Nickel-Catalyzed Atroposelective C-H Alkylation Enabled by Bimetallic Catalysis with Air-Stable Heteroatom-Substituted Secondary Phosphine Oxide Preligands.

The catalytic asymmetric construction of axially chiral C-N atropisomers remains a formidable challenge due to their low rotational barriers and is largely reliant on toxic, cost-intensive, and precious metal catalysts. In sharp contrast, we herein describe the first nickel-catalyzed atroposelective C-H alkylation for the construction of C-N axially chiral compounds with the aid of a chiral heteroatom-substituted secondary phosphine oxide (HASPO)-ligated Ni-Al bimetallic catalyst. A wide range of alkenes, including terminal and internal alkenes, were well compatible with the reaction, providing a variety of benzimidazole derivatives in high yields and enantioselectivities (up to 97:3 e.r.). The key to success was the identification of novel HASPOs as highly effective chiral preligands. Mechanistic studies revealed the catalyst mode of action, and in-depth data science analysis elucidated the key features of the responsible chiral preligands in controlling the enantioselectivity.

Modern Organometallic C-H Functionalizations with Earth-Abundant Iron Catalysts: An Update.

Iron-catalyzed C-H activation has recently emerged as an increasingly powerful synthetic method for the step- and atom- economical direct C-H functionalizations of otherwise inert C-H bonds. Iron's low-cost and toxicity along with its catalytic versatility have encouraged the scientific community to elect this metal for the development of new C-H activation methodologies. Within this review, we aim to present a collection of the most recent examples of iron-catalyzed C-H functionalizations with a particular emphasis on modern synthetic strategies and mechanistic aspects.

Triazole-enabled, iron-catalysed linear/branched selective C-H alkylations with alkenes.

Iron-catalysed C-H alkylations with alkenes were achieved on benzamides by N-triazole assistance. A notable switch of the regioselectivity from linear to branched was observed depending on the nature of the olefin employed. The approach allowed for the synthesis of a family of decorated benzamides with ample scope and high levels of chemo-, regio- and site-selectivity.

Is Lactoferrin More Effective in Reducing Late-Onset Sepsis in Preterm Neonates Fed Formula Than in Those Receiving Mother's Own Milk? Secondary Analyses of Two Multicenter Randomized Controlled Trials.

BACKGROUND: Lactoferrin is the major antimicrobial protein in human milk. In our randomized controlled trial (RCT) of bovine lactoferrin (BLF) supplementation in preterm neonates, BLF reduced late-onset sepsis (LOS). Mother's own milk (MM) contains higher concentrations of lactoferrin than donor milk or formula, but whether BLF is more effective in infants who receive formula or donor milk is uncertain. AIM: To evaluate the incidence of LOS in preterm infants fed MM and in those fed formula and/or donor milk. STUDY DESIGN: This is a (A) post hoc subgroup analysis, in our RCT of BLF, of its effects in preterm infants fed MM, with or without formula, versus those fed formula and/or donor milk (no-MM) and (B) post hoc meta-analysis, in our RCT of BLF and in the ELFIN (Enteral Lactoferrin in Neonates) RCT, of the effect of BLF in subgroups not exclusively fed MM. RESULTS: (A) Of 472 infants in our RCT, 168 were randomized to placebo and 304 were randomized to BLF. Among MM infants, LOS occurred in 22/133 (16.5%) infants randomized to placebo and in 14/250 (5.6%) randomized to BLF (relative risk or risk ratio (RR): 0.34; relative risk reduction (RRR): 0.66; 95% confidence interval (95% CI) for RR: 0.18-0.64; p < 0.0008). Among no-MM infants, LOS occurred in 7/35 (20.0%) randomized to placebo and in 2/54 (3.7%) randomized to BLF (RR: 0.19; RRR: 0.81; 95% CI for RR: 0.16-0.96; p = 0.026). In multivariable logistic regression analysis, there was no interaction between BLF treatment effect and type of feeding (p = 0.628). (B) In 1,891 infants not exclusively fed MM in our RCT of BLF and in the ELFIN RCT, BLF reduced the RR of LOS by 18% (RR: 0.82; 95% CI: 0.71-0.96; p = 0.01). CONCLUSION: Adequately powered studies should address the hypothesis that BLF is more effective in infants fed formula or donor milk than those fed MM. Such studies should evaluate whether a specific threshold of total lactoferrin intake can be identified to protect such patients from LOS.

