Menthacarin, a Proprietary Peppermint Oil and Caraway Oil Combination, Improves Multiple Complaints in Patients with Functional Gastrointestinal Disorders: A Systematic Review and Meta-Analysis.

INTRODUCTION: This systematic review summarizes published data on Menthacarin, the proprietary combination of peppermint oil and caraway oil, in the treatment of functional gastrointestinal disorders. Efficacy was assessed by meta-analysis of placebo-controlled trials. METHODS: We searched PubMed, the Cochrane Library, and the manufacturer's information system for clinical studies investigating the safety and efficacy of Menthacarin. Efficacy analyses included change from baseline of epigastric pain and general improvement of the patients' condition. RESULTS: Five randomized trials involving 580 patients were found, demonstrating significant effects of Menthacarin on symptoms of functional dyspepsia (FD) compared to placebo or similar effects compared to a reference drug. Seven other studies reported favorable results on therapeutic application in FD patients with concomitant Helicobacter pylori infection, in irritable bowel syndrome (IBS), and on tolerability in FD patients from 12 years of age. Three trials in FD with 249 patients were eligible for meta-analysis. Results demonstrate a significant reduction in pain intensity (standardized mean difference: 0.80; 95% confidence interval (CI): 0.39-1.21) and in item 2 of the Clinical Global Impression Scale (risk ratio: 2.65; 95% CI: 1.81-3.87) for Menthacarin. CONCLUSIONS: Menthacarin was shown to be effective and safe for the treatment of FD and represents a promising option for symptoms of IBS.

Faster recovery and reduced paracetamol use - a meta-analysis of EPs 7630 in children with acute respiratory tract infections.

OBJECTIVE: Fever is a very common adaptive immune response in acute respiratory tract disorders during infancy. Antipyretic / analgesic drugs such as paracetamol (acetaminophen) are widely used to improve the comfort of the child but may cause medically unneeded antipyresis and rare but potentially serious side effects. We assess whether treatment with Pelargonium sidoides extract EPs 7630 reduces the administration of paracetamol in children with acute tonsillopharyngitis (ATP) or acute bronchitis (AB). DESIGN: Meta-analysis of randomised, placebo-controlled clinical trials. METHODS: We searched clinical trial registries (ISRCTN, ClinicalTrials.gov ) and medical literature (MEDLINE, EMBASE), for randomised, placebo-controlled trials investigating the administration of EPs 7630 to children with ATP or AB and reporting the co-administration of paracetamol. Based on the individual participant data of the eligible trials, study populations were characterized according to sex and age, and meta-analyses were performed for cumulative paracetamol use and ability to attend school at treatment end. RESULTS: Six trials including a total of 523 children aged 6-10 years (EPs 7630: 265; placebo: 258) and suffering from non-ß-hemolytic streptococcal ATP (3 trials) or from AB (3 trials) were identified and eligible. Children received EPs 7630 or placebo for 6 (ATP) or 7 days (AB). Compared to placebo, EPs 7630 reduced the cumulative dose of paracetamol in 5 out of the 6 trials, by an average of 244 mg (Hedges' g; - 0.28; 95% confidence interval: [- 0.53; - 0.02]; p < 0.03). At treatment end, 30.2% (EPs 7630) and 74.4% (placebo) of the children were still unable to attend school (risk ratio: 0.43; 95% confidence interval: [0.29; 0.65]; p < 0.001). CONCLUSIONS: In children aged 6-10 years with AB or ATP, EPs 7630 alleviated the symptom burden and accelerated recovery. Although EPs 7630 has no known antipyretic effect, concomitant use of paracetamol was reduced.

Antimicrobial efficacy of copper-doped titanium surfaces for dental implants.

