Revisiting human IL-12Rβ1 deficiency: a survey of 141 patients from 30 countries

Interleukin-12 receptor β1 (IL-12Rβ1) deficiency is the most common form of Mendelian susceptibility to mycobacterial disease (MSMD). We undertook an international survey of 141 patients from 102 kindreds in 30 countries. Among 102 probands, the first infection occurred at a mean age of 2.4 years. In 78 patients, this infection was caused by Bacille Calmette-Guérin (BCG; n = 65), environmental mycobacteria (EM; also known as atypical or nontuberculous mycobacteria) (n = 9) or Mycobacterium tuberculosis (n = 4). Twenty-two of the remaining 24 probands initially presented with nontyphoidal, extraintestinal salmonellosis. Twenty of the 29 genetically affected sibs displayed clinical signs (69%); however 8 remained asymptomatic (27%). Nine nongenotyped sibs with symptoms died. Recurrent BCG infection was diagnosed in 15 cases, recurrent EM in 3 cases, recurrent salmonellosis in 22 patients. Ninety of the 132 symptomatic patients had infections with a single microorganism. Multiple infections were diagnosed in 40 cases, with combined mycobacteriosis and salmonellosis in 36 individuals. BCG disease strongly protected against subsequent EM disease (p = 0.00008). Various other infectious diseases occurred, albeit each rarely, yet candidiasis was reported in 33 of the patients (23%). Ninety-nine patients (70%) survived, with a mean age at last follow-up visit of 12.7 years ± 9.8 years (range, 0.5-46.4 yr). IL-12Rβ1 deficiency is characterized by childhood-onset mycobacteriosis and salmonellosis, rare recurrences of mycobacterial disease, and more frequent recurrence of salmonellosis. The condition has higher clinical penetrance, broader susceptibility to infections, and less favorable outcome than previously thought.     

IFN-alpha-induced motor slowing is associated with increased depression and fatigue in patients with chronic hepatitis C

Interferon (IFN)-alpha has been used to investigate pathways by which innate immune cytokines influence the brain and behaviour. Previous studies suggest that altered basal ganglia function may contribute to IFN-alpha-induced neuropsychological and behavioural changes. To further examine IFN-alpha effects on neuropsychological functions related to basal ganglia (as well as other brain regions), and explore the relationship between altered neuropsychological function and IFN-alpha-induced depression and fatigue, a selected subset of the Cambridge Neuropsychological Test Automated Battery was administered to 32 hepatitis C patients at baseline (Visit 1) and following 12 weeks (Visit 2) of either no treatment (n = 12) or treatment with IFN-alpha plus ribavirin (n = 20). Symptoms of depression and fatigue were assessed using the Montgomery-Asberg Depression Rating Scale and the Multidimensional Fatigue Inventory. Compared to control subjects, patients treated with IFN-alpha/ribavirin exhibited significant decreases in motor speed as measured in the simple and five-choice movement segments of the CANTAB reaction time task and slower response times in the rapid visual information processing task, a task of sustained attention. Decreased motor speed on the five-choice movement segments of the reaction time task was in turn correlated with increased symptoms of depression and fatigue (R = 0.47, p < 0.05 and R = 0.48, p < 0.05, respectively). IFN-alpha/ribavirin treatment had no effects on executive function, decision time in the reaction time task, or target detection accuracy in the sustained attention task. Motor slowing and its correlation with psychiatric symptoms suggest that altered basal ganglia function may contribute to the pathogenesis of IFN-alpha-induced behavioural changes.     

Identification and treatment of symptoms associated with inflammation in medically ill patients

Medically ill patients present with a high prevalence of non-specific comorbid symptoms including pain, sleep disorders, fatigue and cognitive and mood alterations that is a leading cause of disability. However, despite major advances in the understanding of the immune-to-brain communication pathways that underlie the pathophysiology of these symptoms in inflammatory conditions, little has been done to translate this newly acquired knowledge to the clinics and to identify appropriate therapies. In a multidisciplinary effort to address this problem, clinicians and basic scientists with expertise in areas of inflammation, psychiatry, neurosciences and psychoneuroimmunology were brought together in a specialized meeting organized in Bordeaux, France, on May 28-29, 2007. These experts considered key questions in the field, in particular those related to identification and quantification of the predominant symptoms associated with inflammation, definition of systemic and central markers of inflammation, possible domains of intervention for controlling inflammation-associated symptoms, and relevance of animal models of inflammation-associated symptoms. This resulted in a number of recommendations that should improve the recognition and management of inflammation-associated symptoms in medically ill patients.     