Zinc exposure for female workers in a galvanizing plant in Northern Italy.

OBJECTIVES: Very little is known regarding the toxicokinetics of inhaled zinc, in particular in the case of female workers and for modern, low exposure settings. Our aim is to evaluate the relationship of external zinc levels to those of serum and urine for female workers. MATERIAL AND METHODS: Eleven female workers (age: 41.7±8 years old, body mass index (BMI): 23.5±4.2 kg/m2) in a galvanizing plant were investigated. Exposure assessment consisted of personal/environmental air samples, and measurement of zinc in serum (collected at the end of first shift of the working week (T1)) and urine, collected before the first shift of the working week (T0), T1 and at the end of the last shift of the working week (T2). RESULTS: Both environmental and personal air samplings for zinc and zinc compounds were below the recommended by the German Research Foundation (Deutsche Forschungsgemeinschaft - DFG) limit values of 2 mg/m3 (7.34±2.8 µg/m3 and 8.31±2.4 µg/ m3, respectively). Serum (118.6±20.9 µg /dl) and urine zinc levels were within reference values for female Italian subjects: the latter increased from 56.4±33.5 µg/dl at T0, to 59.8±37.0 µg/dl at T1, and ultimately 65.4±34.4 µg/dl at T2, but no significant trend was found. End of shift (Spearman's correlation coefficient p value = 0.027) and differential excretion of urinary zinc (both: T0 vs. T1 and T0 vs. T2) were correlated with airborne zinc concentration (p = 0.002 and 0.006, respectively). CONCLUSIONS: In general, our data suggests that urine may be a useful medium also for female in order to assess zinc exposure. Further studies are required in order to evaluate whether differential excretion may be useful for the biomonitoring of zinc exposure in the workplaces also for male workers. Int J Occup Med Environ Health 2018;31(1):113-124.

Exposure to Gastric Acid Inhibitors Increases the Risk of Infection in Preterm Very Low Birth Weight Infants but Concomitant Administration of Lactoferrin Counteracts This Effect.

OBJECTIVE: To investigate whether exposure to inhibitors of gastric acidity, such as H2 blockers or proton pump inhibitors, can independently increase the risk of infections in very low birth weight (VLBW) preterm infants in the neonatal intensive care unit. STUDY DESIGN: This is a secondary analysis of prospectively collected data from a multicenter, randomized controlled trial of bovine lactoferrin (BLF) supplementation (with or without the probiotic Lactobacillus rhamnosus GG) vs placebo in prevention of late-onset sepsis (LOS) and necrotizing enterocolitis (NEC) in preterm infants. Inhibitors of gastric acidity were used at the recommended dosages/schedules based on the clinical judgment of attending physicians. The distribution of days of inhibitors of gastric acidity exposure between infants with and without LOS/NEC was assessed. The mutually adjusted effects of birth weight, gestational age, duration of inhibitors of gastric acidity treatment, and exposure to BLF were controlled through multivariable logistic regression. Interaction between inhibitors of gastric acidity and BLF was tested; the effects of any day of inhibitors of gastric acidity exposure were then computed for BLF-treated vs -untreated infants. RESULTS: Two hundred thirty-five of 743 infants underwent treatment with inhibitors of gastric acidity, and 86 LOS episodes occurred. After multivariate analysis, exposure to inhibitors of gastric acidity remained significantly and independently associated with LOS (OR, 1.03; 95% CI, 1.008-1.067; P = .01); each day of inhibitors of gastric acidity exposure conferred an additional 3.7% odds of developing LOS. Risk was significant for Gram-negative (P < .001) and fungal (P = .001) pathogens, but not for Gram-positive pathogens (P = .97). On the test for interaction, 1 additional day of exposure to inhibitors of gastric acidity conferred an additional 7.7% risk for LOS (P = .003) in BLF-untreated infants, compared with 1.2% (P = .58) in BLF-treated infants. CONCLUSION: Exposure to inhibitors of gastric acidity is significantly associated with the occurrence of LOS in preterm VLBW infants. Concomitant administration of BLF counteracts this selective disadvantage. TRIAL REGISTRATION: isrctn.org: ISRCTN53107700.

