Precision Mass Measurements of Neutron-Rich Neodymium and Samarium Isotopes and Their Role in Understanding Rare-Earth Peak Formation.

The Canadian Penning Trap mass spectrometer at the Californium Rare Isotope Breeder Upgrade (CARIBU) facility was used to measure the masses of eight neutron-rich isotopes of Nd and Sm. These measurements are the first to push into the region of nuclear masses relevant to the formation of the rare-earth abundance peak at A∼165 by the rapid neutron-capture process. We compare our results with theoretical predictions obtained from "reverse engineering" the mass surface that best reproduces the observed solar abundances in this region through a Markov chain Monte Carlo technique. Our measured masses are consistent with the reverse-engineering predictions for a neutron star merger wind scenario.

Determining the rp-process flow through 56Ni: resonances in 57Cu(p,γ)58Zn identified with GRETINA.

An approach is presented to experimentally constrain previously unreachable (p, γ) reaction rates on nuclei far from stability in the astrophysical rp process. Energies of all critical resonances in the (57)Cu(p,γ)(58)Zn reaction are deduced by populating states in (58)Zn with a (d, n) reaction in inverse kinematics at 75 MeV/u, and detecting γ-ray-recoil coincidences with the state-of-the-art γ-ray tracking array GRETINA and the S800 spectrograph at the National Superconducting Cyclotron Laboratory. The results reduce the uncertainty in the (57)Cu(p,γ) reaction rate by several orders of magnitude. The effective lifetime of (56)Ni, an important waiting point in the rp process in x-ray bursts, can now be determined entirely from experimentally constrained reaction rates.

IGF2 is parentally imprinted during human embryogenesis and in the Beckwith-Wiedemann syndrome.

The phenomenon of parental imprinting involves the preferential expression of one parental allele of a subset of chromosomal genes and has so far only been documented in the mouse. We show here, by exploiting sequence polymorphisms in exon nine of the human insulin-like growth factor 2 (IGF2) gene, that only the paternally-inherited allele is active in embryonic and extra-embryonic cells from first trimester pregnancies. In addition, only the paternal allele is expressed in tissues from a patient who suffered from Beckwith-Wiedemann syndrome. Thus the parental imprinting of IGF2 appears to be evolutionarily conserved from mouse to man and has implications for the generation of the Beckwith-Wiedemann syndrome.

Health effects of a subway environment in healthy volunteers.

Environmental particle exposure, often estimated as the particulate mass of particles with a diameter <10 microm, <2.5 microm or <1 microm (PM(10), PM(2.5) or PM(1)), is known to have a negative impact on the health of the population. Little is known about how the size and origin of particles influence the effects. We have previously shown that exposure to a road tunnel environment causes a cellular inflammatory response in the airways of healthy individuals. In the present study, our aim was to investigate potential airway health effects from exposure to a subway environment. 20 healthy volunteers were exposed to a subway and a control environment for 2 h, followed by measurements of lung function and the inflammatory response in the lower airways (bronchoscopy) and in the peripheral blood. No cellular response was found in the airways after exposure to the subway environment. In the blood, we found a statistically significant increase in fibrinogen and regulatory T-cells expressing CD4/CD25/FOXP3. Subway and road tunnel environments have similar levels of PM(10) and PM(2.5), whilst the concentrations of ultrafine particles, nitrogen monoxide and dioxide are lower in the subway. Although no cellular response was detected, the findings indicate a biological response to the subway environment. Our studies show that using gravimetric estimates of ambient particulate air pollution alone may have clear limitations in health-risk assessment.

Noonan syndrome and neurofibromatosis type I in a family with a novel mutation in NF1.

Noonan syndrome (NS) and neurofibromatosis type I (NF1) belong to a group of clinically related disorders that share a common pathogenesis, dysregulation of the RAS-MAPK pathway. NS is characterized by short stature, heart defect, pectus deformity and facial dysmorphism, whereas skin manifestations, skeletal defects, Lisch nodules and neurofibromas are characteristic of NF1. Both disorders display considerable clinical variability. Features of NS have been observed in individuals with NF1 -a condition known as neurofibromatosis-Noonan syndrome (NFNS). The major gene causing NFNS is NF1. Rarely, a mutation in PTPN11 in addition to an NF1 mutation is present. We present the clinical and molecular characterization of a family displaying features of both NS and NF1, with complete absence of neurofibromas. To investigate the etiology of the phenotype, mutational analysis of NF1 was conducted, revealing a novel missense mutation in exon 24, p.L1390F, affecting the GAP-domain. Additional RAS-MAPK pathway genes were examined, but no additional mutations were identified. We confirm that NF1 mutations are involved in the etiology of NFNS. Furthermore, based on our results and previous studies we suggest that evaluation of the GAP-domain of NF1 should be prioritized in NFNS.

