Search

BackgroundSodium–glucose co-transport 2 inhibitors (SGLT2i) lower blood pressure (BP) in normotensive subjects and in hypertensive and normotensive diabetic and non-diabetic patients. However, the mechanisms of these BP changes are not fully understood. Therefore, we examined the clinical and biochemical determinants of the BP response to empagliflozin based on 24-h ambulatory BP monitoring.MethodsIn this post-hoc analysis of a double-blind, randomized, placebo-controlled study examining the renal effects of empagliflozin 10 mg vs. placebo in untreated normotensive non-diabetic subjects, the 1-month changes in 24 h ambulatory BP were analyzed in 39 subjects (13 placebo/26 empagliflozin) in regard to changes in biochemical and hormonal parameters.ResultsAt 1 month, empagliflozin 10 mg decreased 24-h systolic (SBP) and diastolic (DBP) BP significantly by −5 ± 7 mmHg (p < 0.001) and −2 ± 6 mmHg (p = 0.03). The effect on SBP and DBP was more pronounced during nighttime (resp. −6 ± 11 mmHg, p = 0.004; −4 ± 7 mmHg, p = 0.007). The main determinants of daytime and nighttime SBP and DBP responses were baseline BP levels (for daytime SBP: coefficient −0.5; adj. R2: 0.36; p = 0.0007; for night-time SBP: coefficient −0.6; adj. R2: 0.33; p = 0.001). Although empaglifozin induced significant biochemical changes, none correlated with blood pressure changes including urinary sodium, lithium, glucose and urate excretion and free water clearance. Plasma renin activity and plasma aldosterone levels increased significantly at 1 month suggesting plasma volume contraction, while plasma metanephrine and copeptin levels remained the same. Renal resistive indexes did not change with empagliflozin.ConclusionSGLT2 inhibition lowers daytime and nighttime ambulatory systolic and diastolic BP in normotensive non-diabetic subjects. Twenty-four jour changes are pronounced and comparable to those described in diabetic or hypertensive subjects. Baseline ambulatory BP was the only identified determinant of systolic and diastolic BP response. This suggests that still other factors than sustained glycosuria or proximal sodium excretion may contribute to the resetting to lower blood pressure levels with SGLT2 inhibition.Clinical Trial Registration:[https://www.clinicaltrials.gov], identifier [NCT03093103].