The aim of this in vitro study was to quantify the antibacterial effect of a copper-deposited titanium surface as a model for dental implants on the peri-implantitis-associated strain Porphyromonas gingivalis (DSM 20709). A spark-assisted anodization method in a combined deposition-anodization process was applied to deposit copper on discs made of titanium. This method allows the deposition of different concentrations of copper on the surface by varying the process time. Conventional culturing was used to investigate the adhesion of P. gingivalis onto the discs over 2, 4, and 6 h as well as to study the antibacterial effect of copper released in solution. The viability of the bacterial cells is strongly inhibited on copper-deposited discs and reaches a CFU reduction of 3 log-units after 6 h in comparison to the reference. The copper released in solution causes a reduction of 4 log-units after a 6 h incubation time. With a 6 h incubation time, the CFU count decreases with increasing copper concentrations on the disc (by 2% for the 1.3 µg/disc; 32% for the 5.6 µg/disc; and 34% for the 9.5 µg/disc). However, at a higher copper concentration of 17.7 µg/disc, after 6 h, the decrease in the CFU count is less pronounced than that observed in solution, where a further decrease is observed. In conclusion, copper-functionalized titanium significantly reduces the survival of adhered bacteria and decreases the viable bacterial count in the environment surrounding the titanium. Thus, the area surrounding implants is being protected by copper released from the surface, forming a "safe zone" for improved implant healing.

Efficacy and Tolerability of High-dose Pelargonium Extract in Patients With the Common Cold.

Context • The common cold (CC) is usually caused by a viral infection. Antibiotics are often prescribed unnecessarily for it, although no evidence exists for any benefit in the CC. Effective alternatives are needed. Objective • The study intended to evaluate the efficacy of 7630, a proprietary extract of Pelargonium sidoides, the active ingredient in umckaloabo, compared with a placebo for the treatment of the CC. Design • This was a prospective, double-blind, parallel-group, placebo-controlled, phase 3 clinical trial (RCT), with an adaptive group-sequential design with 2 parts, both of which were 2-arm trials. The first used a standard dose (SD) of 3 × 30 drops per day of the active medication and the second used a high dose (HD) of 3 × 60 drops per day of the active medication, against 3 × 30 drops per day and 3 × 60 drops per day of a placebo, respectively. Setting • The study took place in 8 outpatient departments affiliated with hospitals. Participants • For the entire study, 207 adults with predefined cold symptoms that had been present for 24 to 48 h prior were included in the study, with 103 participating in the SD part and 104 participating in the HD part. Intervention • In the HD part, as covered in this article, the intervention group received treatment with 3 × 60 drops per day of the active medication and the control group received a placebo (control group), for a maximum period of 10 d. Outcome Measures • The primary outcome measure was the sum of differences in the cold intensity score (CIS) from day 1 to day 3 and from day 1 to day 5, defined as the sum of the symptom intensity differences (SSID). The criteria for the secondary outcome, efficacy, were (1) diverse response criteria according to the total CIS; (2) changes in individual CIS symptoms; (3) changes in further cold-relevant symptoms; (4) ability to work; (5) activity level; (6) general well-being; (7) health-related quality of life-the EuroQol questionnaire with 5 dimensions (EQ-5D), including the visual analogue scale EQ-VAS; (8) time until onset of treatment effect; (9) treatment outcome; and (10) satisfaction with treatment. Results • From baseline to day 5, the mean CIS decreased by 11.2 ± 4.8 points for the 7630 group and 6.3 ± 4.7 points for the control group. The mean SSID was 16.0 ± 7.6 points for the control group (P < .0001). After 10 d, 90.4% of the group receiving the active medication and 21.2% of the control group were clinically cured (P < .0001). In the treatment group, participants' inability to work was significantly lower, with a mean duration of 6.4 ± 1.6 d vs 8.3 ± 2.1 d for the control group (P < .0001), and treatment outcome-complete recovery or major improvement-was significantly better at day 5 for the active treatment group compared with the control group (P < .0001). Mild-to-moderate adverse events-all nonserious-occurred in 15.4% of those receiving active treatment vs in 5.8% for the control group. Conclusions • The active medication is an effective, well tolerated, and safe treatment for the CC. It significantly reduces the severity of symptoms and shortens the duration of the disease.

LUCAS compared to manual cardiopulmonary resuscitation is more effective during helicopter rescue-a prospective, randomized, cross-over manikin study.

