Predictive value of the number of adverse reaction episodes for the IgE-mediated food allergy diagnosis.

INTRODUCTION AND OBJECTIVES: The reproducibility of the adverse reaction increases the suggestiveness of a history of food allergy. However, the positive predictive value (PPV) of multiple adverse reaction episodes for the diagnosis of IgE-mediated food allergy is not known. This evaluation was the objective of our study. PATIENTS AND METHODS: We retrospectively studied 180 children with a history of non-anaphylactic adverse reactions after the ingestion of a food. All children had the prick test positive for the offending food and performed the oral food challenge (OFC) within 12 months after the last adverse reaction episode (ARE). We have evaluated whether increasing the number of ARE increased the probability that the OFC would be positive (failed). RESULTS: 93 patients (52%) presented one ARE, 49 (27%) presented two ARE, 24 (13%) presented three ARE, 14 (8%) patients presented≥four ARE. The OFC was positive in 94/180 (52%). The outcome of the OFC was found to be positively correlated with the number of ARE (OR=1.56; 95% CI=1.16-2.09; p=0.003). A PPV=100% was observed with a number of ARE≥five. CONCLUSIONS: The number of ARE is an important predictor of the diagnosis of food allergy, although less than we would have imagined. The number of ARE could be used to increase the predictability of the diagnostic tests currently in use, to define clinical prediction rules alternative to OFC and easy to use in clinical practice.

Diagnostic relevance of IgE sensitization profiles to eight recombinant Phleum pratense molecules.

BACKGROUND: Grass pollen-related seasonal allergic rhinoconjunctivitis (SARg) is clinically heterogeneous in severity, comorbidities, and response to treatment. The component-resolved diagnostics disclosed also a high heterogeneity at molecular level. Our study aimed at analyzing the characteristics of the IgE sensitization to Phleum pratense molecules and investigating the diagnostic relevance of such molecules in childhood. METHODS: We examined 1120 children (age 4-18 years) with SARg. Standardized questionnaires on atopy were acquired through informatics platform (AllergyCARD™). Skin prick tests were performed with pollen extracts. Serum IgE to airborne allergens and eight P. pratense molecules (rPhl p 1, rPhl p 2, rPhl p 4, rPhl p 5b, rPhl p 6, rPhl p 7, rPhl p 11, rPhl p 12) were tested by ImmunoCAP FEIA. RESULTS: The analysis of IgE responses against eight P. pratense molecules showed 87 profiles. According to the number of molecules recognized by IgE, the more complex profiles were characterized by higher serum total IgE, higher grass-specific serum IgE, and higher number and degree of sensitization to pollens. The most frequent IgE sensitization profile was the monomolecular Phl p 1. Sensitization to Phl p 7 was a reliable biomarker of asthma, whereas Phl p 12 of oral allergy syndrome. Sensitization to Phl p 7 was associated with a higher severity of SARg, and complex profiles were associated with longer disease duration. CONCLUSIONS: In a large pediatric population, the complexity of IgE sensitization profiles against P. pratense molecules is related to high atopic features although useless for predicting the clinical severity. The detection of serum IgE to Phl p 1, Phl p 7, and Phl p 12 can be used as clinical biomarkers of SARg and comorbidities. Further studies in different areas are required to test the impact of different IgE molecular profiles on AIT response.

Endotypes of pollen-food syndrome in children with seasonal allergic rhinoconjunctivitis: a molecular classification.

