Degradation of haemoglobin-14C and urinary excretion of bilirubin-14C by the normothermic perfused isolated dog kidney

Résumé L'hémoglobine libre du sang, filtrée par les glomérules rénaux et partiellement absorbée par les tubules, est métabolisée par le tissu renal. A l'aide de l'hémoglobine marquée en¹⁴C, formée à partir de la glycine-2-¹⁴C et de la glycine-1-¹⁴C nos résultats prouvent que chez le chien mâle les reins métabolisent l'hémoglobine en bilirubine conjugée et excrètent cette dernière dans les urines.

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Our thanks are due to the Fonds voor wetenschappelijk geneeskundig onderzoek of Belgium for the financial support.     

The Fanconi anaemia gene FANCF encodes a novel protein with homology to ROM

Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder with locus heterogeneity. None of the 'responsible' genes have previously been identified. Some BBS cases (approximately 10%) remain unassigned to the five previously mapped loci. McKusick-Kaufma syndrome (MKS) includes hydrometrocolpos, postaxial polydactyly and congenital heart disease, and is also inherited in an autosomal recessive manner. We ascertained 34 unrelated probands with classic features of BBS including retinitis pigmentosa (RP), obesity and polydactyly. The probands were from families unsuitable for linkage because of family size. We found MKKS mutations in four typical BBS probands (Table 1). The first is a 13-year-old Hispanic girl with severe RP, PAP, mental retardation and obesity (BMI >40). She was a compound heterozygote for a missense (1042GA, G52D) and a nonsense (1679TA, Y264stop) mutation in exon 3. Cloning and sequencing of the separate alleles confirmed that the mutations were present in trans. A second BBS proband (from Newfoundland), born to consanguineous parents, was homozygous for two deletions (1316delC and 1324-1326delGTA) in exon 3, predicting a frameshift. An affected brother was also homozygous for the deletions, whereas an unaffected sibling had two normal copies of MKKS. Both the proband and her affected brother had RP, PAP, mild mental retardation, morbid obesity (BMI >50 and 37, respectively), lobulated kidneys with prominent calyces and diabetes mellitus (diagnosed at ages 33 and 30, respectively). A deceased sister (DNA unavailable) had similar phenotypic features (RP with blindness by age 13, BMI >45, abnormal glucose tolerance test and IQ=64, vaginal atresia and syndactyly of both feet). Both parents and the maternal grandfather were heterozygous for the deletions. Genotyping with markers from the MKKS region confirmed homozygosity at 20p12 in both affected individuals.     

An ultra-relativistic outflow from a neutron star accreting gas from a companion

Collimated relativistic outflows-also known as jets-are amongst the most energetic phenomena in the Universe. They are associated with supermassive black holes in distant active galactic nuclei, accreting stellar-mass black holes and neutron stars in binary systems and are believed to be responsible for gamma-ray bursts. The physics of these jets, however, remains something of a mystery in that their bulk velocities, compositions and energetics remain poorly determined. Here we report the discovery of an ultra-relativistic outflow from a neutron star accreting gas within a binary stellar system. The velocity of the outflow is comparable to the fastest-moving flows observed from active galactic nuclei, and its strength is modulated by the rate of accretion of material onto the neutron star. Shocks are energized further downstream in the flow, which are themselves moving at mildly relativistic bulk velocities and are the sites of the observed synchrotron emission from the jet. We conclude that the generation of highly relativistic outflows does not require properties that are unique to black holes, such as an event horizon.     

The urinary excretion of bilirubin after increased plasma hemoglobin concentration in dogs

Résumé L'excrétion rénale de la bilirubine dans l'urine varie entre 0,1 et 0,8 mg par jour dans une série de 113 chiens normaux. Avec une concentration d'hémoglobine plasmatique libre, excédant 50 mg/100 ml, les auteurs ont remarqué une augmentation sensible de l'excrétion urinaire de la bilirubine, sans que les taux sanguin, de la bilirubine ni le clearance de la créatinine soient changés. Les résultats font supposer un métabolisme local de l'hémoglobine en bilirubine dans les reins.     