OBJECTIVE: High-quality chest-compressions are of paramount importance for survival and good neurological outcome after cardiac arrest. However, even healthcare professionals have difficulty performing effective chest-compressions, and quality may be further reduced during transport. We compared a mechanical chest-compression device (Lund University Cardiac Assist System [LUCAS]; Jolife, Lund, Sweden) and manual chest-compressions in a simulated cardiopulmonary resuscitation scenario during helicopter rescue. METHODS: Twenty-five advanced life support-certified paramedics were enrolled for this prospective, randomized, crossover study. A modified Resusci Anne manikin was employed. Thirty minutes of training was allotted to both LUCAS and manual cardiopulmonary resuscitation (CPR). Thereafter, every candidate performed the same scenario twice, once with LUCAS and once with manual CPR. The primary outcome measure was the percentage of correct chest-compressions relative to total chest-compressions. RESULTS: LUCAS compared to manual chest-compressions were more frequently correct (99% vs 59%, P < .001) and were more often performed correctly regarding depth (99% vs 79%, P < .001), pressure point (100% vs 79%, P < .001) and pressure release (100% vs 97%, P = .001). Hands-off time was shorter in the LUCAS than in the manual group (46 vs 130 seconds, P < .001). Time until first defibrillation was longer in the LUCAS group (112 vs 49 seconds, P < .001). CONCLUSIONS: During this simulated cardiac arrest scenario in helicopter rescue LUCAS compared to manual chest-compressions increased CPR quality and reduced hands-off time, but prolonged the time interval to the first defibrillation. Further clinical trials are warranted to confirm potential benefits of LUCAS CPR in helicopter rescue.

Effects of EPs 7630 on the duration of inability to work in acute bronchitis - a meta-analysis.

Background: Acute bronchitis (AB) has an enormous economic impact through lost working time. We investigated whether treatment with Pelargonium extract EPs 7630 may reduce the time of inability to work. Methods: A meta-analysis of double-blind, randomized, placebo-controlled trials with adult patients suffering from AB was performed. The average number of days of inability to work and the proportion of patients who were still unable to work after one week's treatment were assessed. Results: Four clinical trials with a total of 1,011 evaluable patients who received the marketed dosage of EPs 7630 (n=505) or placebo (n=506) for seven days were included in the meta-analysis. At baseline, 845/1,011 patients (83.6%) were unable to work. In the four trials, the proportion decreased to between 19 and 14% for EPs 7630 and to between 41 and 55% for placebo (meta-analysis risk ratio and 95% confidence interval: 0.35; 0.26-0.45; p<0.001). For the number of sick days, a weighted mean difference of 1.73 days (1.17-2.29 days; p<0.001) favoring EPs 7630 was observed. Conclusions: For adults suffering from AB, this meta-analysis demonstrates that seven days' treatment with Pelargonium sidoides extract EPs 7630 significantly reduces the average number of sick days and significantly increases the proportion of patients who are able to return to work.

Single and Repeated Doses of EGb 761® do not Affect Pharmacokinetics or Pharmacodynamics of Rivaroxaban in Healthy Subjects.

The present drug-drug interaction study investigates whether single or repeated doses of 240 mg Ginkgo biloba extract EGb 761® alter the pharmacokinetics or pharmacodynamics of rivaroxaban in healthy subjects. This was a single-centre, two-period, fixed-sequence trial. In Period 1, rivaroxaban was taken alone. In Period 2, rivaroxaban was given on the first and last of 8 days of EGb 761® treatment. Plasma concentrations of rivaroxaban and anti-Factor Xa activity were determined until 48 h after each rivaroxaban intake. The data of forty-one healthy subjects (25 males, 16 females) aged 21-70 years were evaluable. Geometric mean ratios (90% confidence intervals) for rivaroxaban administered concomitantly with a single or multiple doses of EGb 761® vs. rivaroxaban administered alone were 97.97 (91.78, 104.58) and 96.78 (90.67, 103.31) for maximum concentration (Cmax), 98.55 (94.43, 102.84) and 97.82 (93.73, 102.08) for area under the concentration-time curve (AUC0-∞) of rivaroxaban in plasma (primary endpoints), 98.19 (92.00, 104.80) and 99.78 (93.43, 106.55) for maximum effect (Emax), 99.46 (93.63, 105.66) and 99.12 (93.25, 105.35) for area under the effect curve (AUEC0-48). All 90% confidence intervals were within the prespecified range of 80%-125%. Neither adverse events related to haemorrhages nor clinically significant findings in haematology or coagulation parameters were observed. The treatments were safe and well-tolerated. Single and repeated doses of EGb 761® neither affect plasma concentrations of rivaroxaban nor anti-Factor Xa activity in healthy subjects.