BACKGROUND: Pollen-food syndrome (PFS) is heterogeneous with regard to triggers, severity, natural history, comorbidities, and response to treatment. Our study aimed to classify different endotypes of PFS based on IgE sensitization to panallergens. METHODS: We examined 1271 Italian children (age 4-18 years) with seasonal allergic rhinoconjunctivitis (SAR). Foods triggering PFS were acquired by questionnaire. Skin prick tests were performed with commercial pollen extracts. IgE to panallergens Phl p 12 (profilin), Bet v 1 (PR-10), and Pru p 3 (nsLTP) were tested by ImmunoCAP FEIA. An unsupervised hierarchical agglomerative clustering method was applied within PFS population. RESULTS: PFS was observed in 300/1271 children (24%). Cluster analysis identified five PFS endotypes linked to panallergen IgE sensitization: (i) cosensitization to ≥2 panallergens ('multi-panallergen PFS'); (ii-iv) sensitization to either profilin, or nsLTP, or PR-10 ('mono-panallergen PFS'); (v) no sensitization to panallergens ('no-panallergen PFS'). These endotypes showed peculiar characteristics: (i) 'multi-panallergen PFS': severe disease with frequent allergic comorbidities and multiple offending foods; (ii) 'profilin PFS': oral allergy syndrome (OAS) triggered by Cucurbitaceae; (iii) 'LTP PFS': living in Southern Italy, OAS triggered by hazelnut and peanut; (iv) 'PR-10 PFS': OAS triggered by Rosaceae; and (v) 'no-panallergen PFS': mild disease and OAS triggered by kiwifruit. CONCLUSIONS: In a Mediterranean country characterized by multiple pollen exposures, PFS is a complex and frequent complication of childhood SAR, with five distinct endotypes marked by peculiar profiles of IgE sensitization to panallergens. Prospective studies in cohorts of patients with PFS are now required to test whether this novel classification may be useful for diagnostic and therapeutic purposes in the clinical practice.

Risk of adverse IgE-mediate reaction at the first egg ingestion in children with atopic dermatitis. Results of a case-control study.

BACKGROUND: Studies have reported that children with atopic dermatitis (AD) have a high risk of adverse reactions at first egg ingestion. METHODS: We enrolled 79 children with AD retrospectively and 45 children without AD (control group) prospectively, who had never eaten egg. All children underwent skin prick tests (SPT) with commercial extracts and prick by prick with natural food (raw and boiled egg). Oral food challenge (OFC) was performed in SPT positive patients. RESULTS: Sixty-six percent (52/79) of AD group and 11% (5/45) of Control group had at least one positive SPT (p<0.001), Relative Risk (RR)=5.9 and Odds Ratio=15.4. Of the 46/52 sensitised children in the AD group, 36 children ate egg for the first time in hospital during an OFC and 10 children ate egg at home because of their parents' choice, with 19/46 (41%) resulting in allergic reactions to raw and/or boiled egg. Four/five sensitised children in the control group underwent OFC and three of them (75%) showed an allergic reaction to raw, but not boiled egg. Thirty percent (14/46) of AD group had a systemic reaction vs. 25% (1/4) of Control group. CONCLUSION: A child with AD has a RR of sensitisation to egg six times higher than a child without AD, before the first known ingestion. We propose to test sensitisation to egg in every child with AD who has never eaten egg, and to perform OFC in those with positive SPT in hospital setting.

Predictive value ofMP4 (Milk Prick Four), a panel of skin prick test for the diagnosis of pediatric immediate cow's milk allergy.