Knowledge, attitudes, beliefs and practices of occupational physicians towards vaccinations of health care workers: A cross sectional pilot study in North-Eastern Italy.

OBJECTIVES: This study aims to characterize personal attitudes and knowledge of a sample of Italian occupational physicians (OPhs) towards immunization practice in the case of healthcare workers (HCWs). MATERIAL AND METHODS: A total of 90 OPhs (42.2% of males, 57.8% of females, mean age of 50.1±8.3 years old) compiled a structured questionnaire through a telephonic interview. They were asked about the official Italian recommendations for HCWs, their general knowledge of vaccine practice, their propensity towards vaccines (both in general and about specific immunizations), their risk perception about the vaccine-preventable infectious diseases. Eventually, a regression analysis was performed in order to identify factors predictive for vaccine propensity. RESULTS: Only 12 out of 90 subjects correctly identified all the 7 recommended immunizations. The hepatitis B virus (HBV) vaccine was correctly identified by 95.6% of the sample, and was also associated with the more positive attitude and the more accurate risk perception. Influenza vaccine had the lowest acceptance (75.9%). Eventually, pertussis, measles, parotitis and varicella vaccines were insufficiently recognized as recommended ones (all cases < 50% of the sample). General knowledge of vaccine and knowledge of official recommendations were significantly correlated with the attitude towards immunization practice (r = 0.259, p = 0.014 and r = 0.438, p < 0.0001). In the regression analysis general knowledge (unstandardized coefficient (B) = 0.300, 95% confidence interval (CI): 0.090-0.510, p = 0.006) and risk perception (B = 0.579, 95% CI: 0.155-1.003, p = 0.008) were significant predictors of the propensity to vaccinate. CONCLUSIONS: Vaccinations gaps in HCWs may found their roots in OPhs incomplete knowledge of evidence-based recommendations. Specific training programs and formations courses should then be planned. Int J Occup Med Environ Health 2017;30(5):775-790.

Study of mesenchymal stem cells cultured on a poly(lactic-co-glycolic acid) scaffold containing simvastatin for bone healing.

BACKGROUND: Tissue engineering is a promising alternative for the development of bone substitutes; for this purpose, three things are necessary: stem cells, a scaffold to allow tissue growth and factors that induce tissue regeneration. METHODS: To congregate such efforts, we used the bioresorbable and biocompatible polymer poly(lactic-co-glycolic acid) (PLGA) as scaffold. For the osteoinductive factor, we used simvastatin (SIM), a drug with a pleiotropic effect on bone growth. Mesenchymal stem cells (MSCs) were cultured in PLGA containing SIM, and the bone substitute of PLGA/SIM/MSC was grafted into critical defects of rat calvaria. RESULTS: The in vitro results showed that SIM directly interfered with the proliferation of MSC promoting cell death, while in the pure PLGA scaffold the MSC grew continuously. Scaffolds were implanted in the calvaria of rats and separated into groups: control (empty defect), PLGA pure, PLGA/SIM, PLGA/MSC and PLGA/SIM/MSC. The increase in bone growth was higher in the PLGA/SIM group. CONCLUSIONS: We observed no improvement in the growth of bone tissue after implantation of the PLGA/SIM/MSC scaffold. As compared with in vitro results, our main hypothesis is that the microarchitecture of PLGA associated with low SIM release would have created an in vivo microenvironment of concentrated SIM that might have induced MSC death. However, our findings indicate that once implanted, both PLGA/SIM and PLGA/MSC contributed to bone formation. We suggest that strategies to maintain the viability of MSCs after cultivation in PLGA/SIM will contribute to improvement of bone regeneration.

