Medical Care Use Among Patients with Monogenic Osteoporosis Due to Rare Variants in LRP5, PLS3, or WNT1.

Pathogenic variants in the LRP5, PLS3, or WNT1 genes can significantly affect bone mineral density, causing monogenic osteoporosis. Much remains to be discovered about the phenotype and medical care needs of these patients. The purpose of this study was to examine the use of medical care among Dutch individuals identified between 2014 and 2021 with a pathogenic or suspicious rare variant in LRP5, PLS3, or WNT1. In addition, the aim was to compare their medical care utilization to both the overall Dutch population and the Dutch Osteogenesis Imperfecta (OI) population. The Amsterdam UMC Genome Database was used to match 92 patients with the Statistics Netherlands (CBS) cohort. Patients were categorized based on their harbored variants: LRP5, PLS3, or WNT1. Hospital admissions, outpatient visits, medication data, and diagnosis treatment combinations (DTCs) were compared between the variant groups and, when possible, to the total population and OI population. Compared to the total population, patients with an LRP5, PLS3, or WNT1 variant had 1.63 times more hospital admissions, 2.0 times more opened DTCs, and a greater proportion using medication. Compared to OI patients, they had 0.62 times fewer admissions. Dutch patients with an LRP5, PLS3, or WNT1 variant appear to require on average more medical care than the total population. As expected, they made higher use of care at the surgical and orthopedic departments. Additionally, they used more care at the audiological centers and the otorhinolaryngology (ENT) department, suggesting a higher risk of hearing-related problems.

Carbapenem Consumption and Rate of carbapenemresistant gram-negative bacteria: results from the Sicilian Surveillance System.

Conclusion: The results of the present study highlight the need for comprehensive strategies targeting the appropriate use of antibiotics and infection control measures. Background: In the last decades, multidrug-resistant gram-negative bacteria have been increasing and they are involved in severe healthcare associated infections. In treating drug-resistant gram-negative bacterial infections, carbapenems are generally administered as a last choice. However, the rate of carbapenemresistant bacteria is constantly increasing the last years. The aim of the present study is to describe the relationship between the rate of carbapenem-resistant gram-negative bacteria and antibiotic consumption intensity. Study design: In 2017, the Sicilian Region implemented a regional surveillance system to describe and analyze consumption of antibiotics in hospital settings, as well as prevalence of antibiotic resistant microorganisms. Methods: Resistance data were retrospectively collected from routinary clinical antimicrobial susceptibility tests. Resistance rates (RRs) of carbapenems were calculated and Spearman's correlation analysis was performed to investigate the relationship between annual antibiotic consumption and rate of carbapenem resistance. Results: In 2015, the overall prevalence of carbapenem-resistant Klebsiella pneumoniae isolates was 43.9 %, and was positively correlated with beta-lactam consumption (R=0.529, p<0.01), and with carbapenem consumption (R=0.364, p<0.05). In 2016, the overall prevalence of carbapenem-resistant Klebsiella pneumoniae isolates was 53.8 %, and was positively correlated with carbapenem antibiotic consumption (R=0.364, p<0.05). In 2017, the overall prevalence of carbapenem-resistant Klebsiella pneumoniae isolates was 58.7 %, and was significantly positively correlated with carbapenem antibiotic consumption (R=0.427, p<0.05). In 2015, the overall prevalence of carbapenem-resistant Escherichia coli isolates was 6.5 %, and was significantly positively correlated with antibiotic consumption for the ATC class J01 (i.e., antibacterial for systemic use) (R=0.402, p<0.05).

The association of social and behavioral factors with dietary risks in adults: Evidence from the Kardiovize Brno 2030 study.