Background. Oral food challenge (OFC) is the gold standard for the diagnosis of food allergy (FA), but it is risky, expensive and time-consuming. Many studies aimed to avoid OFC by finding a cut off (CO) of skin prick test (SPT) to predict a positive outcome of OFC. Unfortunately the results of these studies are poorly reproducible for various reasons, including the absence of known protein concentration in the extracts. It has also been documented that some doctors mistakenly attributed some symptom/disease, for example recurrent respiratory infections of the upper airways, to the FA, expecially cow milk allergy (CMA). These doctors often performed SPT in their studies to confirm, if the result was positive, their diagnostic suspicion and prescribe an elimination diet without seeking the advice of allergy specialist (AS) and without making an OFC. Objective. To test the diagnostic performances of SPT with fresh cow's milk and commercial extracts of casein, beta-lactoglobulin, alpha-lactoalbumin at known protein concentrations (Milk Prick Four [MP4] test). To look for 2 clusters of SPT CO with positive predictive value (PPV) > 95%, one for AS, one for general practitioner (GP). Methods. A prospective study was carried out on 191 children referred by their GP to the allergy center for suspected immediate-type CMA (iCMA). Based on the history, the allergist has divided the children into two groups: a) group A, children with suspected (subgroup A1, 55 children) or known (subgroup A2, 27 children) diagnosis of iCMA; b) group B, 109 children with a clinical history incompatible with iCMA suspicion according to the AS (in this case the GP was wrong to send those patients to the allergy center). SPT with MP4 test was performed on all patients, and OFC was performed on all patients of group A. CO with PPV > 95% was calculated separately for the entire population of 191 children (CO for GP) and for the only group A (CO for AS). Results. Fresh cow's milk SPT was the most sensitive single prick test (sensitivity [SE] 94%, negative predictive value [NPV] 98%). The positivity to any of 3 SPT extracts (performed at the same time) had the same SE and NPV of the single fresh cow's milk SPT. Moreover, fresh cow's milk SPT or any of 3 SPT extract had 100% SE and 100% NPV, having excluded 2 children with Food Protein Induced Enterocolitis Syndorme from data analysis. MP4 CO for GP allow a total savings of 4% of OFC, a percentage that rises to 22% in the subgroup A2, and does not give false positives. MP4 CO for AS allow a total saving of 33% of OFC, rising to 67% in the subgroup A2, but they give a 7/82 false positives in group A. SPT CO of alpha-lactoalbumin had the best performance in both settings. Conclusion. MP4 is a safe and cheap test, easy to perform. All doctors may be confident in excluding iCMA if fresh cow's milk SPT is negative. GP could perform SPT to fresh milk at his own clinic, and safely diagnose iCMA by using our CO for GP, although this may happen only in a few cases. MP4 test performed by AS can help save a greater number of OFC, especially among children with known diagnosis of iCMA.

Efficacy of over-the-counter immunostimulants in the prevention of paediatric recurrent acute respiratory tract infections. Criticisms and pitfalls of available metanalyses.

UNLABELLED: Preschool children frequently suffer from acute respiratory tract infections (ARTI). Immunostimulants (ISs) are often administered to reduce their impact. This study aimed to establish the efficacy of ISs in the prevention of pediatric ARTI through the analysis of systematic reviews (SRs). We explored Medline database in October 2010 limiting our search to SRs, that included studies on the effectiveness of ISs in the prevention of pediatric ARTI. Six SRs with meta analysis (MA) were found. The studies included showed a low methodological quality and a high statistical heterogeneity. All papers published on journals with impact factor > 1 and a Jadad score > 3 reviewed the efficacy of OM-85. The number needed to treat (NNT) was between 2 and 11, depending on the setting. CONCLUSIONS: Pediatric ARTI are a social and health care problem. When they impair the quality of life of the family a course of OM-85 might be warranted. Although scientific knowledge of clinicians may be improved by SRs, MA and aggregation of results may not always be the best way to accomplish this.

Very high frequency of the polymorphism for the insulin receptor substrate 1 (IRS-1) at codon 972 (glycine972arginine) in Southern Italian women with polycystic ovary syndrome.