Effects of Pelargonium sidoides extract EPs 7630 on acute cough and quality of life - a meta-analysis of randomized, placebo-controlled trials.

Background: Cough is a leading symptom of viral acute respiratory infections such as acute bronchitis (AB) and the common cold (CC), which can be debilitating and may persist for several weeks. We investigated whether treatment with Pelargonium extract EPs 7630 may reduce cough and improve disease-related quality of life (QoL). Methods: We performed a meta-analysis of randomized, placebo-controlled trials investigating the efficacy of EPs 7630 in AB or CC. Efficacy analyses included change from baseline in a cough intensity score, remission of cough, and disease-associated impairments of QoL. Results: Data of 2,195 participants from 11 trials (3 in children/adolescents with AB, 3 in adults with AB, 5 in adults with CC) were eligible. In children/adolescents with AB, 79.6% of participants treated with EPs 7630 and 41% treated with placebo showed a reduction in the intensity of cough by at least 50% of baseline values at day 7 [meta-analysis rate/risk ratio (RR), EPs 7630 / placebo: 1.86 (95% CI: 1.34; 2.95)], and 18.0% vs 5.5% presented with complete remission of cough [RR: 2.91 (95% CI: 1.26; 6.72)]. In adults with AB, 88.7% of participants in the EPs 7630 group and 47.6% in the placebo group showed a ≥50% response for cough intensity [RR: 2.13 (95% CI: 1.37; 3.31)], while 26.0% vs 6.3% did not cough any more at day 7 [RR: 5.00 [95% CI: 3.10; 8.07)]. Cough scale results were supported by significant improvements over placebo in the pursuit of normal daily activities and other QoL measures. In CC, 56.8% of participants treated with EPs 7630 and 38.8% treated with placebo showed a ≥50% cough intensity reduction [RR: 1.40 (95% CI: 1.19; 1.65)] at day 5, while 26.1% versus 18.4% showed complete remission of cough for EPs 7630 and placebo, respectively [RR: 1.40 (95% CI: 1.06; 1.84)]. CCassociated pain/discomfort and impairment of usual activities were no longer present in 41.5% and 48.8% of participants treated with EPs 7630 compared to less than 40% of patients in the placebo group. Conclusions: The results show that EPs 7630 reduces the burden and leads to earlier remission of cough. Advantages for EPs 7630 were also reflected in self-rated measures of disease-associated QoL. Of note, patients treated with the herbal product felt able to resume their usual daily activities sooner.

Diploid hepatocytes drive physiological liver renewal in adult humans.

Physiological liver cell replacement is central to maintaining the organ's high metabolic activity, although its characteristics are difficult to study in humans. Using retrospective radiocarbon (14C) birth dating of cells, we report that human hepatocytes show continuous and lifelong turnover, allowing the liver to remain a young organ (average age <3 years). Hepatocyte renewal is highly dependent on the ploidy level. Diploid hepatocytes show more than 7-fold higher annual birth rates than polyploid hepatocytes. These observations support the view that physiological liver cell renewal in humans is mainly dependent on diploid hepatocytes, whereas polyploid cells are compromised in their ability to divide. Moreover, cellular transitions between diploid and polyploid hepatocytes are limited under homeostatic conditions. With these findings, we present an integrated model of homeostatic liver cell generation in humans that provides fundamental insights into liver cell turnover dynamics.

In Vivo and In Vitro Characterization of Primary Human Liver Macrophages and Their Inflammatory State.