BACKGROUND AND AIMS: Uncovering the main determinants of diet quality is one of the greatest challenges for Public Health, since it could guide future strategies and interventions against cardiovascular diseases (CVDs). The present cross-sectional analysis of the Kardiovize cohort evaluates the prevalence of dietary risk factors for CVDs and their association with social and behavioural characteristics in a random sample of 1536 adults (aged 25-64 years) from Brno, Czech Republic. METHODS AND RESULTS: A face-to-face health interview guided by structured questionnaires was carried out on socio-demographic characteristics (age, sex, educational level, employment, marital status, income, and household size) and behaviours (smoking status, physical activity, and sleep habits). Twelve dietary risk factors covered by the Global Burden of Diseases comparative risk assessment framework were assessed using a Food Frequency Questionnaire. In general, we observed that the consumption of nearly all healthy foods and nutrients was suboptimal, and that it was also aggravated by high intake of foods and nutrients that constituted dietary risk factors. Moreover, we found several associations of social and behavioural characteristics with specific dietary risk factors. Particularly, being male (ß = 0.466; SE = 0.079; p < 0.001), increasing household size (ß = 0.130; SE = 0.047; p = 0.006), low income (ß = 0.192; SE = 0.091; p = 0.035), and decreasing physical activity level (ß = 0.172; SE = 0.054; p = 0.002) were associated with increasing number of dietary risk factors. CONCLUSION: Thus, our study raises an urgent need for Public Health strategies promoting healthy eating in adulthood, which should be based on traditional and novel determinants of dietary risk.

Dietary patterns and school performance: evidence from a sample of adolescents in Sicily, Italy.

BACKGROUND: Academic success in adolescence is a strong predictor of future wealth, productivity and health. While unhealthy dietary habits might be detrimental for academic outcomes, a positive association between healthy diet and school performance was found in adolescents worldwide. STUDY DESIGN: A total of 213 adolescents (15 to 18 years old; 48% boys), attending three high schools in the urban area of Eastern Sicily, were enrolled in a cross-sectional study. METHODS: Dietary data and informations about weekly consumption of main meals were collected administering a Food Frequency Questionnaire. The Mediterranean Diet Score and Principal Component Analysis were used to identify a priori and a posteriori dietary patterns, respectively. School performance was assessed through school marks, using the previous year as reference. RESULTS: The Mediterranean Diet Score was weakly but positively correlated with performance in Italian, Science and Physical Education (p-values < 0.05). Similarly, the adherence to the prudent dietary pattern weakly positively correlated with marks in Mathematics. In contrast, we demonstrated a weak but significant negative correlation between adherence to the western dietary pattern and the performance in several subjects. The energy dense dietary pattern was instead negatively correlated with mark in Italian. We also showed that adolescents regularly eating all main meals have a better performance in several subjects, when compared to those who skipped at least one meal. CONCLUSION: The promotion of healthy diet in youth should be a priority for Public Health, in order to improve adolescents' quality of life and prevent negative health and social outcomes later in life.

The impact of social determinants and lifestyles on dietary patterns during pregnancy: evidence from the "Mamma & Bambino" study.

BACKGROUND: During pregnancy, maternal dietary patterns play a critical role in determining maternal and new-born health. Recent evidence highlighted the influence of either social determinants and lifestyles on the adherence to different dietary patterns. STUDY DESIGN: In this cross-sectional analysis, we evaluated the association of social determinants and lifestyles with maternal dietary patterns in the "Mother & Child" cohort, a prospective study that enrols mother-child pairs from Catania, Italy. METHODS: Dietary patterns were derived using Food Frequency Questionnaire and Principal Component Analysis. Logistic regression models were used to evaluate the association between socio-demographic factors (i.e., age, educational level and employment status), lifestyles (i.e., smoking status, body mass index, use of folic acid, multivitamin and multi-mineral supplements) and dietary patterns. RESULTS: Overall, 332 women were enrolled and the following dietary patterns were derived: the "western" dietary pattern, characterized by high intake of red meat, fries, dipping sauces, salty snacks and alcoholic drinks; the second one, named "prudent", characterized by high intake of potatoes, raw and cooked vegetables, legumes, rice and soup. Multivariable analysis showed that young age, low educational level and smoking were positively associated with the adherence to the western dietary pattern. In contrast, pre-gestational body mass index was negatively associated with the adherence to the prudent dietary pattern. CONCLUSION: Our results raise the need of strategies for promoting healthy dietary habits among women in their reproductive age, which might also help control their body weight before and during pregnancy. These strategies should be prioritized to young women of low educational level, who generally share other unhealthy behaviours.