Organized cervical cancer screening for underpriviledged women

Individual cervical screening with pap-smears is the major cause of the decrease in incidence and mortality of cervical cancer in France since more than 30 years. But, for the last ten years, the decrease in mortality is limited due to the persistence of poor prognostic cases and the insufficiency of treatment efficacy in such patients. These cases are mostly observed in women who did not participate to regular screening. They are generally from low socioeconomic levels or migrant populations, or both. Such an observation leads us to organize 3 successive pilot campaigns (2001, 2003, 2005) in the Northern part of Marseille city where the rate of such poor population is high (37 to 45%). The women without a pap-smear indexed in the National Insurance Register for the last 3-2 years were invited by individual mailing to perform, free of charge, a pap-smear. The evaluation of each campaign helps us to improve the next one. The major changes from the 1st one to the 3rd one were to increase the number of free screening services, to send a second invitation to the non responders, and to organize local meetings with social workers and nurses to explain to the women the importance of performing regular screening tests. The final results after the 3 campaigns showed : out of the eligible women the participation rates are dramatically low evolving from 1,56 % to 2,48% and 6,87% of pap-smears done along the 3 campaigns ; the selection of women "without pap-smear" from the national Insurance register was not good, a great number of missing data was identified, explaining partly the extremely low rate of participation ; the factors increasing a little the participation are the second mailing of invitation (39 % of pap-smears realised) ; the total gratuitous of the screening (both sampling and reading) ; the oral information delivered locally by social workers and the proximity of the places to perform the test ; the quality of the pap-smears collected by gynecologists was good but insufficient for other health professionals, requiring a specific training for cervical cell collection. The organization of such pilot projects need to be followed to find better solutions to increase the participation to cervical screening of such populations who are at high risk of poor prognosis cervical cancers.     

In Vivo Evaluation of a Retrievable Vena Cava Filter—The Dibie-Musset Filter: Experimental Results

Purpose: To evaluate, in an animal model, the efficacy and safety of a 7 Fr percutaneous vena cava filter for temporary or permanent use. Methods: The Dibie-Musset (DM) filter is a wire preformed into a double-spiral shape with a spring effect. The experiment was performed in 15 adult sheep and consisted of the insertion of 45 filters, clot trapping tests, and filter retrieval. Follow-up in all sheep consisted of radiologic (abdominal radiograph, inferior vena cavogram, abdominal computed tomography), macroscopic, and microscopic examinations between days 8 and 386 after filter placement. Results: Of the 45 filters implanted in 15 sheep, 29 were retrieved between day 0 and day 15. Filtration efficiency was 100% for clots 4 × 4 × 20 mm. No long-term (1 year) side-effects were detectable. Microscopic examination of the vein wall showed only a dense intimal fibrosis without signs of acute inflammation at 1 year. Conclusion: These results support the efficiency and safety of the DM filter in an animal model.     

An original method for submacroscopic metastases visualization in cases of cancer minimal residual disease

Scintigraphic imaging due to its sensitivity is in many cases one of the most powerful techniques for demonstrating metastases. Severe limitations still exist in cancer when it is necessary to detect the presence of a few tumour cells in the residual minimal disease. In preliminary experiments it had been observed that an immunomodulator isolated from Nocardia bacteria (Nocardia Soluble Peptidoglycan Derivative: NSPD) electively bound to a model of activated macrophages. An hypothesis has been put forward that the enhanced detection of macrophages that are usually present in the vicinity or inside tumours should represent a polyspecific test for scintigraphy of a variety of metastases. NSPD radiolabelled with 99mTechnetium is not usable when injected intravenously due to its physiochemical properties. It has therefore been encapsulated into liposomes then administered via the respiratory tract as an aerosol. Amphiphilic properties, as well as its low molecular weight allow a rapid diffusion of NSPD in blood. Scintigraphy of metastases was possible from 1.5 to 6 hours after inhalation. The first stage of the study was carried out on 5 patients bearing known metastases (skin, lymph nodes, bone) from malignant melanoma that all were imaged with 99mTc-NSPD. The test was then applied to patients with a high risk of recurrent cancers (melanoma: 6, breast tumour: 7) based on the detection in their plasmas of high Lipid Associated Sialic Acid (LASA) concentrations. The association of these two sensitive techniques has resulted in the detection of very small metastases that were not seen using conventional scintigraphy; they were then confirmed histologically.     

Influence of interleukin-2 deficiency on the generation of autoimmune B cells

The production of auto-antibodies is one of the predominant characteristics of autoimmune disorders. Because IL-2 deficient mice develop autoimmunity, we asked how IL-2 deficiency might impair endogenous mechanisms of B cell tolerance. To this end, we mated BALB/c anti-dsDNA H chain knock-in mice, in which B cells producing anti-dsDNA antibodies are properly regulated, with IL-2 deficient mice and assessed the phenotype of their offspring. IL-2 deficient mice expressing the anti-dsDNA H chain knock-in allele developed anti-dsDNA antibodies of both IgM and IgG isotypes. Production of these antibodies occurred through the disruption of several mechanisms of endogenous tolerance, including deletion, maturational arrest, and follicular exclusion. In summary, our results suggest that IL-2 plays an important role in regulating B cell tolerance.