Work with visual display units and musculoskeletal disorders: A cross-sectional study.

BACKGROUND: Epidemiological studies have shown that employees working with visual display units (VDU) are more likely to complain about musculoskeletal disorders (MSDs). The aim of this study has been to evaluate associations among MSDs and individuals and work-related factors. MATERIAL AND METHODS: A total of 1032 VDU workers were assessed about their personal (i.e., age, working history, smoking history, physical activity) and work-related factors (i.e., predominant job tasks performed, work posture). Work environment was evaluated regarding fulfillment of the standard ISO 9241-5:1998. The investigation required a direct observation of participants (in order to accurately assess the prevalence of MSDs) and workstations. Adjusted odds ratios (ORa) were calculated by means of the logistic regression model. RESULTS: Prevalence of MSDs was relatively high (53%). In general, MSDs were significantly associated with female sex (OR = 2.832, 95% confidence interval (CI): 2.178-3.683), age ≥ 50 years old (OR = 2.231, 95% CI: 1.236-4.026), longer exposure to VDU, both as working history (10-14 years: OR = 1.934, 95% CI: 1.301-2.875; ≥ 15 years: OR = 2.223, 95% CI: 1.510-3.271) and working time (30-39 h/week: OR = 1.537, 95% CI: 1.087-2.273). Inappropriate workstation design was confirmed by the multivariate analysis as a risk factor for MSDs (ORa = 2.375, 95% CI: 1.124-5.018). CONCLUSIONS: Musculoskeletal disorders were significantly associated with individual factors as well as characteristics of work environment. An appropriate design of workstations may significantly reduce their prevalence amongst VDU workers. Med Pr 2016;67(6):707-719.

Personal risk factors for carpal tunnel syndrome in female visual display unit workers.

OBJECTIVES: Carpal tunnel syndrome (CTS) is the most common nerve entrapment syndrome, which since the beginning of the seventies has been linked to the keyboard and visual display unit (VDU). The objective of this study was to investigate the prevalence and personal factors associated with CTS in female VDU workers in Italy. MATERIAL AND METHODS: Participants in this study were female adult subjects, working ≥ 20 h/week (N = 631, mean age 38.14±7.81 years, mean working age 12.9±7.24 years). Signs and symptoms were collected during compulsory occupational medical surveillance. The binary logistic regression was used to estimate adjusted odds ratios for the factors of interest. RESULTS: Diagnosis of CTS was reported in 48 cases (7.6%, 11 of them or 1.7% after a surgical correction) for the incidence of 5.94/1000 person-years. In general, signs and symptoms of CTS were associated with the following demographic factors: previous trauma of upper limb (adjusted odds ratio (ORa) = 8.093, 95% confidence interval (CI): 2.347-27.904), history (> 5 years) of oral contraceptives therapy/hormone replacement therapy (ORa = 3.77, 95% CI: 1.701-8.354) and cervical spine signs/symptoms (ORa = 4.565, 95% CI: 2.281-9.136). CONCLUSIONS: The prevalence of CTS was similar to the estimates for the general population of Italy. Among personal risk factors, hormone therapy, previous trauma of the upper limb and signs/symptoms of the cervical spine appeared to be associated with a higher risk of CTS syndrome. Eventually, the results reinforce interpretation of CTS in VDU workers as a work-related musculoskeletal disorder rather than a classical occupational disease. Int J Occup Med Environ Health 2016;29(6):927-936.

Knowledge, attitudes, beliefs and practices of construction workers towards tetanus vaccine in Northern Italy.

