Pediatric neurolisteriosis: A diagnosis to consider even in the absence of immunodeficiency.

Neurolisteriosis is known to affect vulnerable groups, for example neonates or children with immunodeficiency. This is a key point of the current clinical guidelines regarding pediatric meningitis. We report a rare case of neurolisteriosis in an immunocompetent infant, without the typical signs of listeriosis, which led to a delay in administering the appropriate antibiotherapy. This case illustrates the clinical heterogeneity of neurolisteriosis and the relevance of appropriate polymerase chain reaction (PCR) tests when the clinical presentation differs from the current guidelines. This case also reminds us that raw or unpasteurized milk-based food products pose a risk even in immunocompetent infants or children.

A multicentre, prospective, non-randomized, sequential, open-label trial to demonstrate the bioequivalence between intravenous immunoglobulin new generation (IGNG) and standard IV immunoglobulin (IVIG) in adult patients with primary immunodeficiency (PID).

OBJECTIVES: To demonstrate the bioequivalence between 2 intravenous immunoglobulin (IVIG) preparations, TEGELINE® and ClairYg®, a ready-to-use 5% IVIG, in primary immunodeficiency (PID). Secondary objectives were to assess the efficacy, safety and pharmacokinetics of ClairYg®. METHODS: Twenty-two adult PID patients receiving stable doses of TEGELINE® (5% lyophilized IVIG) were switched to ClairYg® for 6 months. ClairYg® was administered under the same conditions as TEGELINE®, either every 3 or 4 weeks. The primary endpoint was mean average total IgG trough level at steady state with ClairYg® versus TEGELINE®. Clinical efficacy was also assessed in terms of infections and associated events. RESULTS: Bioequivalence was established with a mean average total IgG trough level at steady state being 8.05g/L with TEGELINE® and 9.17g/L with ClairYg® (i.e. geometric mean for the difference between ClairYg® and TEGELINE® was 1.136; [90% CI: 1.092-1.181] P<0.001), within the pre-specified margin to establish bioequivalence (0.80-1.25). Total IgG trough levels remained clinically adequate (>4-6g/L) throughout the study. No patient was hospitalized for infection or had serious bacterial infections while receiving ClairYg®. The median annualized infections rate per patient was similar for both products: 4.35 [0; 21.8] for TEGELINE® and 4.30 [0; 15.1] for ClairYg®. Infections were less common with higher IgG trough levels (>8.16g/L). ClairYg® showed good safety, in particular good hepatic and renal tolerance, and did not induce hemolysis. ClairYg® pharmacokinetics profile was comparable to that of TEGELINE®. CONCLUSION: ClairYg® is safe and effective in the treatment of adult PID.

Treatment with Hizentra in patients with primary and secondary immunodeficiencies: a real-life, non-interventional trial.

BACKGROUND: Although Hizentra is indicated for immunoglobulin replacement therapy in patients with primary and secondary immunodeficiencies, phase III trials have focused on patients with primary immunodeficiencies. In this 9-month, real-life, prospective, non-interventional, longitudinal, multicenter study of patients with primary and secondary immunodeficiencies in France, treatment modalities (primary endpoint), efficacy, safety, tolerability, quality of life, and treatment satisfaction were evaluated using descriptive statistics. RESULTS: Starting in January 2012, 117 patients were enrolled (99 adults, 18 children). Secondary immunodeficiencies were present in 48.7 % of patients. At follow-up, injections were administered every 7 days in 92.2 % of patients. Nine patients (7.8 %) were taking Hizentra every 10-14 days. The median dose of Hizentra administered was 0.1 g/kg/injection. Fifty-six patients were administered doses <0.1 g/kg/injection and 13 patients were administered doses >0.2 g/kg/injection. Mean trough IgG titers were 9.0 ± 3.3 g/L (median 8.3 g/L). The mean yearly rate of infection was 1.2 ± 1.9. Mean scores on the Short Form-36 physical and mental component summaries were 46.3 ± 10.0 and 46.6 ± 9.3, respectively. Scores on the Treatment Satisfaction Questionnaire for Medication ranged from 69.9 ± 19.9 to 88.3 ± 21.2 depending on the domain. Treatment with Hizentra was well tolerated. No single drug-related systemic reaction occurred in more than one patient and few local reactions were reported (n = 5). CONCLUSIONS: Under real-life conditions and in a cohort that included patients with primary and secondary immunodeficiencies, treatment with Hizentra was effective and well tolerated and patients were generally satisfied with the treatment.

