May viral (antigen) load be the real crucial tool leading to anergy in a "micro-evolutionary" model of host/virus interaction?

HYPOTHESIS: The hypothesis in the present work is that in host/virus/tumor (antigens) interactions, leading to anergy of the immune system, the Viral (antigen) load plays a crucial and central role, which all interactions turn around. BACKGROUND: Notwithstanding apparent strong favorable evidences, the still prevailing concept of "active virus strategies to escape" may be misleading, since it might hide the cited pivotal role in a wide number of researches. This concept could be easily substituted by a microevolutionary model explaining many unresolved questions and allowing to emerge the role of antigen load conditioned reactions of the host's immune system as motivated choices. EVIDENCES: An anergy induced condition can be detected not only in HCV, but also in the course of persistent viral (e.g. HBV, HIV) and non viral parasitic infections (e.g. Leishmania and Helminths) which share the same host's reactions leading to anergy, independently on the infecting agents. The starting point of those reactions is always time elapsing from the primary infection after a short early (often undetected) period of high viral(antigen) load in the lack of clearance. This latter seems then the only conceivable link between such so different infections determining, as far as HBV and HCV are concerned, also Hepatocarcinoma under indirect facilitating conditions. In a wide majority of studies it seems clearly evident that viral load exerts a main role which contributes to determine host chosen reactions aimed at avoiding dangerous outcomes while controlling viral load. Strong clinical (i.e. both HIV infected patients treated with HAART, and helminths infected people with deworming drugs acting directly on viral and parasitic loads) and experimental studies (i.e. chimpanzees (the only animal model of HCV infection) infected with HBV inocula of different size) are here reported or cited to highlight the crucial role of antigen load also on HIV infection transmission, seroconversion, disease progression, treatment initiation and efficacy. CONCLUDING SUGGESTIONS: The new era for antiviral drugs like protease and polymerase inhibitors that seem to be more efficacious and less toxic than Ribavirin, may open the possibility to verify, when administered during the early phase of HCV infection (eventually helped by an immune-stimulant cytokine as IL-2), whether a precocious significant reduction of viral load (threshold) may allow the host to sustain his strong reactions and clear the virus within the due time, confirming the hypothesis about the crucial role of this tool which may be extended to all the cited infections.

Spinocellular carcinoma from warts in a HPV infection natural history lasting 49 years. Virus strategy or host choice? Implications for researches and therapeutic vaccines.

There is a very strong evidence that progression (also to cancer) in variable percentages of cases infected by HPV, HBV, HCV, and HIV depends on host immune response. A large number of observations demonstrate that virus set up a postulated "active strategy" to modify host reactions or to avoid it. But in all those infections it also seems that antigen load (viral RNA or DNA), chronic activation of immune response and time elapsing from the primary infection play a pivotal role in determining clearing or persisting outcomes. My wife's HPV and cancer natural history, lasting 49 years, started at the age of 10 years with facial warts and progressed to CIN 2/3, cervical in situ carcinoma, perineal warts, perianal carcinoma, inguinal lymph nodes, and invasion of bones and muscular structures, until death is paradigmatic: a progressive immune failure was detected in her scaling up all those clinical features, ending in a massive apoptosis of her lymphocytes collected by leukapheresis and cultured with HPV antigens E6/E7, with the aim of obtaining antigen presenting cells and CD8+ specific T lymphocytes. From this experience, a concept of "host choice to reach a tolerance (mainly by a Tregs mediated anergy) or symbiotic-like state" arises, underlining all the affected host's immune-responses to virus persistence (and to consequent tumors). It might be then postulated as the hallmark of a long-term host/parasites co-evolution, and considered a "normal" reaction when the host faces overwhelming numbers of non-self cancer cells (high antigen loads) preceded by persistent virus infections (chronic activation). This happens in patients who do not clear HPV or other viruses soon enough after infection. These observations may lead to a better understanding of many phenomena that are actually difficult to explain or still are open questions. The auto-limiting host's immune-responses are likely to be aimed to avoid risks arising mainly in the protection of "self" (autoimmunity), to prolong its own survival (balance with the virus), to avoid the risk of producing uncontrolled cells (dangerous outcomes). Finally, the postulated negative implications for therapeutic vaccines in cervical cancer, as they really seem to not work till now might be ascribed just to the cited host immune-specific state itself, through an activation induced cell death, elicited by recall antigens (E6/E7 in the case of my wife). Also this latter hypothesis, as well as the previous ones may be of some value to better account for clinical behaviors and researches.