Liver macrophages (LMs) play a central role in acute and chronic liver pathologies. Investigation of these processes in humans as well as the development of diagnostic tools and new therapeutic strategies require in vitro models that closely resemble the in vivo situation. In our study, we sought to gain further insight into the role of LMs in different liver pathologies and into their characteristics after isolation from liver tissue. For this purpose, LMs were characterized in human liver tissue sections using immunohistochemistry and bioinformatic image analysis. Isolated cells were characterized in suspension using FACS analyses and in culture using immunofluorescence staining and laser scanning microscopy as well as functional assays. The majority of our investigated liver tissues were characterized by anti-inflammatory LMs which showed a homogeneous distribution and increased cell numbers in correlation with chronic liver injuries. In contrast, pro-inflammatory LMs appeared as temporary and locally restricted reactions. Detailed characterization of isolated macrophages revealed a complex disease dependent pattern of LMs consisting of pro- and anti-inflammatory macrophages of different origins, regulatory macrophages and monocytes. Our study showed that in most cases the macrophage pattern can be transferred in adherent cultures. The observed exceptions were restricted to LMs with pro-inflammatory characteristics.

Point-of-care determination of neonatal bilirubin with the blood gas analyzer RapidLab 1265.

BACKGROUND: The aim of the study was to evaluate the comparability of the new neonatal bilirubin method on the RapidLab 1265 blood gas analyzer. This point-of-care testing (POCT) device has the option for the determination of neonatal bilirubin, making it potentially valuable for use in neonate intensive care units or in outpatient ambulances. METHODS: We paired 240 patient samples for intermethod comparisons between the new POCT method and the routine laboratory method (Vitros 350 chemistry system with BuBc slide). In parallel, a transcutaneous jaundice meter (JM-103) was applied to the newborns. Low birthweight and premature neonates were excluded from the trial. The turn-around-time (TAT) for the POCT method was also compared with the routine method, and the practicality of the new analyzer was evaluated for clinical purposes. RESULTS: Bilirubin measurements using the RapidLab 1265 are suitable for the application in newborns. For imprecision, coefficients of variation between 5.6% and 23% were found. The correlation between the Vitros 350 (x) and RapidLab 1265 (y) was y=1.0x-0.1 (r=0.91), with a mean bias of +0.1 mg/dL and a 95% limit of agreement of ±2.5 mg/dL. As in all POCT methods, the TAT was significantly lower than that of the core laboratory. CONCLUSIONS: In contrast to the JM-103, the results of the RapidLab 1265 correlated closely with the Vitros 350, although occasional results of both methods were more different than expected. In general, the RapidLab 1265 blood gas analyzer provides clinically useful bilirubin results using neonatal whole blood samples, although imprecision data are higher than for the laboratory method. The POCT device is suitable for neonatal intensive care units after thoroughly training the employees that will use the device.

Treatment of signs and symptoms of the common cold using EPs 7630 - results of a meta-analysis.

The efficacy of Pelargonium sidoides preparation EPs 7630 in the common cold (CC) was assessed by performing meta-analyses of randomized, double-blind, placebo-controlled trials. Mean differences (MD) and risk ratios (RR) with their 95% confidence intervals (CI) were computed. Five trials with a total of 833 patients were included. All trials had a treatment period of ten days with visits at days 3, 5, and 10 after baseline and used a ten-symptom Cold Intensity Score (CIS) as the primary outcome. Significant differences favoring EPs 7630 were observed for total CIS reduction (day 5: MD = -2·30; 95%CI = -4·12,-0·49; day 10: MD = -1·16; 95%CI = -2·22,-0·10), proportion of patients with substantial improvement (day 5: RR = 1·73; day 10: RR = 1·06) and complete remission (day 5: RR = 2·52; day 10: RR = 2·13). Subjects treated with EPs 7630 missed fewer days at work, used less paracetamol and had an improved sleep quality. No serious adverse reactions to EPs 7630 were reported. The results support the efficacy of EPs 7630 in adults with CC.

Effect of glucose and insulin supplementation on the isolation of primary human hepatocytes.

