[Controllable systemic destruction of old collagen fibers as a novel approach for rejuvenating biological aging in mammals.]

Aging of extracellular proteins colloidal systems is one of major synchronizing mechanism in mammal`s «biological clock¼. We hypothesized that induced controllable modification of connective tissue composition could reverse aging. In murine experimental models collagenase was used for selective destruction of old collagen. Oxygen consumption, urine hydroxyproline excretion, density and distribution of mature and old collagen and elastine fibers in dermal biopsies were determined. Collagenase injections significantly increased hydroxyproline excretion. We observed reduced density of mature and old collagen fibers and increased oxygen consumption in dermal biopsies after course of collagenase injections. Collagenase treatment intensified the destruction of mature and old collagen matrix and enhanced synthesis of new collagen and elastine fibers. Furthermore oxygen consumption increased. Our findings can be considered as indicator of collagenase systemic anti-aging (rejuvenation) activity.

Risk factors for colonization with extended-spectrum beta-lactamase-producing enterobacteriaceae on admission to rehabilitation centres.

Patients newly admitted to rehabilitation centres are at high risk of colonization with multidrug-resistant bacteria because many of them have experienced prolonged stays in other healthcare settings and have had high exposure to antibiotics. We conducted a prospective study to determine the prevalence of and risk factors for colonization with extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE) in this population. Subjects were screened by rectal swab for ESBL-PE within 2 days of admission. Swabs were plated on chromagar ESBL plates and the presence of ESBL was verified by a central laboratory. A multilevel mixed effects model was used to identify risk factors for ESBL-PE colonization. Of 2873 patients screened, 748 (26.0%) were positive for ESBL-PE. The variables identified as independently associated with ESBL-PE colonization were: recent stay in an acute-care hospital for over 2 weeks (OR=1.34; 95% CI, 1.12, 1.6), history of colonization with ESBL-PE (OR=2.97; 95% CI, 1.99, 4.43), unconsciousness on admission (OR=2.59; 95% CI, 1.55, 4.34), surgery or invasive procedure in the past year (OR=1.49; 95% CI, 1.2, 1.86) and antibiotic treatment in the past month (OR=1.80; 95% CI, 1.45, 2.22). The predictive accuracy of the model was low (area under the ROC curve 0.656). These results indicate that ESBL-PE colonization is common upon admission to rehabilitation centres. Some risk factors for ESBL-PE colonization are similar to those described previously; however, newly identified factors may be specific to rehabilitation populations. The high prevalence and low ability to stratify by risk factors may guide infection control and empirical treatment strategies in rehabilitation settings.

A multinational study of colonization with extended spectrum ß-lactamase-producing Enterobacteriaceae in healthcare personnel and family members of carrier patients hospitalized in rehabilitation centres.

The study aims were: (i) to define the prevalence of and risk factors for colonization by extended spectrum ß-lactamase (ESBL) -producing Enterobacteriaceae (EPE) among healthcare workers (HCWs) and family members (FMs) of EPE-colonized patients in rehabilitation units and (ii) to compare EPE isolates from these three groups. The study included 286 FMs of 194 EPE-carrying patients identified in five rehabilitation units located in Israel, Italy, France and Spain. The EPE were detected in rectal swabs from 26 (9%) of 286 FMs screened. In multivariate analyses, older age of FM, greater mean number of hours spent with the patient, being a daughter or a female spouse of a patient, and chronic lung disease of the patient were significantly associated with carriage in the FM. Escherichia coli was the most common organism (76%), followed by Klebsiella pneumoniae (19%). Isolates were typed by pulsed field gel electrophoresis and multilocus sequence typing, and ESBLs were identified by PCR sequencing. A comparison of paired species isolates from FMs and their respective patient showed that 17 of 23 strains were indistinguishable. EPE were detected in 35 (3.5%, E. coli = 34) of the 1001 HCWs screened. Feeding patients was associated with EPE carriage by HCWs. Only 7 of 23 E. coli subclones cultured from HCWs were also represented among 376 patient-derived ESBL-producing E. coli isolates from the same rehabilitation units. In Spain, a higher proportion of HCWs and FMs were ESBL carriers than elsewhere (p <0.05). In conclusion, the molecular and epidemiological data suggest that FMs are at higher risk of EPE acquisition from their relative patients than HCWs.

