Uncovering the Neoproterozoic carbon cycle.

Interpretations of major climatic and biological events in Earth history are, in large part, derived from the stable carbon isotope records of carbonate rocks and sedimentary organic matter. Neoproterozoic carbonate records contain unusual and large negative isotopic anomalies within long periods (10-100 million years) characterized by δ(13)C in carbonate (δ(13)C(carb)) enriched to more than +5 per mil. Classically, δ(13)C(carb) is interpreted as a metric of the relative fraction of carbon buried as organic matter in marine sediments, which can be linked to oxygen accumulation through the stoichiometry of primary production. If a change in the isotopic composition of marine dissolved inorganic carbon is responsible for these excursions, it is expected that records of δ(13)C(carb) and δ(13)C in organic carbon (δ(13)C(org)) will covary, offset by the fractionation imparted by primary production. The documentation of several Neoproterozoic δ(13)C(carb) excursions that are decoupled from δ(13)C(org), however, indicates that other mechanisms may account for these excursions. Here we present δ(13)C data from Mongolia, northwest Canada and Namibia that capture multiple large-amplitude (over 10 per mil) negative carbon isotope anomalies, and use these data in a new quantitative mixing model to examine the behaviour of the Neoproterozoic carbon cycle. We find that carbonate and organic carbon isotope data from Mongolia and Canada are tightly coupled through multiple δ(13)C(carb) excursions, quantitatively ruling out previously suggested alternative explanations, such as diagenesis or the presence and terminal oxidation of a large marine dissolved organic carbon reservoir. Our data from Namibia, which do not record isotopic covariance, can be explained by simple mixing with a detrital flux of organic matter. We thus interpret δ(13)C(carb) anomalies as recording a primary perturbation to the surface carbon cycle. This interpretation requires the revisiting of models linking drastic isotope excursions to deep ocean oxygenation and the opening of environments capable of supporting animals.

An unusual histological finding following myomectomy.

Ancient schwannomas are benign tumours arising from the neural sheath of peripheral, cranial and autonomic nerves. They are commonly situated in the inner ear and spine with pelvic manifestations being rare. We present the case of a 30-year-old patient, who presented with an abdominal mass. MRI imaging suggested a broad ligament fibroid and open surgery was undertaken to remove it. Subsequent histology confirmed an ancient schwannoma. This case report details the rarity of such a condition and the need for a high index of suspicion as well as outlining management options and surveillance.

Epigenotype-phenotype correlations in Silver-Russell syndrome.

BACKGROUND: Silver-Russell syndrome (SRS) is characterised by intrauterine growth restriction, poor postnatal growth, relative macrocephaly, triangular face and asymmetry. Maternal uniparental disomy (mUPD) of chromosome 7 and hypomethylation of the imprinting control region (ICR) 1 on chromosome 11p15 are found in 5-10% and up to 60% of patients with SRS, respectively. As many features are non-specific, diagnosis of SRS remains difficult. Studies of patients in whom the molecular diagnosis is confirmed therefore provide valuable clinical information on the condition. METHODS: A detailed, prospective study of 64 patients with mUPD7 (n=20) or ICR1 hypomethylation (n=44) was undertaken. RESULTS AND CONCLUSIONS: The considerable overlap in clinical phenotype makes it difficult to distinguish these two molecular subgroups reliably. ICR1 hypomethylation was more likely to be scored as 'classical' SRS. Asymmetry, fifth finger clinodactyly and congenital anomalies were more commonly seen with ICR1 hypomethylation, whereas learning difficulties and referral for speech therapy were more likely with mUPD7. Myoclonus-dystonia has been reported previously in one mUPD7 patient. The authors report mild movement disorders in three further cases. No correlation was found between clinical severity and level of ICR1 hypomethylation. Use of assisted reproductive technology in association with ICR1 hypomethylation seems increased compared with the general population. ICR1 hypomethylation was also observed in affected siblings, although recurrence risk remains low in the majority of cases. Overall, a wide range of severity was observed, particularly with ICR1 hypomethylation. A low threshold for investigation of patients with features suggestive, but not typical, of SRS is therefore recommended.

The novel sodium glucose transporter 2 inhibitor dapagliflozin sustains pancreatic function and preserves islet morphology in obese, diabetic rats.