A major component of the polycystic ovary syndrome (PCOS) is the insulin resistance. Only a few studies have evaluated the IRS-1 polymorphism at codon 972, sometimes in the absence of a control group, and with great variability in frequency (0-23% in PCOS vs. 0-17% in controls), and with no unequivocal relationships between the polymorphism and clinical or biochemical indexes. The aim of the work was to evaluate the frequency of the IRS-1 polymorphism at codon 972 in PCOS, and correlate it to clinical and biochemical indexes. We assessed the rs 1801278 polymorphic variant in the IRS-1 gene (Gly972Gly=wild-type; Gly972Arg=heterozygosity; Arg972Arg=homozygosity) in genomic DNA by restriction fragment length polymorphism. The study was conducted at an academic medical center with the participation of 65 women with PCOS and 27 age-matched healthy women (controls). Compared to controls, Gly972Arg was very frequent in PCOS (77% vs. 18%, p<0.0001); one PCOS woman was homozygous. Compared to wild-type PCOS, heterozygous PCOS women had only three significantly different indexes: higher fasting insulin, insulin resistance index, and lower 120 min OGTT glucose. Moreover, in the correlation analysis between any two clinical or biochemical variables, the Pearson's correlation coefficients were frequently of different magnitude in heterozygous PCOS versus wild-type PCOS. Overall, heterozygous PCOS had a greater number of statistically significant relationships between different clinical, metabolic and hormonal indexes: 44 direct and 9 inverse versus 6 and 3, respectively. The IRS-1 Gly972Arg has the highest frequency reported world-wide for PCOS women. This variant is associated with insulin resistance and higher fasting insulin in PCOS women.

Specific oral tolerance induction for food. A systematic review.

BACKGROUND: Specific oral tolerance induction (SOTI) is a new therapeutic approach in the treatment of persistent food allergy. OBJECTIVE: The purpose of this article is to systematically review the literature in order to identify, appraise, and synthesize the evidence about SOTI efficacy and safety. METHODS: A comprehensive search for citations was conducted on May 2, 2009 using MEDLINE via PubMed. Randomized controlled trials (RCTs) including subjects of any age were considered. All these studies were assessed, discussed in details and evaluatedfor quality by authors in a standardized independent way. RESULTS: 15 clinical trials were found. Of these, six trials met the inclusion criteria: three were open label RCT, three were double blind placebo controlled RCT. Two were conducted using sublingual immunotherapy, four using oral desensitization. Overall, the methodological quality of the studies was sufficient. The mean Jadad score of the studies was 3.33 (range = 2-5). Main characteristics and results of the studies were showed and discussed. CONCLUSIONS: SOTI seems to be a possible approach to accelerate the development of tolerance in children affected by food allergy. However, other studies are needed to clarify which is the best treatment and protocol to follow in order to reduce the adverse events and to increase the percentage of success, before thinking that SOTI might be part of the clinical practice.

Does treatment with proton pump inhibitors for gastroesophageal reflux disease (GERD) improve asthma symptoms in children with asthma and GERD? A systematic review.

OBJECTIVE: To evaluate pediatric studies of the effect on asthma symptoms of treatment with proton pump inhibitors (PPI) used to treat gastroesophageal reflux disease (GERD). METHODS: We entered the MeSH terms "gastroesophageal reflux AND asthma AND children" in the PubMed tool Clinical Queries, selecting "therapy" and "broad, sensitive search." The search ended on April 14, 2008. We included only clinical trials performed in pediatric patients. RESULTS: Four studies were considered to be relevant, although only 1 was a randomized, double-blind, placebo-controlled trial. The 3 nonrandomized trials showed that PPIs benefited patients with asthma. The randomized, double-blind, placebo-controlled trial found that omeprazole did not improve asthma symptoms. An improved (although not statistically significant) score was observed in the quality of life questionnaire in children with a reflux index greater than 10% and in those with more severe asthma treated with omeprazole compared with the placebo group. CONCLUSIONS: Scant data in these studies mean that we cannot make solid recommendations. However, in specific cases, we think that treatment of asthma symptoms with a PPI is valid as long as at least 2 conditions are satisfied: asthma must not respond to standard treatment, and 1 instrumental parameter of GERD severity must be satisfied, that is, a reflux index greater than or equal to 10 must be present.

Hexavalent vaccines in preterm infants: an update by Italian Society of Pediatric Allergy and Immunology jointly with the Italian Society of Neonatology.