[EN] The objective of the POCTEFA - MOMPA project (Monitoring of Ground Movements and Action Protocol) is to provide a useful technical-operational tool for the prevention and management of risks due to slope movements, at a cross-border level, based on the satellite monitoring technique InSAR (Synthetic Aperture Radar Inteferometry). The tool includes two main elements: the risk evaluation, and the integration of the technique in an action protocol for the administrations in charge of Civil Protection. The study area covers around 4,000 km2 and includes a part of the eastern Pyrenees, including the countries of Spain, France, and Andorra. The project deals with risk assessment based on the ground displacement map at an interregional scale and on the detected Active Deformation Areas (ADA), to select movements with potential risk where it will then focus on an analysis at a local scale using traditional methods (photo interpretation and field work). Both the free medium-resolution data, acquired by the Sentinel-1 satellite, as well as the high-resolution data acquired by COSMO-SkyMed are used. In addition, the project focuses on the landslide event of “la Portalada” (in Andorra) that occurred in 2019. Today the slope shows a slow movement that could affect a main road located at the bottom of the valley. The Government of Andorra is implementing measures to monitor and characterize the current movement of the slope. Therefore, nine artificial reflectors were installed along this forested slope. The data obtained will be integrated into the risk prevention protocol. Here, the project and the first results obtained through satellite interferometry are presented., [ES] El objetivo del proyecto POCTEFA - MOMPA (MOnitorización de Movimientos del terreno y Protocolo de Actuación) es proporcionar una herramienta técnico-operativa útil para la prevención y la gestión de los riesgos ocasionados por movimientos de ladera, a nivel transfronterizo, basada en la técnica de seguimiento satelital InSAR. (Interferometría Radar a Apertura Sintética) La herramienta incluye dos elementos principales: la evaluación del riesgo; y la integración de la técnica en un protocolo de actuación para las administraciones encargadas de la Protección Civil. El área de estudio cubre alrededor de 4.000 km2 e incluye una parte de los Pirineos orientales, incluyendo los países España, Francia y Andorra. El proyecto trata la evaluación de riesgos a partir del mapa de movimientos del terreno a escala interregional y de las Áreas de Deformación Activa (ADA), para seleccionar movimientos con riesgo potencial donde luego se enfocará en un análisis a escala local mediante el uso de métodos tradicionales (básicamente fotointerpretación y trabajo de campo). Se utilizan tanto los datos libres y gratuitos de resolución media, adquiridos por el satélite Sentinel-1, como los datos de alta resolución adquiridos por COSMO-SkyMed. Además, el proyecto centra su atención en el caso particular del deslizamiento de “la Portalada” (Andorra) ocurrido en 2019. En la actualidad, la ladera presenta un movimiento lento que podría afectar el eje principal de comunicación entre Andorra y España ubicado en el fondo del valle. El Gobierno de Andorra está implementando medidas para monitorear y caracterizar el movimiento actual de la ladera. Por tanto, nueve reflectores artificiales se instalaron a lo largo de esta ladera ocupada por un bosque. Los datos obtenidos se integrarán en el protocolo de prevención de riesgos. En este trabajo se presentan el proyecto y los primeros resultados obtenidos mediante interferometría satelital., Este trabajo ha sido co-financiado por el Fondo Europeo de Desarrollo Regional (“European Regional Development Fund”) a través de Interreg V-A España, Francia y Andorra (POCTEFA 2014-2020), proyecto EFA295/19. En el caso de la Portalada, los autores agradecen a la administración local de La Portalada, el Comú de Sant Julià de Lòria, por permitir la implementación de los reflectores, y al Ministerio de Ordenación Territorial del Gobierno de Andorra por facilitar su gestión. La obra de implementación de los reflectores fue contratada a la empresa INACCÉS.

International audience; -Riskcoast est un projet financé par le fond européen Interreg SudOE à hauteur de 1,07 M€ qui se concentre sur l'étude des risques géologiques en zone côtière, liés au changement climatique. Riskcoast intervient sur la chaîne complète du risque, de la compréhension de l'aléa à l'amélioration de la gestion du risque, de la prévention à la crise possible ainsi que la réhabilitation de zones sinistrées. Il a démarré en novembre 2019 et s'achèvera en octobre 2022. ABSTRACT-Riskcoast project is funded by the European fund Interreg Sudoe for 1.07 M€. It focuses on the study of geological risks in coastal areas related to climate change. Riskcoast intervenes on the whole risks, from a better understanding of the hazard to the improvement of the risk management, from the prevention to the possible crisis as well as the rehabilitation of disaster areas. It starts on November 2019 and lasts 3 years.

BACKGROUND: Contact allergy is common in children, but may be underdiagnosed. Importantly, the clinical relevance of specific allergies is subject to constant change, and it is therefore important to continuously monitor the trends and changes of contact allergies in the paediatric population.OBJECTIVES: To identify possible changes in contact allergy and allergic contact dermatitis among Danish children referred for patch testing.METHODS: A retrospective study was performed based on patch test data from the Danish National Database of Contact allergy. The current data were compared with previously published data on Danish children referred for patch testing.RESULTS: Between 2012 and 2016, 1573 children and adolescents were patch tested. Overall, 385 (24.5%) had at least 1 positive patch test reaction. The overall prevalence was similar in boys and girls, across age groups, and in patients with and without atopic dermatitis. Statistically significant increases in contact allergy to fragrances and isothiazoliones were seen, whereas a decrease in nickel allergy was found.CONCLUSION: Allergic contact dermatitis continues to be a common disease in children, and is even significantly increasing for some allergens.