Increased visceral adipose tissue is associated with increased circulating insulin and decreased sex hormone binding globulin levels in massively obese adolescent girls.

The current study was designed to examine the relationship between body fat distribution, as evaluated by anthropometry and magnetic resonance imaging (MRI), and circulating insulin, sex hormone and SHBG levels in obese adolescent girls. Twenty-nine obese adolescent girls, aged 12.6-16.9 years with a mean BMI of 30.51+/-1.86 participated in this study. All girls had breast stage B4-5 and pubic hair stage P4-5. Percent obesity and BMI as indices of being overweight were calculated; the waist-to-hip ratio (WHR) and the waist-to-thigh ratio (WTR) were calculated to obtain two anthropometric indices for the pattern of body fat distribution. The areas of visceral (VAT) and subcutaneous adipose tissue (SAT) were evaluated by MRI at the L4-L5 level. Serum concentrations of total T, DHEAS, 17beta-estradiol, progesterone and SHBG were measured. Plasma glucose and insulin concentrations were evaluated during an oral glucose tolerance test. WHR was the only anthropometric parameter that was significantly associated with the area of VAT. Insulin level showed correlation with both WHR and the area of VAT; no correlation was found between insulin levels and WTR. Both WHR and VAT were negatively correlated with serum DHEAS level and positively correlated with T level. There were strong negative correlations between serum SHBG level and the area of VAT and WHR. Inverse correlation was found between serum SHBG level and insulin. Serum 17beta-estradiol and progesterone levels showed no significant correlation with all the patterns of body fat distribution. SAT was not significantly correlated with both anthropometric parameters and any of the sex hormones evaluated. We can draw two main conclusions. Firstly, in massively obese adolescent girls, the WHR seems to be a good indicator for the accumulation of VAT, and abdominal obesity, rather than adiposity per se, appears to be related to biochemical complications. Secondly, increased upper body adiposity and, in particular, the intra-abdominal fat area are associated with increased insulin levels in massively obese adolescent girls. The associated reductions in SHBG and DHEAS levels represent an early general risk factor for the development of metabolic and cardiovascular diseases in this population, as previously described for obese adult women.

[Biliary lithiasis in childhood. A spectrum of diseases with different clinical significance during fetal life, childhood and adolescence]. / La litiasi biliare in età pediatrica. Uno spettro di patologie con diverso significato clinico nella vita fetale nel lattante, nell'infanzia e nell'adolescenza.

On the basis of a research on fetal cholelithiasis, a review on the various form of cholelithiasis in pediatric age has been carried out. These include, in addition to fetal cholelithiasis, lithiasis in the first year of life and lithiasis in infancy and adolescence. These various expressions of the same pathology differ for incidence, predisposing factors, clinical situation, therapy and follow-up. The research conducted on fetal cholelithiasis showed an incidence of 0.39%, higher than expected. There isn't any maternal, obstetrical or fetal predisposing factor. The diagnosis is purely instrumental and is not correlated with known clinical or humoral data. The most frequent evolution is spontaneous resolution of the biliary echogenic images in absence of clinical manifestations; the complications are rare and not well documented. Cholelithiasis in the first years of life is correlated with malformative, pharmacologic or iatrogenic predisposing factors. The clinical situations include symptomless cases with spontaneous resolution and cases with serious complications. Therapy is to be chosen in each case in accordance with clinical features. Pediatric cholelithiasis beyond the first year of life, especially in the later childhood and adolescence, can be similar to cholelithiasis of adults for epidemiology, pathogenesis, symptomatology and therapy.

[Hemicrania and photosensitive epilepsy in pediatric age]. / Emicrania ed epilessia fotosensibile in età pediatrica.

OBJECTIVE: Photosensitive epilepsy is joined to headache. Aim of the present study was the follow up of children suffering from headaches in order to verify if headache can be the only symptom of epileptic photosensitivity. PATIENTS AND METHODS: Thirteen children affected by headache were examined. They were screened on the basis of photosensitivity showed on the EEG. During following 6 patients had seizures. RESULTS: Antiepileptic drugs (VPA, CBZ, CZM) improved seizures and headache. In the others patients migraine therapy improved epileptic photosensitivity on the EEG. CONCLUSIONS: Headache can be the only symptom of epileptic photosensitivity. Migraine and photosensitive epilepsy in childhood are of particular interest because of growing features of occipital lobe. This has therapeutic significance.