Comparative population analysis of Klebsiella pneumoniae strains with extended-spectrum ß-lactamases colonizing patients in rehabilitation centers in four countries.

The international project MOSAR was conducted in five rehabilitation centers; patients were screened for rectal carriage of extended-spectrum ß-lactamase (ESBL)-producing members of the Enterobacteriaceae. Among 229 Klebsiella pneumoniae isolates, four clonal groups (CG) or complexes (CC) prevailed: CG17 in France, CG101 in Italy, CG15 in Spain, and CC147 in Israel. ESBLs, mainly CTX-Ms, were produced by 226 isolates; three isolates expressed AmpC-like cephalosporinases. High genetic diversity of K. pneumoniae populations was observed, with specific characteristics at each center.

Clonal structure, extended-spectrum ß-lactamases, and acquired AmpC-type cephalosporinases of Escherichia coli populations colonizing patients in rehabilitation centers in four countries.

The prospective project MOSAR was conducted in five rehabilitation units: the Berck Maritime Hôpital (Berck, France), Fondazione Santa Lucia (Rome, Italy), Guttmann Institute (GI; Barcelona, Spain), and Loewenstein Hospital and Tel-Aviv Souraski Medical Center (TA) (Tel-Aviv, Israel). Patients were screened for carriage of Enterobacteriaceae resistant to expanded-spectrum cephalosporins (ESCs) from admission until discharge. The aim of this study was to characterize the clonal structure, extended-spectrum ß-lactamases (ESBLs), and acquired AmpC-like cephalosporinases in the Escherichia coli populations collected. A total of 376 isolates were randomly selected. The overall number of sequence types (STs) was 76, including 7 STs that grouped at least 10 isolates from at least three centers each, namely, STs 10, 38, 69, 131, 405, 410, and 648. These clones comprised 65.2% of all isolates, and ST131 alone comprised 41.2%. Of 54 STs observed only in one center, some STs played a locally significant role, like ST156 and ST393 in GI or ST372 and ST398 in TA. Among 16 new STs, five arose from evolution within the ST10 and ST131 clonal complexes. ESBLs and AmpCs accounted for 94.7% and 5.6% of the ESC-hydrolyzing ß-lactamases, respectively, being dominated by the CTX-M-like enzymes (79.9%), followed by the SHV (13.5%) and CMY-2 (5.3%) types. CTX-M-15 was the most prevalent ß-lactamase overall (40.6%); other ubiquitous enzymes were CTX-M-14 and CMY-2. Almost none of the common clones correlated strictly with one ß-lactamase; although 58.7% of ST131 isolates produced CTX-M-15, the clone also expressed nine other enzymes. A number of clone variants with specific pulsed-field gel electrophoresis and ESBL types were spread in some locales, potentially representing newly emerging E. coli epidemic strains.

A binational cohort study of intestinal colonization with extended-spectrum ß-lactamase-producing Proteus mirabilis in patients admitted to rehabilitation centres.