Hidradenitis suppurativa (HS) is a debilitating disease and is difficult to treat. Validation of surgical techniques is therefore of great importance in the management of HS. Carbon dioxide (CO2) laser evaporation has been shown effective, but larger-scale studies are scarce.To determine the recurrence rate, time to recurrence, and factors influencing disease recurrence in skin treated with CO2 laser evaporation, and healing by secondary intention; and patients' satisfaction with treatment.Fifty-eight patients treated with CO2 laser evaporation were interviewed regarding recurrence and satisfaction after a mean of 25.7 months.Seventeen of 58 (29%) reported recurrence of HS lesions within the borders of the treated areas after a mean of 12.7 months. Obesity was a risk factor for recurrence with a hazard ratio of 4.53. Fifty-five patients (95%) reported some or great improvement, and 91% would recommend the CO2 laser surgery to other HS patients.This study supports the claim that CO2 laser treatment is an effective modality for recurrent HS lesions in a majority of patients. The authors identified obesity as a risk factor for recurrence. Self-reported satisfaction is high, and only 3 of 58 report no change in the condition. None reported a worsening.

Hidradenitis suppurativa (HS) is a chronic, relapsing, inflammatory skin condition that typically occurs after puberty. The primary clinical presentation is painful inflamed nodules or boils in the apocrine gland-bearing regions (armpits, genital area, groin, breasts and buttocks/anus) that progress to abscesses, sinus tracts and scarring. Severity is typically described according to three Hurley categories, with most patients having mild or moderate disease. Estimated prevalence is 1–4% worldwide and HS is three times more common in women than men. Patients’ disease burden includes intense pain, work disability and overall poor quality of life. Although the clinical signs of the disease can often be hidden by clothing, active HS is associated with a malodorous discharge that contributes to the disabling social stigma. Risk factors include smoking and obesity. Comorbidities include inflammatory bowel disease and spondyloarthropathies. The presentation of the disease is distinct, yet HS is not well-recognised except in dermatology clinics.

The deferred behaviour of underground cavities is often encountered in geotechnical engineering. This paper presents an analytical approach for the post-closure behaviour of a deep tunnel inside a rock mass considering both creep and hydromechanical couplings. Creep, supposed slower than hydraulic flow, is described by a linear Norton–Hoff law in the particular case of an elastically incompressible rock mass (i.e. Poisson's ratio ν = 0.5 ). The resolution uses Laplace transform and Stehfest's algorithm. Numerical examples are carried out to enlighten the hydromechanical responses around the tunnel and to show the consistency of the solution.

Hidradenitis suppurativa is a chronic recurrent inflammatory skin disease with abscess formation and scarring predominantly in the inverse areas. The disease is often difficult to treat and patients experience a decreased quality of life (QoL) and related psychosocial morbidity. Current knowledge on improving QoL in patients with hidradenitis suppurativa is therefore reviewed. The literature is limited but indicates that there are two ways of improving patients’ QoL: therapy of the somatic disease or psychosocial interventions.

We report the results of a re-examination of a series of 57 biopsies from 50 patients with the clinical diagnosis of hidradenitis suppurativa, submitted to the Department of Pathology at the University Hospital of Northern Norway, Tromso, Norway. The biopsy material came from hospitals and physicians all over northern Norway in the years 2000-2007. All tissue material was resectioned and stained with the immunohistochemical reagent, cytokeratin (AE1/AE3/PKC26), and that made it possible to divide the material into two different disease categories: (1) 36 biopsies from 30 cases had tissue inflammation after rupture of keratin-rich epidermal cysts, which we call 'horny cell inflammation', followed by extensive cutaneous thrombi and infarcts, and (2) 21 biopsies from 20 cases had 'apocrinitis' defined here as an inflammatory destruction of apocrine skin glands, and partly of close eccrine glands. The two disease populations differed: the patients with a diagnosis of horny cell inflammation were younger and mainly women; those with a diagnosis of apocrinitis, as defined here, were older, men and women equally represented.