AIMS: To investigate whether glucose lowering with the selective sodium glucose transporter 2 (SGLT2) inhibitor dapagliflozin would prevent or reduce the decline of pancreatic function and disruption of normal islet morphology. METHODS: Female Zucker diabetic fatty (ZDF) rats, 7-8 weeks old, were placed on high-fat diet. Dapagliflozin (1 mg/kg/day, p.o.) was administered for ∼33 days either from initiation of high-fat diet or when rats were moderately hyperglycaemic. Insulin sensitivity and pancreatic function were evaluated using a hyperglycaemic clamp in anaesthetized animals (n = 5-6); ß-cell function was quantified using the disposition index (DI) to account for insulin resistance compensation. Pancreata from a matched subgroup (n = 7-8) were fixed and ß-cell mass and islet morphology investigated using immunohistochemical methods. RESULTS: Dapagliflozin, administered from initiation of high-fat feeding, reduced the development of hyperglycaemia; after 24 days, blood glucose was 8.6 ± 0.5 vs. 13.3 ± 1.3 mmol/l (p < 0.005 vs. vehicle) and glycated haemoglobin 3.6 ± 0.1 vs. 4.8 ± 0.26% (p < 0.003 vs. vehicle). Dapagliflozin improved insulin sensitivity index: 0.08 ± 0.01 vs. 0.02 ± 0.01 in obese controls (p < 0.03). DI was improved to the level of lean control rats (dapagliflozin 0.29 ± 0.04; obese control 0.15 ± 0.01; lean 0.28 ± 0.01). In dapagliflozin-treated rats, ß-cell mass was less variable and significant improvement in islet morphology was observed compared to vehicle-treated rats, although there was no change in mean ß-cell mass with dapagliflozin. Results were similar when dapagliflozin treatment was initiated when animals were already moderately hyperglycaemic. CONCLUSION: Sustained glucose lowering with dapagliflozin in this model of type 2 diabetes prevented the continued decline in functional adaptation of pancreatic ß-cells.

A low temperature transfer of ALH84001 from Mars to Earth.

The ejection of material from Mars is thought to be caused by large impacts that would heat much of the ejecta to high temperatures. Images of the magnetic field of martian meteorite ALH84001 reveal a spatially heterogeneous pattern of magnetization associated with fractures and rock fragments. Heating the meteorite to 40 degrees C reduces the intensity of some magnetic features, indicating that the interior of the rock has not been above this temperature since before its ejection from the surface of Mars. Because this temperature cannot sterilize most bacteria or eukarya, these data support the hypothesis that meteorites could transfer life between planets in the solar system.

Has the Scottish Managed Clinical Network for Sarcoma influenced the survival outcomes for primary malignant bone tumours?

Primary malignant bone tumours (PMBT) are rare. We have reviewed patient outcomes in Scotland over a 20 year period and provided an update on the principles of current management strategies for the non-specialist practitioner. The Scottish Managed Clinical Network for Sarcoma (MCN) connects the three main management centres for sarcoma in Scotland: Glasgow, Aberdeen and Edinburgh. Prior to the formation of the MCN, all centres were connected via the Scottish Bone Tumour Registry (SBTR), where they would meet on a quarterly basis and all the bone/soft tissue tumour cases were discussed retrospectively. The MCN was introduced in 2006. Our primary aims were to assess the impact of the MCN on patient outcomes and to update clinicians on the recognition, assessment and staging of PMBT. A secondary aim was to compare results from the Scottish centres with other UK sites. The patient information was gathered from the Scottish Bone Tumour Registry, held at the Queen Elizabeth University Hospital in Glasgow. All patients with diagnoses of Osteosarcoma, Chondrosarcoma and Ewing Sarcoma between 1994 and 2014 were included. Results showed that there was no significant change in outcome following the formation of the Scottish Managed Clinical Network for Sarcoma, and that there were little differences in outcome amongst the three major management centres in Scotland. Findings also show Scotland to have similar outcomes to that of the rest of the UK following diagnosis of a primary malignant bone tumour.

Biologically agglutinated eukaryotic microfossil from Cryogenian cap carbonates.

