Author Correction: Forearc carbon sink reduces long-term volatile recycling into the mantle.

An Amendment to this paper has been published and can be accessed via a link at the top of the paper.

Author Correction: Forearc carbon sink reduces long-term volatile recycling into the mantle.

Change history: In this Article, the original affiliation 2 was not applicable and has been removed. In addition, in the Acknowledgements there was a statement missing and an error in a name. These errors have been corrected online.

Forearc carbon sink reduces long-term volatile recycling into the mantle.

Carbon and other volatiles in the form of gases, fluids or mineral phases are transported from Earth's surface into the mantle at convergent margins, where the oceanic crust subducts beneath the continental crust. The efficiency of this transfer has profound implications for the nature and scale of geochemical heterogeneities in Earth's deep mantle and shallow crustal reservoirs, as well as Earth's oxidation state. However, the proportions of volatiles released from the forearc and backarc are not well constrained compared to fluxes from the volcanic arc front. Here we use helium and carbon isotope data from deeply sourced springs along two cross-arc transects to show that about 91 per cent of carbon released from the slab and mantle beneath the Costa Rican forearc is sequestered within the crust by calcite deposition. Around an additional three per cent is incorporated into the biomass through microbial chemolithoautotrophy, whereby microbes assimilate inorganic carbon into biomass. We estimate that between 1.2 × 108 and 1.3 × 1010 moles of carbon dioxide per year are released from the slab beneath the forearc, and thus up to about 19 per cent less carbon is being transferred into Earth's deep mantle than previously estimated.

Identification of three novel mutations (E196K, V203I, E211Q) in the prion protein gene (PRNP) in inherited prion diseases with Creutzfeldt-Jakob disease phenotype.

Inherited prion diseases are characterized by mutations in the PRNP gene encoding the prion protein (PrP). As the other sporadic or infectious prion disease forms, they are almost all characterized by the accumulation in the brain of an abnormal misfolded form of the patient's PrP. Brain extracts can often transmit the disease once inoculated in a recipient animal. Inherited prion diseases with Creutzfeldt-Jakob disease (CJD) phenotype are autosomal forms, although sporadic cases have been reported. We report three novel mutations of the PRNP gene in unrelated patients with clinical and histopathologic features of CJD. The three mutations were missense: c635G>A (E196K), c656G>A (V203I) and c680G>C (E211Q). Familial history of neurologic disorders was evidenced for patients carrying the E196K and E211Q mutations. E196K would be predicted to have more severe effects on protein stability than V203I and E211Q. These mutations expand the spectrum of mutations in PRNP and reduce the proportion of CJD patients in whom genetic alterations have not been found.

Prion-like protein Doppel expression is not modified in scrapie-infected cells and in the brains of patients with Creutzfeldt-Jakob disease.

Doppel protein has been discovered in prnp knock-out mouse lines, with overproduction of this protein in the brain causing ataxia and neurodegeneration. We investigated whether Doppel expression (i) affected or was affected by the course of prion propagation in neuroblastoma cells, or (ii) modulated Creutzfeldt-Jakob disease pathogenesis. No change in Doppel production was detected in N2a cells, before or after infection. Transient murine Doppel gene expression had no effect on N2a viability or PrP(Sc) production. A sensitive immunometric assay revealed low levels of Doppel in human brain, reflecting weak transcription of the corresponding gene. No difference in brain Doppel levels was observed between Creutzfeldt-Jakob disease patients and controls, adding further evidence that Doppel is unlikely to be involved in prion disease pathogenesis.

Demyelinating peripheral neuropathy with Creutzfeldt-Jakob disease and mutation at codon 200 of the prion protein gene.

We performed a study of the distribution of PrP27-30, the proteinase-K-resistant form of prion protein, in the central and peripheral nervous system of a patient with a Glu200Lys mutation of the prion protein gene, cerebellar ataxia, subcortical dementia, rigidity, and demyelinating peripheral neuropathy. In the CNS, there was neuron loss and spongy degeneration, principally in the cerebellum, and with progressively lower density in the caudate nucleus, thalamus, temporal cortex, frontal cortex, and brainstem. Evaluation of the expression of PrP27-30 by Western blot showed that its distribution correlated with the intensity of the lesions in these regions. In contrast, we did not detect PrP27-30 in the peripheral nervous system where lesions consisted of demyelination, and remyelination that predominated in the proximal nerve trunks and roots.