Background Hidradenitis suppurativa (HS) is a chronic recurrent inflammatory skin disease with abscess formation and scarring predominantly in the inverse areas. The disease is often difficult to treat and patients experience a decreased quality of life (QoL). It is hypothesized that depression is more common in HS patients than among other dermatological patients. Objectives To evaluate the prevalence of depression in patients with HS. Methods In total 211 HS patients were included in the study and 233 were dermatological control patients. Their QoL and depression scores were assessed using the Dermatology Life Quality Index (DLQI) and the Major Depression Inventory (MDI) questionnaires. HS severity was recorded with a questionnaire and Hurley stages were extracted from the case records. Results The DLQI was significantly higher for HS patients than for the control patients, 8.4 +/- 7.5 vs. 4.3 +/- 5.6 (P

Summary Background Hidradenitis suppurativa (HS) has an impact on patients’ quality of life. Treatment of HS is generally unsatisfactory, thus new treatments are needed. Objectives To test the efficacy of adalimumab in HS. Methods This was a prospective, randomized, double-blinded, placebo-controlled, two-centre clinical trial conducted in Denmark. Inclusion criteria were age above 18 years and a clinical diagnosis of moderate to severe HS defined as Hurley stage II or III for at least 6 months. The patients were randomized 1 : 2 (placebo/active). Actively treated patients received adalimumab 80 mg subcutaneously (s.c.) at baseline followed by 40 mg s.c. every other week for 12 weeks. Placebo-treated patients received identical-looking injections with no active ingredient. The medicine was dispensed in sequentially numbered computer-randomized containers. Participants, care givers and those assessing the outcomes were blinded to group assignment. The primary efficacy endpoints were changes in the HS scores (Sartorius and Hurley scoring systems). Secondary efficacy endpoints included changes in pain (visual analogue scale), days with lesions and Dermatology Life Quality Index, and evaluation of scarring. Recruitment was terminated early due to expiry date of trial medication. Results Twenty-one patients were included, of whom 15 received adalimumab and six received placebo. All participants were analysed according to the intention to treat principle. A significant reduction was seen in Sartorius score after 6 weeks and an almost significant reduction was seen after 12 weeks of active treatment (−10·7 vs. 7·5, P = 0·024 and −11·3 vs. 5·8, P = 0·07) when compared with the placebo group. Conclusions A significant reduction in HS severity was gained after 6 weeks. No long-term curative effect was uniformly seen.

Summary Background Estimates of the prevalence of hidradenitis suppurativa (HS) range from 0·33% to 4%. Further epidemiological data are therefore needed. Because of the hidden nature of the disease, physical screening may be cumbersome and questionnaire-based screening may be more appropriate. Objectives To establish the sensitivity (SE), specificity (SP) and positive predictive value (PPV) of simple diagnostic questions used in HS. Methods Potential diagnostic questions regarding HS were identified and sent to 85 patients with HS and to an age- and sex-matched control group randomly selected among outpatients not being treated for HS. All respondents were recruited in the Department of Dermatology in Roskilde Hospital. Results In total, 74 of 85 patients with HS (87%) returned the questionnaire (61 women and 13 men). Of these, 72 reported repeated outbreaks of painful nodules or boils in locations typical for HS compared with 13 patients in the control group. The SE ranged from 0·92 to 0·97, the SP from 0·82 to 0·86 and the PPV from 0·85 to 0·89. Boils appeared significantly more often in patients with HS, who also reported significantly greater suffering from their lesions. Conclusions The high diagnostic power suggests that all the questions are potentially useful. The clear symptomatology of HS may be a key factor. It is suggested that further improvement may be achieved by adding definitions of pimples, nodules or boils to future questionnaires. Similarly, adding the possibility to indicate uncommon locations, duration and quality-of-life impairment may benefit the diagnostic power.

