Alerting and tuning the immune response by extracellular nucleotides

The interplay between pro- and anti-inflammatory mechanisms during inflammatory and immune responses is critical for avoiding excessive tissue damage. Extracellular nucleotides (e.g., adenosine 5'-triphosphate) may represent constitutive signals that can alert the immune system of abnormal cell death. Relatively high doses of nucleotides induce rapid release of proinflammatory mediators and favor pathogen killing. However, recent findings on antigen presenting cells, particularly dendritic cells, revealed a more complex role for these molecules. Chronic exposure to low-dose nucleotides can redirect cellular responses to prototypic activation stimuli, leading to suppressed inflammation and immune deviation.     

Localized cutaneous hyalohyphomycosis caused by a Fusarium species infection in a renal transplant patient

Fusariosis is a hyalohyphomycosis due to Fusarium species that mainly occurs in immunocompromised hosts. The clinical spectrum of Fusarium infection comprises localized and disseminated forms. A case of localized cutaneous fusariosis caused by Fusarium solani in a renal transplant patient is described, and the skin manifestations of the disease are discussed.     

Comparison between rules-based human immunodeficiency virus type 1 genotype interpretations and real or virtual phenotype: concordance analysis and correlation with clinical outcome in heavily treated patients

We compared 2 rules-based genotype interpretation systems and real or virtual phenotype through a retrospective analysis of a prospective trial. Genotypes were determined with VircoGEN II (VIRCO) and were interpreted with either RetroGram 1.4 or TRUGENE HIV-1 (guidelines 3.0) or original virtual phenotype (Virtual Phenotype; VIRCO), as available in the year 2000. Among 188 human immunodeficiency virus (HIV) type 1 isolates, overall concordance (kappa agreement) was observed for the 2 rules-based systems, whereas striking discordances were noted between them and real and virtual phenotype interpretations for stavudine, didanosine, zalcitabine, abacavir, and amprenavir (kappa<0.4). Clinical evaluation of a subset of 173 patients showed that both rules-based sensitivity scores were independently associated with HIV RNA loads <400 copies/mL at week 16 of during-treatment analysis (TRUGENE: odds ratio [OR], 2.90; 95% confidence interval [CI], 1.52-5.52; P=.001; RetroGram: OR, 2.34; 95% CI, 1.21-4.55; P=.012), whereas, in contrast to real or virtual phenotype, interpretations according to biological cut-offs were not (OR, 1.91; 95% CI, 0.77-4.76; P=.162).     

Pediatric sentinel surveillance of vaccine-preventable diseases in Italy

BACKGROUND: Planning and evaluating vaccination programs depend on reliable systems of monitoring disease incidence in the community. In Italy vaccine-preventable diseases are subject to statutory notification, but they are often unreported. In January, 2000, a pediatric sentinel network was launched, with the aim of monitoring in a timely and accurate way the geographic and temporal trends of vaccine-preventable diseases. METHODS: The network consists of National Health System primary care pediatricians; participation is voluntary. The diseases under surveillance include measles, mumps, rubella, pertussis and varicella. Case definitions are based on specific clinical criteria, and pediatricians report cases on a monthly basis. Incidence rates are estimated and compared with those obtained by statutory notifications. The proportion of vaccinated cases is also computed. RESULTS: In 2000 an average of 468 pediatricians participated each month of a total of 7276 pediatricians under contract for primary care by the National Health System. The population under surveillance consisted of 371 670 children younger than 15 years (of a national total of 8.347.804 children of the same age). The annual national incidence per 100.000 children was estimated at 5345 for varicella, 1972 for mumps, 279 for pertussis, 108 for rubella and 62 for measles, although wide variations were observed among geographic areas. The national estimates are 3 to 7 times higher than those obtained through statutory notifications. For all of the diseases the ratio between the two sources of data was significantly higher in southern Italy, compared with the rest of the country. The proportion of vaccinated cases was similar for measles and rubella (21 and 17%) but was approximately 3 times higher for mumps (59%). Most (74%) of the vaccinated mumps cases had received the Rubini vaccine strain. CONCLUSIONS: The sentinel surveillance system is considerably more sensitive than statutory notifications, particularly in southern Italy. The high percentage of mumps cases vaccinated with the Rubini strain indicates a reduced effectiveness of this vaccine. Although further improvements are needed, pediatrician-based sentinel surveillance is a useful tool for evaluating vaccine-preventable disease trends.     