Noonan and cardio-facio-cutaneous syndromes: two clinically and genetically overlapping disorders.

BACKGROUND: Noonan syndrome (NS) and cardio-facio-cutaneous syndrome (CFC) are related disorders associated with disrupted RAS/RAF/MEK/ERK signalling. NS, characterised by facial dysmorphism, congenital heart defects and short stature, is caused by mutations in the genes PTPN11, SOS1, KRAS and RAF1. CFC is distinguished from NS by the presence of ectodermal abnormalities and more severe mental retardation in addition to the NS phenotype. The genetic aetiology of CFC was recently assigned to four genes: BRAF, KRAS, MEK1 and MEK2. METHODS: A comprehensive mutation analysis of BRAF, KRAS, MEK1, MEK2 and SOS1 in 31 unrelated patients without mutations in PTPN11 is presented. RESULTS: Mutations were identified in seven patients with CFC (two in BRAF, one in KRAS, one in MEK1, two in MEK2 and one in SOS1). Two mutations were novel: MEK1 E203Q and MEK2 F57L. The SOS1 E433K mutation, identified in a patient diagnosed with CFC, has previously been reported in patients with NS. In one patient with NS, we also identified a mutation, BRAF K499E, that has previously been reported in patients with CFC. We thus suggest involvement of BRAF in the pathogenesis of NS also. CONCLUSIONS: Taken together, our results indicate that the molecular and clinical overlap between CFC and NS is more complex than previously suggested and that the syndromes might even represent allelic disorders. Furthermore, we suggest that the diagnosis should be refined to, for example, NS-PTPN11-associated or CFC-BRAF-associated syndromes after the genetic defect has been established, as this may affect the prognosis and treatment of the patients.

A novel nonsense mutation of the mineralocorticoid receptor gene in a Swedish family with pseudohypoaldosteronism type I (PHA1).

Pseudohypoaldosteronism type I (PHA1) is a condition associated with salt wasting leading to dehydration, hypotension, hyperkalemia, and metabolic acidosis. Sporadic cases and two familial forms, one autosomal dominant and one autosomal recessive form, have been described. The autosomal dominant or sporadic form manifests milder salt wasting that remits with age. Mutations in the gene encoding the mineralocorticoid receptor (MR) have been identified in patients with the autosomal dominant inheritance. However, recent studies suggest that the autosomal dominant and sporadic forms are genetically heterogeneous and that additional genes might be involved. We report on the study of 15 members of a Swedish five-generation family with the autosomal dominant form of PHA1. Interestingly, neuropathy was found in two of five affected individuals. A novel heterozygous nonsense mutation C436X in exon 2 was identified in the index patient by linkage analysis, PCR, and direct sequencing of the MR gene. Analysis of the family demonstrated that the mutation segregated with PHA1 in the family. It is unclear whether the neuropathy is associated with the mutation found. Our results together with previously published data suggest that loss-of-function mutations of the MR gene located at 4q31.1, commonly are associated with the autosomal dominant form of PHA1.

Debilitating chronic pain syndromes after presumed intraneural injections.

This report presents seven patients with severe disability established at the time of a peripheral nerve block. In most of the cases, the injection was administered as a routine procedure by an experienced anesthesiologist. The patient histories suggest that the condition, which can be resistant to all treatment, in most cases could have been avoided if careful attention had been given to the occurrence of pain during the nerve block. It is likely that the risk of devastating iatrogenic disability can be minimized if a few basic principles are respected during the administration of peripheral nerve blocks.

Characterisation of a novel series of aprotinin-derived anticoagulants. II. Comparative antithrombotic effects on primary thrombus formation in vivo.

Upon vascular damage platelet activation and blood coagulation are initiated. Interference at the initial level of the activation of the coagulation cascade can result in effective inhibition of thrombus formation. The in vivo antithrombotic properties of a series of bovine pancreatic trypsin inhibitor mutants (BPTI, aprotinin) 4C2, 7L22, 5L15, 5L15-PEG, 6L15 and 5L84, as described in the accompanying paper, with a combined inhibitory activity on factor Xa, factor VIIa-tissue factor complex, factor XIa and plasma kallikrein were compared to rTAP, r-hirudin, heparin and enoxaparin in a platelet rich thrombosis model in hamsters. Platelet dependent thrombus deposition was quantified by dedicated image analysis after transillumination of the femoral vein to which a standardised vascular trauma was applied. After increasing intravenous bolus injections all tested agents, except for aprotinin, induced a dose dependent decrease of thrombus formation and a concomitant prolongation of the aPTT. From the linear correlation between these two parameters it was found that 5 out of the 6 tested aprotinin analogues, rTAP and r-hirudin completely inhibited thrombus formation at a therapeutical (2- to 3-fold) aPTT prolongation while 4C2, heparin and enoxaparin only inhibited thrombus formation for 40 to 50 percent at a 2-fold aPTT prolongation. Based on the calculated IC50 values for thrombus formation rTAP was found to be the most active compound in this model. It is concluded that acceptable interference at the initial level of the blood coagulation, e.g. within a therapeutical aPTT prolongation, can significantly inhibit platelet deposition at a site of vascular injury.

