohort of SA children with moderate to severe AD, comorbidity with respiratory allergies was high. The prevalence of respiratory allergies increased with age while food allergy decreased with age, in keeping with the pattern of the allergic march. Seasonal allergies increased with age, while house-dust mite and pet allergy peaked in younger children, in keeping with early exposure via a defective skin barrier. Early and effective restoration of the skin barrier in AD may be a target for reducing aeroallergen-related diseases.

Dopamine in the nucleus accumbens modulates the memory of social defeat in Syrian hamsters (Mesocricetus auratus).

Conditioned defeat (CD) is a behavioral response that occurs in Syrian hamsters after they experience social defeat. Subsequently, defeated hamsters no longer produce territorial aggression but instead exhibit heightened levels of avoidance and submission, even when confronted with a smaller, non-aggressive intruder. Dopamine in the nucleus accumbens is hypothesized to act as a signal of salience for both rewarding and aversive stimuli to promote memory formation and appropriate behavioral responses to significant events. The purpose of the present study was to test the hypothesis that dopamine in the nucleus accumbens modulates the acquisition and expression of behavioral responses to social defeat. In Experiment 1, bilateral infusion of the non-specific D1/D2 receptor antagonist cis(z)flupenthixol (3.75 µg/150 nl saline) into the nucleus accumbens 5 min prior to defeat training significantly reduced submissive and defensive behavior expressed 24h later in response to a non-aggressive intruder. In Experiment 2, infusion of 3.75 µg cis-(Z)-flupenthixol 5 min before conditioned defeat testing with a non-aggressive intruder significantly increased aggressive behavior in drug-infused subjects. In Experiment 3, we found that the effect of cis-(Z)-flupenthixol on aggression was specific to defeated animals as infusion of drug into the nucleus accumbens of non-defeated animals did not significantly alter their behavior in response to a non-aggressive intruder. These data demonstrate that dopamine in the nucleus accumbens modulates both acquisition and expression of social stress-induced behavioral changes and suggest that the nucleus accumbens plays an important role in the suppression of aggression that is observed after social defeat.

Gender (in) differences in prevalence and incidence of traumatic experiences among orphaned and separated children living in five low- and middle-income countries.

BACKGROUND: Approximately 153 million children worldwide are orphaned and vulnerable to potentially traumatic events (PTEs). Gender differences in PTEs in low- and middle-income countries (LMIC) are not well-understood, although support services and prevention programs often primarily involve girls. METHODS: The Positive Outcomes for Orphans study used a two-stage, cluster-randomized sampling design to identify 2837 orphaned and separated children (OSC) in five LMIC in sub-Saharan Africa and Asia. We examined self-reported prevalence and incidence of several PTE types, including physical and sexual abuse, among 2235 children who were ≥10 years at baseline or follow-up, with a focus on gender comparisons. RESULTS: Lifetime prevalence by age 13 of any PTE other than loss of a parent was similar in both boys [91.7% (95% confidence interval (CI) (85.0-95.5)] and girls [90.3% CI (84.2-94.1)] in institutional-based care, and boys [92.0% (CI 89.0-94.2)] and girls [92.9% CI (89.8-95.1)] in family-based care; annual incidence was similarly comparable between institution dwelling boys [23.6% CI (19.1, -29.3)] and girls [23.6% CI (18.6, -30.0)], as well as between family-dwelling boys [30.7% CI (28.0, -33.6)] and girls [29.3% CI (26.8,-32.0)]. Physical and sexual abuse had the highest overall annual incidence of any trauma type for institution-based OSC [12.9% CI (9.6-17.4)] and family-based OSC [19.4% CI (14.5-26.1)], although estimates in each setting were no different between genders. CONCLUSION: Prevalence and annual incidence of PTEs were high among OSC in general, but gender-specific estimates were comparable. Although support services and prevention programs are essential for female OSC, programs for male OSC are equally important.

South African food allergy consensus document 2014.

The prevalence of food allergy is increasing worldwide and is an important cause of anaphylaxis. There are no local South African food allergy guidelines. This document was devised by the Allergy Society of South Africa (ALLSA), the South African Gastroenterology Society (SAGES) and the Association for Dietetics in South Africa (ADSA). Subjects may have reactions to more than one food, and different types and severity of reactions to different foods may coexist in one individual. A detailed history directed at identifying the type and severity of possible reactions is essential for every food allergen under consideration. Skin-prick tests and specific immunoglobulin E (IgE) (ImmunoCAP) tests prove IgE sensitisation rather than clinical reactivity. The magnitude of sensitisation combined with the history may be sufficient to ascribe causality, but where this is not possible an incremental oral food challenge may be required to assess tolerance or clinical allergy. For milder non-IgE-mediated conditions a diagnostic elimination diet may be followed with food re-introduction at home to assess causality. The primary therapy for food allergy is strict avoidance of the offending food/s, taking into account nutritional status and provision of alternative sources of nutrients. Acute management of severe reactions requires prompt intramuscular administration of adrenaline 0.01 mg/kg and basic resuscitation. Adjunctive therapy includes antihistamines, bronchodilators and corticosteroids. Subjects with food allergy require risk assessment and those at increased risk for future severe reactions require the implementation of risk-reduction strategies, including education of the patient, families and all caregivers (including teachers), the provision of a written emergency action plan, a MedicAlert necklace or bracelet and injectable adrenaline (preferably via auto-injector) where necessary.