Quasi-periodic X-ray brightness fluctuations in an accreting millisecond pulsar

The relativistic plasma flows onto neutron stars that are accreting material from stellar companions can be used to probe strong-field gravity as well as the physical conditions in the supra-nuclear-density interiors of neutron stars. Plasma inhomogeneities orbiting a few kilometres above the stars are observable as X-ray brightness fluctuations on the millisecond dynamical timescale of the flows. Two frequencies in the kilohertz range dominate these fluctuations: the twin kilohertz quasi-periodic oscillations (kHz QPOs). Competing models for the origins of these oscillations (based on orbital motions) all predict that they should be related to the stellar spin frequency, but tests have been difficult because the spins were not unambiguously known. Here we report the detection of kHz QPOs from a pulsar whose spin frequency is known. Our measurements establish a clear link between kHz QPOs and stellar spin, but one not predicted by any current model. A new approach to understanding kHz QPOs is now required. We suggest that a resonance between the spin and general relativistic orbital and epicyclic frequencies could provide the observed relation between QPOs and spin.     

Nuclear-powered millisecond pulsars and the maximum spin frequency of neutron stars

Millisecond pulsars are neutron stars that are thought to have been spun-up by mass accretion from a stellar companion. It is not known whether there is a natural brake for this process, or if it continues until the centrifugal breakup limit is reached at submillisecond periods. Many neutron stars that are accreting mass from a companion star exhibit thermonuclear X-ray bursts that last tens of seconds, caused by unstable nuclear burning on their surfaces. Millisecond-period brightness oscillations during bursts from ten neutron stars (as distinct from other rapid X-ray variability that is also observed) are thought to measure the stellar spin, but direct proof of a rotational origin has been lacking. Here we report the detection of burst oscillations at the known spin frequency of an accreting millisecond pulsar, and we show that these oscillations always have the same rotational phase. This firmly establishes burst oscillations as nuclear-powered pulsations tracing the spin of accreting neutron stars, corroborating earlier evidence. The distribution of spin frequencies of the 11 nuclear-powered pulsars cuts off well below the breakup frequency for most neutron-star models, supporting theoretical predictions that gravitational radiation losses can limit accretion torques in spinning up millisecond pulsars.     

Control charts to check yearly predictions by monthly observations

In many cases an organization makes predictions of a variable on a yearly scale although the variable is actually observed at shorter time intervals. Given such a yearly prediction, the question will arise as to under which conditions one can say that the actual development of the variable at shorter time intervals deviates so much from the year estimate as to render the latter implausible. Policy makers confronted with such a problem tend to use rather primitive statistical methods of inference. In this paper the situation is judged from a statistical point of view and placed in the context of the ‘significance test’ approach to control chart theory. It is assumed that the variables are generated by a multivariate autoregressive moving average model. Thus we derive an approximate distribution of the future observations of the series given the values of some linear compounds of the variables. With this, three control charts can be constructed. The approach is illustrated by an example based on the monthly tax returns of the Dutch central government. The example suggests the usefulness of the approach in many practical situations of forecasting and planning.     

A cooperative microRNA-tumor suppressor gene network in acute T-cell lymphoblastic leukemia (T-ALL)

The importance of individual microRNAs (miRNAs) has been established in specific cancers. However, a comprehensive analysis of the contribution of miRNAs to the pathogenesis of any specific cancer is lacking. Here we show that in T-cell acute lymphoblastic leukemia (T-ALL), a small set of miRNAs is responsible for the cooperative suppression of several tumor suppressor genes. Cross-comparison of miRNA expression profiles in human T-ALL with the results of an unbiased miRNA library screen allowed us to identify five miRNAs (miR-19b, miR-20a, miR-26a, miR-92 and miR-223) that are capable of promoting T-ALL development in a mouse model and which account for the majority of miRNA expression in human T-ALL. Moreover, these miRNAs produce overlapping and cooperative effects on tumor suppressor genes implicated in the pathogenesis of T-ALL, including IKAROS (also known as IKZF1), PTEN, BIM, PHF6, NF1 and FBXW7. Thus, a comprehensive and unbiased analysis of miRNA action in T-ALL reveals a striking pattern of miRNA-tumor suppressor gene interactions in this cancer.