Hexavalent vaccines, protecting against six diseases (diphtheria, tetanus, pertussis [DTaP], poliovirus, hepatitis B virus [HBV], and Haemophilus influenzae type b [Hib], are routinely the standard of care in Europe. The use of combined vaccines allows the reduction of number of injections and side effects, the reduction of costs, and the increase in adherence of the family to the vaccination schedule both in terms of the number of doses and timing. The safety profile, efficacy and effectiveness of hexavalent vaccines have been extensively documented in infants and children born at term, and data are accumulating in preterm infants. Hexavalent vaccines are particularly important for preterm infants, who are at increased risk for severe forms of vaccine preventable diseases. However, immunization delay has been commonly reported in this age group. All the three hexavalent vaccines currently marketed in Italy can be used in preterm infants, and recent data confirm that hexavalent vaccines have a similar or lower incidence of adverse events in preterm compared to full-term infants; this is likely due to a weaker immune system response and reduced ability to induce an inflammatory response in preterm infants. Apnoea episodes are the adverse events that can occur in the most severe preterm infants and / or with history of respiratory distress. The risk of apnoea after vaccination seems to be related to a lower gestational age and a lower birth weight, supporting the hypothesis that it represents an unspecific response of the preterm infant to different procedures. High seroprotection rates have been reported in preterm infants vaccinated with hexavalent vaccine. However, a lower gestational age seems to be associated with lower antibody titres against some vaccine antigens (e.g. HBV, Hib, poliovirus serotype 1, and pertussis), regardless of the type of hexavalent vaccine used. Waiting for large effectiveness studies, hexavalent vaccines should be administered in preterm infants according to the same schedule recommended for infants born at term, considering their chronological age and providing an adequate monitoring for cardio-respiratory events in the 48-72 h after vaccination, especially for infants at risk of recurrence of apnoea.

Hospitalizations for pediatric anaphylaxis.

The aim of the study is to examine the epidemiology of anaphylaxis in hospitalized children in Lazio (Central Italy) and to evaluate the incidence and case fatality rate. We also verified the concordance of diagnosis between the Emergency Department and Ordinary hospitalizations. In order to obtain these results, we reviewed all ICD-9 codes indicative of anaphylaxis in all primary and secondary diagnoses from 2000 to 2003 in all Emergency Departments, Ordinary Hospitalizations and Day Hospitals in Lazio. We then identified 203 ICD-9 diagnoses of anaphylaxis in children aged between 0 and 17 years. Anaphylactic shock (995.0) accounted for 109 (53.7%) of cases. Food anaphylaxis (995.60 onwards) accounted for 87 (43.0%) of cases. Food anaphylaxis was more frequent in the first years of life. In fact, it decreased from 12.5/100,000 resident children/year in the first year of life to 6.1/100,000 resident children/year in the first two years of life, and less than 3/100,000 resident children/year after the seventh year (p <0.001). Only 12.5% of cases of anaphylaxis diagnosed in Ordinary Hospitalizations were subsequently diagnosed by the Emergency Department as anaphylaxis. Moreover, only 42.3% of the diagnoses of anaphylaxis made in the Emergency Department were later confirmed during ordinary hospitalization. In the four years of study, one child died from anaphylaxis. Thus, mortality was 0.038 cases/100,000 resident children/year. In conclusion, the incidence of hospitalization was highest in the first years of life, during which food anaphylaxis accounted for most hospitalizations. The inconsistency of diagnoses between Emergency Departments and Ordinary Hospitalizations suggests the need to increase awareness of anaphylaxis among health workers.

Acetyl-L-carnitine feeding to unloaded rats triggers in soleus muscle the coordinated expression of genes involved in mitochondrial biogenesis.