Does the route of immunoglobin replacement therapy impact quality of life and satisfaction in patients with primary immunodeficiency? Insights from the French cohort "Visages".

BACKGROUND: IgG replacement therapy (IgRT) in primary immunodeficiencies (PID) is a lifelong treatment which may be administered intravenously (IVIg) or subcutaneously (SCIg), at hospital or at home. The objective of the VISAGE study was to investigate if route and/or place for IgRT impact patients' satisfaction regarding IgRT and quality of life (QoL) in real-life conditions. METHODS: The study enrolled PID patients at least 15 years old receiving IgRT for at least 3 months. Satisfaction and QoL were evaluated at enrollment and over a 12-month follow-up period by Life Quality Index (LQI) which measures 3 dimensions of satisfaction: treatment interference, therapy related problems and therapy settings (factors I, II and III) and SF-36 v2 questionnaire. RESULTS: The study included 116 PID patients (mean age 42 ± 18 years, 44 % males, 58 % with scholar or professional occupation) receiving IgRT for a mean of 8.5 ± 8.4 years. At enrollment they were receiving either home-based SCIg (51 %), hospital-based IVIg (40 %) or home-based IVIg (9 %). Patients exhibited a high degree of satisfaction regarding IgRT whatever the route and place for administration. LQI factor I was higher for home-based SCIg (86 ± 2) than for hospital-based IVIg (81 ± 3) and home-based IVIg (73 ± 5; p = 0.02 versus home-based SCIg); no difference was found for LQI factor II; LQI factor III was higher for home-based SCIg (92 ± 2) than for hospital-based IVIg (87 ± 5) and hospital-based IVIg (82 ± 3; p = 0.005 versus home-based SCIg). By contrast, every dimension of QoL was impaired. Over the follow-up period, 10 patients switched from hospital-based IVIg to home-based SCIg and improved LQI factor I (p = 0.004) and factor III (p = 0.02), while no change was noticed in LQI factors II and QoL. Meanwhile, no change in satisfaction or QoL was found in patients with stable route of IgRT. When asked on their preferred place of treatment all but one patient with home-based treatment would choose to be treated at home and 29 % of patients treated at hospital would prefer home-based IgRT. CONCLUSION: PID patients expressed a high degree of satisfaction regarding IgRT, contrasting with impaired QoL. In real-life conditions awareness of patient's expectations regarding the route or place of IgRT may be associated with further improvement of satisfaction.

[Anaphylactic shock from an iodine contrast medium: role of the allergy check-up in one case]. / Choc anaphylactique à un produit de contraste iodé : intérêt du bilan allergologique à propos d'un cas.

Anaphylactoid reactions to iodine contrast media are rare but serious, possibly life-threatening and calling an appropriate and urgent care. The physiopathological mechanism of these reactions remains to be fully elucidated. This reaction is still mostly called "pseudoallergic" in the literature. However, recent papers emphasise that a true allergic process is more frequent than previously expected. They also insist on the interest of running allergy tests including skin testing. We report the case of an anaphylactic shock to iodine contrast media, occurring during coronary angiography. We performed an allergy check-up and found the culprit allergen. We also evidenced a cross-reaction to another contrast media from the similar group. On the other hand, there was no reaction to contrast media of other types. With these results, another coronary angiography could be performed without any adverse event. When hypersensitivity reactions to iodine contrast media occur, it is mandatory to perform a complete allergy check-up. This will help determine the precise mechanism of the reaction and find the culprit allergen.

Comparison between major histocompatibility complex class II tetramer staining and surface expression of activation markers for the detection of allergen-specific CD4⁺ T cells.