Inhibitory effect of piracetam on platelet-rich thrombus formation in an animal model.

Intravenous administration of piracetam to hamsters reduced the formation of a platelet-rich venous thrombus induced by a standardised crush injury, in a dose-dependent fashion with an IC50 of 68 +/- 8 mg/kg. 200 mg/kg piracetam also significantly reduced in vivo thrombus formation in rats. However, in vitro aggregation of rat platelets was only inhibited with piracetam-concentrations at least 10-fold higher than plasma concentrations (6.2 +/- 1.1 mM) obtained in the treated animals. No effects were seen on clotting tests. In vitro human platelet aggregation, induced by a variety of agonists, was inhibited by piracetam, with IC50's of 25-60 mM. The broad inhibition spectrum could be explained by the capacity of piracetam to prevent fibrinogen binding to activated human platelets. Ex vivo aggregations and bleeding times were only minimally affected after administration of 400 mg/kg piracetam i.v. to healthy male volunteers, resulting in peak plasma levels of 5.8 +/- 0.3 mM. A possible antiplatelet effect of piracetam could be due to the documented beneficial effect on red blood cell deformability leading to a putative reduction of ADP release by damaged erythrocytes. However similarly high concentrations were needed to prevent stirring-induced "spontaneous" platelet aggregation in human whole blood. It is concluded that the observed antithrombotic action of piracetam cannot satisfactorily be explained by an isolated direct effect on platelets. An additional influence of piracetam on the rheology of the circulating blood and/or on the vessel wall itself must therefore be taken into consideration.

Characterisation of a novel series of aprotinin-derived anticoagulants. I. In vitro and pharmacological properties.

Previous investigations have indicated that interference with the initial level of the blood coagulation may lead to effective antithrombotic therapy. Recently a series of potential coagulation inhibitors derived from bovine pancreatic trypsin inhibitor (BPTI, aprotinin) was described. We have determined their inhibition constants, effects on coagulation assays, effects in an in vitro human thrombosis model and pharmacological profiles in hamsters. The aprotinin-derived analogues (4C2, 7L22, 5L15, 6L15, 5L84) showed significantly increased inhibitory activity towards factor Xa, factor VIIa-tissue factor (TF) complex, factor XIa and plasma kallikrein or a combination of them, and a significantly decreased plasmin inhibition as compared to aprotinin. In the coagulation assays, 4C2 and 7L22 mainly inhibited factor Xa, 5L15 and 6L15 inhibited factor VIIa-TF complex and 5L84 inhibited factor Xa, factor VIIa-TF complex and the contact activation. In flow chamber experiments with human blood 7L22, 5L15, 6L15, 5L84 and rTAP significantly inhibited fibrin formation and platelet deposition on extracellular matrix from phorbol ester stimulated human endothelial cells both under high and low shear stress and in the presence of low molecular weight heparin. The pharmacological profiles of the aprotinin analogues and rTAP with a mean residence time of 64 to 140 min were not significantly different. Modification of an aprotinin analogue with PEG (5L15-PEG) resulted in a 10-fold decrease of the inhibition constant for the factor VIIa-TF complex and in a significant prolongation of the secondary half-life, while the initial half-life was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Expression of a high molecular weight form of insulin-like growth factor II in a Beckwith-Wiedemann syndrome associated adrenocortical adenoma.

Beckwith-Wiedemann syndrome is a rare condition (1/13,700 live births) occurring in both inherited and sporadic forms in the population. It is manifest as a fetal overgrowth syndrome, in which hypertrophy dominates the clinical picture. An additional complication is that these children are predisposed to a specific subset of childhood neoplasms, amongst which are Wilms' tumour and adrenocortical carcinoma. We report here the synthesis by an associated adrenal tumour of large quantities of a high molecular weight form of insulin-like growth factor II (IGF-II), associated with profound suppression of circulating IGFs in the patient's serum. As with other tumours of this type, the tumours showed loss of material on chromosome 11p.

Comparison of a diffractive bifocal and a monofocal intraocular lens.