Growth after recombinant human growth hormone (rhGH) treatment in transplanted thalassemic patients.

The aim of this study was to evaluate the treatment effects with recombinant human growth hormone (rhGH) in a group of patients after bone marrow transplantation for thalassemia major. At the end of treatment we divided the subjects into two groups according to the outcome of the therapy: responder and nonresponder. Responder group: after 24 months of rhGH administration, growth rate was still significantly higher in respect to start of treatment (P < 0.0001). Plasma levels of IGF-I rose significantly (P < 0.003). The serum levels of serum asparate aminotransferase (SGOT) and alanine aminotransferase (SGPT) were higher compared to normal values but improved in non-responder patients. There was no difference in the mean concentration of these parameters before and after treatment (P = NS). Non-responder group: these patients had a worsening of the growth rate during rhGH administration. There was no increase of the IGF-I levels. Single values of transaminase and ferritin levels were higher than in responder patients before and after treatment. There was a significant correlation between IGF-I, SGOT, SGPT and ferritin in all patients before and after therapy. It appears from these data that rhGH administration is worth serious consideration in patients after BMT for thalassemia major presenting impaired growth hormone secretion. This treatment can offer good results only in cases where the normal hepatic synthesis of IGF-I is conserved and where liver damage has not reached irreversible conditions, as we have seen in the responder group.

Screening for coeliac disease: the meaning of low titers of anti-gliadin antibodies (AGA) in non-coeliac children.

Coeliac disease is diagnosed by means of jejunal biopsy, an invasive procedure. Anti-gliadin antibodies (AGA) have therefore been used in the first screening of the disease. On the other hand, low titers of AGA are widely detected also in normal subjects. In order to investigate if low levels of AGA could be correlated with laboratory and clinical data, we performed a study on 167 subjects with various illnesses, such as recurrent abdominal pain, failure to thrive, short stature, diarrhoea or constipation, cow-milk protein intolerance and/or food allergy, recurrent vomiting or previous gastroenteritis, all non coeliac conditions which have been associated with AGA presence. Seventy coeliac children, all biopsied, were selected as a control group. Among the 167 cases we found 60 subjects positive for AGA (35.9%), a high proportion as compared with the general population. Only 33/167 patients, all IgG and IgA AGA positive, fulfil our laboratory and clinical criteria to perform a 'confirming' biopsy. For the 134 residual cases (14 IgA, 13 only IgG AGA positive, 107 AGA negative) a diagnosis of coeliac disease has been excluded by clinical criteria (scoring). As a whole, the patients with coeliac disease had significantly higher levels of AGA of both IgG and IgA classes (p < 0.01). On the other hand, no significant difference emerged for all the anamnestic and laboratory parameters considered between AGA+ and AGA- non-coeliac subjects. However, laboratory parameters of IgG-AGA and/or IgA-AGA positive patients were similar to those of coeliac children for ion, Xylose, total IgA count. As no biopsied case showed mucosal atrophy, it is suggested that the presence of even low AGA levels in non-coeliac children may represent a highly sensitive index of intestinal alteration causing an increased permeability to macromolecules, but it is very unlikely that one could detect coeliac children by means of Ig-AGA among such illnesses and normal subjects. Strong clinical diagnosis and laboratory parameters are required to justify intestinal biopsies. In fact, the production of AGA seems to be a merely immunological phenomenon linked to an increased and probably transient permeability to macromolecules of the intestinal mucosa.

[Epidemiologic correlation between microhematuria in children and hypertension in their parents]. / Correlazione epidemiologica fra microematuria nei bambini ed ipertensione nei genitori.