BACKGROUND: Major histocompatibility complex (MHC) class II tetramers (tetramers) allow to detect allergen-specific CD4(+) T cells at a single-cell level. Limits to this technology include HLA restriction and the need to identify immunodominant T cell epitopes. OBJECTIVE: Assessing the expression of various activation markers following allergen stimulation to replace tetramer staining. METHODS: Peripheral blood mononuclear cells (PBMCs) from 25 birch pollen, grass pollen or house dust mite allergic individuals were stimulated with peptide mixes encompassing immunodominant epitopes from corresponding major allergens. After 2 weeks of in vitro amplification, cells were stained with both the appropriate tetramer and antibodies directed to CD25, CD30, CD39, CD69, CD137, CD154, GITR, HLA-DR and ICOS, before FACS analysis. RESULTS: Following allergen stimulation, percentages of tetramer(+) cells among CD4(+) CD154(+) cells range from 5% to 87%, depending upon donors. As for CD154, a large inter-individual variability is observed in terms of surface expression for all activation markers tested in allergen-stimulated PBMCs. T cells reactive with either tetramers (0.4-10.4% CD4(+) T cells) or anti-marker antibodies (2.2-32.7% CD4(+) T cells), but not both, are observed, reflecting the presence of anergic as well as non-specifically activated cells. Tetramer(+) /marker(+) , tetramer(+) /marker(-) and tetramer(-) /marker(+) cells were compared for their capacity to express cytokines, demonstrating that only the former represent bona fide allergen-specific activated CD4(+) T cells, based upon a higher expression of cytokines or corresponding genes in presence of the allergen. CONCLUSION AND CLINICAL RELEVANCE: No strict correlation exists between tetramer staining and the expression of multiple activation markers in stimulated CD4(+) T cells. Dual staining allows to discriminate functional tetramer(+) /marker(+) vs. anergic (tetramer(+) /marker(-) ) allergen-specific T cells or non-specifically activated (tetramer(-) /marker(+) ) T cells. Combining tetramer staining with the detection of activation markers helps understanding patient heterogeneity regarding specific CD4(+) T cell responses. This approach has immediate relevance for monitoring immune changes induced during specific immunotherapy.

Distinct characteristics of seasonal (Bet v 1) vs. perennial (Der p 1/Der p 2) allergen-specific CD4(+) T cell responses.

BACKGROUND: A better understanding of allergen-specific CD4(+) T cell responses is needed to help improving immunological therapies. Objective To compare CD4(+) T cell responses against seasonal (Bet v 1) and perennial (Der p 1, Der p 2) allergens. METHODS: Major histocompatibility complex class II peptide tetramers were engineered to monitor allergen-specific T cell responses. After in vitro expansion, tetramer(+) cells were tested for surface markers using cytofluorometry. Cytokine gene expression and production were assessed using quantitative PCR and cytokine surface capture assays, respectively. RESULTS: Tetramer(+) cells were detected in 19 patients allergic to house dust mites (HDM), seven allergic to birch pollen, 13 allergic to both and nine non-allergics with either an HLA-DRB1(*) 0101, (*) 0301, (*) 1501 or an HLA-DPB1(*) 0401 background. High-avidity T cells are elicited against the immunodominant Bet v 1(141-155) epitope, whereas broader low-avidity T cell responses are induced against Der p 1(16-30) ,(110-124) ,(171-185) and Der p 2(26-40,107-121) epitopes. Responses against Bet v 1 involve effector (CDL62 low, CCR7 low) or central (CD62L(+) , CCR7(+) ) memory cells in allergic and non-allergic individuals, respectively, whereas central memory cells are mostly detected against mite allergens. In non-allergics, both mite and Bet v 1-specific T cells produce IFN-γ and IL-10. In contrast to Bet v 1-driven Th2 responses, mite allergens induce highly polymorphic responses in allergics, including Th1, Th2/Th17 or mixed Th1/Th2 profiles. Mite-specific T cell frequencies in the blood remain in the range of 1-6 × 10(-4) CD4(+) T cells throughout the year. CONCLUSION: Different memory CD4(+) T cell responses are elicited in the context of chronic vs. seasonal stimulation with the allergen(s). The heterogeneity in the patterns of CD4(+) T cell responses observed in patients allergic to HDMs should be taken into account for specific immunotherapy.

[Cutaneous ulcers and glycogen storage disease type 1b]. / Ulcères cutanés au cours d'une glycogénose de type 1b.

BACKGROUND: Glycogen storage disease type 1b is a rare disorder caused by 6-glucose-phosphatase transport deficiency. It is characterised primarily by metabolic disorders combined with hypoglycaemia and hyperlactacidaemia and a predisposition to staphylococcal infections associated with polynuclear neutrophil abnormality. Herein, we report the case of a patient with glycogen storage disease type 1b who developed ulcers of the lower limbs and we discuss the possible significance of this association which, to our knowledge, has not yet been described in the medical literature. PATIENTS AND METHODS: A 38-year-old man, presenting glycogen storage disease type 1b diagnosed when he was 13 months old, was hospitalised for ulcers of the lower limbs occurring over the preceding five years. The patient had a quantitative polynuclear neutrophil deficit that was treated with filgrastim. The various ulcers all developed according to the same pattern, namely pustules progressing towards necrosis followed by painful ulceration. No fever or collection of pus was observed. A number of samples of pustules proved sterile while others contained Staphylococcus aureus, sensitive to numerous antibiotics. Histopathological examination proved relatively inconclusive and laboratory tests showed no vascular cause of the ulcers. DISCUSSION: Hypothetical diagnoses of staphylococcal ecthyma suggested by the neutrophil deficiency and of pyoderma gangrenosum were proposed but could not be confirmed with certainty. Involvement of other predisposing factors independent of the patient's glycogen storage disease cannot be ruled out. This combination, not previously reported, nevertheless deserves to be singled out, despite its as yet unclear significance.