Construction workers (CWs) are both more exposed to tetanus and at higher risk to be inadequately immunized. Our aim was to evaluate tetanus immunization status and knowledge/attitudes towards tetanus vaccination in CWs in Italy. In this field report, the immunization status of 554 unskilled CWs (i.e. labourers). Immunization status was assessed recalling immunization booklets/certificates. Attitudes and knowledge were collected through a standardized questionnaire. In 240/554 CWs, immunization status was inadequate/not documented: in 184 subjects (33.2%), the last vaccination shot was older than 10 years, whereas basal immunization was incomplete in 20 cases, more frequently in foreign-born people (FBP) than in Italian born (IBP) (OR=7.116). In 198 cases (35.7%), an Occupational Physician (OPh) performed last booster, usually with monovalent (T, n=173) vaccine. The main reason for inadequate immunization was having forgotten the periodic booster (148/554; 26.7%), whereas 42 subjects (7.6%) deliberately avoided tetanus vaccine because of personal/religious beliefs, more frequently in FBP than in IBP (OR=3.182). In summary, the prevalence of inadequate immunization status was relatively high (43.4%): the high prevalence of "forgotten boosters" enlightens the key role of OPh in recalling and promoting vaccination policies. Moreover, the inappropriate use of Td vaccine points out the opportunity for educational campaigns in OPh.

Quantitative olfactory disorders and occupational exposure to phenolic resins.

BACKGROUND: To investigate whether exposure to phenolic resins (PR) is associated with quantitative olfactory disorders (QOD), a cross-sectional study of self-reported olfactory impairment (SROI) was performed in occupationally exposed subjects. MATERIAL AND METHODS: Sixty-six workers (45 males, 21 females) at the age (mean ± standard deviation) of 39.8±10.15 years old were divided into 3 exposure groups on the basis of biological exposure indices (BEI) for urinary phenols. It was asked whether the sense of smell has been normal or abnormal during the recent 2 months: the participants were eventually divided into self-reported normosmic, hyposmic, hyperosmic groups. RESULTS: Prevalence of the SROI was 45.5%, with 21 (31.8%) workers complaining about the hyposmia, 12 (18.2%) - anosmia and 9 (13.6%) - hyperosmia. In univariate analyses, female sex was associated with the SROI and the hyperosmia. Highly exposed workers showed the SROI more frequently (odds ratio (OR) = 4.714; 95% confidence interval (CI): 1.077-20.626) than those not exposed (reference) or low exposed (OR = 1.333; 95% CI: 0.416-4.274). In multivariate analyses, female sex was the main risk factor for the SROI (adjusted odds ratio (ORa) = 5.622; 95% CI: 1.525-20.722) and the hyperosmia (ORa = 25.143; 95% CI: 2.379-265.7) but a high exposure to phenol (ORa = 11.133; 95% CI: 1.060-116.9) was the main risk factor for the anosmia. CONCLUSIONS: This study has found slight evidence among the cross-section of chemical industry workers that the exposure to phenol may be associated with the SROI. On the other hand, self-reporting of the QOD may be biased by personal factors and further research with objective measurement is therefore required. Med Pr 2016;67(2):173-186.

Bovine lactoferrin supplementation for prevention of necrotizing enterocolitis in very-low-birth-weight neonates: a randomized clinical trial.

