[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.

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.

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.

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.

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.

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.

Increased urinary enzyme excretion in workers exposed to nephrotoxic chemicals.

Nephrotoxic chemicals are commonly present in the environment, particularly in the workplace. The level of occupational exposure to these chemicals has been so reduced that exposure to these agents now rarely causes clinically evident acute renal disease. A sensitive indicator of renal injury, urinary excretion of N-acetyl-beta-glucosaminidase, was utilized to evaluate persons exposed in the workplace to lead, mercury, or organic solvents, for evidence of renal effects from this exposure. None of the persons had clinically evident renal disease by history, none had hypertension, and all had normal findings on urinalysis. When compared with appropriate control populations, workers exposed to lead, workers exposed to mercury, and two of three groups of workers exposed to organic solvents had significant increases in urinary acetyl glucosaminidase activity. The third group of laboratory workers with low exposure to organic solvents had no increase in urinary acetyl glucosaminidase activity. It is concluded that exposure to environmental nephrotoxins at levels currently considered safe can produce renal effects as manifested by elevations of urinary acetyl glucosaminidase excretion. It is speculated that these renal effects are not always innocuous.

Acute mercury poisoning with severe chronic pulmonary manifestations.

This report describes a patient who developed acute chemical pneumonitis following overexposure to metal mercury vapor. The exposure occurred in a gold extraction facility where a gold-mercury amalgam was heated in a confined area. Prompt treatment with penicillamine and corticosteroids was instituted; radiologic pulmonary infiltrates disappeared within a week, but there was little change in the pulmonary function abnormalities (restriction and diffusion impairment) over the period of 11 months of follow-up. This raises the possibility of persistent pulmonary function impairment after metal mercury vapor-induced chemical pneumonitis.

The characteristics of bronchial asthma among a young adult population.

A total of 107, 636 subjects of both sexes who were drafted into the Israeli Defense Forces during 1986 to 1988 were analyzed for the presence of asthma based on questionnaire responses and the results of pulmonary function tests. Most patients (79%) had either mild or inactive disease. Lifetime prevalence increased by 21.7% from 5.3% in 1986 to 6.5% in 1988. The results of a follow-up carried out over 5 to 7 years showed no major change in severity in most patients. The incidence rate remained stable throughout 1987 to 1989 (275, 245, and 243 per 100,000, respectively), without there being any major change in the severity of the asthma during the subsequent 3 to 5 years. It was also revealed that the more physically demanding jobs were associated with a higher prevalence of job transfer. The results of this study suggest that the factors causally associated with asthma are relatively more active during early childhood.

Assessment of hazardous dust exposure by BAL and induced sputum.

OBJECTIVES: BAL, an important tool in assessing occupational lung diseases, is unsuitable for screening programs, exposure evaluation, or monitoring hazardous dust because it is an invasive technique. The results of induced sputum (IS) analysis were compared with BAL and evaluated as a possible alternative. METHODS: We compared BAL with IS analysis of 5 workers exposed to asbestos and 14 exposed to silica and hard metals. Pulmonary function tests and BAL were performed by conventional methods. IS induction was performed after a 20-min inhalation of 3.5% saline solution with an ultrasonic nebulizer. Giemsa-stained cytopreparations were differentially counted. T-lymphocyte subsets were analyzed by flow-activated cell sorter, and messenger RNA (mRNA) was transcribed by reverse transcriptase-polymerase chain reaction. Mineralogic particles were analyzed by scanning electron microscopy and polarizing light microscopy and quantified by an analyzer. RESULTS: The percentage of neutrophils was significantly lower in BAL fluid than in IS specimens, whereas no differences were found in the percentage of lymphocytes and subsets profile. Asbestos fibers were found in BAL but not in IS samples from workers exposed to asbestos. Polarizing particles were found in both samples. Similar mineral elements were found in qualitative analysis by scanning electron microscopy. Quantitative studies showed similar size distribution with a small shift toward larger particles in sputum; mRNA showed the same cytokine profile. CONCLUSIONS: A comparison of BAL and IS specimens in the evaluation of the study population yielded similar quantitative and qualitative results. Further research is needed to evaluate the hypothesis that IS, being a noninvasive technique, may be useful in monitoring exposed workers.

Epidemiology of acute diarrheal diseases in children in a high standard of living rural settlement in Israel.

Epidemiologic patterns of acute diarrheal diseases in a high standard of living communal settlement, situated in a region endemic for enteric diseases, were evaluated by a historical prospective study of 284 children (12,064 child months) from August, 1988, through July, 1992. Three hundred eighty-three episodes of acute diarrhea were identified, yielding a rate of 0.38 episode per 12 child months. One hundred and children (35.6%) were reported to have 1 to 4 diarrheal episodes and 29 (10.2%) children had 5 or more diarrheal episodes during the follow-up period. The mean number of episodes of acute diarrhea per 12 child months in children ages 0 to 2 years was 2.28, in 2- to 6-year-olds 0.44, in 6- to 13-year-olds 0.12 and in 13- to 18-year-olds 0.03 (P < 0.001). Children less than 12 months of age had a lower incidence of acute diarrheal diseases during the months they were being breast-fed than children that were fed with formula during the same period (1.22 vs. 3.06 episodes per 12 child months, respectively; P < 0.001). Enteropathogens were isolated in 40% of diarrheal episodes in which stool cultures were obtained. The identification rates of the various enteropathogens were: diarrheagenic Escherichia coli, 11%; Shigella spp., 10%; Giardia lamblia, 10%; Salmonella spp., 4%; Staphylococcus aureus, 3%; Campylobacter jejuni, 1%. Potential interventions against acute diarrhea in this set up of a high standard of living rural community are education of caretakers and parents on hygienic practices that can prevent transmission of pathogens among the young children and encouraging mothers to breast-feed their children.

