Developing medical device software in compliance with regulations.

In the last decade, the use of information technology (IT) in healthcare has taken a growing role. In fact, the adoption of an increasing number of computer tools has led to several benefits related to the process of patient care and allowed easier access to social and health care resources. At the same time this trend gave rise to new challenges related to the implementation of these new technologies. Software used in healthcare can be classified as medical devices depending on the way they are used and on their functional characteristics. If they are classified as medical devices they must satisfy specific regulations. The aim of this work is to present a software development framework that can allow the production of safe and high quality medical device software and to highlight the correspondence between each software development phase and the appropriate standard and/or regulation.

Temozolomide 3 weeks on and 1 week off as first-line therapy for recurrent glioblastoma: phase II study from gruppo italiano cooperativo di neuro-oncologia (GICNO).

The efficacy of temozolomide strongly depends on O(6)-alkylguanine DNA-alkyl transferase (AGAT), which repairs DNA damage caused by the drug itself. Low-dose protracted temozolomide administration can decrease AGAT activity. The main end point of the present study was therefore to test progression-free survival at 6 months (PFS-6) in glioblastoma patients following a prolonged temozolomide schedule. Chemonaïve glioblastoma patients with disease recurrence or progression after surgery and standard radiotherapy were considered eligible. Chemotherapy cycles consisted of temozolomide 75 mg/m(2)/daily for 21 days every 28 days until disease progression. O(6)-methyl-guanine-DNA-methyl-tranferase (MGMT) was determined in 22 patients (66.7%). A total of 33 patients (median age 57 years, range 31-71) with a median KPS of 90 (range 60-100) were accrued. The overall response rate was 9%, and PFS-6 30.3% (95% CI:18-51%). No correlation was found between the MGMT promoter methylation status of the tumours and the overall response rate, time to progression and survival. In 153 treatment cycles delivered, the most common grade 3/4 event was lymphopoenia. The prolonged temozolomide schedule considered in the present study is followed by a high PFS-6 rate; toxicity is acceptable. Further randomised trials should therefore be conducted to confirm the efficacy of this regimen.

Control of matrix metalloproteinase production in human intestinal fibroblasts by interleukin 21.

BACKGROUND: T cell-mediated immunity plays a central part in the pathogenesis of tissue damage in inflammatory bowel disease (IBD). The mechanism by which T cells mediate tissue damage during IBD remains unclear, but evidence indicates that T cell-derived cytokines stimulate fibroblasts to synthesise matrix metalloproteinases (MMPs), which then mediate mucosal degradation. We have previously shown that, in IBD, there is high production of interleukin (IL) 21, a T cell-derived cytokine, which enhances Th1 activity. AIM: To investigate whether IL21 controls MMP production by intestinal fibroblasts. METHODS: IL21 receptor (IL21R) was evaluated in intestinal fibroblasts by reverse transcriptase-polymerase chain reaction (RT-PCR) and western blotting. Fibroblasts were stimulated with IL21 and MMPs were evaluated by RT-PCR and western blotting. The effect of a neutralising IL21R fusion protein (IL21R/Fc) on the induction of MMPs in fibroblasts stimulated with IBD lamina propria mononuclear cell (LPMC) supernatants was also evaluated. RESULTS: Intestinal fibroblasts constitutively express both IL21R and the common gamma chain receptor, which are necessary for IL21-driven signalling. IL21 enhances fibroblast production of MMP-1, MMP-2, MMP-3 and MMP-9, but not tissue inhibitors of MMP-1 and MMP-2. Moreover, IL21 synergises with tumour necrosis factor alpha to increase synthesis of MMP synthesis. IL21 enhances MMP secretion without affecting gene transcription and protein synthesis. IBD LPMC supernatants stimulate MMP secretion by intestinal fibroblasts, and this effect is partly inhibited by IL21R/Fc. CONCLUSIONS: These results suggest that fibroblasts are a potential target of IL21 in the gut and that IL21 controls MMP secretion by fibroblasts.