Acupuncture in the prophylactic treatment of migraine without aura: a comparison with flunarizine

OBJECTIVES: In a randomized controlled trial extending over 6 months, we evaluated the effectiveness of acupuncture versus flunarizine in the prophylactic treatment of migraine without aura. METHODS: One hundred sixty women with migraines were randomly assigned to acupuncture treatment (group A, n = 80) or to an oral therapy with flunarizine (group F, n = 80). In group A, acupuncture was carried out in weekly sessions for the first 2 months and then once a month for the next 4 months. The same acupoints were used at each treatment: LR3 Taichong, SP6 Sanyinjiao, ST36 Zusanli, CV12 Zhongwan, LI4 Hegu, PC6 Neiguan, GB20 Fengchi, GB14 Yangbai, EX-HN5 Taiyang, GV20 Baihui. In group F, 10 mg flunarizine were given daily for the first 2 months and then for 20 days per month for the next 4 months. RESULTS: The frequency of attacks and use of symptomatic drugs significantly decreased during treatment in both groups. The number of attacks after 2 and 4 months of therapy was significantly lower in group A than in group F, and analgesic consumption was significantly lower in group A at 2 months of treatment. At 6 months no such differences existed between the two treatment groups. Pain intensity was significantly reduced only by acupuncture treatment. Side effects were significantly less frequent in group A. CONCLUSIONS: Acupuncture proved to be adequate for migraine prophylaxis. Relative to flunarizine, acupuncture treatment exhibited greater effectiveness in the first months of therapy and superior tolerability.     

Medicinal chemistry of A2A adenosine receptor antagonists

Due to the clearly demonstrated receptor-receptor interaction between adenosine A(2A) and dopamine D(2) receptors in the basal ganglia, the discovery and development of potent and selective A(2A)adenosine receptor antagonists became, in the last ten years, an attractive field of research to discovery new drugs for the treatment of neurodegenerative disorders, such as Parkinsons disease. Different compounds have been deeply investigated as A(2A) adenosine receptor antagonists, which could be classified in two great families: xanthine derivatives and nitrogen poliheterocyclic systems. These studies led to the discovery of some highly potent and selective A(2A) adenosine receptor antagonists such as ZM241385, SCH58261 and some xanthine derivatives (KW6002), which have been used as pharmacological tools for studying this receptor subtype. However, those compounds showed some problems that do not permit their use in clinical studies, such as poor water solubility (SCH58261, and xanthine derivatives) or good affinity for A(2B) adenosine receptor subtype (ZM241385). In the last few years great efforts have been made to overcome these problems, trying to optimize not only the pharmacological profile but also the pharmacokinetic character of this class of compounds. The aim of this report is to briefly summarize the recent progress made in this attractive field of research.     

Prevalence estimates for chronic diseases in Italy: exploring the differences between self-report and primary care databases

BACKGROUND: The aim of this study was to describe population and primary care morbidity and to examine how the differences vary across the diseases and are influenced by patients' demographic characteristics. METHODS: A comparison of the prevalence of four chronic conditions for 432747 patients from the Health Search Database (HSD) and 119799 individuals from a Health Interview Survey was carried out. A linear regression was performed to study the associations between age and difference in morbidity. RESULTS: Similar prevalence was found for diabetes and hypertension, whereas for chronic obstructive pulmonary disease (COPD) and gastroduodenal ulcer lower HSD prevalence was reported. Among females, age was always associated with morbidity difference. Among males, significant associations were found only for COPD (R2 = 0.81; p = 0.001) and gastroduodenal ulcer (R2 = 0.93; p < 0.001). CONCLUSIONS: The difference between population and primary care morbidity is affected by disease under investigation and patients' demographic characteristics. Therefore, in choosing the more cost-effective approach to collect data such evidence should be taken into account, and results should be interpreted with great caution.     

Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine derivatives as adenosine receptor antagonists. Influence of the N5 substituent on the affinity at the human A 3 and A 2B adenosine receptor subtypes: a molecular modeling investigation

A new series of pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines bearing various substituents at both the N5-pyrimidinyl and N8-pyrazolyl positions have been synthesized, and their binding affinities at the four human adenosine receptor subtypes (hA(1), hA(2A), hA(2B), and hA(3)) have been evaluated. All the described compounds contain arylacetyl moieties at the N5 position and arylalkyl substituents at the N8 position. Surprisingly, all the compounds present their most potent affinities at the hA(2B) adenosine receptor with a range of selectivities against the other subtypes. When bulky groups are present simultaneously at the N5 and N8 positions (e.g., compound 9), the best selectivity for the hA(2B) receptor was observed (K(i)(hA(1)) = 1100 nM; K(i)(hA(2A)) = 800 nM; K(i)(hA(2B)) = 20 nM; K(i)(hA(3)) = 300 nM, K(i)(hA(1)/A(2B)) = 55, K(i)(hA(2A)/A(2B)) = 40, K(i)(hA(3)/hA(2B)) = 15). To understand the molecular significance of these results, we compared the putative TM (transmembrane) binding motif of compound 9 on both hA(2B) and hA(3) receptors. From our docking studies, compound 9 fits neatly inside the TM region of the hA(2B) receptor but not in the corresponding hA(3) region, illustrating significant differences between the two subtypes. The study herein presented permits an understanding of why the bioisosteric replacement of an -NH, present in previously reported hA(3) receptor antagonists, with a -CH(2) group at the N5 position induces such large differences in hA(2B)/hA(3) affinity. In the molecular structure of the hA(3) receptor, two residues, Ser243 (TM6) and Ser271 (TM7), create a hydrophilic region, which seems to permit a better accommodation of the phenylurea series into this putative hA(3) binding site than the phenylacetyl series.     

New active series of growth hormone secretagogues

New growth hormone secretagogue (GHS) analogues were synthesized and evaluated for growth hormone releasing activity. This series derived from EP-51389 is based on a gem-diamino structure. Compounds that exhibited higher in vivo GH-releasing potency than hexarelin in rat (subcutaneous administration) were then tested per os in beagle dogs and for their binding affinity to human pituitary GHS receptors and to hGHS-R 1a. Compound 7 (JMV 1843, H-Aib-(d)-Trp-(d)-gTrp-formyl) showed high potency in these tests and was selected for clinical studies.(1)     

The role of anthracyclines in combination chemotherapy for the treatment of follicular lymphoma: retrospective study of the Intergruppo Italiano Linfomi on 761 cases

In order to elucidate the role of anthracycline based combination chemotherapy regimens for the treatment of follicular lymphoma we conducted a retrospective study on a large series of patients with a histologically confirmed diagnosis of follicular lymphoma. The Italian lymphoma intergroup (ILI) promoted a retrospective study of patients with follicular lymphoma treated in cooperative trials between 1985 and 1996. Six hundred and thirty three cases were treated with an anthracycline-containing regimen and 128 patients were treated without anthracyclines. The two groups were prognostically comparable; in particular, no difference was observed according to both IPI and ILI prognostic index. Results showed a complete remission (CR) rate for patients treated with anthracyclines was 69.2% and overall response rate was 92.5%. After a median follow-up of 51 months (54 months for patients still alive), the 5- and 10-year overall survival (OS) rates were 80 and 66%, respectively. Disease-free survival (DFS) and failure-free survival (FFS) rates at 5 years were 61 and 49%, respectively. In the group of patients treated with combination chemotherapy not including anthracyclines, the CR rate was 67.5% and the overall response rate was 85.4%. A longer OS (80% at 5 years) was observed in patients treated with anthracyclines compared to 67% OS rate in patients treated without anthracyclines (p = 0.0004). FFS was significantly longer in patients treated with anthracyclines (49 vs. 34% p = 0.006). Patients treated with anthracyclines with low or intermediate risk according to ILI prognostic index showed a significantly longer OS (p = 0.0001 andp = 0.0009, respectively); those in the high-risk group showed a trend for a longer survival. In conclusion, this retrospective study shows that patients with follicular lymphoma treated with an anthracycline containing regimen had a better outcome compared to patients treated with other combination regimens non including anthracyclines in terms of CRs, OS and FFS. On the basis of these results anthracycline-containing regimens (ACR) should be considered as the standard treatment of patients with advanced follicular lymphoma.