International audience

Background: There is a need to improve the safety and efficacy of allergen-specific immunotherapy. Long synthetic peptide-based immunotherapy was proven safe, immunogenic, and protective in preclinical trials. Objective: To evaluate the safety and immunogenicity of an allergen-derived long synthetic overlapping peptide (LSP) immunotherapy, we designed a double-blind, placebo-controlled phase I clinical trial in patients hypersensitive to bee venom. Methods: Patients from the active group were injected at day 0 with a mixture of 3 LSPs mapping the entire PLA2 molecule, a major bee venom allergen, in a dose-escalating protocol to a maintenance dose of 100 μg per peptide repeated at days 4, 7, 14, 42, and 70. The control group was injected with human albumin. Results: Whereas specific T-cell proliferation in the peptide group increased up to day 14, a sharp decline was observed thereafter, ending in specific T-cell hyporesponsiveness at day 80. Serum-specific IgG4 response was enhanced, in contrast to anti-PLA2 IgE. Specific T-cell cytokine modulation was marked by increased IL-10 and IFN-γ secretion. LSP injections were well tolerated in all patients except for mild, late allergic reactions in 2 patients at day 70. Conclusions: The results of this short-term study demonstrate that LSP-based allergen immunotherapy was safe and able to induce T H 1-type immune deviation, allergen-specific IL-10 production, and T-cell hyporesponsiveness. LSPs, which offer the advantage of covering all possible T-cell epitopes for any HLA genotype, can be considered candidates for a novel and safe approach of specific immunotherapy. (J Allergy Clin Immunol 2003;111:854-61.)

Background Murine models of hypersensitivity to allergens are useful tools for the evaluation of preclinical strategies to down-regulate the IgE response. Objective To monitor the long-term kinetics of T and B cell responses to allergen as a function of allergen dosage and to investigate the effect of parallel immunization with a second antigen; to correlate B cell response with anaphylaxis. Methods CBA/J mice were sensitized every other week by subcutaneous injections of phospholipase A2 (PLA2) and/or ovalbumin (OVA) adsorbed to alum. Specific antibody isotype responses, T cell proliferation, T cell cytokine production and anaphylaxis were assessed throughout the sensitization phase. Results Low-dose immunization with PLA2 (0.1 µg) favoured a long-term, specific T helper (Th)2 response with high IgE and IL-4 production in contrast to high-dose PLA2 (10 µg) immunization, which biased the immune response towards a Th1 response with high IgG2a and low IL-4 production. Parallel immunization with an unrelated antigen (ovalbumin) had a significant bystander effect on the immunization with PLA2, which was also dose-dependent. Finally, although anaphylaxis as measured by rectal temperature drop was allergen-specific, it could be induced in the high- and low-dose immunization groups, and was not solely dependent on IgE levels. Conclusion Though low-dose allergen immunization appears to induce an efficient IgE response, the intensity and quality of this response may be modulated by bystander effects of parallel immunization and does not correlate strictly with anaphylaxis. This observation has relevance to the design of clinical immunotherapy protocols using murine model-based data.

Sirs, Hidradenitis suppurativa (HS) is a chronic, inflammatory, recurrent, debilitating follicular skin disease that usually presents after puberty with painful deep-seated, inflamed lesions in the...

Naevus comedonicus is a rare, benign hamartoma consisting of grouped abnormal hair follicles and, occasionally, associated with other diseases. We describe an infant who developed hidradenitis-like lesions in an inguinal naevus comedonicus following increased mechanical stress on the region. It is speculated that the degree of strain on a hair follicle is increased when its diameter is increased, leading to wall ruptures. We hypothesise that this serendipitous observation provides a model for the way mechanical stress can account for the development of hidradenitis suppurativa in some patients.

To assess the capacity of a peptide-based immunotherapy to induce systemic tolerance via the nasal route, we designed three long overlapping peptides of 44–60 aa covering the entire sequence of phospholipase A2 (PLA2), a major bee venom allergen. Both prophylactic and therapeutic intranasal administrations of long peptides to PLA2-hypersensitive CBA/J mice induced specific T cell tolerance to the native allergen. In prophylactic conditions, this tolerance was marked by a suppression of subsequent specific IgE response, whereas the therapeutic approach in presensitized mice induced a more than 60% decrease in PLA2-specific IgE. This decline was associated with a shift in the cytokine response toward a Th1 profile, as demonstrated by decreased PLA2-specific IgG1 and enhanced IgG2a levels, and by a decline in the specific IL-4/IFN-γ ratios. T cell transfer from long peptide-tolerized mice to naive animals abrogated the expected anti-PLA2 IgE and IgG1 Ab response, as well as specific T cell proliferation, but enhanced specific IgG2a response upon sensitization with PLA2. These events were strongly suggestive of a clonal anergy affecting more profoundly Th2 than the Th1 subsets. In conclusion, these results demonstrate that allergen-derived long peptides delivered via the nasal mucosa may offer an alternative to immunotherapy with native allergens without the inherent risk of systemic anaphylactic reactions. Moreover, long peptides, in contrast to immunotherapy strategies based on short peptides, have the advantage of covering all potential T cell epitopes, and may represent novel and safe tools for the therapy of allergic diseases.