Sex differences in the humoral antibody response to live measles vaccine in young adults.

BACKGROUND: Following vaccination of children using high-titre live measles vaccine, excess non-specific mortality was reported, particularly among females. Since vaccination with live measles virus results in a temporary depression of the immune response to other antigens, the female predominance in subsequent non-measles mortality may be due to sex differences in response to live measles vaccines. METHODS: In this study, the immunogenicity of standard titre live Schwarz strain measles vaccine was examined 2 and 4 weeks post-vaccination in 223 males and 66 female aged 18-20 years in Israel in 1991. RESULTS: Females had higher post-vaccination geometric mean titre (GMT) at all levels of pre-vaccination titres at both 2 and 4 weeks. Furthermore, after controlling for differences in pre-vaccination titres, overall the post-vaccination GMT for females was about 50% higher than for males (P < 0.001). CONCLUSIONS: These findings indicate that females exhibit a stronger humoral immune response to measles vaccine. Possible sex differences in immunosuppression following measles vaccination should be explored.

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.

Epidemiology of bronchial asthma and chronic rhinitis in schoolchildren of different ethnic origins from two neighboring towns in Israel.

Allergic diseases have increased significantly in developed countries for reasons yet to be determined. We studied the epidemiology of bronchial asthma (B.A.) and chronic rhinitis (Ch.R.) among Israeli school children from two neighboring towns, one Jewish (Zichron Yaakov, school population = 585) and the other Arab (Paradis, school population = 658). The children (age range 8-17 years, 567 males, 676 females) shared the same climate and had similar demographic characteristics. They received similar medical care and had the same rates of hospitalization and emergency room visits. The Jewish children had a higher prevalence of B.A. (13.7% vs. 9.4%), Ch.R. (19.7% vs. 9.7%), and stuffy nose (31% vs. 14%) than their Arab counterparts. In addition to ethnicity, parental smoking habits were the major differentiating factor between the two groups: 20% of the mothers and 29% of the fathers from Zichron Yaakov and 2% of the mothers and 60% of the fathers from Paradis were smokers. Smoking fathers increased the rate of B.A. in both towns as well as emergency room visits, but not the rate of Ch.R. or stuffy nose. A familial history of B.A. was the main determinant for having childhood asthma or chronic rhinitis. We conclude that in addition to family history and ethnicity, smoking among mothers was the major contributing factor for the higher prevalence of atopic diseases among Jewish schoolchildren compared to their Arab counterparts.

Induced sputum compared to bronchoalveolar lavage for evaluating patients with sarcoidosis and non-granulomatous interstitial lung disease.

Bronchoalveolar lavage (BAL), an important tool for evaluating interstitial lung diseases (ILDs), has limited utility due to its invasiveness and the difficulty of performing it in clinically contraindicated patients. We compared BAL with the induced sputum (IS) technique to analyse cells and T lymphocytes in patients with sarcoidosis (SA) and non-granulomatous ILD (NG-ILD). Pulmonary function tests and BAL were performed by conventional methods. IS induction was done 20 sec after inhalation of 3.5% saline with an ultrasonic nebulizer. Giemsa-stained cytopreps were differentially counted. T lymphocyte subsets were analysed by flow activated cell sorter (FACS). Patients with NG-ILD had impaired total lung capacity (TLC). Transbronchial biopsy demonstrated lung fibrosis in NG-ILD and non-caseating granuloma in SA. The differential cell count in both groups demonstrated a significantly lower percentage of neutrophils and a significantly higher percentage of macrophages in BAL than in IS. The IS samples of patients with SA were significantly richer in metachromatic cells and eosinophils, but had a lower percentage of lymphocytes, compared to the BAL samples. The profiles of T cell subsets showed the same pattern, in both samples, in both groups. A CD4/CD8 ratio of 2.5 or greater had a sensitivity of 100% and a specificity of 81.2%, with a positive predictive value of 81.2% to distinguish SA from NG-ILD. IS is an effective non-invasive technique to identify CD4+ inflammation which distinguishes sarcoidosis from other NG-ILDs.

Cost-benefit analysis of active vaccination campaigns against hepatitis A among daycare centre personnel in Israel.

OBJECTIVE: To evaluate, in economic terms, active vaccination campaigns against hepatitis A in comparison with the use of nonspecific immune globulin for the prevention of the disease among daycare centre employees in Israel. SETTING: Hypothetical analysis of the costs and benefits related to vaccination campaigns of workers currently employed in daycare centres in Israel. METHODS: A cost-benefit analysis was performed, comparing mass and selective active vaccination strategies for the daycare centre working force. Direct and indirect costs of diagnosis, treatment and immunisation as well as productivity loss were considered. A Markov-based model was developed using data from previous epidemiological studies and literature. RESULTS: The benefit-to-cost ratios of selective and mass active vaccination strategies were 1.50 [net present value (NPV) $US606 396] and 0.04 (NPV-$US2.36 million), respectively (2000 values). CONCLUSION: Under these study assumptions, the practice of administering hepatitis A active vaccine to serologically proven non-immune daycare centre workers has a cost-benefit justification, and should be widely considered in countries with a similar hepatitis A epidemiology to that in this study.