Primary human hepatocytes (PHHs) remain the gold standard for in vitro investigations of xenobiotic metabolism and hepatotoxicity. However, scarcity of liver tissue and novel developments in liver surgery has limited the availability and quality of tissue samples. In particular, warm ischemia shifts the intracellular metabolism from aerobic to anaerobic conditions, which increases glycogenolysis, glucose depletion and energy deficiency. Therefore, the aim of the present study was to investigate whether supplementation with glucose and insulin during PHH isolation could reconstitute intracellular glycogen storage and beneficially affect viability and functionality. Furthermore, the study elucidated whether the susceptibility of the tissue's energy status correlates with body mass index (BMI). PHHs from 12 donors were isolated from human liver tissue obtained from partial liver resections using a two-step EDTA/collagenase perfusion technique. For a direct comparison of the influence of glucose/insulin supplementation, we modified the setup, enabling the parallel isolation of two pieces of one tissue sample with varying perfusate. Independent of the BMI of the patient, the glycogen content in liver tissue was notably low in the majority of samples. Furthermore, supplementation with glucose and insulin had no beneficial effect on the glycogen concentration of isolated PHHs. However, an indirect improvement of the availability of energy was shown by increased viability, plating efficiency and partial cellular activity after supplementation. The plating efficiency showed a striking inverse correlation with increasing lipid content of PHHs. However, 60 h of cultivation time revealed no significant impact on the maintenance of albumin and urea synthesis or xenobiotic metabolism after supplementation. In conclusion, surgical procedures and tissue handling may decrease hepatic energy resources and lead to cell stress and death. Consequently, PHHs with low energy resources die during the isolation process without supplementation of glucose/insulin or early cell culture, while their survival rates are improved with glucose/insulin supplementation.

EPs 7630 is effective and safe in children under 6 years with acute respiratory tract infections: clinical studies revisited.

OBJECTIVE: Pelargonium sidoides preparation EPs 7630 has been proven safe and effective in acute respiratory tract infections (aRTIs), but data for young children have not been presented separately. This study reviewed clinical studies and presents an overview of known and newly analyzed data from children <6 years. METHODS: MEDLINE and EMBASE were searched for interventional and non-interventional studies which investigated the effects of EPs 7630 in aRTIs and included children <6 years of age. Sub-group analyses for this age range were performed for symptom scales, global efficacy or effectiveness assessments, and safety outcomes. RESULTS: Seven studies with 1067 children <6 years exposed to EPs 7630 were identified. Efficacy of EPs 7630 was significantly superior to placebo in reducing symptom intensity and time until complete recovery in two randomized, double-blind trials in patients with acute bronchitis (AB). Similar symptom time courses were observed in two non-comparative observational studies in AB. One non-comparative, open-label study was identified in acute tonsillopharyngitis (ATP), and one in acute rhinosinusitis (ARS). In both indications, nearly all children showed complete recovery or major symptom improvements during the treatment period, with changes that were similar to those observed in controlled trials investigating older patient populations. The results were supported by an additional observational study including children with various diagnoses of aRTIs. EPs 7630 was safe and well-tolerated. CONCLUSIONS: EPs 7630 is efficacious in children <6 years suffering from AB. The analyses also support the effectiveness of the product in ATP and in ARS. No safety concerns were identified.

Influence of PCO2 Control on Clinical and Neurodevelopmental Outcomes of Extremely Low Birth Weight Infants.

BACKGROUND: Levels or fluctuations in the partial pressure of CO2 (PCO2) may affect outcomes for extremely low birth weight infants. OBJECTIVES: In an exploratory analysis of a randomized trial, we hypothesized that the PCO2 values achieved could be related to significant outcomes. METHODS: On each treatment day, infants were divided into 4 groups: relative hypocapnia, normocapnia, hypercapnia, or fluctuating PCO2. Ultimate assignment to a group for the purpose of this analysis was made according to the group in which an infant spent the most days. Statistical analyses were performed with analysis of variance (ANOVA), the Kruskal-Wallis test, the χ2 test, and the Fisher exact test as well as by multiple logistic regression. RESULTS: Of the 359 infants, 57 were classified as hypocapnic, 230 as normocapnic, 70 as hypercapnic, and 2 as fluctuating PCO2. Hypercapnic infants had a higher average product of mean airway pressure and fraction of inspired oxygen (MAP × FiO2). For this group, mortality was higher, as was the likelihood of having moderate/severe bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), and poorer neurodevelopment. Multiple logistic regression analyses showed an increased risk for BPD or death associated with birth weight (p < 0.001) and MAP × FiO2 (p < 0.01). The incidence of adverse neurodevelopment was associated with birth weight (p < 0.001) and intraventricular hemorrhage (IVH; p < 0.01). CONCLUSIONS: Birth weight and respiratory morbidity, as measured by MAP × FiO2, were the most predictive of death or BPD and NEC, whereas poor neurodevelopmental outcome was associated with low birth weight and IVH. Univariate models also identified PCO2. Thus, hypercapnia seems to reflect greater disease severity, a likely contributor to differences in outcomes.

