Ultrashort pulse written fiber Bragg gratings as narrowband filters in multicore fibers.

We present the inscription of narrow-linewidth fiber Bragg gratings (FBGs) into different types of multicore fibers (MCFs) using ultrashort laser pulses and the phase mask technique, which can act as notch filters. Such filters are required, e.g., to suppress light emitted by hydroxyl in the Earth's upper atmosphere, which disturbs ground-based observation of extraterrestrial objects in the near infrared. However, the inscription into a commercially available seven-core fiber showed a quite large core-to-core deviation of the resonance wavelength of up to 0.45 nm. Two options are presented to overcome this: first, we present the photo-treatment of the FBGs to tune the resonance wavelength, which allows for sufficient resonance shifts. Second, adapted MCFs containing 12 cores, arranged on a circle, are fabricated. For this, two different fabrication procedures were investigated, namely, the mechanical drilling of the preform for a rod-in-tube version as well as a stack-and-draw approach. Both adapted MCFs yielded significant improvements with core-to-core wavelength variations of the FBGs of only about 0.18 nm and 0.11 nm, respectively, sufficient to fulfill the requirements for astronomical filter applications as discussed above.

Femtosecond inscription of semi-aperiodic multi-notch fiber Bragg gratings using a phase mask.

We present an innovative concept of a semi-aperiodic phase mask design that enables the realization of multi-notch fiber Bragg gratings (FBG). This design utilizes the overlap and interference of near-infrared ultrashort laser pulses diffracted by short sequenced phase mask sections, which not only allows for a highly stable and reproducible inscription of a large number of wavelength filters but also paves the way towards full aperiodic phase masks. The semi-aperiodic FBG inscribed by this phase mask enables versatile notch filters showing multiple non-equidistant resonances. Those filters target applications, for instance in ground-based telescopes, where a large number of hydroxyl emission lines emitted in the upper atmosphere at near-infrared wavelengths restrict the observation of faint extraterrestrial objects.

Population pharmacokinetics of ϵ-aminocaproic acid in adolescents undergoing posterior spinal fusion surgery.

BACKGROUND: Despite demonstrated efficacy of ϵ-aminocaproic acid (EACA) in reducing blood loss in adolescents undergoing spinal fusion, there are no population-specific pharmacokinetic data to guide dosing. The aim of this study was to determine the pharmacokinetics of EACA in adolescents undergoing spinal fusion surgery and make dosing recommendations. METHODS: Twenty children ages 12-17 years were enrolled, with 10 children in each of two groups based on diagnosis (idiopathic scoliosis or non-idiopathic scoliosis). Previously reported data from infants undergoing craniofacial surgery were included in the model to enable dosing recommendations over a wide range of weights, ages, and diagnoses. A population non-linear mixed effects modelling approach was used to characterize EACA pharmacokinetics. RESULTS: Population pharmacokinetic parameters were estimated using a two-compartment disposition model with allometrically scaled weight and an age effect on clearance. Pharmacokinetic parameters for the typical patient were a plasma clearance of 153 ml min(-1) 70 kg(-1) (6.32 ml min(-1) kg(-0.75)), intercompartmental clearance of 200 ml min(-1) 70 kg(-1) (8.26 ml min(-1) kg(-0.75)), central volume of distribution of 8.78 litre 70 kg(-1) (0.13 litre kg(-1)), and peripheral volume of distribution of 15.8 litre 70 kg(-1) (0.23 litre kg(-1)). Scoliosis aetiology did not have a clinically significant effect on drug pharmacokinetics. CONCLUSIONS: The following dosing schemes are recommended according to patient weight: weight <25 kg, 100 mg kg(-1) loading dose and 40 mg kg(-1) h(-1) infusion; weight ≤25 kg-<50 kg, 100 mg kg(-1) loading dose and 35 mg kg(-1) h(-1) infusion; and weight ≥50 kg, 100 mg kg(-1) loading dose and 30 mg kg(-1) h(-1) infusion. An efficacy trial employing this dosing strategy is warranted. CLINICAL TRIAL REGISTRATION: NCT01408823.

Population pharmacokinetics of epsilon-aminocaproic acid in infants undergoing craniofacial reconstruction surgery.