Functional cloning vectors for use in directional cDNA cloning using cohesive ends produced with T4 DNA polymerase.

This paper describes the construction of 'Prime' cloning vectors, which include phage lambda and plasmid vectors useful for functional cloning in oocytes, yeast, and mammalian cells, and their use in a 'Prime' cloning system. The system takes advantage of the very active and precise 3' exonuclease activity of T4 DNA polymerase to produce single-stranded (ss) ends (cut-back) of vector and insert DNA. This results in the highly efficient directional cloning of cDNA and PCR-amplified DNA. The system obviates the need to digest insert DNA with a restriction endonuclease to unveil cloning sites, and thus eliminates the chance of internal digestion of the insert DNA. The cloning of PCR-amplified DNA, which is sometimes difficult, is made routine with this system. The 'Prime' sequence is included in vector cloning sites and cDNA and PCR primers. The 'Prime' sequence was chosen so that the ss sticky ends are nonpalindromic and will hybridize only to the appropriate partners. This makes cloning with the 'Prime' system very efficient, because neither the vector nor insert DNA is lost to unproductive self-hybridization.

Assaying the quality of cDNA libraries.

Once a cDNA library has been constructed, it is very useful to be able to easily assess the quality of the library. Because actin is a ubiquitous sequence, this assessment has been accomplished by probing filter lifts and Southern blots of libraries with an actin cDNA probe. These methods provide information about the percent of actin-positive clones and the degree of completeness of cDNA clones in a library. Results of these methods are correlated with the success of finding full-length clones of interest.

Changes in continuity of enrollment among high-risk children following implementation of TennCare.

BACKGROUND: TennCare, Tennessee's Medicaid managed care program, was introduced in 1994 with the goals of controlling spending and of improving access to health care. OBJECTIVE: To assess changes in the continuity of enrollment following the implementation of TennCare for 2 groups: infants in the first year of life (defined as persons aged 0-12 months in this study) and children hospitalized with a chronic health condition (defined as persons aged 0-18 years in this study). DESIGN: Retrospective cohort analysis. SETTING AND POPULATION: Infants born during 1992 or 1995 to women enrolled in Medicaid or TennCare and 0- to 18-year-old children enrolled in Medicaid or TennCare who were discharged from a hospital during 1992 or 1995 with a chronic health condition. MAIN OUTCOME MEASURES: For infants, failure to enroll an infant in the first 30 days of life or subsequent gaps in enrollment for 7 days or longer during the first year of life. For children hospitalized with a chronic health condition, any gap in enrollment lasting 7 days or longer by 1 year after discharge from a hospital. RESULTS: There was a reduction in the proportion of infants without continuous enrollment in the first year of life following TennCare (19.4% after vs 25.1% before TennCare; odds ratio, 0.69; 95% confidence interval, 0.67-0.72). Improvements in continuity of enrollment for infants occurred despite an increase in the proportion of infants who were not enrolled in TennCare in the first 30 days of life, even though their mother was enrolled at delivery (14.0% after vs 8.0% before TennCare; odds ratio, 1.86; 95% confidence interval, 1.78-1.96). There was a decrease in the proportion of children hospitalized with a chronic health condition who had subsequent gaps in enrollment by 1 year following discharge from a hospital (14.3% after vs 23.3% before TennCare; odds ratio, 0.52; 95% confidence interval, 0.46-0.59). CONCLUSION: For infants in the first year of life and for children hospitalized with a chronic health condition, implementation of TennCare improved continuity of coverage.