Association between eating time interval and frequency with ideal cardiovascular health: Results from a random sample Czech urban population.

BACKGROUND AND AIMS: The frequency and timing of meals may affect cardiovascular health (CVH) outcomes, but large-scale epidemiological studies are lacking. The aim of this study was to understand the relationship between eating time interval and frequency, and measures of ideal CVH in the Kardiovize Brno cohort study, a random urban sample population in Central Europe. METHODS AND RESULTS: 1659 members of the Kardiovize Brno 2030 cohort were included in a cross-sectional study (mean age = 46.86 years; 44.6% male). Exposure variables were eating time interval and frequency, and skipping meals. Primary outcomes were indices of CVH, including body mass index, diet, physical activity, smoking, blood pressure, glucose and cholesterol, and the composite CVH score. Cluster analysis and binary logistic regression analysis were used to evaluate eating habits and the association between variables. After adjustment for well-known risk factors, subjects who skipped breakfast or the afternoon snack had a higher risk of poor CVH (OR = 1.613; 95%CI = 1.121-2.320; p = 0.010; OR = 1.409; 95%CI = 1.110-1.788; p = 0.005, respectively). Moreover, we identified three clusters of individuals based on eating habits; from cluster 1 to cluster 3, eating time interval and frequency increased and this was associated with increases in CVH score from 8.70 (SEM = 0.10) in cluster 1, and 9.06 (SEM = 0.08) in cluster 2 to 9.42 (SEM = 0.09) in cluster 3 (p-trend = 0.019). CONCLUSIONS: Our findings suggest that skipping breakfast or the afternoon snack are risk factors for poor CVH, while higher eating time interval and frequency may promote ideal CVH.

Appropriateness of perioperative antibiotic prophylaxis in two Italian hospitals: a pilot study.

BACKGROUND: Appropriate perioperative antibiotic prophylaxis has been shown to be an effective measure for preventing surgical site infections and to avoid complications including increased antimicrobial resistance. The objective of the present study was to evaluate the appropriateness of perioperative antibiotic prophylaxis in two Italian hospitals. STUDY DESIGN: In 2016 a survey was prospectively carried out at two hospitals (identified as A and B) and all patients who underwent a surgical operation were enrolled. METHODS: For each patient, perioperative antibiotic prophylaxis data were collected and appropriateness of perioperative antibiotic prophylaxis was assessed according to the national guidelines (SNLG-17, 2011). RESULTS: During the study period, 107 and 467 operations were included. Compliance to perioperative antibiotic prophylaxis according to indication was 72.3% (hospital A) and 77.9% (hospital B). Perioperative antibiotic prophylaxis was administered <60 min before the skin incision in 89.1% of surgical procedures in hospital A and in 78.4% in hospital B. In hospital A, the recommended molecule of antibiotic was correctly administered in 87.8% of surgeries (n= 36), while, in hospital B, the antibiotic was correctly administered only in 9.8% of surgeries. Antibiotic prophylaxis was not extended postoperatively or did not exceed 24 hours after the end of the surgery in 99% and 8.9% of the procedures in hospital A and B, respectively. CONCLUSION: Our study found an overall low compliance to perioperative antibiotic prophylaxis mainly regarding antibiotic choice and total duration of prophylaxis. The Italian Study Group of Hospital Hygiene - Italian Society of Hygiene, Preventive Medicine and Public Health, together with the National Association of Hospital Physician, promoted the implementation of the project "Choosing wisely - Hospital Hygiene", and, among the list of the 5 procedures with the highest evidence of inappropriateness, the timing and the duration of administration of perioperative antibiotic prophylaxis have been included and a multicenter study has been launched to evaluate the appropriateness of perioperative antibiotic prophylaxis components in all the participating Italian hospitals.

Recognizing the tenascin-X deficient type of Ehlers-Danlos syndrome: a cross-sectional study in 17 patients.