IMPORTANCE: NEC is a common and severe complication in premature neonates, particularly those with very-low-birth-weight (VLBW, <1500 g at birth). Probiotics including lactobacillus rhamnosus GG (LGG) proved effective in preventing NEC in preterm infants in several RCTs. OBJECTIVE: Lactoferrin, a mammalian milk glycoprotein involved in innate immune host defences, can reduce the incidence of NEC in animal models, and its action is enhanced by LGG. We tried to assess whether bovine lactoferrin (BLF), alone or with the probiotic LGG, has a similar effect in human infants, something that has not yet been studied. DESIGN: An international, multicenter, randomized, double-blind, placebo-controlled trial conducted from October 1st, 2007 through July 31st, 2010. SETTING: Thirteen Italian and New Zealand tertiary neonatal intensive care units. PARTICIPANTS: 743 VLBW neonates were assessed until discharge for development of NEC. INTERVENTION: Infants were randomly assigned to receive orally either BLF (100 mg/day) alone (group LF; n = 247) or with LGG (at 6×10(9) CFU/day; group BLF + LGG; n = 238), or placebo (Control group; n = 258) from birth until day 30 of life (45 for neonates <1000 g at birth). MAIN OUTCOME MEASURES: ≥ stage 2 NEC; death-and/or-≥ stage 2 NEC prior to discharge. RESULTS: Demographics, clinical and management characteristics of the 3 groups were similar, including type of feeding and maternal milk intakes. NEC incidence was significantly lower in groups BLF and BLF + LGG [5/247 (2.0%)] and 0/238 (0%), respectively] than in controls [14/258 (5.4%)] (RR = 0.37; 95% CI: 0.136-1.005; p = 0.055 for BLF vs. control; RR = 0.00; p < 0.001 for BLF + LGG vs. control). The incidence of death-and/or-NEC was significantly lower in both treatment groups (4.0% and 3.8% in BLF and BLF + LGG vs. 10.1% in control; RR = 0.39; 95% CI: 0.19-0.80; p = 0.008. RR = 0.37; 95% CI: 0.18-0.77; p = 0.006, respectively). No adverse effects or intolerances to treatment occurred. CONCLUSIONS AND RELEVANCE: Compared with placebo, BLF supplementation alone or in combination with LGG reduced the incidence of ≥ stage 2 NEC and of death-and/or ≥ stage 2 NEC in VLBW neonates. BLF might be a promising strategy to prevent NEC in NICU settings. Further data on larger sample sizes are warranted before BLF can be widespreadly used in clinical settings. TRIAL REGISTRATION: ISRCTN53107700-http://www.controlled-_trials.com/ISRCTN53107700.

Serratia marcescens in a neonatal intensive care unit: two long-term multiclone outbreaks in a 10-year observational study.

We investigated two consecutive Serratia marcescens (S. marcescens) outbreaks which occurred in a neonatal intensive care unit (NICU) of a tertiary level hospital in North Italy in a period of 10 years (January 2003-December 2012). Risk factors associated with S. marcescens acquisition were evaluated by a retrospective case-control study. A total of 21,011 clinical samples was examined: S. marcescens occurred in 127 neonates: 43 developed infection and 3 died. Seven clusters were recorded due to 12 unrelated clones which persisted for years in the ward, although no environmental source was found. The main epidemic clone A sustaining the first cluster in 2003 reappeared in 2010 as an extended spectrum ?-lactamase (ESBL)-producing strain and supporting the second epidemic. Birth weight, gestational age, use of invasive devices and length of stay in the ward were significantly related to S. marcescens acquisition. The opening of a new ward for non-intensive care-requiring neonates, strict adherence to alcoholic hand disinfection, the timely identification and isolation of infected and colonized neonates assisted in containing the epidemics. Genotyping was effective in tracing the evolution and dynamics of the clones demonstrating their long-term persistence in the ward.

Human milk feeding prevents retinopathy of prematurity (ROP) in preterm VLBW neonates.