The significance of asymptomatic microhematuria in children is unknown. In 1976 Dodge et al. found a "surprising" high prevalence of proteinuria and haematuria in 12,000 healthy schoolchildren and, in the absence of knowledge of the natural history, this finding prompted them to postpone urinary mass screening. Nonetheless, the progressive course of most chronic renal disease in adulthood argues for investigation of microhematuria in children to uncover any sub-groups "at risk" of kidney diseases. The sensitivity of screening for microhematuria could be increased by a questionnaire on family medical history? We have investigated 1554 boys and 1484 girls aged 3-12 years, from the school population of a rural district near Rome. A self-administered questionnaire on renal disease and related symptoms in families was distributed to the parents. Urinalyses were done on all the children except for those with diseases or symptoms related to the urinary apparatus and girls who were menstruating. Haematuria was tested for by dipstick ("Combur 7"; Boehringer), children with microhematuria were retested 10 day and 1 year later. On the initial 3038 dipstick tests 175 (5.76%) were positive, and 52 children (1.71%) had haematuria in all three specimens. The questionnaires were used only if they had been filled in properly (1821/3038). Of the 1821 valid questionnaires 121 (6.64%) revealed a family history of hypertension, but the frequency of such a family history was significantly higher for the 128 children with haematuria (14.8%, p < 0.005) and the 52 with persistent haematuria (23.0%; p < 0.001).

Early wheezing and breast feeding.

There is uncertainty as to whether breast feeding protects against subsequent illnesses; it has been suggested that breast feeding may have some protective effects on the severity of long-term outcome of bronchiolitis and in reducing morbidity. We have assessed the effects of breast feeding in 266 patients and 199 controls, all patients were early wheezers (i.e., under 2 years old). Between these groups we found differences in socioeconomic, environmental, and atopic conditions, but there were no significant differences in the numbers who had been breastfed. However, within the group who had had early wheezing we found that infants who had been breastfed for at least one month subsequently had less severe wheezing. These results suggest that breast feeding may be a protective factor for early wheezing only during the first month of life, and a delaying factor in the following months.

Atopy and environmental factors in upper respiratory infections: an epidemiological survey on 2304 school children.

Upper respiratory infections (URI) during the first years of life are mostly viral in origin. However, a number of observations suggest the influence of both predisposing and triggering factors. Atopy in particular seems to play an important role as do environmental factors. Many children with early symptoms such as blocked or runny nose are likely to become skin-positive later in life to antigens such as, e.g., D. pteronissinus. A standardized questionnaire was administered to 2304 schoolchildren in order to ascertain the URI frequency and to correlate it with family and environmental factors and with results of prick tests for main allergens in our climate (D. pteronissinus and Grasses). Results showed a wide overlapping of URI and lower respiratory illnesses (in particular, asthma), which are widely distributed in the families of patients. Passive smoking and the quality of housing are the main triggering environmental factors. In our sample, skin positivity for D. pteronissinus and Grasses largely exceeds the symptomatic portion of the whole population. It is therefore suggested that many asymptomatic children are "at risk" for allergic respiratory illness. The highest incidence of winter rhinitis in skin-negative subjects (71.7%) and the skin positivity for D. pteronissinus in patients with perennial symptoms, suggest the importance of both atopy and viral infections in the occurrence of URI. Nasal troubles are most frequent in asthmatic subjects and may be considered the actual additional symptom in asthma.

Bronchiolitis in the history of the asthmatic child.

In a retrospective analysis of the history of 1,700 asthmatic children, 167 (9.8%) were found to have had bronchiolitis during the first 2 years of life. These 167 cases with asthma and bronchiolitis were matched against 215 selected cases of asthma without bronchiolitis. Both groups attended our Ambulatory Care Unit for Asthma. Data were collected from the clinical cards of the children. Asthmatics who had bronchiolitis were found to have an earlier onset of asthma (p less than 0.001), earlier resolution of symptoms (p less than 0.05 total; p less than 0.01 females), and less evidence of atopy (p less than 0.005). It is suggested therefore that the bronchial hyperreactivity in asthma following bronchiolitis may have different underlying mechanisms than in the typical atopic case, without preceding bronchiolitis. Long-term follow-up studies in infants with bronchiolitis are still necessary in order to clarify the process by which bronchiolitis predisposes to bronchial hyperreactivity and asthma. The consequences of the viral infection itself may lead to pathophysiological processes that promote bronchial hyperreactivity. On the contrary, an underlying condition of bronchial hyperreactivity could be the "primum movens" of the bronchiolitis itself.

Evaluating bronchial hyperreactivity tests in epidemiology.