[The value of allergy survey in a retrospective series of 40 patients with burning-mouth syndrome (stomatodynia)]. / Stomatodynies: intérêt de l'enquête allergologique dans une série rétrospective de 40 malades.

BACKGROUND: By definition, stomatodynia or burning-mouth syndrome involves oral pain with no causes being found on history taking or examination. An allergic origin is often suspected by doctors and patients alike. In this study, we attempted to assess the value of epicutaneous tests in demonstrating allergic causes for patients presenting stomatodynia. PATIENTS AND METHODS: This was a single-centre retrospective study of patients undergoing epicutaneous tests between 1996 and 2003 to screen for allergic causes of mouth pain not accounted for by any abnormalities seen during examination performed at consultations for mouth disease. RESULTS: Forty patients were included (11 male, 29 female; mean age: 58 years), and 39 were excluded. Sixteen patients presented at least one positive test, with a total of 35 positive tests in all. In decreasing order of frequency, the causes were metals, mercury derivatives (nickel salts: n=5; chrome salts: n=3; palladium salts: n=2; phenylmercuric acetate: n=2; thiomersal: n=2; cobalt salts: n=1; gold salts: n=1; mercury: n=1) and resins (acrylates: n=4). The relevance of these test results was considered probable in three cases and possible in five cases, associated with the existence of metals or resins in patients' mouths. The Peru balm test was positive in four cases but was not relevant. Tests for personal products were negative in all cases, with the exception of one case of resin from a prosthesis and one case of tixocortol pivalate. COMMENTS: Type I stomatodynia (daily occurrence with gradually increase in discomfort throughout the day) and type II stomatodynia (permanent) are not normally attributable to allergies. However, for type III stomatodynia (non-permanent, with acute episodes followed by remission), an allergy survey guided by questioning may be undertaken to determine the cause, primarily prostheses or diet. The relevance of positive test results must be interpreted with caution in view of the incidence of positive epicutaneous tests for metals and Peru balm among the general population studied.

A novel method to determine lean body water using localized skin biopsies: correlation between lean skin water and lean body water in an overhydration model.

To determine the relationship between total body water (TBW) fraction and local water content measured in the skin (SW) this study assessed eight anesthetized piglets in an overhydration model. TBW was assessed by deuterium oxide dilution and body mass measurements taken throughout the experiments, and by whole body carcass analysis at the end of each experiment. Additionally, extracellular water and plasma volume were assessed using bromide dilution and Evan's blue dilution, respectively. SW was assessed by tissue biopsies taken at 60-min intervals throughout the experiment. Lean body water (LBW) fraction and lean skin water (LSW) fraction were assessed by extracting the fat from the carcass and biopsy samples. A correlation does exist between TBW fraction and SW fraction with r2=0.58 (P<0.05); however, the strongest correlation occurred between the LBW fraction and LSW fraction with r2=0.87 (P<0.05) and an SE of prediction of 0.77%. These data demonstrate that LSW gives an accurate and precise estimate of LBW and could therefore be used to determine the hydration index in appropriate research settings.

A high prevalence of sensitization still persists in leg ulcer patients: a retrospective series of 106 patients tested between 2001 and 2002 and a meta-analysis of 1975-2003 data.