The expressional profile of mitochondrial transcripts and of genes involved in the mitochondrial biogenesis pathway induced by ALCAR daily supplementation in soleus muscle of control and unloaded 3-month-old rats has been analyzed. It has been found that ALCAR treatment is able to upregulate the expression level of mitochondrial transcripts (COX I, ATP6, ND6, 16 S rRNA) in both control and unloaded animals. Interestingly, ALCAR feeding to unloaded rats resulted in the increase of transcript level for master factors involved in mitochondrial biogenesis (PGC-1alpha, NRF-1, TFAM). It also prevented the unloading-induced downregulation of mRNA levels for kinases able to transduce metabolic (AMPK) and neuronal stimuli (CaMKIIbeta) into mitochondrial biogenesis. No significant effect on the expressional level of such genes was found in control ALCAR-treated rats. In addition, ALCAR feeding was able to prevent the loss of mitochondrial protein content due to unloading condition. Correlation analysis revealed a strong coordination in the expression of genes involved in mitochondrial biogenesis only in ALCAR-treated suspended animals, supporting a differentiated effect of ALCAR treatment in relation to the loading state of the soleus muscle. In conclusions, we demonstrated the ability of ALCAR supplementation to promote only in soleus muscle of hindlimb suspended rats an orchestrated expression of genes involved in mitochondrial biogenesis, which might counteract the unloading-induced metabolic changes, preventing the loss of mitochondrial proteins.

Urinary excretion of L-carnitine and its short-chain acetyl-L-carnitine in patients undergoing carboplatin treatment.

PURPOSE: To evaluate the effect of the anti-cancer drug carboplatin on plasma concentrations and urinary excretion of L-carnitine (LC) and its main ester, acetyl-L-carnitine (ALC), in cancer patients. METHODS: Plasma and urine concentrations of LC and ALC from 11 patients on carboplatin therapy (1 h intravenous infusion; AUC dose 4.8 +/- 1.1 mg/ml min) in combination with docetaxel, paclitaxel or vinorelbine, were determined by high-performance liquid chromatography with fluorimetric detection. RESULTS: Before carboplatin therapy, the mean +/- SD plasma concentrations of LC and ALC were 47.8 +/- 10.9 and 7.04 +/- 1.04 nmoles/ml, respectively, and remained constant throughout the entire study period. In contrast, urinary excretion of LC and ALC, increased significantly during the chemotherapy from 115 +/- 105 to 480 +/- 348 micromoles/day (P < 0.01) and from 41 +/- 41 to 89 +/- 52 micromoles/day (P < 0.05) for LC and ALC, respectively, subsequently reverting to normal 6 days after the end of chemotherapy. Similarly, the renal clearance of LC and ALC increased substantially during chemotherapy from 1.67 +/- 1.43 to 9.05 +/- 9.52 ml/min (P < 0.05) and from 4.02 +/- 4.51 to 7.97 +/- 5.05 ml/min (P = not significant) for LC and ALC, respectively, reverting to normal 6 days after the end of chemotherapy. Plasma concentrations and urinary excretion of glucose, phosphate and urea nitrogen and creatinine clearance, however, were not affected by carboplatin therapy, indicating no impaired kidney function. CONCLUSION: Treatment with carboplatin was associated with a marked urinary loss of LC and ALC, most likely due to inhibition of carnitine reabsorption in the kidney.

L-Carnitine in the treatment of fatigue in adult celiac disease patients: a pilot study.

BACKGROUND: Fatigue is common in celiac disease. L-Carnitine blood levels are low in untreated celiac disease. L-Carnitine therapy was shown to improve muscular fatigue in several diseases. AIM: To evaluate the effect of L-carnitine treatment in fatigue in adult celiac patients. METHODS: Randomised double-blind versus placebo parallel study. Thirty celiac disease patients received 2 g daily, 180 days (L-carnitine group) and 30 were assigned to the placebo group (P group). The patients underwent clinical investigation and questionnaires (Scott-Huskisson Visual Analogue Scale for Asthenia, Verbal Scale for Asthenia, Zung Depression Scale, SF-36 Health Status Survey, EuroQoL). OCTN2 levels, the specific carnitine transporter, were detected in intestinal tissue. RESULTS: Fatigue measured by Scott-Huskisson Visual Analogue Scale for Asthenia was significantly reduced in the L-carnitine group compared with the placebo group (p=0.0021). OCTN2 was decreased in celiac patients when compared to normal subjects (-134.67% in jejunum), and increased after diet in both celiac disease treatments. The other scales used did not show any significant difference between the two celiac disease treatment groups. CONCLUSION: L-Carnitine therapy is safe and effective in ameliorating fatigue in celiac disease. Since L-carnitine is involved in muscle energy production its decreased absorption due to OCTN2 reduction might explain muscular symptoms in celiac disease patients. The diet-induced OCTN2 increase, improving carnitine absorption, might explain the L-carnitine treatment efficacy.