To evaluate a long peptide-based allergy vaccine in a murine model, CBA/J mice were sensitized with low dose alum-adsorbed phospholipase A2 (PLA2), a major bee venom allergen. Presensitized mice were treated by daily i.p. injections of a mixture of three long overlapping peptides (44- to 60-mer) spanning the entire PLA2 molecule (100 microg/peptide) for 6 consecutive days. This therapeutic approach induced a sharp drop in PLA2-specific IgE, an increase in specific IgG2a, and a marked T cell hyporesponsiveness. T cell cytokine secretion was characterized by a shift from a Th2 to a Th1 profile. Prophylactic treatment of naive mice with long peptides prior to sensitization with PLA2 induced a comparable modulation of B and T cell responses. Upon i.p. challenge with native PLA2, presensitized mice treated with the long peptide mixture were fully protected from anaphylaxis. This indicated that allergen-derived long overlapping peptides were safe and able to modulate an established Th2 response or to prevent its development. Furthermore, long peptide-based immunotherapy provided clinical protection against anaphylaxis, thus appearing as a promising approach of the therapy of allergic diseases.

Hidradenitis suppurativa (HS; or acne inversa) is a scar -ring and frequently persistent inflammatory disorder of the terminal hair follicles of apocrine gland-bearing skin in adults. Treatments include local or systemic antibiotics, hormones, retinoids and systemic immunosuppressive agents (1), although on evaluation these have been shown to have only limited or temporary effect. In refractory cases, surgery is necessary, and should be radical and performed as early as possible (2, 3). It is essential to establish a registry of HS in order to address the following important issues: to assess the safety and effectiveness of different treatments; to identify which specific patient subgroups have the best risk/benefit ratio for a given treatment; and to create benchmark data for quality assurance of the medical service. This manuscript presents the Scandinavian Registry for HS, HISREG.METHodS

The reactions of organolithium compounds of the type (R3Si)2CHLi (R3 = Me3 or Me2Ph) with the gold(I) complex Ph3PAuCl afford the monoaurated bis(silyl)methanes (R3Si)2- CHAuPPh3 (1a, b) in high yield. These compounds are converted into complex salts with hypercoordinate methanium cations {(R3Si)2C[Au(PPh3)]3}+BF−4 (3a, b) by treatment with {[(Ph3P)Au]3O}+ BF−4. In the reaction mixtures small amounts of the neutral dinuclear intermediates {(R3Si)2C[Au(PPh3)]2} (2a, b) have been detected and characterized by their spectroscopic data. Compounds 1a, b and 3a, b have been studied by single crystal X-ray diffraction analyses. While the mononuclear molecules 1a, b have conventional structures with parameters representing classical types of bonding, the novel trinuclear complexes 3a, b feature cations with a pentacoordinate carbon atom in a distorted trigonal-bipyramidal environment of two silicon atoms and one gold atom in equatorial positions and the remaining two gold atoms at the axial vertices of the polyhedra. The main axis of the bipyramid is strongly bent at the central carbon atoms. This distortion leads to short axial/equatorial Au…Au distances indicating peripheral metal-metal bonding.

We report the results of a re-examination of a series of 57 biopsies from 50 patients with the clinical diagnosis of hidradenitis suppurativa, submitted to the Department of Pathology at the University Hospital of Northern Norway, Tromsø, Norway. The biopsy material came from hospitals and physicians all over northern Norway in the years 2000-2007. All tissue material was resectioned and stained with the immunohistochemical reagent, cytokeratin (AE1/AE3/PKC26), and that made it possible to divide the material into two different disease categories: (1) 36 biopsies from 30 cases had tissue inflammation after rupture of keratin-rich epidermal cysts, which we call 'horny cell inflammation', followed by extensive cutaneous thrombi and infarcts, and (2) 21 biopsies from 20 cases had 'apocrinitis' defined here as an inflammatory destruction of apocrine skin glands, and partly of close eccrine glands. The two disease populations differed: the patients with a diagnosis of horny cell inflammation were younger and mainly women; those with a diagnosis of apocrinitis, as defined here, were older, men and women equally represented.