The aims of our study were to analyse the risk factors for colonization by Extended-spectrum ß-lactamases (ESBL)-producing Proteus mirabilis (ESBL-PM) in rehabilitation patients and to characterize the molecular features of these strains. The study was conducted in two rehabilitation centres located in Rome, Italy (Fondazione Santa Lucia IRCCS (FSL)), and Tel-Aviv, Israel (Tel-Aviv Sourasky Medical Center (TASMC)). Carriage of ESBL-PM was surveyed by rectal swabs. Strain typing was performed by pulsed-field gel electrophoresis (PFGE). Identification of ESBL genes was done by PCR and sequencing. Patients admitted to the same institutions without ESBL carriage were included as controls. The study group included 70 and 41 patients from FSL and TASMC, respectively. In FSL, the multivariate analysis identified severe acute brain injury (OR = 15, 95% CI = 3.2-69.5, p 0.001), decubitus ulcer (OR = 3.5, 95% CI = 1.2-9.8, p 0.018) and recent treatment with quinolones (OR = 5.7, 95% CI = 1.07-30.1, p 0.042) as independent risk factors. ESBL-PM carriers stayed longer in the hospital on average and were less likely to be discharged home. No significant risk factor was identified in TASMC. There were no similarities in PFGE types or ESBL genes between the ESBL-PM isolates from the two institutions. In both hospitals, a variety of PFGE types existed but a single ESBL type predominated, namely TEM-92 in FSL (n = 64/70; 91%) and CTX-M-2 in TASMC (n = 37/41; 90%). A new TEM ESBL variant, TEM-177 was identified in FSL. The clonal diversity and the predominance of a single ESBL type suggested that horizontal gene transfer played an important role in dissemination of resistance. The development of a population analysis tool that would allow tracing deeper genetic relationships is required.

Transmission dynamics of ESBL-producing Escherichia coli clones in rehabilitation wards at a tertiary care centre.

Increasing resistance due to the production of ESBL in Escherichia coli (ESBL-E. coli) has become a major threat to public health. Our aims were to study the incidence of ESBL-E. coli acquisition during hospitalization and the transmission rates of different ESBL-E. coli clones. This was a prospective case-control study, conducted in two geriatric rehabilitation wards in Tel-Aviv. Serial rectal cultures were collected from admission till discharge. All patient-unique ESBL-E. coli isolates were subjected to molecular typing by PFGE, MLST and determination of ESBL genes. An acquisition of ESBL-E. coli was defined as traceable when a patient with the same ST, PFGE type and ESBL gene was hospitalized in the same ward in parallel to the acquisition case. ESBL-E. colis were recovered from 125 patients out of 492 enrolled: 52 were recovered upon admission, 59 acquired ESBL-E. coli during their stay, and there was undetermined status in 14 patients. A low Norton's score was associated with acquisition (O.R. 1.14 for each point, 95% C.I. 1.01-1.29, p < 0.05). ESBL-E. coli infections (n = 9) had occurred only in ESBL-E. coli carriers. The pandemic ST131 clone was the most common (48/125). The majority of the isolates (101/125) produced CTX-M-type ESBL. Of the 59 acquisition cases, 32 were traced to another patient. In-hospital dissemination was highest in the CTX-M-27-producing ST131 and the SHV-5-producing ST372 sub-clones (acquisition/admission ratios of 17/11 and 9/3, respectively), with almost all cases traced to other patients. In conclusion, most ESBL-E. coli acquisition cases were traceable to other patients. The transmission potential varied significantly between ESBL-E. coli clones.

Carriage of methicillin-resistant Staphylococcus aureus on admission to European rehabilitation centres--a prospective study.

This study aimed to determine the prevalence of and risk factors for methicillin-resistant Staphylococcus aureus (MRSA) carriage among patients newly admitted to rehabilitation centres. It is a prospective study examining MRSA carriage on admission to seven rehabilitation wards in four countries. Risk factors for MRSA carriage were analysed using univariate and multivariate analyses. A total of 1204 patients were studied. Among them, 105 (8.7%) had a positive admission MRSA screening result. The MRSA carriers were more likely to be male, to have had a recent stay in another long-term-care facility or >2 weeks acute-care hospital stay, history of colonization with MRSA, reduced level of consciousness, peripheral vascular disease and pressure sores. In multivariable logistic regression male gender (odds ratio (OR) 2.2, 95% confidence interval (CI) 1.4-3.6, p 0.001), history of MRSA positivity (OR 6.8, 95% CI 3.8-12.3, p <0.001), peripheral vascular disease (OR 2.5, 95% CI 1.2-5, p 0.013), recent stay in another long-term-care facility (OR 2.1, 95% CI 1.3-3.5, p 0.004), or long (>2 weeks) acute-care hospital stay (OR 1.9, 95% CI 1.2-3, p 0.004), remained significant risk factors for MRSA carriage. MRSA carriage is common on admission to rehabilitation centres but less so, than previously described in long-term-care facilities. Male gender, history of MRSA positivity, previous hospitalization and peripheral vascular disease may predict MRSA carriage, and may serve as indicators for using pre-emptive infection control measures.