The tenascin-X (TNX) deficient type Ehlers-Danlos syndrome (EDS) is similar to the classical type of EDS. Because of the limited awareness among geneticists and the challenge of the molecular analysis of the TNXB gene, the TNX-deficient type EDS is probably to be under diagnosed. We therefore performed an observational, cross-sectional study. History and physical examination were performed. Results of serum TNX measurements were collected and mutation analysis was performed by a combination of next-generation sequencing (NGS), Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). Included were 17 patients of 11 families with autosomal recessive inheritance and childhood onset. All patients had hyperextensible skin without atrophic scarring. Hypermobility of the joints was observed in 16 of 17 patients. Deformities of the hands and feet were observed frequently. TNX serum level was tested and absent in 11 patients (seven families). Genetic testing was performed in all families; 12 different mutations were detected, most of which are suspected to lead to non-sense mRNA mediated decay. In short, patients with the TNX-deficient type EDS typically have generalized joint hypermobility, skin hyperextensibility and easy bruising. In contrast to the classical type, the inheritance pattern is autosomal recessive and atrophic scarring is absent. Molecular analysis of TNXB in a diagnostic setting is challenging.

Pre-pregnancy BMI, gestational weight gain, and telomere length in amniotic fluid: a causal graph analysis.

Previous investigations have suggested a potential association between pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) with telomere length (TL) in various tissues of pregnant women and newborns. Nonetheless, as association does not imply causation, our objective was to investigate the causal connections among pre-pregnancy BMI, GWG, and TL in amniotic fluid. The analysis included 136 mother-child pairs from the Mamma & Bambino cohort, and three causal graph models were developed to depict the interconnections between pre-pregnancy BMI, GWG, and TL. Causal graph analysis was conducted utilizing the do-operator to estimate the causal effect of GWG and the controlled direct effect of pregestational BMI. We revealed that transitioning from non-adequate to adequate GWG had a positive impact on the probability of having "long" TL (i.e., a value greater than the population median) in all three models. When considering the effect of pre-pregnancy BMI, the highest probability of "long" TL was observed in normal weight women with adequate GWG. In contrast, the effect of adequate GWG became minimal among overweight women. These results shed light on the potential causality between pre-pregnancy BMI, GWG, and TL in amniotic fluid, emphasizing the importance of appropriate weight management before and during pregnancy for optimal TL outcomes.

The intertwining of healthcare-associated infections and COVID-19 in Italian intensive care units: an analysis of the SPIN-UTI project from 2006 to 2021.

BACKGROUND: Although healthcare-associated infections (HAIs) pose an extraordinary burden on public health, the impact of coronavirus disease 2019 (COVID-19) is still a matter of debate. AIM: To describe trends of HAIs in Italian intensive care units (ICUs) from 2006 to 2021, and to compare characteristics and outcomes of patients with or without COVID-19. METHODS: We evaluated patients participating in the 'Italian Nosocomial Infections Surveillance in Intensive Care Units' (SPIN-UTI) project, who were admitted to ICUs for more than 48 h. Data regarding diagnosis, clinical conditions, therapies, treatments and outcomes of COVID-19 patients were also collected. FINDINGS: From a total of 21,523 patients from 2006 to 2021, 3485 (16.2%) presented at least one HAI. We observed an increasing trend for both the incidence of patients with HAI and the incidence density of HAIs (P-trend <0.001). Compared with the pre-pandemic period, the incidence density of HAIs increased by about 15% in 2020-2021, with pneumoniae being the greatest contributors to this increase (P-trend <0.001). Moreover, incidence of HAIs was higher in ICUs dedicated to COVID-19 patients (P<0.001), who showed a greater risk of HAIs and death than patients without COVID-19 (P-values <0.001). Accordingly, the mortality in ICUs increased over the years and doubled during the pandemic (P-trend <0.001). Notably, co-infected patients had higher mortality (75.2%) than those with COVID-19 (66.2%) or HAI (39.9%) alone, and those without any infection (23.2%). CONCLUSIONS: Our analysis provides useful insight into whether and how the COVID-19 pandemic influenced HAI incidence and death in Italian ICUs, highlighting the need for evaluation of the long-term effects of the pandemic.