BACKGROUND: Retinopathy of prematurity (ROP) is a multifactorial disease, but little is known about its relationships with neonatal nutritional policies. Human, maternal milk is the best possible nutritional option for all premature infants, including those at high risk for severe complications of prematurity, such as ROP. OBJECTIVE: This is a secondary analysis of data collected during two multicenter RCTs performed consecutively (years 2004 through 2008) by a network of eleven tertiary NICUs in Italy. The two trials aimed at assessing effectiveness of fluconazole prophylaxis (Manzoni et al., N Engl J Med 2007 Jun 14;356(24):2483-95), and of bovine lactoferrin supplementation (Manzoni et al., JAMA 2009 Oct 7;302(13):1421-8), in prevention of invasive fungal infection, and of late-onset sepsis in VLBW infants, respectively. We tested the hypothesis that exclusive feeding with fresh maternal milk may prevent ROP of any stage - as defined by the ETROP study - in VLBW neonates, compared to formula feeding. METHODS: We analyzed the database from both trials. Systematic screening for detection of ROP was part of the protocol of both studies. The definition of threshold ROP was as defined by the ETROP study. Univariate analysis was performed to look for significant associations between ROP and several possible associated factors, and among them, the type of milk feeding (maternal milk or formula for preterms). When an association was indicated by p < 0.05, multiple logistic regression was used to determine the factors significantly associated with ROP. RESULTS: In both trials combined, 314 infants received exclusively human maternal milk (group A), and 184 a preterm formula because their mothers were not expected to breastfeed. The clinical, demographical and management characteristics of the neonates did not differ between the two groups, particularly related to the presence of the known risk factors for ROP. Overall, ROP incidence (any stage) was significantly lower in infants fed maternal milk (11 of 314; 3.5%) as compared to formula-fed neonates (29 of 184; 15.8%) (RR 0.14; 95% CI 0.12-0.62; p = 0.004). The same occurred for threshold ROP (1.3% vs. 12.3%, respectively; RR 0.19; 95% CI 0.05-0.69; p = 0.009). At multivariate logistic regression controlling for potentially confounding factors that were significantly associated to ROP (any stage) at univariate analysis (birth weight, gestational age, days on supplemental oxygen, systemic fungal infection, outborn, hyperglycaemia), type of milk feeding retained significance, human maternal milk being protective with p = 0.01. CONCLUSIONS: Exclusive human, maternal milk feeding since birth may prevent ROP of any stage in VLBW infants in the NICU.

PLDLA/PCL-T Scaffold for Meniscus Tissue Engineering.

The inability of the avascular region of the meniscus to regenerate has led to the use of tissue engineering to treat meniscal injuries. The aim of this study was to evaluate the ability of fibrochondrocytes preseeded on PLDLA/PCL-T [poly(L-co-D,L-lactic acid)/poly(caprolactone-triol)] scaffolds to stimulate regeneration of the whole meniscus. Porous PLDLA/PCL-T (90/10) scaffolds were obtained by solvent casting and particulate leaching. Compressive modulus of 9.5±1.0 MPa and maximum stress of 4.7±0.9 MPa were evaluated. Fibrochondrocytes from rabbit menisci were isolated, seeded directly on the scaffolds, and cultured for 21 days. New Zealand rabbits underwent total meniscectomy, after which implants consisting of cell-free scaffolds or cell-seeded scaffolds were introduced into the medial knee meniscus; the negative control group consisted of rabbits that received no implant. Macroscopic and histological evaluations of the neomeniscus were performed 12 and 24 weeks after implantation. The polymer scaffold implants adapted well to surrounding tissues, without apparent rejection, infection, or chronic inflammatory response. Fibrocartilaginous tissue with mature collagen fibers was observed predominantly in implants with seeded scaffolds compared to cell-free implants after 24 weeks. Similar results were not observed in the control group. Articular cartilage was preserved in the polymeric implants and showed higher chondrocyte cell number than the control group. These findings show that the PLDLA/PCL-T 90/10 scaffold has potential for orthopedic applications since this material allowed the formation of fibrocartilaginous tissue, a structure of crucial importance for repairing injuries to joints, including replacement of the meniscus and the protection of articular cartilage from degeneration.

Bovine lactoferrin prevents invasive fungal infections in very low birth weight infants: a randomized controlled trial.