Molecular genetics of prion diseases in France. French Research Group on Epidemiology of Human Spongiform Encephalopathies.

Human prion diseases are characterized by the accumulation in the brain of an abnormal form of the prion protein. Prion protein polymorphisms seem to play a key role in the pathogenesis of these diseases, probably by enhancing the amyloidogenic properties of the protein. We performed prion protein gene (PRNP) coding sequence analysis in 57 French subjects with Creutzfeldt-Jakob disease (CJD) and found a mutation of the PRNP coding sequence in nine subjects (15.8%); the mutation corresponded with a known family history of CJD in only three of these subjects. In 41 definite and probable cases without known PRNP mutations, codon 129 genotyping revealed an excess of the homozygous 129Met/Met genotype corresponding to a 3.4-fold increased risk of developing CJD when compared with the two other genotypes. We also found that the 129Val/Val genotype, which mainly governs susceptibility to iatrogenic CJD, does not seem to predispose to sporadic CJD.

A new point mutation in the prion protein gene at codon 210 in Creutzfeldt-Jakob disease.

We screened 16 cases of sporadic Creutzfeldt-Jakob disease (CJD) and 28 healthy control subjects to detect possible polymorphisms in their prion protein gene (PRNP). The molecular analysis of the PRNP coding sequence was performed using denaturing gradient gel electrophoresis of polymerase chain reaction products and direct sequencing. We identified (1) a silent mutation at codon 177 in a healthy individual, (2) a codon 200 glutamate-to-lysine substitution in a 48-year-old CJD-affected Libyan Jew, and (3) a G-to-A point substitution at codon 210, leading a valine-to-isoleucine change, in a 63-year-old French CJD patient. This new mutation occurs in a highly conserved part of the PRNP coding sequence, close to the known CJD-associated codon 200 mutation, and might be linked to a symptomatologic and neuropathologic pattern of typical sporadic CJD. This mutation was also present in a sister of the patient who died at the age of 67 without neurologic symptomatology.

Creutzfeldt-Jakob disease after extracranial dura mater embolization for a nasopharyngeal angiofibroma.

We report a 25-year-old man with Creutzfeldt-Jakob disease (CJD) who had received dura mater embolization in the external carotid artery for a nasopharyngeal angiofibroma 90 months earlier. The patient was heterozygotous (Met/Val) at codon 129. This case suggests that dura mater embolization can be responsible for the CJD.

The timing of tuberculin tests in relation to immunization with live viral vaccines.

The validity of the recommendation that routine screening for tuberculosis precede the administration of live viral vaccines was tested in a field study. One hundred and ten children already known to be tuberculin-positive, mostly on the basis of prior vaccination with BCG, were immunized with live viral vaccine and retested with tuberculin at the same time. Reversion to a negative tine test occurred in 3% of children given measles, mumps, or rubella vaccine, and 3.6% of controls who received no vaccine but had the tuberculin test repeated at the same interval. Very few Mantoux reactions (two of 68) reverted to negative in children given one of the three vaccines, singly or in combination; some became smaller, but there was no significant difference in the changes in the size of the Mantoux reaction between the vaccinated group and the control group, with the exception of an unexplained increase in the size of the reaction in many of those who received rubella vaccine. Screening for tuberculosis by tine or Mantoux test is not invalidated by simultaneous administration of vaccines against measles, mumps, or rubella, given singly or in combination, as part of preventive care programs.

Late effect of nocturnal mist tent therapy related to the severity of airway obstruction in children with cystic fibrosis.