Cryogenian cap carbonates that overlie Sturtian glacial deposits were formed during a post-glacial transgression. Here, we describe microfossils from the Kakontwe Formation of Zambia and the Taishir Formation of Mongolia-both Cryogenian age, post-Sturtian cap carbonates-and investigate processes involved in their formation and preservation. We compare microfossils from these two localities to an assemblage of well-documented microfossils previously described in the post-Sturtian Rasthof Formation of Namibia. Microfossils from both new localities have 10 ± 1 µm-thick walls composed of carbonaceous matter and aluminosilicate minerals. Those found in the Kakontwe Formation are spherical or ovoid and 90 ± 5 µm to 200 ± 5 µm wide. Structures found in the Taishir Formation are mostly spherical, 50 ± 5 µm to 140 ± 5 µm wide, with distinct features such as blunt or concave edges. Chemical and mineralogical analyses show that the walled structures and the clay fraction extracted from the surrounding sediments are composed of clay minerals, especially muscovite and illite, as well as quartz, iron and titanium oxides, and some dolomite and feldspar. At each locality, the mineralogy of the microfossil walls matched that of the clay fractions of the surrounding sediment. The abundance of these minerals in the walled microfossils relative to the surrounding carbonate matrix and microbial laminae, and the presence of minerals that cannot precipitate from solution (titanium oxide and feldspar), suggests that the composition represents the original mineralogy of the structures. Furthermore, the consistency in mineralogy of both microfossils and sediments across the three basins, and the uniformity of size and shape among mineral grains in the fossil walls indicate that these organisms incorporated these minerals by primary biological agglutination. The discovery of new, mineral-rich microfossil assemblages in microbially laminated and other fine-grained facies of Cryogenian cap carbonates from multiple localities on different palaeocontinents demonstrates that agglutinating eukaryotes were widespread in carbonate-dominated marine environments in the aftermath of the Sturtian glaciation.

Sodium-lithium countertransport activity and insulin resistance in normotensive IDDM patients.

In insulin-dependent diabetes (IDDM), an overactivity of sodium-lithium countertransport (Na+/Li+ CT) has been associated with the risk of nephropathy and hypertension, two conditions of insulin resistance. We investigated the sensitivity to insulin with a hyperinsulinemic (approximately 719 pM [approximately 100 microU/ml]) euglycemic clamp in two groups of normotensive nonproteinuric IDDM patients; 12 (10 men, 2 women) had high Na+/Li+ CT activity (mean 0.47, range 0.42-0.68 mmol/L red blood cells [RBC]/h, group 1) and 12 (9 men, 3 women) had normal Na+/Li+ CT activity (mean 0.24, range 0.12-0.31 mmol/L RBC/h, group 2). The two groups were similar in age (mean +/- SE 36 +/- 2 vs. 33 +/- 1 yr), duration of diabetes (19 +/- 3 vs. 18 +/- 2 yr), body mass index (26 +/- 0.8 vs. 24 +/- 0.6 kg/m2), arterial blood pressure (systolic/diastolic 121 +/- 4/79 +/- 2 vs. 122 +/- 3/77 +/- 2 mmHg), and glycemic control (HbA1 8.5 +/- 0.4 vs. 8.0 +/- 0.4%). Albumin excretion rate (AER) ranged between 4.7 and 148 (geometric mean 14) micrograms/min in group 1 and between 2.7 and 93 (geometric mean 11) micrograms/min in group 2. There were four microalbuminuric patients (AER greater than 30 micrograms/min) in each group. Whole-body glucose uptake was significantly reduced on average in group 1 compared with group 2 (41.6 +/- 2.2 mumol.kg-1.min-1 [7.48 +/- 0.4 mg.kg-1.min-1] vs. 49.6 +/- 2.2 mumol.kg-1.min-1 [8.93 +/- 0.4 mg.kg-1.min-1, P = 0.03), but some overlap existed between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Mutation analysis of the MECP2 gene in British and Italian Rett syndrome females.

Rett syndrome is an X-linked dominant neurological disorder, which appears to be the commonest genetic cause of profound combined intellectual and physical disability in Caucasian females. Recently, this syndrome has been associated with mutations of the MECP2 gene, a transcriptional repressor of still unknown target genes. Here we report a detailed mutational analysis of 62 patients from UK and Italian archives, representing the first comparative study among different populations and one of the largest number of cases so far analyzed. We review the literature on MECP2 mutations in Rett syndrome. This analysis has permitted us to produce a map of the recurrent mutations identified in this and previous studies. Bioinformatic analysis of the mutations, taking advantage of structural and evolutionary data, leads us to postulate the existence of a new functional domain in the MeCP2 protein, which is conserved among brain-specific regulatory factors.

Cryptic von Hippel-Lindau disease: germline mutations in patients with haemangioblastoma only.

