A multicenter experience on the prevalence of ARMC5 mutations in patients with primary bilateral macronodular adrenal hyperplasia: from genetic characterization to clinical phenotype.

ARMC5 mutations have recently been identified as a common genetic cause of primary bilateral macronodular adrenal hyperplasia (PBMAH). We aimed to assess the prevalence of ARMC5 germline mutations and correlate genotype with phenotype in a large cohort of PBMAH patients. A multicenter study was performed, collecting patients from different endocrinology units in Italy. Seventy-one PBMAH patients were screened for small mutations and large rearrangements in the ARMC5 gene: 53 were cortisol-secreting (two with a family history of adrenal hyperplasia) and 18 were non-secreting cases of PBMAH. Non-mutated and mutated patients' clinical phenotypes were compared and related to the type of mutation. A likely causative germline ARMC5 mutation was only identified in cortisol-secreting PBMAH patients (one with a family history of adrenal hyperplasia and ten apparently sporadic cases). Screening in eight first-degree relatives of three index cases revealed four carriers of an ARMC5 mutation. Evidence of a second hit at somatic level was identified in five nodules. Mutated patients had higher cortisol levels (p = 0.062), and more severe hypertension and diabetes (p < 0.05). Adrenal glands were significantly larger, with a multinodular phenotype, in the mutant group (p < 0.01). No correlation emerged between type of mutation and clinical parameters. ARMC5 mutations are frequent in cortisol-secreting PBMAH and seem to be associated with a particular pattern of the adrenal masses. Their identification may have implications for the clinical care of PBMAH cases and their relatives.

Screening for mutations in the ISL1 gene in patients with thyroid dysgenesis.

CONTEXT: Congenital hypothyroidism (CH) is a common endocrine disorder with an incidence of 1:3000- 4000 newborns. In 80-85% of cases, CH is caused by defects in thyroid organogenesis, resulting in absent, ectopically located, and/or severely reduced gland, all conditions indicated as "thyroid dysgenesis" (TD). A higher prevalence of congenital heart diseases has been documented in children with CH compared to the general population. This association suggests a possible pathogenic role of genes involved in both heart and thyroid development. Among these, it can be included Isl1, a transcription factor containing a LIM homeodomain that is expressed in both thyroid and heart during morphogenesis. OBJECTIVE: In the present study, we investigate the role of ISL1 in the pathogenesis of TD. SETTINGS AND PATIENTS: By single stranded conformational polymorphism, we screened for mutations the entire ISL1 coding sequence in 96 patients with TD and in 96 normal controls. RESULTS: No mutations have been found in patients and controls. CONCLUSION: Our data indicate that, despite the relevant role of ISL1 in thyroid and heart morphogenesis, mutations in its coding region are not associated with TD in our group of patients.

Mutations in TAZ/WWTR1, a co-activator of NKX2.1 and PAX8 are not a frequent cause of thyroid dysgenesis.

AIM: In 80-85% of cases, congenital hypothyroidism is associated with thyroid dysgenesis (TD), but only in a small percentage of cases mutations in thyroid transcription factors (NKX2.1, PAX8, FOXE1, and NKX2.5) have been associated with the disease. Several studies demonstrated that the activity of the transcription factors can be modulated by the interaction with other proteins, such as coactivators and co-repressors, and TAZ (transcriptional co-activator with PDZ-binding motif or WWTR1) is a co-activator interacting with both NKX2.1 and PAX8. In the present study we investigate the role of TAZ in the pathogenesis of TD. MATERIAL AND METHODS: By Single Stranded Conformational Polymorphism, we screened the entire TAZ coding sequence for mutations in 96 patients with TD and in 96 normal controls. RESULTS: No mutations were found in patients and controls, but we found several polymorphisms in both groups. No significant differences could be demonstrated in the prevalence of the mutations between patients and controls. CONCLUSIONS: Our data indicate that TAZ mutations are not a cause of TD in the series of patients studied.