The probiotics in dentistry: a narrative review.

The total number of microbes that colonize the human body is far greater than the number of cells that make it up. In recent years, it has been shown that bacteria play an essential role in the body; in fact, they are essential for the maturation of the intestine, the development and control of the immune system, the development of the brain, the metabolism of macronutrients, the synthesis of vitamins, and the energy balance. Bacteria play an essential role in defense of their territory against the entry of other bacteria that may be pathogenic to health. Metchnikoff, about a century ago, invented probiotics, assuming that the use of certain bacteria could be beneficial to maintaining health. Bacteria colonize our body from birth and breastfeeding, using the bacterial flora of the mother by accessing newborns through the mouth. Antibiotic therapies in pregnancy or cesarean section prevent this flow of probiotics to infants and open the way for very important diseases, such as diabetes and obesity. The alterations of oral bacterial flora are responsible for numerous diseases of the oral cavity and the idea of the use of probiotics is leading the way to new therapeutic perspectives.

tBid induces alterations of mitochondrial fatty acid oxidation flux by malonyl-CoA-independent inhibition of carnitine palmitoyltransferase-1.

Recent studies suggest a close relationship between cell metabolism and apoptosis. We have evaluated changes in lipid metabolism on permeabilized hepatocytes treated with truncated Bid (tBid) in the presence of caspase inhibitors and exogenous cytochrome c. The measurement of beta-oxidation flux by labeled palmitate demonstrates that tBid inhibits beta-oxidation, thereby resulting in the accumulation of palmitoyl-coenzyme A (CoA) and depletion of acetyl-carnitine and acylcarnitines, which is pathognomonic for inhibition of carnitine palmitoyltransferase-1 (CPT-1). We also show that tBid decreases CPT-1 activity by a mechanism independent of both malonyl-CoA, the key inhibitory molecule of CPT-1, and Bak and/or Bax, but dependent on cardiolipin decrease. Overexpression of Bcl-2, which is able to interact with CPT-1, counteracts the effects exerted by tBid on beta-oxidation. The unexpected role of tBid in the regulation of lipid beta-oxidation suggests a model in which tBid-induced metabolic decline leads to the accumulation of toxic lipid metabolites such as palmitoyl-CoA, which might become participants in the apoptotic pathway.

Redox modulation of heat shock protein expression by acetylcarnitine in aging brain: relationship to antioxidant status and mitochondrial function.

There is significant evidence to show that aging is characterized by a stochastic accumulation of molecular damage and by a progressive failure of maintenance and repair processes. Protective mechanisms exist in the brain which are controlled by vitagenes and include members of the heat shock system, heme oxygenase-I, and Hsp70 as critical determinants of brain stress tolerance. Given the broad cytoprotective properties of the heat shock response, molecules inducing this defense mechanism appear to be possible candidates for novel cytoprotective strategies. Acetyl-L-carnitine is proposed as a therapeutic agent for several neurodegenerative disorders, and the present study reports that treatment for 4 months of senescent rats with acetyl-L-carnitine induces heme oxygenase-1 as well as Hsp70 and SOD-2. This effect was associated with upregulation of GSH levels, prevention of age-related changes in mitochondrial respiratory chain complex expression, and decrease in protein carbonyls and HNE formation. We hypothesize that maintenance or recovery of the activity of vitagenes may delay the aging process and decrease the risk of age-related diseases. Particularly, modulation of endogenous cellular defense mechanisms via acetyl-L-carnitine may represent an innovative approach to therapeutic intervention in diseases causing tissue damage, such as neurodegeneration.