Role of gemcitabine in cancer therapy.

Gemcitabine, a pyrimidine nucleoside antimetabolite, is one of the most promising new cytotoxic agents. The drug has shown activity in a variety of solid tumors, and has been approved for the treatment of non-small cell lung cancer, pancreatic, bladder, and breast cancer. Recent data showed that gemcitabine is also active against ovarian cancer. Gemcitabine has a good toxicity profile, with myelosuppression being the most common side effect, while non-hematological events are relatively uncommon. The low toxicity profile makes the drug a valid option for unfit and elderly patients. Due to the synergistic activity with other chemotherapeutic compounds, mainly cisplatinum, several trials have been conducted to evaluate the efficacy and tolerability of gemcitabine in combination with other cytotoxic agents. Current clinical trials are evaluating the role of gemcitabine in combination with new targeted therapies.

Genotype frequencies of the +874T-->A single nucleotide polymorphism in the first intron of the interferon-gamma gene in a sample of Sicilian patients affected by tuberculosis.

In the light of the key role played by interferon (IFN)-gamma in the control of tuberculosis, in the present paper we have evaluated the distribution of the functional +874T --> A IFN-gamma single nucleotide polymorphism (SNP) in Sicilian patients affected by tuberculosis. Our aim was to determine whether there is an association between the TT genotype, which has been suggested to be linked to an increased production of IFN-gamma, and resistance to chronic tuberculosis. DNA samples were obtained from 45 patients and 97 healthy controls. Polymorphism at +874 was identified using amplification refractory mutational system methodology. The +874T SNP was less frequent in patients than in controls (0.42 vs. 0.50) but the difference was not significant. The +874TT genotype, which has been suggested to be associated with high IFN-gamma production, was significantly decreased in the patients. Thus, resistance to chronic lung tuberculosis might be associated with a genetically determined high IFN-gamma production capacity. In conclusion, the present data add another piece of evidence to the complex puzzle of genetic and environmental factors involved in control of infectious diseases. Studies on cytokine gene polymorphisms may elucidate the complex network of trans-interactive genes influencing the type and strength of responses to environmental stressors and may help to identify the genetic factors that affect survival in humans.

Evaluation of polycyclic aromatic hydrocarbon-DNA adducts in exfoliated oral cells by an immunohistochemical assay.

Polycyclic aromatic hydrocarbon-DNA adducts were evaluated in oral cells from 98 healthy volunteers by an immunohistochemical method using a specific antiserum against benzo(a)pyrene-DNA adducts revealed by the immunoperoxidase reaction. Mean adduct content, determined as relative staining intensity by absorbance image analyzer, was significantly higher in the cells from tobacco smokers compared with nonsmokers (330 +/- 98, n = 33 versus 286 +/- 83, n = 64, respectively) with a P = 0.013 obtained by two-sample t test with equal variances. We found that in the smoker group, the PAH-DNA adduct content increases with the number of cigarettes. Thus, the relative staining intensity was 305 +/- 105 in the group smoking 1-10 cigarettes/day (n = 16), 347 +/- 77 in the 11-20 group (n = 14), and 386 +/- 112 in the group smoking more than 20 cigarettes/day (n = 3; P = 0.03 by nonparametric test for trend). No significant association was detected between PAH-DNA adducts in oral cells and variables such as residential area, oral infections, alcohol or vitamin intake, grilled food consumption, and professional activity. This work confirms and extends previous data suggesting that this immunohistochemical method might be used as a valuable dosimeter of genotoxic damage in a carcinogen-exposed population, although further studies are needed to verify the applicability of the test in high-risk populations other than smokers.

Liver inflammation and acute respiratory distress syndrome in a patient receiving hepatitis B vaccine: a possible relationship?