Chest wall shrapnel-induced beryllium-sensitization and associated pulmonary disease.

Chronic beryllium disease (CBD) is an exposure-related granulomatous disease mimicking sarcoidosis. Beryllium exposure-associated disease occurs mainly via inhalation, but skin may also be a source of sensitization. A 65-year-old male with a history of war-related shrapnel wounds was initially diagnosed with pulmonary sarcoidosis. Twenty years later, the possibility of a metal-related etiology for the lung disease was raised. A beryllium lymphocyte proliferation test, elemental analysis of removed shrapnel, and genetic studies were consistent with a diagnosis of CBD. This case demonstrates that retained beryllium-containing foreign bodies can be linked to a pathophysiologic response in the lung consistent with CBD.

Dissemination of an NDM-2-producing Acinetobacter baumannii clone in an Israeli rehabilitation center.

New Delhi metallo-ß-lactamase (NDM-1) was initially identified in various Enterobacteriaceae and recently in Acinetobacter baumannii. This study described the clonal dissemination of an NDM-2-producing A. baumannii isolate in an Israeli rehabilitation ward and the genetic surroundings of the gene. The bla(NDM-2) gene was surrounded by the ble and trpF genes downstream and two copies of the ISAba125 on both sides. These are the first NDM-producing A. baumannii strains in Israel from patients with no previous travel or hospitalization on the Indian subcontinent.

Non-invasive diagnosis of chronic beryllium disease in workers exposed to hazardous dust in Israel.

OBJECTIVES: Chronic beryllium disease (CBD) is caused by prolonged occupational exposure to beryllium and is characterised by various clinical presentations, mostly pulmonary. The inflammatory process involves non-caseous granulomas and proliferation of CD4+ cells. CBD is diagnosed by lung biopsy showing tissue granuloma formation, and by the beryllium lymphocyte proliferation test (BeLPT) for past exposure and sensitisation to beryllium. The induced sputum (IS) technique was developed for diagnosing asthma, chronic obstructive pulmonary disease and interstitial lung diseases. A CD4/CD8 ratio >2.5 in T cells from IS is a positive result for granulomatous lung diseases. We previously revealed that dental technicians are exposed to excessive levels of beryllium. The efficacy of IS (CD4/CD8 >2.5) and BeLPT in diagnosing CBD in 17 workplaces where beryllium was present was evaluated. METHODS: All consecutive patients with a clinical suspicion of CBD referred to our institution for diagnosis and management were enrolled. Results of the gold standard lung biopsy with BeLPT were compared to the non-invasive IS+BeLPT. Kappa and McNemar tests evaluated agreement levels. Correlations between demographic and clinical parameters and a confirmed diagnosis of CBD were analysed. RESULTS: The two approaches were compared in 57 of 98 subjects. There was a high level of agreement (kappa 0.920) between IS+BeLPT and biopsy+BeLPT. IS+BeLPT had a specificity of 97.3% and sensitivity of 87.5%. 21 of 87 exposed workers (24%) had CBD, of whom 12 were dental technicians (p=0.044 dental technicians versus all other occupations). CONCLUSIONS: This study demonstrated that the CD4/CD8 ratio in IS together with positive/negative BeLPT findings can be used in diagnosing CBD.

Sexual activity and erectile dysfunction in elderly men with angiographically documented coronary artery disease.

We studied the prevalence of erectile dysfunction (ED) in elderly men, aged 65 years or above, with coronary artery disease (CAD) documented by coronary angiography. A total of 123 men (112 men with CAD and 11 men without CAD), mean age 74.6+/-5.9 years, was included. To detect ED and assess its severity, all participants were asked to complete the Sexual Health Inventory for Males (SHIM) questionnaire. Lack of sexual activity was more prevalent among men with CAD relative to men without CAD (31.3 vs 0.0%). Among the sexually active men, ED was more prevalent among men with CAD relative to men without CAD (85.7 vs 72.7%). A general linear model showed that age was the only factor associated with SHIM scores among the sexually active men with CAD (P=0.001). Other factors, such as the number of occluded coronary arteries, diabetes mellitus, hypertension, smoking, various medications and marital status, were not associated with SHIM scores in elderly men with CAD. We conclude that lack of sexual activity and ED are very common in elderly men with CAD. Among the sexually active men with CAD, ED severity is associated only with age.