OBJECTIVES: Central nervous system haemangioblastoma (HAB) is a major feature of von Hippel-Lindau (VHL) disease, and it is estimated that about 30% of HAB patients have VHL disease. Consequently, it is widely recommended that sporadic HAB patients are screened for clinical and radiological features of VHL disease because of the risk of multiple tumours. We investigated the frequency of VHL germline mutations in patients with HAB only with no clinical or radiological evidence of VHL disease to define the role of molecular genetic analysis in the management of such patients. METHODS: Eighty four patients with a single HAB (23 Dutch, 61 UK) and four with multiple HAB (two Dutch, two UK) were studied by direct sequencing of the coding region and quantitative Southern blotting. RESULTS: A VHL germline mutation was found in three of 69 (4.3%) single HAB patients aged 50 years or less (three of 84 (3.6%) total single HAB patients). A germline VHL mutation was detected in a 44 year old woman with a solitary cerebellar HAB, as well as in four clinically unaffected close relatives, and in two single HAB cases presenting at the ages of 29 and 36 years. Germline VHL mutations were detected in two of four cases with multiple HAB. CONCLUSIONS: Early detection of VHL disease is important to reduce morbidity and mortality and therefore we recommend that, in addition to conventional clinical and radiological investigations, VHL gene mutation analysis should be offered to all HAB patients younger than 50 years. HAB patients aged >50 years will have a lower a priori risk of VHL disease and further data are required to evaluate the role of routine molecular genetic investigations in late onset HAB cases. The failure to detect germline VHL mutations in some patients with multiple HAB may indicate the presence of somatic mosaicism or additional HAB susceptibility genes.

Limb girdle and facial weakness in female carriers of X-linked myotubular myopathy mutations.

Although X-linked myotubular myopathy (XLMTM) is a recessive disorder, heterozygous female carriers of MTM1 mutations may present with limb girdle and facial weakness. It is proposed that manifesting heterozygote females with XLMTM have a skewed pattern of X-chromosome inactivation. However, skewed X-chromosome inactivation was not detected in either the lymphocyte or muscle DNA of a woman who presented with limb girdle/facial weakness and was found to be heterozygous for the R224X mutation.

Biodegradable emboli and antibody targetting of colorectal and gastric hepatic metastases: a pilot study.

The effect of degradable starch microspheres (DSM) on the passage of a low molecular weight marker through the liver of patients with metastases was compared with the passage of an anti-carcinoembryonic antigen monoclonal antibody. In all six patients studied DSM reduced the passage of the marker into the systemic circulation. In three patients who received labelled whole antibody, DSM had no effect. In two of three who received antibody fragments a similar delay to the low molecular weight marker was observed. This delay is likely to be a result of the smaller size of the fragments and may represent accumulation within the extravascular space.

Effect of propranolol on respiratory function and exercise tolerance in patients with chronic obstructive lung disease.

Ten patients with chronic obstructive lung disease (COLD) (group 1) and five patients with combined COLD and cardiac disease (group 2) were studied at rest and during exercise after an intravenous (IV) slaine control followed by IV propranolol (0.2 mg/kg). During rest propranolol did not alter significantly measurements of lung volume in groups 1 or 2. Following propranolol the mean airway resistance (AR) in group 1 increased from 4.49 to 5.2 cm H2O/L/sec (P smaller than 0.02) and airway conductance (Gaw) decreased from 0.28 to 0.24 L/sec-1 cm. H2O1 (P smaller than 0.02). In group 2 following propranolol, the mean AR increased from 3.60 to 4.67 cm H2O1 (P smaller than 0.05), and Gaw decreased from 0.30 to 0.23 L/sec-1/cm H2O1 (P smaller than 0.05). During exercise, from control to propranolol, the heart rate (HR), blood pressure (BP), and heart rate blood pressure (HR x BP) decreased significantly for both groups 1 and 2 except for the systolic pressure in group 2. The duration of exercise and exercising PO2 were not significantly altered from control to propranolol in groups 1 and 2, indicating that the small but statistically significant changes in AR and Gaw did not interfere with symptom tolerated maximal exercise in these patients and were therefore not clinically important.

Pulmonary toxicity recurring after a six week course of busulfan therapy and after subsequent therapy with uracil mustard.

A growing number of drugs, including a number of alkylating agents, have been implicated as the cause of pulmonary diseases. A patient with chronic myelogenous leukemia presented with typical cytology, biopsy, and roentgenologic findings of lung toxicity after only six weeks of therapy with busulfan. There was subsequent clearing. A similar roentgenologic change also occurred after administration of uracil mustard. This has not been reported previously.

Effects of theophylline on breathlessness and exercise tolerance in patients with chronic airflow obstruction.