New fluoroquinolones in lower respiratory tract infections and emerging patterns of pneumococcal resistance.

The increasing resistance of Streptococcus pneumoniae, the most important community respiratory pathogen, to beta-lactams and other first-line antimicrobial agents usually employed for the empirical treatment of lower respiratory tract infections has led to the inclusion, in several current guidelines, of a fluoroquinolone with improved activity against pneumococci as the first choice agent for the management of such infections. The excellent microbiological, pharmacokinetic, and pharmacodynamic characteristics of the new fluoroquinolones (levofloxacin, moxifloxacin, gemifloxacin, and gatifloxacin) have encouraged their growing use, probably contributing to the emergence of fluoroquinolone-resistant pneumococci; although pneumococcal resistance to new fluoroquinolones is currently low, there is still concern about the potential for widespread emergence of resistance to these agents if they become indiscriminately used. Levofloxacin clinical failures have already been reported in the management of patients with pneumococcal community-acquired pneumonia; development of resistance in clinical isolates of S. pneumoniae has prompted a critical reexamination of the newer fluoroquinolones to assess their potency and to preserve their activity. An understanding of the pharmacokinetic and pharmacodynamic properties, allowing selection of the most potent fluoroquinolone, will reduce the opportunity for resistance to develop. Finally, a targeted use of these agents will maintain class efficacy.

[The epidemiology of adverse reactions to nonsteroidal anti-inflammatory drugs. Nimesulide is tolerated by patients with adverse reactions to NSAIDs and modulates in man the skin response to histamine and codeine]. / Epidemiologia delle reazioni avverse ai farmaci antiinfiammatori non steroidei. La nimesulide è tollerata dai pazienti con reazioni avverse ai FANS e modula nell'uomo la risposta cutanea all'istamina ed alla codeina.

We evaluated the tolerance to NIM in patients with adverse reactions to NSAIDs, expressed by urticaria-angioedema, bronchial asthma or erythema polymorphous on 92 patients among which 32 atopics affected by asthma, rhinitis or contact dermatitis. Challenge test has been performed with increasing amounts of NIM per os every 2 hrs to a maximum of 100 mg/dose. The last dosage was repeated every 12 hrs for 4 times more. No reactions were observed in 86 patients (93.4%). Moreover we evaluated the efficacy of NIM in modulating pomphoid cutaneous reaction to histamine (HIS) and codeine (COD). Three subjects were prick tested with HIS and COD solutions at different concentrations (0.1 to 10 mg/ml), before and after a 5 days therapy with NIM at different dosages/kg/die. At NIM dosages of 3.7 and 2.7 mg/kg/die we observed a strong reduction of pomphoid activity of both HIS and COD. No clear effects were detected at 2.2 mg/kg/die dosage. We assume a dose-related in vivo inhibitory effect of NIM on cutaneous mast cells releasability or a direct anti-histaminic effect. We point out the possible therapeutic role of NIM in the treatment of allergic flogosis at steroid and cromon's side.

The clinical nurse specialist role in product research and development.

Think about the variety of products used each day in the critical care environment. They include everything from the most sophisticated monitors to the many disposable products. Most products function very well, but when they do not, do you wish you could talk to the person who designed that product? How can your input make medical products work better? The authors describe a career opportunity open to critical care nurses, that of a clinical nurse specialist for a medical products corporation, whose job it is to influence the design and quality of medical products.

Isoelectrofocusing of organic esterases in the postnatally developing and adult ovoviviparous teleost, Poecilia reticulata.

In the ovoviviparous teleost, Poecilia reticulata, the esterases give rise to around 13 variants when separated by electrofocusing. These variants show histochemical characteristics (e.g. substrate utilization and sensitivity to inhibiting substances) which can be related to postnatal developmental stages and to adult sex. A few variants, moreover, appear to be typical of the stage examined (newborn, young, adult male and female). Very few variants can be classified by the criteria of Masters and Holmes (1975).