PURPOSE: To compare a Pharmacia diffractive bifocal intraocular lens (IOL) with a monofocal lens of the same design without the diffractive grating. SETTING: Multicenter study. METHODS: This randomized, prospective study comprised 70 patients with a monofocal IOL and 79 with a diffractive bifocal IOL. Follow-up was 5 to 6 months. Near and distance visual acuities, contract sensitivity, patient satisfaction, and spectacle use were evaluated. RESULTS: All patients achieved a best corrected visual acuity of 0.5 or better; 80% in the monofocal and 71% in the bifocal group had a best corrected visual acuity of 1.0 or better. Without correction, 93% of the bifocal and 9% of the monofocal group could read J3 or better. With distance correction, 99% and 4%, respectively, could read J3 or better. Contrast sensitivity was slightly lower in the bifocal group at distance and near for all spatial frequencies. In the bifocal group, 46% never used spectacles for near tasks. Overall satisfaction was rated good by 86% of the monofocal and 85% of the bifocal group. CONCLUSIONS: The diffractive bifocal IOL performed well at distance and near. Patients who no longer require spectacles will benefit significantly from a bifocal IOL, but many with a bifocal IOL in one eye will require spectacles for the fellow eye.

Contrast sensitivity after implantation of diffractive bifocal and monofocal intraocular lenses.

PURPOSE: To compare contrast sensitivity (CS) after implantation of a diffractive bifocal intraocular lens (IOL) and a monofocal IOL of similar design. SETTING: Seven European centers. METHODS: In this randomized, prospective study, CS was tested 5 months after cataract and IOL implantation surgery in 115 patients with a diffractive bifocal IOL and 106 patients with a monofocal IOL. It was also tested in a subgroup of 38 patients who had bilateral implantation of a diffractive bifocal IOL. Contrast sensitivity was tested using the Vision Contrast Test System (VCTS). RESULTS: In patients with a best corrected visual acuity (BCVA) of 1.0 or better, the CS at all spatial frequencies (1.5 to 18 cycles/degree), both at distance and near, was slightly lower in the bifocal IOL group than in the monofocal group. Mean values were within the normal range. In patients with a BCVA of less than 1.0, the CS was lower and the difference between the bifocal and monofocal groups was less. In patients with bilateral bifocal IOLs, CS was better when tested bilaterally than when testing the better eye alone. Pupil size affected the results to a small degree. Contrast sensitivity appeared to improve over time after implantation of a diffractive bifocal IOL. CONCLUSIONS: In patients with cataract and no other eye pathology, the diffractive bifocal IOL with slightly reduce the CS at all spatial frequencies. In those with reduced visual acuity after cataract surgery, CS will be reduced accordingly. In this situation, the reduction from the diffractive bifocal optic would be minor.

Intraoperative thrombolytic treatment of microarterial occlusion by selective rt-PA infusion.

The development of microvascular thrombosis during replantation surgery or free-flap transfer is generally best treated by identification of the problem, vascular revision, and reanastomosis. It is not unique, however, that surgical measures alone are insufficient or undesirable. Pharmacologic adjuncts are widely used for the prevention and sometimes treatment of microvascular thrombosis in surgical practice, but the benefit of thrombolytic agents, effective in dissolving an already established thrombus, is usually considered counterlevered by the fear of uncontrollable bleeding. However, selective infusion of the drug reduces the risk for systemic complications considerably and may therefore be considered in peripheral microvascular reconstruction. The technique was used successfully in a case of digital revascularization, where an arterial thrombosis was dissolved with the use of recombinant tissue plasminogen activator (rt-PA).

Natural history of scaphoid non-union, with special reference to "asymptomatic" cases.

33 patients with non-union of the carpal scaphoid were diagnosed by X-ray examination two to 37 years following the original trauma. All of the patients could be contacted and summoned for a re-examination ten to 17 years later. X-rays revealed a 100% incidence of progressive radio-carpal osteoarthritis. It is concluded that freedom of pain is not a reliable prognostic indicator, and that all patients with non-union of the carpal scaphoid are likely to benefit from surgical treatment of the pseudarthrosis. The only exception to this rule might be the patient in whom the radio-carpal joint is already deteriorated by an advanced degenerative arthritis.

Incidence of post-traumatic arthrosis after primary healing of scaphoid fractures: a clinical and radiological study.

In a retrospective study of 229 patients with healed fractures of the waist of the scaphoid, the incidence and development of post-traumatic radiocarpal arthrosis was studied. With a minimum follow-up period of seven years, 5.2% of patients showed radiological evidence of radiocarpal arthrosis. It is concluded that an alteration of the carpal dynamics, due to deformation and shortening of the scaphoid, is the most likely cause of post-traumatic arthrosis after primary healing of scaphoid fractures.

Replantation of the completely avulsed thumb using long arterial and venous grafts.

Long arterial and venous grafts (10-15 cm. in length) were used in the replantation of thumbs amputated by avulsion. All replanted parts survived and thrombosis requiring anastomotic revision did not occur in any of the cases. Based upon a consideration of different factors that may lead to the formation of thrombus in reconstructed vessels, a method is recommended for routine use in replantation of the thumb, with specific reference to avulsion injuries.