HO-1 and VEGF gene expressions are time dependant during exposure to welding fumes.

Hemeoxygenase-1 (HO-1) is a defensive enzyme against oxidative stress. Vascular epithelial growth factor (VEGF) is a potent cytokine which promotes angiogenesis. We used induced sputum (IS) technology to study HO-1 and VEGF expressions in neutrophilic inflammation in asymptomatic welders. Aircraft plant employees were divided into three groups: Welders 1 (n=30) had short-term exposure to aluminum/iron, Welders 2 (n=16) had long-term exposure to cadmium/chromium/iron/nickel, and controls (n=27 non-exposed individuals). Participants underwent pulmonary function tests (PFTs), IS, differential cell counts, and determination of particle size distribution in IS samples. HO-1 and VEGF gene expressions were analyzed by real-time polymerase chain reaction, and protein levels were measured by bilirubin reductase-dependant reaction and ELISA, respectively. All subjects had normal PFTs. Welders 2 had neutrophilic inflammation and higher percentages of particles between 2-5 micron than the other groups. HO-1 inversely correlated with VEGF gene expression: HO-1 was significantly higher and VEGF was significantly lower in the Welders 1 group than in the other groups. There was a correlation between HO-1 expression and protein activity (r=0.33, P=0.05). Particulate matters significantly influenced HO-1 and VEGF gene expressions, caused neutrophilic inflammation and promoted oxidative stress in welders with long-term exposure.

Pre-immigration screening process and pulmonary tuberculosis among Ethiopian migrants in Israel.

More than 75,000 displaced Ethiopians have moved to Israel. Tuberculosis (TB) incidence in Ethiopia is 44 times higher than in Israel (344 versus 8 cases per 100,000 inhabitants, respectively). The aims of the present retrospective cohort study were to evaluate the pre-immigration screening process initiated in 2001 on pulmonary TB (PTB) morbidity and to assess its cost-effectiveness. Ethiopian immigrants who were screened before departure (study group) were compared with those who were screened after arrival (comparison group). Between 1998 and 2005, 24,051 Ethiopian immigrants arrived in Israel. PTB was diagnosed in 332 (1.4%) immigrants, an incidence density of 325 patients per 100,000 person-yrs. PTB cumulative incidence was lower in the study group than in the comparison group: 711 compared with 1,746 patients per 100,000 immigrants, respectively (rate ratio 0.4). PTB was detected significantly earlier in the study group than in the comparison group: 193 versus 487 days after entry, respectively. Disease incidence declined significantly during the first 2 yrs following immigration. A 5-yr predictive model indicated that 98 individuals would be free of PTB, saving US$91,055 on annual treatment cost, due to screening. The pre-immigration screening process reduced pulmonary tuberculosis incidence in subsequent years following immigration. Pulmonary tuberculosis was diagnosed earlier in the screened group than in the comparison group and the process was found to be both cost-beneficial and cost-effective.

Redefining idiopathic interstitial lung disease into occupational lung diseases by analysis of chemical composition of inhaled dust particles in induced sputum and/or lung biopsy specimens.