Neurodevelopmental outcomes of extremely low birthweight infants randomised to different PCO2 targets: the PHELBI follow-up study.

BACKGROUND: Tolerating higher partial pressures of carbon dioxide (PCO2) in mechanically ventilated extremely low birthweight infants to reduce ventilator-induced lung injury may have long-term neurodevelopmental side effects. This study analyses the results of neurodevelopmental follow-up of infants enrolled in a randomised multicentre trial. METHODS: Infants (n=359) between 400 and 1000 g birth weight and 23 0/7-28 6/7 weeks gestational age who required endotracheal intubation and mechanical ventilation within 24 hours of birth were randomly assigned to high PCO2 or to a control group with mildly elevated PCO2 targets. Neurodevelopmental follow-up examinations were available for 85% of enrolled infants using the Bayley Scales of Infant Development II, the Gross Motor Function Classification System (GMFCS) and the Child Development Inventory (CDI). RESULTS: There were no differences in body weight, length and head circumference between the two PCO2 target groups. Median Mental Developmental Index (MDI) values were 82 (60-96, high target) and 84 (58-96, p=0.79). Psychomotor Developmental Index (PDI) values were 84 (57-100) and 84 (65-96, p=0.73), respectively. Moreover, there was no difference in the number of infants with MDI or PDI <70 or <85 and the number of infants with a combined outcome of death or MDI<70 and death or PDI<70. No differences were found between results for GMFCS and CDI. The risk factors for MDI<70 or PDI<70 were intracranial haemorrhage, bronchopulmonary dysplasia, periventricular leukomalacia, necrotising enterocolitis and hydrocortisone treatment. CONCLUSIONS: A higher PCO2 target did not influence neurodevelopmental outcomes in mechanically ventilated extremely preterm infants. Adjusting PCO2 targets to optimise short-term outcomes is a safe option. TRIAL REGISTRATION NUMBER: ISRCTN56143743.

Permissive hypercapnia in extremely low birthweight infants (PHELBI): a randomised controlled multicentre trial.

BACKGROUND: Tolerating higher partial pressure of carbon dioxide (pCO2) in mechanically ventilated, extremely low birthweight infants might reduce ventilator-induced lung injury and bronchopulmonary dysplasia. We aimed to test the hypothesis that higher target ranges for pCO2 decrease the rate of bronchopulmonary dysplasia or death. METHODS: In this randomised multicentre trial, we recruited infants from 16 tertiary care perinatal centres in Germany with birthweight between 400 g and 1000 g and gestational age 23-28 weeks plus 6 days, who needed endotracheal intubation and mechanical ventilation within 24 h of birth. Infants were randomly assigned to either a high target or control group. The high target group aimed at pCO2 values of 55-65 mm Hg on postnatal days 1-3, 60-70 mm Hg on days 4-6, and 65-75 mm Hg on days 7-14, and the control target at pCO2 40-50 mmHg on days 1-3, 45-55 mm Hg on days 4-6, and 50-60 mm Hg on days 7-14. The primary outcome was death or moderate to severe bronchopulmonary dysplasia, defined as need for mechanical pressure support or supplemental oxygen at 36 weeks postmenstrual age. Cranial ultrasonograms were assessed centrally by a masked paediatric radiologist. This trial is registered with the ISRCTN registry, number ISRCTN56143743. RESULTS: Between March 1, 2008, and July 31, 2012, we recruited 362 patients of whom three dropped out, leaving 179 patients in the high target and 180 in the control group. The trial was stopped after an interim analysis (n=359). The rate of bronchopulmonary dysplasia or death in the high target group (65/179 [36%]) did not differ significantly from the control group (54/180 [30%]; p=0·18). Mortality was 25 (14%) in the high target group and 19 (11%; p=0·32) in the control group, grade 3-4 intraventricular haemorrhage was 26 (15%) and 21 (12%; p=0·30), and the rate of severe retinopathy recorded was 20 (11%) and 26 (14%; p=0·36). INTERPRETATION: Targeting a higher pCO2 did not decrease the rate of bronchopulmonary dysplasia or death in ventilated preterm infants. The rates of mortality, intraventricular haemorrhage, and retinopathy did not differ between groups. These results suggest that higher pCO2 targets than in the slightly hypercapnic control group do not confer increased benefits such as lung protection. FUNDING: Deutsche Forschungsgemeinschaft.

