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.     

Anticipatory reward signals in ventral striatal neurons of behaving rats

It has been proposed that the striatum plays a crucial role in learning to select appropriate actions, optimizing rewards according to the principles of 'Actor-Critic' models of trial-and-error learning. The ventral striatum (VS), as Critic, would employ a temporal difference (TD) learning algorithm to predict rewards and drive dopaminergic neurons. This study examined this model's adequacy for VS responses to multiple rewards in rats. The respective arms of a plus-maze provided rewards of varying magnitudes; multiple rewards were provided at 1-s intervals while the rat stood still. Neurons discharged phasically prior to each reward, during both initial approach and immobile waiting, demonstrating that this signal is predictive and not simply motor-related. In different neurons, responses could be greater for early, middle or late droplets in the sequence. Strikingly, this activity often reappeared after the final reward, as if in anticipation of yet another. In contrast, previous TD learning models show decremental reward-prediction profiles during reward consumption due to a temporal-order signal introduced to reproduce accurate timing in dopaminergic reward-prediction error signals. To resolve this inconsistency in a biologically plausible manner, we adapted the TD learning model such that input information is nonhomogeneously distributed among different neurons. By suppressing reward temporal-order signals and varying richness of spatial and visual input information, the model reproduced the experimental data. This validates the feasibility of a TD-learning architecture where different groups of neurons participate in solving the task based on varied input information.     

Clearance and persistence of hepatitis C virus in a Tunisian population: association with HLA class I and class II

Human leukocyte antigens (HLAs) of class I and class II are reported to influence the outcome of hepatitis C virus (HCV) infection. The aim of this study was to assess the role of HLA class I and class II in influencing spontaneous viral clearance or persistence in HCV-infected patients. HLA class I (A and B) typing was performed by lymphocytotoxicity test and HLA class II (DRB1) was determined by low-resolution PCR-SSP (polymerase chain reaction amplification with sequence-specific primers) for 99 subjects (48 men and 51 women). Of these, 75 had chronic infection and 24 had viral clearance. No significant differences were observed between individuals with spontaneous viral clearance or chronic HCV infection for age, sex, source of infection, and risk factors. HLAB-w35 and HLA-DRB1*08 occurred more frequently in those with viral clearance (21.7 and 16.6%, respectively) compared with those with chronic infection (5.5 and 2.6%; p < 0.04 and p < 0.01, respectively). DRB1*15 occurred more often in those with chronic infection (29.3%) compared with those with viral clearance (16.66%), but the difference did not reach statistical significance. These results support the hypothesis that specific HLA class I and class II alleles might influence the clearance or persistence of HCV infection. Both Bw35 and DRB1*08 are associated with clearance of circulating HCV whereas DRB1*15 appears to predispose to progression of liver disease in Tunisian patients. Taken together, our results and those previously reported suggest that HLA associations with the outcome of hepatitis C viremia vary in relation to the ethnicity of the population studied. Further prospective studies of larger cohorts of HCV-infected subjects are needed to evaluate, in different populations, the role of specific HLA class I and class II alleles in the outcome of HCV infection.     

Recurrent inverted duplication of 2p with terminal deletion in a patient with the classical phenotype of trisomy 2p23-pter

Inverted duplications with terminal deletions have been reported in an increasing number of chromosomes and are probably more frequent than suspected until recently. We describe the cytogenetic and molecular characterization of an inverted duplication of chromosome 2p in an 8-year-old girl. Firstly interpreted as partial duplication 2p, the rearrangement was in fact an inverted duplication associated with a terminal deletion of the short arm of the rearranged chromosome 2, the latter not being detectable by cytogenetic analysis. The complete karyotype was: 46,XX,add(2)(p23)dn.ish inv dup del(2)(:p23.2-->p25.3::p25.3-->qter) (wcp2+,N-MYC++,2pter-)dn. We precisely define the extension of both the duplication and the deletion using bacterial artificial chromosomes clones spanning the regions. The size of the inverted duplicated segment was estimated to be 28 Mb, spanning from 2p23.2 to 2p25.3, and an approximately 1.6 Mb segment at 2pter-p25.3 was deleted in the abnormal chromosome. The physical findings noted in our patient include prominent forehead, hypertelorism, flat nasal bridge, and low-set and large ears. In addition, she had congenital heart defect and scoliosis. Her psychomotor development was severely delayed from the beginning. All these clinical features are the same as observed for the typical trisomy 2p23-pter syndrome. The phenotypic effects of the terminal deletion of 2p in addition to the trisomy are discussed. This is the third patient presenting with a severe clinical phenotype and a de novo inv dup del (2p).     