Altered collagen I and premature pulmonary embryonic differentiation in patients with OI type II.

Pulmonary hypoplasia and respiratory failure are primary causes of death in patients with osteogenesis imperfecta (OI) type II. OI is a genetic skeletal disorder caused by pathogenic variants in genes encoding collagen type I. It is still unknown if the collagen defect also affects lung development and structure, causing lung hypoplasia in OI type II. The aim of this study was to investigate the intrinsic characteristics of OI embryonic lung parenchyma and to determine whether altered collagen type I may compromise airway development and lung structure. Lung tissue from nine fetuses with OI type II and six control fetuses, matched by gestational age, was analyzed for TTF-1 and collagen type I expression by immunohistochemistry, to evaluate the state of lung development and amount of collagen. The differentiation of epithelium into type 2 pneumocytes during embryonic development was premature in OI type II fetuses compared to controls (p < 0.05). Collagen type I showed no significant differences between the two groups. However, the amount of alpha2(I) chains was higher in fetuses with OI and the ratio of alpha1(I) to alpha2(I) lower in OI compared to controls. Cell differentiation during lung embryonic development in patients with OI type II is premature and impaired. This may be the underlying cause of pulmonary hypoplasia. Altered cell differentiation can be secondary to mechanical chest factors or a consequence of disrupted type I collagen synthesis. Our findings suggest that collagen type I is a biochemical regulator of pulmonary cell differentiation, influencing lung development.

A machine learning approach to predict healthcare-associated infections at intensive care unit admission: findings from the SPIN-UTI project.

BACKGROUND: Identifying patients at higher risk of healthcare-associated infections (HAIs) in intensive care units (ICUs) represents a major challenge for public health. Machine learning could improve patient risk stratification and lead to targeted infection prevention and control interventions. AIM: To evaluate the performance of the Simplified Acute Physiology Score (SAPS) II for HAI risk prediction in ICUs, using both traditional statistical and machine learning approaches. METHODS: Data for 7827 patients from the 'Italian Nosocomial Infections Surveillance in Intensive Care Units' project were used in this study. The Support Vector Machines (SVM) algorithm was applied to classify patients according to sex, patient origin, non-surgical treatment for acute coronary disease, surgical intervention, SAPS II at admission, presence of invasive devices, trauma, impaired immunity, and antibiotic therapy in 48 h preceding ICU admission. FINDINGS: The performance of SAPS II for predicting HAI risk provides a receiver operating characteristic curve with an area under the curve of 0.612 (P<0.001) and accuracy of 56%. Considering SAPS II along with other characteristics at ICU admission, the SVM classifier was found to have accuracy of 88% and an AUC of 0.90 (P<0.001) for the test set. The predictive ability was lower when considering the same SVM model but with the SAPS II variable removed (accuracy 78%, AUC 0.66). CONCLUSIONS: This study suggested that the SVM model is a useful tool for early prediction of patients at higher risk of HAIs at ICU admission.

Cluster analysis identifies patients at risk of catheter-associated urinary tract infections in intensive care units: findings from the SPIN-UTI Network.

BACKGROUND: Although preventive strategies have been proposed against catheter-associated urinary tract infections (CAUTIs) in intensive care units (ICUs), more efforts are needed to control the incidence rate. AIM: To distinguish patients according to their characteristics at ICU admission, and to identify clusters of patients at higher risk for CAUTIs. METHODS: A two-step cluster analysis was conducted on 9656 patients from the Italian Nosocomial Infections Surveillance in Intensive Care Units project. FINDINGS: Three clusters of patients were identified. Type of admission, patient origin and administration of antibiotics had the greatest weight on the clustering model. Cluster 1 comprised more patients with a medical type of ICU admission who came from the community. Cluster 2 comprised patients who were more likely to come from other wards/hospitals, and to report administration of antibiotics 48 h before or after ICU admission. Cluster 3 was similar to Cluster 2 but was characterized by a lower percentage of patients with administration of antibiotics 48 h before or after ICU admission. Patients in Clusters 1 and 2 had a longer duration of urinary catheterization [median 7 days, interquartile range (IQR) 12 days for Cluster 1; median 7 days, IQR 11 days for Cluster 2] than patients in Cluster 3 (median 6 days, IQR 8 days; P<0.001). Interestingly, patients in Cluster 1 had a higher incidence of CAUTIs (3.5 per 100 patients) compared with patients in the other two clusters (2.5 per 100 patients in both clusters; P=0.033). CONCLUSION: To the authors' knowledge, this is the first study to use cluster analysis to identify patients at higher risk of CAUTIs who could gain greater benefit from preventive strategies.