Respiratory comorbidity in South African children with atopic dermatitis

Background. Atopic dermatitis (AD) is an early and important step in the propagation of the allergic march, enhancing food and respiratory allergies via epicutaneous sensitisation to allergens.Objectives. To determine the prevalence and patterns of aeroallergen sensitisation, asthma and allergic rhinitis in South African (SA) children with AD. Methods. This was a prospective, observational study in a paediatric university hospital in Cape Town, SA. Children with moderate to severe AD, aged 6 months - 10 years, were recruited randomly and investigated for food sensitisation and allergy. They were assessed for sensitisation to aeroallergens by the immuno solid-phase allergen chip test. House-dust mite DerP and DerF, dust mite Eur m, Timothy grass, Bermuda grass, tree pollen, mould (Alternaria), cat and dog sensitisation patterns were analysed. Symptoms of asthma and allergic rhinitis were elicited using a questionnaire modified from the International Study of Asthma and Allergies in Childhood study questions.Results. One hundred participants (59 black Africans and 41 of mixed ethnicity) were enrolled (median age 42 months). Of the participants, 39% had symptoms of asthma and 53% symptoms of allergic rhinitis; 89% tested positive to at least one aeroallergen, most commonly house-dust mite DerP or DerF (81%), dust mite Eur m (51%), Timothy grass (36%) and cat (35%). Asthma, allergic rhinitis and aeroallergen sensitisation all increased with increasing age, while food allergy decreased with age. Food allergy was not an independent risk factor for respiratory allergies. Children were sensitised to indoor allergens (house-dust mite, pets) from an early age, while pollen allergies increased with age. Conclusions. In this cohort of SA children with moderate to severe AD, comorbidity with respiratory allergies was high. The prevalence of respiratory allergies increased with age while food allergy decreased with age, in keeping with the pattern of the allergic march. Seasonal allergies increased with age, while house-dust mite and pet allergy peaked in younger children, in keeping with early exposure via a defective skin barrier. Early and effective restoration of the skin barrier in AD may be a target for reducing aeroallergen-related diseases

The use of disinfection tunnels or disinfectant spraying of humans as a measure to reduce the spread of the SARS-CoV-2 virus

In endeavouring to mitigate the spread of the SARS-CoV-2 virus, a concerning practice of spraying individuals with disinfectant via so-called 'disinfection tunnels' has come to light. The Allergy Society of South Africa supports the World Health Organization in strongly condemning all human spraying, owing to lack of efficacy and potential dangers, especially to patients with coexisting allergic conditions

Interstitial pregnancy.

A case of ruptured interstitial pregnancy is reported, along with review of the literature. Although sonography did not differentiate between interstitial and intrauterine pregnancy, I believe it will prove to be one of the most accurate diagnostic aids in detecting this condition.

Drug-seeking behavior in urolithiasis in the noncontrast computed tomography era: 2 cases.

Symptomatic urolithiasis is usually treated with narcotic pain management. This leads to the potential for use of its symptoms for personal gain. Historically, the typical presentation of a narcotic-seeking "stone patient" was a history of radiolucent stones and an intravenous contrast allergy. With the increased use of non-contrast-enhanced computed tomography to evaluate patients suspected of having acute urolithiasis, we have seen a change in the strategy of narcotic-seeking patients. We report 2 patients with pelvic calcifications on non-contrast-enhanced computed tomography feigning symptoms of urolithiasis to receive narcotic drugs.

Serum and WBC pharmacokinetics of 1500 mg of azithromycin when given either as a single dose or over a 3 day period in healthy volunteers.

Owing to azithromycin's prolonged half-life, shorter and shorter dosage regimens are being studied for treatment of respiratory tract infections. Previous studies have concluded that the 3 and 5 day (1.5 g total) regimens not only provide at least equal serum and WBC exposures but also equal efficacy rates. An earlier clinical study using the entire 1.5 g dose at once or the current 3 day regimen in patients with atypical pneumonia noted equal efficacy. Similar trials are currently underway in both adult and paediatric populations. The goal of the present study was to investigate whether there were equal serum and WBC exposures when azithromycin was dosed as the current 3 day regimen or as a single large dose. Equal exposures would help validate future clinical trials of single dose regimens. Twelve healthy volunteers received both azithromycin regimens (1.5 g single dose and 500 mg/day for 3 days) in random order. Serum and WBC samples were collected at baseline and repeatedly for 10 days following the first dose of each regimen. Serum samples were assayed via HPLC (CV% < 10) and WBC samples via liquid chromatography/mass spectrometry (CV% < 10). Data were modelled using noncompartmental methods. Statistics were via ANOVA with significance defined as P < 0.05. All subjects completed both regimens with minimal incidence of adverse effects. Serum data [mean (range)] demonstrated no significant difference in exposure between the two regimens [single 13.1 (3.02-20.6) mg x h/L versus 3 day 11.2 (2.98-24.5) mg x h/L: P = 0.12], although it favoured the shorter regimen. WBC results demonstrated much higher exposures than seen with serum, but no significant difference between the two regimens was identified. These results suggest that a single oral 1.5 g regimen of azithromycin for respiratory tract infections should provide exposure at least equal to currently approved treatment regimens.

Ovarian pregnancy associated with intrauterine contraceptive devices.

Four cases of ovarian pregnancy, occurring over a two-year period in the same hospital, are presented. Each case fulfills Spiegelberg's criteria. Each patient conceived with Cu-7 intrauterine contraceptive device (IUD) in situ. Review of the literature reveals an apparent increase in the frequency of ovarian pregnancy associated with IUD's. This aspect of the problem, as well as the management of this unusual type of ectopic pregnancy, is discussed. The data available do not justify a conclusion that ovarian pregnancies are caused by IUD's. Unless future studies demonstrate a cause-and-effect relationship, this may be merely an interesting coincidence. However, it seems that more than just coincidence is involved, even though the mechanism is unclear.