There has been increased public awareness of the potential danger from exposure to hazardous dust in various occupations. This study aims to validate the qualitative analysis of scanning electron microscopy (SEM) of lung samples by 1) correlation of induced sputum (IS) findings to clinical findings, 2) comparing hazardous particles in IS to those in biopsied lung specimens, and 3) assessing whether the particles present in the lungs of transplanted patients correlate with occupational history of dust exposure. Forty patients with occupational history were included; of whom 35 filled in questionnaires. Twenty-four of them had SEM analysis of their IS, and 11 of these 24 also had SEM analysis of their lung tissue. Another 11 lung biopsies from patients with occupational history were scanned by SEM and compared with 10 lung biopsies from patients with no occupational history. SEM analysis of IS was as efficient for detecting hazardous particles as was SEM analysis of lung tissue; silica was detected better in sputum. Exposure to silica was the main chemical element associated with a high likelihood to show abnormalities in IS (Odds ratio 19.41 CI = 0.270-1398.33). The average number of detected hazardous chemical elements in patients with an occupational history of exposure was 4 +/- 1.61 in IS and 3.55 +/- 2.02 in lung tissue (P = 0.57); it was 1.5 +/- 0.85 from transplanted occupationally exposed patients compared with 0.36 +/- 0.67 in transplanted non-exposed patients (P = 0.003). SEM analysis of particles in IS and lung tissue can elucidate the causative agent(s) of otherwise idiopathic interstitial lung disease among occupationally exposed workers.

The risk of hepatitis A infection among healthcare workers: a review of reported outbreaks and sero-epidemiologic studies.

All reports of hepatitis A (HA) outbreaks in healthcare settings published between 1975 and 2003 were studied to determine the background immunity or susceptibility of healthcare workers (HCWs) to HA. Twenty-six reports were found. The number of infected personnel ranged from one to 66 and, in most outbreaks, nurses accounted for the majority of personnel infected, reflecting high attack rates reaching 15-41%. In addition, we found 23 sero-epidemiological studies for HA among HCWs that had been performed in 13 different countries. Seroprevalence rates of HCWs with anti-HA antibody ranged between 4% among paramedical workers in Germany to 88% among hospital maintenance workers in Portugal. Effective infection control of HA outbreaks in hospitals demands early recognition, including awareness of atypical presentations of the infection, and strict adherence to universal infection control measures. Education programmes are of special importance for HCWs in neonatal, paediatric and intensive care units. The findings of the current study suggest that a pre-employment screening policy and administration of active vaccination to susceptible HCWs, particularly nurses, should be seriously considered in high-risk settings.

Seroepidemiology of varicella-zoster virus antibodies among health-care workers and day-care-centre workers.

Inclusion of live varicella vaccine in the routine occupational health vaccination schedule requires knowledge of the natural immunity to varicella zoster virus (VZV) among high-risk occupations. This study aims were to evaluate VZV antibody positivity among health-care workers (HCWs) and day-care-centre workers (DCWs) and to assess its association with potential risk factors. Three groups of workers were tested for VZV antibody positivity: hospitals and community clinic HCWs (n = 335), DCWs (n = 117) and blue-collar workers as controls (n = 121). The total VZV antibody positivity was 94.4%. There was no significant difference in VZV antibody positivity among study groups. DCWs had the lowest VZV seroprevalence (90.9%, 95% CI 85.7-96.1) and controls the highest (96.6%, 95% CI 93.2-99.9). This high VZV antibody positivity suggests that no special occupational measures are indicated in health-care or day-care occupational settings in Israel. On-going monitoring of the natural immunity to VZV is necessary to detect trends over time.

Hepatitis A virus seropositivity among hospital and community healthcare workers in Israel-the role of occupation, demography and socioeconomic background.

Hospital and community-clinic workers were tested for hepatitis A virus antibodies (HAV)-IgG to identify variables associated with presence of (HAV-IgG) and to determine whether sociodemographic background may explain all differences in HAV seropositivty among healthcare workers. Logistic regression analysis was used to identify variable associated with HAV-immunity. Multivariate logistic regression analysis revealed that HAV-seroprevalence correlated significantly (P<0.01) with age, siblings, residence in rural areas and origin. Nurse aides had an increased risk for HAV seropositivity (OR=5.04; 95% CI: 1.49-17.08) whereas physicians had a lower risk (OR=0.54: 95% CI: 0.30-0.98). Age and socioeconomic background were independently correlated with HAV immunity but did not explain all difference in HAV-seroprevalence. The higher susceptibility and elevated incidence of hepatitis A amongst physicians, prioritize primary prevention in this group.