NGS panel analysis in 24 ectopia lentis patients; a clinically relevant test with a high diagnostic yield.

BACKGROUND: Several genetic causes of ectopia lentis (EL), with or without systemic features, are known. The differentiation between syndromic and isolated EL is crucial for further treatment, surveillance and counseling of patients and their relatives. Next generation sequencing (NGS) is a powerful tool enabling the simultaneous, highly-sensitive analysis of multiple target genes. OBJECTIVE: The aim of this study was to evaluate the diagnostic yield of our NGS panel in EL patients. Furthermore, we provide an overview of currently described mutations in ADAMTSL4, the main gene involved in isolated EL. METHODS: A NGS gene panel was analysed in 24 patients with EL. RESULTS: A genetic diagnosis was confirmed in 16 patients (67%). Of these, four (25%) had a heterozygous FBN1 mutation, 12 (75%) were homozygous or compound heterozygous for ADAMTSL4 mutations. The known European ADAMTSL4 founder mutation c.767_786del was most frequently detected. CONCLUSION: The diagnostic yield of our NGS panel was high. Causative mutations were exclusively identified in ADAMTSL4 and FBN1. With this approach the risk of misdiagnosis or delayed diagnosis can be reduced. The value and clinical implications of establishing a genetic diagnosis in patients with EL is corroborated by the description of two patients with an unexpected underlying genetic condition.

Genotyping microarray (gene chip) for the ABCR (ABCA4) gene.

Genetic variation in the ABCR (ABCA4) gene has been associated with five distinct retinal phenotypes, including Stargardt disease/fundus flavimaculatus (STGD/FFM), cone-rod dystrophy (CRD), and age-related macular degeneration (AMD). Comparative genetic analyses of ABCR variation and diagnostics have been complicated by substantial allelic heterogeneity and by differences in screening methods. To overcome these limitations, we designed a genotyping microarray (gene chip) for ABCR that includes all approximately 400 disease-associated and other variants currently described, enabling simultaneous detection of all known ABCR variants. The ABCR genotyping microarray (the ABCR400 chip) was constructed by the arrayed primer extension (APEX) technology. Each sequence change in ABCR was included on the chip by synthesis and application of sequence-specific oligonucleotides. We validated the chip by screening 136 confirmed STGD patients and 96 healthy controls, each of whom we had analyzed previously by single strand conformation polymorphism (SSCP) technology and/or heteroduplex analysis. The microarray was >98% effective in determining the existing genetic variation and was comparable to direct sequencing in that it yielded many sequence changes undetected by SSCP. In STGD patient cohorts, the efficiency of the array to detect disease-associated alleles was between 54% and 78%, depending on the ethnic composition and degree of clinical and molecular characterization of a cohort. In addition, chip analysis suggested a high carrier frequency (up to 1:10) of ABCR variants in the general population. The ABCR genotyping microarray is a robust, cost-effective, and comprehensive screening tool for variation in one gene in which mutations are responsible for a substantial fraction of retinal disease. The ABCR chip is a prototype for the next generation of screening and diagnostic tools in ophthalmic genetics, bridging clinical and scientific research.

The expanding roles of ABCA4 and CRB1 in inherited blindness.