BACKGROUND: Understanding the clinical pharmacology of the antifibrinolytic epsilon-aminocaproic acid (EACA) is necessary for rational drug administration in children. The aim of this study is to determine the pharmacokinetics (PKs) of EACA in infants aged 6-24 months undergoing craniofacial reconstruction surgery. METHODS: Cohorts of six infants were enrolled sequentially to one of the three escalating loading dose-continuous i.v. infusion (CIVI) regimens: 25 mg kg(-1), 10 mg kg(-1) h(-1); 50 mg kg(-1), 20 mg kg(-1) h(-1); 100 mg kg(-1), 40 mg kg(-1) h(-1). Plasma EACA concentrations were determined using a validated high-performance liquid chromatography-tandem mass spectrometry assay. A population non-linear mixed effects modelling approach was used to characterize EACA PKs. RESULTS: Population PK parameters of EACA were estimated using a two-compartment disposition model with weight expressed as an allometric covariate and an age effect. The typical patient in this study had an age of 38.71 weeks and a weight of 8.82 kg. PK parameters for this typical patient were: pre-/postoperative plasma drug clearance of 32 ml min(-1) (3.6 ml kg(-1) min(-1)), inter-compartmental clearance of 42.4 ml min(-1) (4.8 ml min(-1) kg(-1)), central volume of distribution of 1.27 litre (0.14 litre kg(-1)), and peripheral volume of distribution of 2.53 litre (0.29 litre kg(-1)). Intra-operative clearance and central volume of distribution were 89% and 80% of the pre-/postoperative value, respectively. CONCLUSIONS: EACA clearance increased with weight and age. The dependence of clearance on body weight supports weight-based dosing. Based on this study, a loading dose of 100 mg kg(-1) followed by a CIVI of 40 mg kg(-1) h(-1) is appropriate to maintain target plasma EACA concentrations in children aged 6-24 months undergoing these procedures.

Prospective randomized observer-blinded study comparing the analgesic efficacy of ultrasound-guided rectus sheath block and local anaesthetic infiltration for umbilical hernia repair.

BACKGROUND: Umbilical hernia repair, a common day-surgery procedure in children, is associated with considerable postoperative discomfort. Possible modes of postoperative analgesia for umbilical hernia repair are rectus sheath block (RSB) and local anaesthetic infiltration of the surgical site (LAI). METHODS: We undertook an observer-blinded, randomized, prospective, observational study to compare the efficacy of ultrasound-guided RSB and LAI in providing postoperative analgesia for umbilical hernia repair. Our primary objective was to compare the use of opioid medication between patients who receive RSB and those who receive LAI. Our secondary objectives were to compare the duration of analgesia based on time to first rescue analgesic, to compare the quality of analgesia based on revised FACES scale, and to determine the incidence of side-effects. RESULTS: Fifty-two patients (26 in each group) completed the study. There was a statistically significant difference in the perioperative opioid medication consumption between the LAI group [mean: 0.13 mg kg(-1), confidence interval (0.09-0.17 mg kg⁻¹)] and the RSB group [mean: 0.07 mg kg⁻¹, confidence interval (0.05-0.09 mg kg⁻¹)] (P=0.008). When we compared the postoperative opioid consumption between the LAI group [mean: 0.1 mg kg⁻¹, 95% confidence interval (0.07-0.13 mg kg⁻¹)] and the RSB group [mean: 0.07 mg kg(-1), 95% confidence interval (0.05-0.09 mg kg⁻¹)] (P=0.09), there was a trend towards statistical significance between the two groups. The difference in time to rescue analgesic administration between the RSB group [49.7 (36.9) min] and the LAI group [32.4 (29.4) min] was not statistically significant (P=0.11). CONCLUSIONS: This study demonstrates that ultrasound-guided RSB provides superior analgesia in the perioperative period compared with infiltration of the surgical site after umbilical hernia repair. In comparing only the postoperative period, analgesia provided by an ultrasound-guided RSB showed a trend towards statistically significant improvement compared with infiltration of the surgical site.

Loss of RAF kinase inhibitor protein is a somatic event in the pathogenesis of therapy-related acute myeloid leukemias with C-RAF germline mutations.