To evaluate the long-term effect of nocturnal mist tent therapy on the progression of airway obstruction in children with cystic fibrosis (CF) of varying severity, two matched groups each consisting of 24 children with CF were studied during 18 months on mist tent therapy and 18 months of therapy. The progression in airway obstruction was measured by change in serial measurements of maximal midexpiratory flow (MMEF), from which a regression equation of MMEF against time was obtained for each individual. Changes in MMEF value with or without therapy were compared in patients matched for severity of disease as indicated by initial MMEF values. For the group as a whole no differences were found in the progression of the airway obstruction whether the patients received mist tent therapy or not. This therapy failed to benefit any of the groups of children with CF who had early, moderate, or advanced airway obstruction as judged from their initial MMEF value. It is concluded that nocturnal mist tent therapy neither decreases airway obstruction nor prevents its progression in children with CF.

Differential effects of transforming growth factor-beta 1 on the expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in young and old human fibroblasts.

The balance between the activities of matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs) is an important control point in tissue remodeling. Previous studies have demonstrated elevated expression of the MMPs collagenase and stromelysin-1 by aged human diploid fibroblasts compared to early-passage cultures. We show here that aging cells display an altered response to transforming growth factor-beta 1 (TGF beta 1) that selectively affects MMP mRNA expression. In both young and old cells, phorbol myristoyl-13 acetate (PMA) induced the expression of transcripts of collagenase, stromelysin-1, gelatinase-B, TIMP-1, and TIMP-3. In young cells, TGF beta 1 reciprocally modulated PMA-induced MMP and TIMP gene expression leading to reduced levels of transcripts for the MMPs and augmented accumulation of TIMP-1 and TIMP-3 mRNAs. However, repressing effects of TGF beta 1 on collagenase, stromelysin-1, and gelatinase-B RNA expression were not apparent in old cells, though induction of the TIMP genes was unimpaired. By electrophoretic mobility shift analysis the nuclear transcription factors AP1 and serum response factor (SRF) showed reduced levels of DNA binding activities in old fibroblasts compared to young cells. A probe for the TGF beta-inhibitory element (TIE) gave equivalent levels of complexes with nuclear extracts from both types of cells, though of different mobilities. We conclude that the effects of TGF beta 1 on MMP and TIMP gene expression involve different cellular intermediaries, and suggest that altered composition or modification of TIE binding factors in aging cells may underlie the failure of TGF beta 1-mediated transcription repression. This mechanism may contribute to elevated constitutive expression of MMPs in old cells and to the connective tissue deterioration that accompanies the aging process.

Clonazepam in the treatment of patients with recurrent panic attacks.

Imipramine, phenelzine, and alprazolam have each been shown to be efficacious in the treatment of panic disorder and in agoraphobia with panic attacks. Clonazepam is a high-potency 1,4-benzodiazepine derivative with an intermediate to long elimination half-life that is used mainly in neurology as an antiepileptic. Eight cases of recurrent panic attacks successfully treated with clonazepam are reported.

Sources of error in flow-volume curves. Effect of expired volume measured at the mouth vs that measured in a body plethysmograph.

The popularity of the maximum expiratory flow-volume curve (FVC) is in part due to the effort independence of expiratory flow. Of interest are expiratory flow rates at specific lung volumes, usually 50 and 25 percent of vital capacity (VC); Vmax50 and Vmax25, which make accurate assessment of lung volumes essential. Changes in lung volume during the test are due to both the volume of gas expired and the volume change due to gas compression (Vcomp). In normal subjects, Vcomp is small but may be considerable in those with airflow obstruction. When the FVC is measured in a plethysmograph (FVCp), both expired volume and Vcomp are measured. When the volume of the FVC is derived from gas expired at the mouth (FVCm), Vcomp is not considered and differences in Vmax25 or Vmax50 may occur. The magnitude of these errors was assessed in 30 children and young adults: nine normal subjects, ten with cystic fibrosis (CF) and 11 with asthma. For Vmax50, use of FVCm instead of FVCp resulted in an error of 8 +/- 7 percent (mean +/- 1 SD) in the normal subjects compared to 32 +/- 23 in those with CF (p less than 0.01) and 24 +/- 18 for those with asthma (p less than 0.05). For Vmax25, the errors were similar. These errors were not predictable from FEV1 or RV/TLC but were related to a combination of expiratory effort, the shape of the FVCp, and the absolute volume of gas that was being compressed (p less than 0.0001). These findings suggest that expiratory flows in the FVCm are not effort-independent in the face of significant airflow obstruction and that comparisons of values derived from an FVCp with those from an FVCm may not be valid.