Mutations in the ABCA4 gene cause Stargardt disease (STGD), most cases with autosomal recessive (ar) cone-rod dystrophy (CRD), and some cases with atypical ar retinitis pigmentosa (arRP). We found compound heterozygous ABCA4 mutations in two unrelated patients with STGD and homozygous splice site mutations in their 2nd and 4th degree cousins with RP. Some ABCA4 mutations display strong founder effects. In Dutch and German STGD patients, the 768G > T mutation is present in 8% and 0.6% of ABCA4 alleles respectively. Vice versa, the complex L541P;A1038V allele is found in 70% of ABCA4 alleles in German STGD patients but absent in Dutch patients. As approximately 70% of ABCA4 mutations are known, a microarray-based analysis of known ABCA4 gene variants allows routine DNA diagnostics in Caucasian patients. Mutations in the CRB1 gene underlie RP12, some cases with classic arRP, 55% of cases with RP and Coats-like exudative vasculopathy, and 13% of patients with Leber congenital amaurosis (LCA), rendering CRB1 a significant cause of autosomal recessive retinal dystrophy. Different combinations of mutations in ABCA4 or CRB1 can be correlated with disease severity, suggesting that small increments of protein activities in patients might have significant therapeutic effects. Mouse and Drosophila studies strongly suggest that both patient groups might benefit from reduced light exposure and therefore should be detected as early as possible using molecular techniques.

ABCR unites what ophthalmologists divide(s)

Over the last years, the molecular causes of monogenic chorioretinal diseases have been elucidated at an increasing pace. In contrast, only recently have genetic factors been found that contribute to multifactorial eye disorders such as age-related macular degeneration (AMD). Mutations in the retina-specific ATP-binding cassette transporter gene (ABCR) cause recessive Stargardt's disease (STGD) and fundus flavimaculatus (FFM), and were also found in 16% of patients with AMD. In addition, ABCR mutations were identified in families with recessive retinitis pigmentosa (RP), cone dystrophy (COD), and cone-rod dystrophy (CRD). In this review, we summarize these findings and propose a model which provides a framework to explain the observed genotypes and phenotypes. We hypothesize that most ABCR mutations can be classified in different classes of severity, and that, depending on the remaining total activity of ABCR, the phenotype can range from AMD at the mild end to RP at the severe end of the spectrum. This model allows us to make several predictions on the type and/or severity of ABCR mutations that are present in patients with AMD, STGD/FFM, COD, CRD, and RP.

Cell kinetics in breast cancer.

In breast cancer the study of prognostic factors has been well developed during last years and many biologic and biochemical parameters have been analyzed. Cell kinetics parameters demonstrated the capability to select patients with different risk of evolution of the neoplasia and in some cases treatment protocols are established by means of proliferation rate. The present study deals with the determination of Thymidine Labelling Index in breast tumors mostly T1-T2 with negative lymph nodes. Results demonstrated that the proliferative activity is higher in younger patients, in T2 cancers compared to T1, and in ductal infiltrating forms compared to the other more frequent histotypes. A significant correlation has been observed between TLI and nuclear grade. The preliminary analysis of the prognostic value of TLI has been two performed using an experimental cut off that is able to discriminate groups of patients with overall survival rate of 67% and 88%, depending on the different proliferative activity of the tumor.

Steady-state pharmacokinetics of idebenone in healthy volunteers.

An open study was conducted with 12 healthy male Caucasian volunteers to determine the single dose and steady-state pharmacokinetics in plasma after a total daily dose of 90 mg of idebenone administered as 45 mg twice daily for 10 consecutive days. In the dose regimen investigated, multiple daily doses of 90 mg of idebenone were well tolerated by healthy male volunteers and were not associated with any clinically relevant changes in ECG or clinical laboratory parameters. The results of the physical examinations after study termination revealed normal findings in all volunteers. To evaluate the single dose and steady-state pharmacokinetic profile, blood samples were collected at predetermined time points during the study. In those subjects examined, generally good systemic exposure with rapid absorption of idebenone was obtained throughout the entire dosing period. Exposures to idebenone and its metabolites after both single and repeated oral doses of idebenone were comparable in magnitude. Further, the exposures attained were generally consistent with those observed in a previous study after 30 mg three times daily. All pharmacokinetic assessments were associated with a low to moderate degree of inter-subject variability.