We recently described oncogenic and anti-apoptotic C-RAF germline mutations in patients with therapy-related acute myeloid leukemia (t-AML). Activation of the RAF effector ERK was restricted to transformed cells, suggesting the requirement for cooperating events in leukemogenesis. Western blot analysis of blast cells from patients with C-RAF germline mutations revealed loss of the tumor and metastasis suppressor RAF kinase inhibitor protein (RKIP). Immunohistochemistry of the patients' primary tumors revealed normal RKIP expression levels, indicating that the loss of RKIP is a somatic, t-AML-specific event. In focus formation assays, the oncogenic potential of human mutant C-RAF was strongly influenced by expression levels of RKIP. Although the number of colonies formed by C-RAF(S427G) was significantly increased by RKIP silencing, the opposite was observed after RKIP overexpression. These results show that the loss of RKIP is a functional somatic event in carriers of C-RAF germline mutations, which contributes to the development of t-AML.

Identification of the amino-acetonitrile derivative monepantel (AAD 1566) as a new anthelmintic drug development candidate.

Anthelmintic resistance has become a global phenomenon in gastro-intestinal nematodes of farm animals, including multi-drug resistance against the three major classes of anthelmintics. There is an urgent need for an anthelmintic with a new mode of action. The recently discovered amino-acetonitrile derivatives (AADs) offer a new class of synthetic chemicals with anthelmintic activity. The evaluation of AADs was pursued applying in vitro assays and efficacy and tolerability studies in rodents, sheep, and cattle. Amongst various suitable compounds, AAD 1566 eliminated many tested pathogenic nematode species, both at larval and adult stages, at a dose of 2.5 mg/kg bodyweight in sheep and 5.0 mg/kg bodyweight in cattle. The same doses were sufficient to cure animals infected with resistant or multi-drug-resistant nematode isolates. These findings, complemented by the good tolerability and low toxicity to mammals, suggest that AAD 1566, monepantel, would be a suitable anthelmintic drug development candidate.

Inhibition of hypusine biosynthesis in plasmodium: a possible, new strategy in prevention and therapy of malaria.

The increasing drug resistance of malaria parasites against chemotherapeutics enforces new strategies in finding new drugs. Here, we describe a new class of compounds the piperidone 3-carboxylates which show an antiplasmodial effect in vitro and in vivo. This effect might be caused by inhibition of eukaryotic initiation factor (eIF-5A).

Severe congenital myasthenic syndrome due to homozygosity of the 1293insG epsilon-acetylcholine receptor subunit mutation.

Recently, a congenital myasthenic syndrome (CMS) with end-plate acetylcholine receptor (AChR) deficiency due to missense mutations in the genes for the AChR subunit was described. The first observed patient with this CMS was heteroallelic for the two epsilon-AChR subunit mutations epsilon1101insT and epsilon1293insG. This patient had only a moderate phenotype with mild muscle weakness and abnormal fatigue. We have now found homozygosity for the epsilon1293insG mutation in a severely affected CMS patient, who lost the ability to walk in midchildhood and shows profound weakness and muscle wasting. Our observation allows a genotype-phenotype correlation illustrating how differences in the AChR mutation haplotype can profoundly influence disease severity.

The colonization of beringia and the peopling of the new world.

The colonization of Beringia appears closely linked to the arrival of the oldest firmly documented archeological tradition in mid-latitude North America (Paleoindian). The discovery of a Paleoindian complex in central Alaska, combined with the recent redating of the Bering Land Bridge and key archeological sites, suggests that Beringia was settled during the final Pleistocene interstadial (12,000 to 11,000 years before present). Its population expanded rapidly into other parts of the New World. Beringia probably was colonized in response to changes in climate and vegetation that occurred during this interstadial. Access to the Americas was controlled by Beringian environments and not by changing sea levels or continental ice masses.

[Dyslipoproteinemia and diabetes mellitus in a metabolic syndrome]. / Dyslipoproteinämie und Diabetes mellitus beim metabolischen Syndrom.