The aim of this study is to assess the value of the most common tests which can be used in epidemiological surveys to identify asthmatic children. We reviewed anamnestic information from a self-administered questionnaire, bronchial reactivity by means of exercise-test, bronchodilation-test with trimethochinol, carbachol-test (PD20 FEV1 was reported), cutaneous reactivity monitored by prick-test. (Data from a polycentric epidemiological study). We conclude that, while these tests are very useful in the initial study and in the further follow-up of the asthmatic child, providing also information about the possibilities of management of bronchoconstriction and its pharmacologic prevention, they show a limited value in the absolute diagnosis of asthma.

Modification of nonspecific bronchial reactivity in hypothyroid children under different regimens of substitutive opotherapy.

Although it has been experimentally proved that thyroid hormones stimulate beta 2 receptor activity and tissue responsiveness to catecholamines, previous studies have established that asthma and nonspecific bronchial reactivity (NSBR) can worsen if complicated by hyperthyroidism. Our study is an effort toward the analysis of this contradiction. In 20 congenitally hypothyroid children, substitutive opotherapy was completely withdrawn for 1 month, resumed in the original dosage for 2 months, and then increased by 20% from day 91 to day 110. Mean NSBR, expressed in carbachol-related PD20-FEV1 and PD25-V25, was significantly increased by day 30, remained significantly elevated by day 90, and returned to initial values by day 110. These results suggest that thyroid hormones per se in nonasthmatic subjects decrease bronchial reactivity. This observation should be taken into consideration when attempting to explain the worsening condition of asthmatics who became affected with hypothyroidism. Bronchial reactivity appears to be under the control of many factors (including thyroid hormone levels). Once it is altered, a period of time seems necessary to restore the original bronchomotor tone (2 months in our study).

[Growth and chronic bronchopneumopathies]. / Accrescimento e broncopneumopatie croniche.

The relationship between growth and pulmonary disease has been studied mainly in asthma and cystic fibrosis. In asthma, the most frequent chronic pulmonary disease in childhood, results were conflicting, until the degree of severity of the disease and growth phases were taken into account. Research on 683 children has shown that the percentage of underweight was higher in chronic than intermittent asthma. Moreover, the distribution of underweight patients by ages is different in the two types of asthma: uniform in intermittent asthma; two peaks below the age of 2 and above the age of 12 respectively in chronic asthma. Further data of 65 children treated with slow-releasing theophylline for approximately two years corroborates that puberty is a particularly vulnerable period. Indeed, in the most severe asthmatic males, theophylline is able to completely normalize the growth pattern in childhood but not in puberty. In cystic fibrosis malabsorption makes the study of the relationship between growth and pulmonary disease more complex. The pattern of growth in patients with cystic fibrosis is moving away from the normal pattern with ageing, hence the worsening of pulmonary disease is responsible for the worsening in the growth pattern. The growth pattern today is far better than that of 20 years ago. However, puberty, especially in female patients, is a critical period. Often the puberal spurt is delayed for a few years or is even completely absent. In a group of patients with chronic pulmonary disease due to different causes, weight is more implicated than height and the same pattern was observed in cystic fibrosis. Moreover, as in asthma, weight and height are more implicated in females than males. The entity of alteration observed is midway between the minimal in asthma and the maximal in cystic fibrosis.

PiM subtypes in bronchiolitis.

Decreased alpha-1-antitrypsin (alpha 1AT) levels have been observed in children affected by bronchiolitis; however, variant alleles Pi (S, Z) which are usually associated with reduction of the inhibitor do not show a higher incidence in children affected by this disease. Subtypes M2 and M3 of alpha 1AT have recently been considered to play a role in the development of allergic states in children as well as in chronic obstructive lung disease in adults. In the present study we have investigated the incidence of PiM subtypes in 98 children affected by bronchiolitis. No greater incidence of subtypes M2 and M3 was observed in these children than in controls. These results rule out the hypothesis of a pathogenetic role of M subtypes in the development of bronchiolitis in children.

The role of IgE in childhood asthma.

The influence of age and sex has been in 208 asthmatic children on the basis of the following parameters: total serum IgE concentration (RIST), serum concentration of specific IgE antibodies (RAST), and positive prick tests against Dermatophagoides Pleronissynus, grasses, and Alternaria Tenuis. The results indicate that all these parameters are significantly influenced by age. Arithmetic values for RIST show a significant difference between the sexes which is obscured by logarithmic calculation. The data strongly suggest that IgE antibodies cannot be considered the main mechanism by which asthma is produced in small children.