It is beneficial if teledermatology is integrated in an existing structure for optimum utilisation of resources. Teledermatology has been used to redistribute the workload of specialists. Teledermatology provides continuous access to specialist assessment of patients in collaboration with local physicians. Simple store-and-forward teledermatology is well suited for follow-up of patients initially seen by a specialist. Milder cases of some clinically characteristic diseases such as acne are well suited to management through teledermatology. Teledermatology offers the possibility of case-based continued medical education of non-specialists. Teledermatology generally follows the life curve of other successful new organisational models and does not affect demand for health services.

Complexes of the types [CH3Hg(aza)], [CH3Hg(Haza)]X, and [(CH3Hg)2(aza)]X are obtained by reacting CH3HgOH and/or CH3HgX (X = NO3, ClO4) with 7-azaindole (Haza). The weakly acidic N1-H proton on the pyrrole ring is displaced by the hydroxide, whereas the perchlorate and nitrate salts lead to CH3Hg+ coordination to the N7 lone pair on the pyridine ring. Detailed analysis of the infrared spectra of the complexes and their N-deuterated derivatives provides diagnostic regions for eventual prediction of the coordination mode in other systems. All compounds are characterized by means of 1H, 13C, and 199Hg NMR spectra in DMSO solution and solid-state CP-MAS 13C spectra. Comparison of the solution and solid-state 13C spectra show that the species present in the solids remain undissociated in DMSO. Each type of complex can be identified from a characteristic pattern of large displacements of the ligand 13C signals. The 1H spectra are less informative because substitution of the N1-H proton by CH3Hg+ induces only minor shifts. Metal solvation appears to have a major influence on the 13C and 199Hg chemical shifts of the CH3Hg+ groups.

Crystals of 7-azaindole ([Formula: see text], a = 11.312(4), b = 14.960(6), c = 15.509(5) Å, α = 102.86(3), β = 108.78(3), γ = 90.71(3)°, Z = 16, R = 0.052) contain tetrameric units of approximate S4 symmetry, in which the molecules are associated by means of four complementary N—H … N hydrogen bonds. [CH3Hg(7-azaindole)]NO3 ([Formula: see text], a = 7.818(3), b = 7.884(3), c = 9.135(4) Å, α = 97.89(3), β = 109.13(3), γ = 103.28(3)°, Z = 2, R = 0.039) contains well-separated nitrate ions and complex cations in which the methylmercury group is linearly bonded to the pyridine nitrogen atom, whereas the five-membered ring remains protonated. In the neutral [CH3Hg(azaindolate)] complex ([Formula: see text], a = 10.926(10), b = 11.333(8), c = 11.647(10) Å, α = 92.13(8), β = 104.83(9), γ = 111.86(7)°, Z = 6, R = 0.048), methylmercury groups have substituted the N—H proton in the five-membered ring for the three symmetry-independent molecules. Intermolecular secondary Hg … N bonds are found with pyridine nitrogens. Keywords: azaindole, methylmercury, crystal structure.

To better define the role of 3' untranslated region (3'UTR) on transcriptional regulation of the human tumor necrosis factor (TNF)-alpha gene, monocytic human THP-1 cells were transfected with two TNF-alpha promoter constructs spanning base pairs -1897/-1 and -1214/-1, respectively, and linked to the rabbit beta-globin gene. Quantitative globin gene expression of chimerae was measured by reverse transcription-polymerase chain reaction. A construct linking the chicken beta-actin promoter and a deleted portion of the beta-globin gene was cotransfected and used as internal standard. Unexpectedly, when THP-1 cells were stimulated with lipopolysaccharide or toxic shock syndrome toxin-1, gene regulation was hardly detected. In contrast, endogenous TNF-alpha gene regulation measured by the same reverse transcription-polymerase chain reaction procedure was vigorous. Remarkably, ligation of 3'UTR to chimeric constructs led to a drastic drop in the basal level of chimeric gene expression, resulting in a 15- to 40-fold induction of the reporter gene. Consistently, when the TNF-alpha promoter was replaced by the cytomegalovirus early immediate promoter, gene expression was also uniformly reduced but was no longer up-regulated upon stimulation with lipopolysaccharide and toxic shock syndrome toxin-1. These data provide the first line of evidence that, in addition to its role in TNF-alpha transcript stability and translation, human TNF-alpha 3'UTR also participates in modulating gene expression at the transcriptional level.