BACKGROUND: Lactoferrin is a mammalian milk glycoprotein involved in innate immunity. Recent data show that bovine lactoferrin (bLF) prevents late-onset sepsis in preterm very low birth weight (VLBW) neonates. METHODS: This is a secondary analysis of data from a multicenter randomized controlled trial where preterm VLBW neonates randomly received bLF (100 mg/day; group A1), bLF + Lactobacillus rhamnosus GG (10(6) colony-forming units per day; group A2), or placebo (group B) for 6 weeks. Here we analyze the incidence rates of fungal colonization, invasive fungal infection (IFI), and rate of progression from colonization to infection in all groups. RESULTS: This study included 472 neonates whose clinical, nutritional, and demographical characteristics were similar. Overall, the incidence of fungal colonization was comparable (17.6%, 16.6%, and 18.5% in A1, A2, and B, respectively; P = .89 [A1] and .77 [A2]). In contrast, IFIs were significantly decreased in A1 and A2 (0.7% and 2.0%, respectively) compared with B (7.7%; P = .002 [A1] and .02 [A2]), and this was significantly true both in <1000 g (0.9% [A1] and 5.6% [A2], vs 15.0%) and in 1001 to 1500 g infants (0% and 0% vs 3.7%). The progression rate colonization-infection was significantly lower in the bLF groups: 3.7% (A1) and 12% (A2), vs 41.9%; P < .001 (A1) and P = .02 (A2). No IFI-attributable deaths occurred in the treatment groups, versus 2 in placebo. No adverse effects or intolerances occurred. CONCLUSIONS: Prophylactic oral administration of bLF reduces the incidence of IFI in preterm VLBW neonates. No effect is seen on colonization. The protective effect on IFI is likely due to limitation of ability of fungal colonies to progress toward invasion and systemic disease in colonized infants.

Bovine lactoferrin supplementation for prevention of late-onset sepsis in very low-birth-weight neonates: a randomized trial.

CONTEXT: Sepsis is a common and severe complication in premature neonates, particularly those with very low birth weight (VLBW) (<1500 g). Whether lactoferrin, a mammalian milk glycoprotein involved in innate immune host defenses, can reduce the incidence of sepsis is unknown. In animal models, the probiotic Lactobacillus rhamnosus GG (LGG) enhances the activity of lactoferrin but has not been studied in human infants. OBJECTIVE: To establish whether bovine lactoferrin (BLF), alone or in combination with LGG, reduces the incidence of late-onset sepsis in VLBW neonates. DESIGN, SETTING, AND PATIENTS: Prospective, multicenter, double-blind, placebo-controlled, randomized trial conducted in 11 Italian tertiary neonatal intensive care units. Patients were 472 VLBW infants enrolled from October 1, 2007, through July 31, 2008, and assessed until discharge for development of sepsis. INTERVENTION: Infants were randomly assigned to receive orally administered BLF (100 mg/d) alone (n = 153), BLF plus LGG (6 x 10(9) colony-forming units/d) (n = 151), or placebo (n = 168) from birth until day 30 of life (day 45 for neonates <1000 g at birth). MAIN OUTCOME MEASURE: First episode of late-onset sepsis, ie, sepsis occurring more than 72 hours after birth with isolation of any pathogen from blood or from peritoneal or cerebrospinal fluid. RESULTS: Demographic, clinical, and management characteristics of the 3 groups were similar, including type of feeding and intake of maternal milk. Incidence of late-onset sepsis was significantly lower in the BLF and BLF plus LGG groups (9/153 [5.9%] and 7/151 [4.6%], respectively) than in the control group receiving placebo (29/168 [17.3%]) (risk ratio, 0.34; 95% confidence interval, 0.17-0.70; P = .002 for BLF vs control and risk ratio, 0.27; 95% confidence interval, 0.12-0.60; P < .001 for BLF plus LGG vs control). The decrease occurred for both bacterial and fungal sepsis. No adverse effects or intolerances to treatment occurred. CONCLUSION: Compared with placebo, BLF supplementation alone or in combination with LGG reduced the incidence of a first episode of late-onset sepsis in VLBW neonates. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN53107700.