Theophylline is commonly prescribed for patients with nonasthmatic chronic airflow obstruction (CAO) even though clinical efficacy is not well established. We studied objective and subjective responses to theophylline in 14 men with CAO. Subjects randomly received week-long treatments of placebo or theophylline at two dosages: one that produced low (8.7-13.0 micrograms/ml) and the other high (16.0-23.6 micrograms/ml plasma concentrations. During the final three days of each treatment, we measured spirometric and hemodynamic function. Exercise tolerance was assessed with the 12 minute walk and progressive cycle ergometry. The patients' perception of breathlessness during the usual activities of daily living was evaluated with the oxygen cost diagram and the breathlessness rating. For low and high dose theophylline there were significant (p less than .05) increases in forced vital capacity (7.1 +/- 2.1 percent; 12.0 +/- 1.7 percent), forced expiratory volume at one second (14.6 +/- 4.9 percent; 12.1 +/- 3.3 percent) and in pulse rate (8.3 +/- 1.2 percent; 19.1 +/- 3.1 percent), but no changes in blood pressure. There were also no significant differences among the three treatments for any of the tests which assessed exercise tolerance or breathlessness. These results suggest that most patients with CAO experience little symptomatic benefit from taking theophylline.

Demonstration of carcinoembryonic antigen (CEA) expression in normal, chronically inflamed, and malignant pancreatic tissue by immunohistochemistry.

The expression of carcinoembryonic antigen (CEA) was evaluated by immunoperoxidase staining with two anti-CEA monoclonal antibodies in normal, chronically inflamed, and malignant pancreatic tissue. Positive staining was not observed in normal specimens. In pancreatic cancer the expression of CEA was related to the degree of differentiation of the tumour. Positive staining was also observed in chronic pancreatitis.

Expression of CEA, CA125, CA19-9 and human milk fat globule membrane antigen in ovarian tumours.

The expression of five different antigens in ovarian tumours was studied by means of an immunohistochemical test with anti-CEA, HMFG1 and HMFG2, NS19-9 and OC125 antibodies. Considerable variation was noted not only between different histological types and between tumours of one type but also between areas in a single tumour. HMFG1 and HMFG2 were the most reactive of all the antibodies; NS19-9 and OC125 were expressed by different populations of cells. It is concluded that specific combinations of antibodies are more effective both for the monitoring of ovarian cancer as well as for immunodiagnosis and treatment, than any single one used.

Oxytocin augmentation of labor and perinatal outcome in nulliparas.

Recent pharmacologic observations in vivo suggest the use of a lower starting dose (0.5-0.1 mU/minute) of oxytocin and a longer interval between dose augmentations (30-60 minutes) than previously advocated. In this study, a high-dose oxytocin protocol was used to augment nonprogressive labor in normal nulliparous women. The rate of oxytocin infusion started at 6 mU/minute and was increased by 6 mU/minute every 15 minutes to a maximum dose of 40 mU/minute. Charts were reviewed of 1080 nulliparous women for whom the principles of active management of labor were followed and delivery occurred between March 1, 1986 and December 31, 1988. Four hundred fifty-six who required oxytocin augmentation in labor were compared with 624 who did not receive oxytocin. There were no statistically significant differences in birth asphyxia or perinatal morbidity.

Inducible proteinase of Candida albicans in diagnostic serology and in the pathogenesis of systemic candidosis.

The extracellular acid proteinase of Candida albicans was purified from culture filtrates by a single-column chromatographic step. The purity of the enzyme and its unique antigenic properties were confirmed by polyacrylamide-gel electrophoresis and by reaction with homologous and heterologous anti-sera. The purified enzyme (PP), which was a carboxyl proteinase, contained mannan as an integral part of the molecule. C. albicans proteinase was detected in experimental candida kidney lesions by indirect immunoflourescence. Precipitating antibodies to PP and to cytoplasmic extract (CE) were detected in sera from rabbits with chronic, experimental, systemic candidosis; however precipitins to PP were not found in sera from infected rabbits in which tissue invasion was prevented by antifungal treatment. In retrospective tests with sera from healthy subjects and from patients with and without proven systemic candidosis a qualitative distinction between true and false-positive precipitins to PP was not found; however, whereas 72% of sera from proven cases of deep-seated candida infection had anti-PP titres greater than 4 and greater than or equal to anti-CE titres, these same quantitative criteria were met by only 15% of sera from patients for whom information of a diagnosis of candidosis was not available. The purified proteinase was therefore a more specific antigen than the widely used cytoplasmic extract for detection of antibodies in cases of candidosis.