Summary Background Venom immunotherapy is definitely indicated in severe systemic anaphylactic reactions to bee stings. but is not devoided of risks of anaphylaxis. Safer methods of Immunotherapy need to be developed. Objective To delineate phospholipase A2 Tcell epitopes using shoti I5mer vs long 40–60mer overlapping peptides, and to approach the potential interest of a venom immunotherapy based on the use of long peptides (1–60. 51–99. 90–134) mapping the whole phospholipase A2 molecule vs a restricted number of immunodominant epitopes. Methods Proliferation of a CD8+ T cell depleted peripheral blood mononuclear cell fraction and short-term T-cell lines from unselected bee venom hypersensitive patients in response to phospholipase A2 synthetic peptides. Results Whereas T-cell proliferation to 15mer overlapping peptides was weak, T-cell response to long overlapping peptides was in contrast vigorous in all patients, mostly directed to C-terminal peptide 90–134. Our results did not support the concept of rare dominant T-cell epitopes. and disclosed T-cell responses to multiple epitopes in several patients. No significant IgE-binding to long overlapping peptides was detected except in one patient against peptide 90–134. Conclusion 15mer peptides might not be sensitive enough to fully delineate all potential T-cell epitopes scattered along the allergen. Since they do not bind IgE in vitro or only weakly, and taking into account a T-cell response frequently directed to multipie epitopes, long overlapping peptides may represent ideal tools for immunotherapy.

Background: Immunologic mechanisms of desensitization are still incompletely understood. Safer methods of immunotherapy with reduced risks of anaphylaxis need to be developed. Objective: To study the effects of conventional venom immunotherapy (VIT) on phospholipase A 2 (PLA 2 )-specific T cells and on T-cell reactivity to short and long synthetic peptides that map the PLA 2 molecule. Method: Proliferation of a CD4 + cell–enriched peripheral blood mononuclear cell fraction and cytokine secretion by T cell lines from patients hypersensitive to bee venom and undergoing VIT in response to PLA 2 and PLA 2 synthetic peptides were measured. Results: T-cell proliferation in response to three synthetic peptides, 40 to 60 amino acids long and mapping the entire PLA 2 molecule with an overlap of 10 residues (1 to 59, 51 to 99, and 90 to 134) steadily increased during the first 14 weeks of VIT corresponding to the treatment period with incremental doses of antigen. These results are in contrast to the low proliferation indices obtained with short (15 amino acid–long) peptides, and the inability to characterize the immunodominant region of the molecule with short peptides. At the end of VIT (after 3 to 5 years), there was correspondingly, a marked decrease in T cell responsiveness to PLA 2 and to its long synthetic peptides. This response was paralleled by a shift in the pattern of cytokine secretion by T cell lines from a T H0 -type to a T H1 -type pattern. Conclusion: After a transient increase in T-cell proliferation, late VIT was characterized by T-cell hyporesponsiveness to allergen and by modulation of cytokine secretion from a T H 0 -type to a T H 1 -type pattern. Because of their capacity to recruit multiple T-cell epitopes, long peptides mapping the entire PLA 2 molecule appear to be efficient T cell stimulators and may represent potential candidates for peptide immunotherapy. (J Allergy Clin Immunol 1997;100:96-103.)

1,2 λ 3 azaphosphiridines 4a,b are obtained by reacting a dihalogenated phospha-alkene (Me 3 Si) 2 NPCCl 2 with two equivalents of lithium silylated amides.