We describe a patient in whom clinical evidence of liver and lung dysfunction developed after he received the second dose of recombinant hepatitis B vaccine, despite no serologic evidence of viral hepatitis. However, liver biopsy specimens demonstrated both surface antigens and core antigens, possibly indicating silent hepatitis B virus infection. A search for an infective etiology for the patient's subsequent clinical deterioration in lung function did not yield pathogens: postmortem examination revealed evidence of immune complex-mediated organ injury in the liver, lungs, and kidneys.

[Adult myocarditis in a general hospital: observations on 605 autopsies]. / La miocardite dell'adulto in un ospedale generale: osservazioni su 605 autopsie.

We studied 605 necropsies carried out in a general hospital (San Giovanni battista in Turin), during the years 1985-86 (405 cases) and 1993-94 (200 cases). A standardized sample of myocardium was systematically taken and submitted to histological examination. Thirty-one cases of myocarditis were found (5.1%). Th disease was more frequently observed in the age group from 30 to 49 years and in people dying of malignancies: females showed higher frequency than males (7.4% vs. 4%), with differences nearly significant from a statistical point of view. None of these cases was recognized by the physicians. The prevalence rate of myocarditis in the present series is higher than in retrospective reviews, where microscopic examination of myocardium was not systematically performed. The discrepancies between clinical results and pathological findings confirm that myocarditis is often unsuspected by the physicians.

Efficacy and tolerability of azithromycin versus amoxicillin/clavulanic acid in acute purulent exacerbation of chronic bronchitis.

An open randomized trial was conducted in 142 hospitalized and out-patients with acute purulent exacerbation of chronic bronchitis to compare the clinical efficacy and tolerability of azithromycin (n = 69) and amoxicillin/clavulanic acid (n = 73). Azithromycin (500 mg) was administered as a single dose for three days and amoxicillin/clavulanic acid (amoxicillin 875 mg-clavulanic acid 125 mg) was given b.i.d. for 8 days (8.16 +/- 1.18). Before therapy and 24-48 hours after the end of treatment, sputum culture (by positioning five orthodontal swabs at the opening of salivary gland ducts after a washing of the oral cavity with sterile saline solution to avoid oral contamination), chest X-rays, arterial blood gas analysis, trials of respiratory functions and routine blood tests were performed. In the azithromycin group (69 patients) the efficacy rate was 67.6% (46 patients: 34 cured and 12 improved); in 22 patients (32.4%) the treatment failed; 1 patient was not evaluated because of no follow-up. The overall efficacy rate in the amoxicillin/clavulanic acid group (73 patients) was 97.3% (71 patients: 60 cured and 11 improved); in 1 patient (1.4%) the treatment failed and 1 patient was a drop-out for side effects. All pathogens isolated before treatment were susceptible to the antibiotics administered. At the end of treatment microbiological efficacy was 67.1% in the azithromycin group and 98.6% in the amoxicillin/clavulanic acid group. The tolerability was judged good in both treatment groups. Side effects were observed in 1 patient treated with amoxicillin/clavulanic acid (diarrhea), which imposed interruption of treatment, and in 2 patients from the azithromycin group (gastralgia and biochemical laboratory tests: renal function).(ABSTRACT TRUNCATED AT 250 WORDS)

Foreshortening of the inferior conjunctival fornix associated with chronic glaucoma medications.

The authors designed a device to measure the depth of the inferior conjunctival fornix at the slit lamp using topical anesthesia. The fornices of 179 glaucoma patients receiving topical medications for glaucoma and 420 control subjects who had no history of ocular disease were measured. These measurements were age-stratified by decade. A significant foreshortening of the inferior conjunctival fornix was found with aging (P less than 0.01). Patients in their sixth through ninth decades using miotics for 3 years or longer and patients using nonmiotic agents for 3 years or longer exhibited significant foreshortening of the inferior fornix when compared with age-stratified (by decade) control subjects (P less than 0.01). These observations suggest that increasing age and topical medications for glaucoma, or the preservatives, used for 3 years or longer, are independently associated with conjunctival shrinkage.