BACKGROUND: Sensitization to topical treatments used in leg ulcers is common. Questioning and patch testing are used to identify causative drugs or dressings. OBJECTIVES: To study the current frequency of sensitization in our centre, to analyse previously published studies, and to compare sensitization in recent years with studies published before 1990. METHODS: A retrospective study was undertaken of all patients admitted with leg ulcers in 2001 and 2002. Of the files of 235 patients with leg ulcers reviewed, we identified 106 patients (group A) who had been patch tested in our institution between 2001 and 2002 with the European standard series and an additional series. The frequency of sensitization was compared with an earlier unpublished retrospective study in our centre of 36 leg ulcer patients tested in 1988 (group B), with a group of unselected contact dermatitis patients tested between 1 January 1997 and 31 December 2000 in our centre (group C), and with results published in the literature. We performed a computerized database search of MEDLINE and compared results obtained in recent years with those obtained before 1990 to obtain evidence of changing trends. RESULTS: Seventy-five per cent of the 106 patients had at least one positive reaction, and 57% had two or more positive reactions. Balsam of Peru was positive in 40% of cases, followed by lanolin (21%), fragrance mix (18%), trichlocarban (13%), colophony (11%), Cetavlon (cetrimide cream) (9%) and neomycin (9%). Thirty-five of the 36 group B patients had at least one positive reaction. Lanolin was the most frequent (31%), followed by balsam of Peru (22%), Cetavlon (19%), colophony (14%), terebenthene (14%), quinoline mix (11%) and benzocaine (8%). Two hundred and eighty-six of 526 patients of group C were positive in at least one test (54.4%). Three allergens gave a sensitization rate >10%: balsam of Peru (12.5%), fragrance mix (15.2%) and nickel sulphate (21.1%). Review of the literature and calculation of sensitization rates in a pool of 3043 patients extracted from 24 series, plus our own, showed persistence of high sensitization rates and a significant (8.5%) increase in sensitization between the two periods compared. There was a decrease in sensitivity to lanolin, constant sensitization to aminoglycosides, a slight increase in sensitivity to thiuram mix and glucocorticoids, and a marked increase in sensitivity to balsam of Peru in France. Newer topical treatments and dressings showed very low rates of sensitivity with the exception of hydrogels. CONCLUSIONS: Despite warnings, sensitization to topical treatments for leg ulcers is still frequent and, moreover, continues to increase, some variations reflecting local nursing practices and variations in topical treatment available. Although a decrease in sensitization rate with lanolin has been observed throughout the world, no decrease in sensitization rate has been demonstrated with aminoglycosides, and sensitization to glucocorticoids, thiuram mix and new products (hydrogels) is now increasingly being reported.

A concise total synthesis of the azaphenanthrene alkaloid eupolauramine.

A six-step total synthesis of the azaphenanthrene alkaloid eupolauramine 1 has been achieved using combinational metalation-cyclization tactics. The synthetic route involved first the construction of the azaisoindolinone 9 by aryne-mediated cyclization of he phosphorylated pyridocarboxamide 7 and subsequent dephosphorylation. Metalation of 9 followed by connection of the hydroxybenzyl appendage and E(1)CB anti-elimination allowed the formation of the halogenoarylmethylene azaisoindolinone 4 in the exclusive E-form. Oxidative radical cyclization gave rise to the azaphenanthrene skeleton and regioselective bromination of 3 induced the incorporation of the bromine atom at the 6-position of the azaphenanthrene lactam. Ultimate replacement of the bromine atom of 2 by the methoxy functionality by sequential transmetalation, in situ oxidation, and O-methylation of the phenolic derivative 14 completed the synthesis of the target natural product eupolauramine.

A mild anionic method for generating o-quinone methides: facile preparations of ortho-functionalized phenols.

A low-temperature method for generating o-quinone methides is described which permits facile introduction of assorted R substituents onto the aryl ring system at low temperature. The method is useful for the efficient preparation of ortho-ring-alkylated phenols.

[Congenital syphilis: update and perspectives]. / Syphilis congénitale. Mise au point et perspectives.

Congenital syphilis is responsible for a variety of clinical symptoms, from subclinical attacks to septicemic forms that may be fatal. The most frequently encountered forms typically involve low birth weight, heptosplenomegaly and jaundice. Premature birth, anemia, cutaneous lesions, coryza, anasarca and pseudoparalysis may also occur. Neonatal X rays generally show characteristic but nonspecific osteochondrocyte lesions and periosteous dystrophy. A clinical form partly associated with growing tissues may be detected late. Diagnosis of fetal syphilis depends on the detection by immunofluorescence of specific IgM immunoglobulins in the newborn. Parenteral antibiotic treatment with 100,000 IU penicillin/kg.day for 15 days is given to newborns with symptoms. The classification and treatment of asymptomatic forms is unclear. A single injection of benzathine-penicillin is a good compromise between simple surveillance and admission to hospital for 10 days of intravenous treatment. In any case, serological surveillance is required to check that IgM disappears from the blood or that the titer of IgG decreases. Reinfection is always possible, even in a newborn treated correctly. In developing countries, pediatricians must be aware of the various clinical forms of congenital syphilis. In addition, national programs to combat sexually transmitted diseases should be supported and developed by international aid agencies. In economically advanced countries, attention is currently focused on the restricted nature of medical treatment. Improvements in the management of congenital syphilis depend above all on dealing with the social and cultural problems of populations affected by syphilis.