AIMS: Presentation of important aspects of the metabolic syndrome, taking diabetes mellitus and the metabolic status in advanced age as an example. MAIN TOPICS: The metabolic syndrome represents a combination of diabetes mellitus, dyslipoproteinemia, adiposity, hypertension, and hyperuricemia, together with the sequelae of atherosclerosis, fatty liver and gallstones. In industrialized countries it is considered the most common metabolic sequela of affluence. Owing to the complexity of the disorders presenting, treatment must not be limited to normalization of glucose metabolism. In addition to dietetic and physiotherapeutic measures and anti-diabetic agents, treatment with lipid-lowering agents is also necessary. Since a main feature of disordered lipid metabolism, is hypertriglyceridemia, fibrates in particular are indicated. These lower not only the triglycerides, but also elevated fibrinogen levels, and, in the case of fenofibrate, uric acid levels. Glucose tolerance remains unaffected.

Intraoperative versus routine hemodialysis in end-stage renal disease patients undergoing open-heart surgery.

Of 13 chronic hemodialysis end-stage renal disease (ESRD) patients undergoing open-heart surgery, 7 received intraoperative hemodialysis (IHD) during cardiopulmonary bypass and 6 received hemodialysis on a routine basis (RHD). Within the groups, IHD patients had significantly lower post-operative mean serum potassium and mean plasma creatinine concentrations compared to mean preoperative values. Postoperative mean BUN tended to decrease and mean serum bicarbonate concentration was unchanged as compared to mean preoperative values. In the RHD group, however, post-operative mean serum potassium concentration tended to increase, mean serum bicarbonate concentration significantly declined and mean BUN was unchanged as compared to mean preoperative values. An average of 2.1 +/- 0.5 liters of fluid was removed from the IHD patients during cardiopulmonary bypass. Post-operatively, 0 of 7 IHD patients versus 4 of 6 RHD patients required parenteral sodium bicarbonate therapy (chi 2, p less than 0.01). On average, RHD patients required hemodialysis 1 day after surgery, whereas IHD patients were hemodialyzed 2 days after surgery (p = 0.009). We conclude that IHD lessened postoperative hyperkalemia and metabolic acidosis and delayed postoperative hemodialysis by an additional day. IHD should be considered as an adjunct to RHD therapy in the management of ESRD patients undergoing open-heart surgery.

A copy-number mutant of plasmid pSC101.

Copy-number mutants of plasmid pSC101 were isolated by u.v. mutagenesis and selection for elevated expression of ampicillin resistance. Three independent mutations were identical and mapped in codon 93 of the initiation protein RepA. The mutated plasmids were maintained at a level four to five times higher than that of the wild type. For one of them, it was determined that: (i) the mRNA of the autoregulated repA gene, cloned onto a pUC19 plasmid under the control of its own promoter, was expressed at a level 1.7 times higher than that of the wild type; (ii) the RepA protein, under the same conditions, was expressed at a similarly higher level; (iii) the affinity of the mutated protein for three repeated sequences in the origin region of the plasmid was, on average, 3.4 times higher than that of the wild-type protein. We postulate that the copy-number effect is due to a combination of these two effects, i.e. higher protein concentration and increased affinity of the protein for the repeated sequences.

Analysis of a copy number mutant of plasmid pSC101: co-maintenance of wild type and mutant plasmids.

We have isolated a high copy number mutant of plasmid pSC101 which is maintained at a level 4 times higher than that of the wild type. The mutation is a single base change that maps in codon 93 of the initiation protein RepA. We find that the mutation relaxes the autoregulation of the protein but increases its affinity for the repeated sequences in the origin. The wild type and the mutant repA genes are co-dominant and the mutated protein acts in trans even in the presence of the wild type protein. Co-maintenance of the two types of plasmids results in an intermediate copy number. Computer simulation indicates that simple models can explain the behaviour of the two plasmids.

The par region of pSC101 affects plasmid copy number as well as stability.

The par locus is a segment of pSC101 that has been identified as a cis-acting determinant of plasmid stability. We show that par also determines copy number and must, therefore, play a role in plasmid replication. The segregation defect, but not the copy-number reduction, of par- replication origins is completely suppressed by a short sequence from the bacteriophage lambda gene O which is present in plasmid pKO-4. Thus, replication and segregation functions are separable from each other.