Cefaclor in the treatment of infective exacerbations of chronic bronchitis in cigarette smokers.

There is a direct correlation between number of cigarettes smoked and the incidence of lower respiratory tract infection in humans. In studies with smokers suffering from exacerbations of chronic bronchitis, the most common bacterial pathogens found were Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus and Branhamella catarrhalis. Antibiotics should be effective against such possible pathogens. Cefaclor has demonstrated in vitro activity against all these pathogens. We designed the present study to evaluate the efficacy and safety of cefaclor in the treatment of acute exacerbations of chronic bronchitis in cigarette smokers. A total of 106 patients were enrolled in the study. H. influenzae was the most common bacterial species isolated in the sputum (in 23.6% of the total sample), followed by S. pneumoniae (18.9%), S. aureus (17.0%), K. pneumoniae (7.5%) and B. catarrhalis (5.7%), while mixed forms were present in 22.6% of cases and other pathogens in 4.7%. Cefaclor (500 mg) was given orally every 8h for 7 to 16 days (mean 10.73 +/- 2.11). Analysis of clinical response data indicates that 75.5% of patients were cured and 17.0% improved. This finding is important because it demonstrates that cefaclor's spectrum of activity encompasses all the most likely pathogens encountered in smokers. Because of its excellent response rate, cefaclor is of particular value in the treatment of lower respiratory tract infections in cigarette smokers.

Bacterial isolates and cigarette smoking in patients with chronic bronchitis: results from an Italian multicenter survey.

Patients who were cigarette smokers suffering exacerbations of chronic bronchitis were examined in eight outpatient clinics in five regions of Italy, three from the South (Campania, 82 patients; Sicily, 82 patients; and Puglia, 29 patients) and two from North (Lombardy, 33 patients; and Liguria, 50 patients). Haemophilus influenzae was the most frequently isolated bacterium in the patients' sputum (in 30% of the total group), followed by Streptococcus pneumoniae (in 20%), Staphylococcus aureus (in 25%), and Branhamella catarrhalis (in 7%). H. influenzae was the most common bacterium in the South (in 37%) and S aureus in the North (in 13%). Smoking index scores (number of cigarettes smoked daily x years of smoking) were 827 in patients in whom H influenzae was isolated; 691 in patients with S aureus; 599 in patients with S pneumoniae; 542 in patients with B catarrhalis; and 446 in patients in whom no isolates were found. Pulmonary function was most severely decreased in patients positive for H influenzae and S aureus. The results indicate an association between heavy cigarette smoking and lower respiratory tract infections that is influenced by regional differences.

The anatomy of the lateral canthal tendon.

This report documents the anatomy of the lateral canthus using gross dissection, histologic examination, computed tomography, magnetic resonance imaging, and clinical measurement. Lateral canthal dissections of 16 cadaver orbits demonstrated a well-defined attachment of the tarsal plates to the orbital rim, averaging 10.6 mm in length and 10.2 mm in width at their insertion on Whitnall's tubercle, 1.5 mm behind the orbital rim and 9.7 mm inferior to the frontozygomatic suture. Histologic examination showed a band of dense fibrous tissue attached to the tarsal plates, with intermingled muscle fibers from the pretarsal orbicularis oculi muscle. A small pocket of fat was identified posterior to the orbital septum and anterior to the lateral canthal tendon. Clinical measurements of normal adults revealed 2 mm of lateral movement of the canthal angle during abduction, apparently caused by posterior fibrous attachments to the check ligament of the lateral rectus muscle.

Ionized calcium/total calcium ratio during biofiltration.

The transmembrane transfer of calcium during hemodialysis is related to many factors (calcium gradient, plasma volume flow, plasma concentration of phosphate). During biofiltration the high ultrafiltration rate reduces the net transfer of calcium from dialysate to patient. Prolonged metabolic alkalosis occurs during biofiltration, lowering the ionized calcium/total calcium ratio. These two factors may stimulate PTH secretion, with negative long-term effects in dialysis bone disease.