The effect of digoxin on exercise capacity and exercising cardiac function in cystic fibrosis.

The ability of digoxin to increase exercise capacity and stroke volume (SV) during exercise was evaluated in ten patients with cystic fibrosis (CF) ages 12 to 20 years with moderate to severe degrees of airway obstruction but no history of heart failure. A double-blind crossover trial of digoxin versus placebo was carried out. An evaluation of exercise performance was undertaken upon entry into the study, and after each of the one-week periods in which digoxin 0.25 mg/day or placebo was taken. Exercise testing consisted of a progressive exercise test on a cycle ergometer to measure maximum work capacity (Wmax) and a steady state test at 2/3 of the baseline Wmax. During the steady state test, the oxygen consumption and carbon dioxide production were measured and cardiac output (Q) was calculated by the indirect Fick (CO2) method. From Q and heart rate (HR), SV was derived. After digoxin, Wmax was unchanged. On steady state exercise HR was unchanged, but there was a slight but significant fall in Q due to a fall in SV. The decrease in SV was associated with exercising hypoxemia. We conclude that digoxin did not increase exercise capacity or improve exercising cardiac function in patients with moderate to severe airway obstruction due to CF.

Antithrombin III and Factor VIII in patients with neoplasms.

Possible increased activation of the coagulation pathway was measured in a group of patients with neoplastic diseases. In addition to standard tests, the thromboplastin generation test, thrombin generation test and immunologic and coagulant activities of both Factor VIII and antithrombin III were utilized in the evaluation. The correlation between immuno-Factor VIII (VIII-Ag) and its clotting activity (VIII-C1) was good (r = 0.83). In contrast, this was not the situation for antithrombin III-Ag and its clotting activity. Thromboplastin generation was accelerated in 60% and thrombin generation was accelerated in 40% of the patients. Fibrinogen was elevated in half the cases: in most of these patients, thrombin times were slightly prolonged. These results indicate that some patients who have cancer have abnormal clotting patterns and are often in a potentially hypercoagulable state that is reflected by the thromboplastin generation test, thrombin generation test, and high levels of Factor VIII (both VIII-Ag and VIII-C1).

Antiepileptic drugs in the treatment of neuroleptic-induced supersensitivity psychosis.

1. Supersensitivity psychosis (SSP) has emerged as a potential side-effect of long term neuroleptic therapy similar to tardive dyskinesia. 2. Five schizophrenic patients with SSP and considered to be drug-resistant were treated with antiepileptic drugs. All 5 improved initially, and in three the improvement was maintained at follow-up. 3. The proposed mechanism of action of the antiepileptic drugs is through correcting a pharmacological kindling effect in the limbic system which results from chronic neuroleptic therapy.

Comparison of withdrawal of buspirone and diazepam: a placebo controlled study.

In a 8-week double-blind placebo controlled study, 48 outpatients with generalized anxiety disorder were randomized to diazepam, buspirone, a non-benzodiazepine anxiolytic, or placebo. During the treatment phase of 4 weeks duration diazepam was found to be significantly better than placebo and buspirone. Following abrupt withdrawal by placebo substitution the diazepam group showed a gradual relapse maximal after two weeks while the buspirone and the placebo groups did not differ. There were more cases of rebound anxiety with diazepam as compared to buspirone or placebo. In addition, there were three early terminations related to rebound anxiety in the diazepam group while there were none in the placebo and buspirone groups. There were significantly more new symptoms in the diazepam group than in the placebo or buspirone group.

An open clinical trial of clonazepam in the treatment of patients with recurrent panic attacks.

Imipramine, phenelzine and alprazolam have each been shown to be efficacious in the treatment of panic disorder and in agoraphobia with panic attacks. Clonazepam, a 1,4 benzodiazepine derivative used mainly in neurology as an anti-epileptic, has specific pharmacodynamic and pharmacokinetic properties which would make it an advantageous antipanic agent. We report 8 cases of recurrent panic attacks which were successfully treated with clonazepam.