Effects of chlorin-mediated photodynamic therapy combined with fluoropyrimidines in vitro and in a patient.

Although photodynamic therapy (PDT) is becoming an additional cancer therapy, only little is known about its interactions with other drugs and treatment modalities in vitro and in vivo. We investigated the combination of 5-fluoro-2'-deoxyuridine (5FdUr), a chemotherapeutic drug, with 5,10,15,20-tetra( m-hydroxyphenyl)chlorin (mTHPC), a potent photosensitizer. Two cell lines, MCF-7 and LNCaP, were either simultaneously or consecutively incubated with both drugs and irradiated with laser light to activate mTHPC, and cell survival was determined. The combination of the two treatments was additive or antagonistic in LNCaP cells but additive or synergistic in MCF-7 cells depending on the protocol and concentration of 5FdUr. In one patient with multiple basal cell carcinoma, the effect of the combination of 5-fluorouracil administration followed by PDT resulted in significantly stronger effects than expected, leading to severe oedema, redness and ulceration. The healing process was delayed by 2 months compared to PDT alone. It is therefore important to find optimal conditions under which PDT and chemotherapy combinations do not fall outside the therapeutic window.

Prolongation of pregnancy following eclampsia.

Eclampsia is a serious complication of preeclampsia with high maternal and perinatal mortality and morbidity rates. The recommended management is induction of labour when convulsions are controlled and the women's condition is stabilised. Here, we report about stabilisation after eclampsia followed by prolongation of a preterm pregnancy for 11 days within early gestational weeks.

Effect of reducing the n-6:n-3 long-chain PUFA ratio during pregnancy and lactation on infant adipose tissue growth within the first year of life: an open-label randomized controlled trial.

BACKGROUND: The composition of long-chain PUFAs (LCPUFAs) in the maternal diet may affect obesity risk in the mother's offspring. OBJECTIVE: We hypothesized that a reduction in the n-6 (omega-6):n-3 (omega-3) LCPUFA ratio in the diet of pregnant women and breastfeeding mothers may prevent expansive adipose tissue growth in their infants during the first year of life. DESIGN: In a randomized controlled trial, 208 healthy pregnant women were randomly assigned to an intervention (1200 mg n-3 LCPUFAs as a supplement per day and a concomitant reduction in arachidonic acid intake) or a control diet from the 15th wk of pregnancy to 4 mo of lactation. The primary outcome was infant fat mass estimated by skinfold thickness (SFT) measurements at 4 body sites at 3-5 d, 6 wk, and 4 and 12 mo postpartum. Secondary endpoints included sonographic assessment of abdominal subcutaneous and preperitoneal fat, fat distribution, and child growth. RESULTS: Infants did not differ in the sum of their 4 SFTs at ≤1 y of life [intervention: 24.1 ± 4.4 mm (n = 85); control: 24.1 ± 4.1 mm (n = 80); mean difference: -0.0 mm (95% CI: -1.3, 1.3 mm)] or in growth. Likewise, longitudinal ultrasonography showed no significant differences in abdominal fat mass or fat distribution. CONCLUSIONS: We showed no evidence that supplementation with n-3 fatty acids and instructions to reduce arachidonic acid intake during pregnancy and lactation relevantly affects fat mass in offspring during the first year of life. Prospective long-term studies are needed to explore the efficacy of this dietary approach for primary prevention. This trial was registered at clinicaltrials.gov as NCT00362089.