Antitumoral Potency by Immunomodulation of Chloroform Extract from Leaves of Nitraria retusa,Tunisian Medicinal Plant,via its Major Compounds β-sitosterol and Palmitic Acid in BALB/c Mice Bearing Induced Tumor

This study evaluated the antitumoral effect of Chloroform extract from Nitraria retusa leaves, via its major compounds β-sitosterols and palmitic acid. BALB/c mice were subcutaneously inoculated with B16-F10 cells, then treated intra-peritoneally after 7 days with the chloroform extract for 21 days. They were then euthanized, and the tumors were weighed. Lung parenchyma was analyzed. Lymphocyte and macrophages proliferation, cytotoxic T lymphocyte (CTL) activities were evaluated using the MTT assay. Macrophage phagocytosis was evaluated by measuring the lysosomal activity and nitric oxide production. Antioxidant activity was studied by cellular antioxidant activity on macrophage and splenocytes and by lipid peroxidation inhibitory activity in liver cells, kidney, and serum.

β-sitosterols and palmitic acid, major compounds of chloroform extract, impeded remarkably the expansion of the transplantable tumor, protected the lung parenchyma, and increased splenocytes proliferation and both CTL activities in tumor-bearing mice. β-sitosterols and palmitic acid were also seen to have enhanced lysosomal activity of host macrophages and antioxidant cellular activity. Also, they showed an inhibitory effect of lipid peroxidation.

Our results suggest that antitumoral effect of β-sitosterols and palmitic acid from chloroform extract is related with its immunomodulatory activity, and opens the way for a nutrition application and coprocessing phytotherapy against cancer.     

Monitoring of adverse events during the 2003 mass vaccination campaign with a trivalent meningococcal A/C/W135 polysaccharide vaccine in Burkina Faso

During a mass campaign with a newly licensed meningococcal polysaccharide ACW135 vaccine in Burkina Faso, adverse events following immunization (AEFI) were monitored up to 4 weeks after the campaign. Eighty-six AEFI cases (5.9 cases per 100,000 vaccine doses distributed) were reported. Among 22 serious events, 4 severe local reactions were considered very likely and 4 severe allergic reactions were considered probably related to the vaccination. One fatal case in a child followed protracted seizures of undetermined cause. In a setting with no prior surveillance system, adverse events were reported at rates comparable to documented rates for meningococcal polysaccharide vaccines in other settings. The findings confirm the benefits of the vaccine in the control of meningococcal meningitis.     

Study of lipid profile and parieto-temporal lipid peroxidation in AlCl<Subscript>3</Subscript> mediated neurotoxicity. modulatory effect of fenugreek seeds

Background  

Peroxidation of lipid (LPO) membrane and cholesterol metabolism have been involved in the physiopathology of many diseases of aging brain. Therefore, this prospective animal study was carried firstly to find out the correlation between LPO in posterior brain and plasmatic cholesterol along with lipoprotein levels after chronic intoxication by aluminium chloride (AlCl₃). Chronic aluminum-induced neurotoxicity has been in fact related to enhanced brain lipid peroxidation together with hypercholesterolemia and hypertriglyceridemia, despite its controversial etiological role in neurodegenerative diseases. Secondly an evaluation of the effectiveness of fenugreek seeds in alleviating the engendered toxicity through these biochemical parameters was made.     

Synthesis of lipophilic tyrosyl esters derivatives and assessment of their antimicrobial and antileishmania activities

Background  

Preparation of tyrosyl lipophilic derivatives was carried out as a response to the food, cosmetic and pharmaceutical industries' increasing demand for new lipophilic antioxidants.