GDF15 linked to maternal risk of nausea and vomiting during pregnancy.

GDF15, a hormone acting on the brainstem, has been implicated in the nausea and vomiting of pregnancy, including its most severe form, hyperemesis gravidarum (HG), but a full mechanistic understanding is lacking1-4. Here we report that fetal production of GDF15 and maternal sensitivity to it both contribute substantially to the risk of HG. We confirmed that higher GDF15 levels in maternal blood are associated with vomiting in pregnancy and HG. Using mass spectrometry to detect a naturally labelled GDF15 variant, we demonstrate that the vast majority of GDF15 in the maternal plasma is derived from the feto-placental unit. By studying carriers of rare and common genetic variants, we found that low levels of GDF15 in the non-pregnant state increase the risk of developing HG. Conversely, women with ß-thalassaemia, a condition in which GDF15 levels are chronically high5, report very low levels of nausea and vomiting of pregnancy. In mice, the acute food intake response to a bolus of GDF15 is influenced bi-directionally by prior levels of circulating GDF15 in a manner suggesting that this system is susceptible to desensitization. Our findings support a putative causal role for fetally derived GDF15 in the nausea and vomiting of human pregnancy, with maternal sensitivity, at least partly determined by prepregnancy exposure to the hormone, being a major influence on its severity. They also suggest mechanism-based approaches to the treatment and prevention of HG.

Fetally-encoded GDF15 and maternal GDF15 sensitivity are major determinants of nausea and vomiting in human pregnancy.

Human pregnancy is frequently accompanied by nausea and vomiting that may become severe and life-threatening, as in hyperemesis gravidarum (HG), the cause of which is unknown. Growth Differentiation Factor-15 (GDF15), a hormone known to act on the hindbrain to cause emesis, is highly expressed in the placenta and its levels in maternal blood rise rapidly in pregnancy. Variants in the maternal GDF15 gene are associated with HG. Here we report that fetal production of GDF15, and maternal sensitivity to it, both contribute substantially to the risk of HG. We found that the great majority of GDF15 in maternal circulation is derived from the feto-placental unit and that higher GDF15 levels in maternal blood are associated with vomiting and are further elevated in patients with HG. Conversely, we found that lower levels of GDF15 in the non-pregnant state predispose women to HG. A rare C211G variant in GDF15 which strongly predisposes mothers to HG, particularly when the fetus is wild-type, was found to markedly impair cellular secretion of GDF15 and associate with low circulating levels of GDF15 in the non-pregnant state. Consistent with this, two common GDF15 haplotypes which predispose to HG were associated with lower circulating levels outside pregnancy. The administration of a long-acting form of GDF15 to wild-type mice markedly reduced subsequent responses to an acute dose, establishing that desensitisation is a feature of this system. GDF15 levels are known to be highly and chronically elevated in patients with beta thalassemia. In women with this disorder, reports of symptoms of nausea or vomiting in pregnancy were strikingly diminished. Our findings support a causal role for fetal derived GDF15 in the nausea and vomiting of human pregnancy, with maternal sensitivity, at least partly determined by pre-pregnancy exposure to GDF15, being a major influence on its severity. They also suggest mechanism-based approaches to the treatment and prevention of HG.

Multifocal calcific periarthritis with distinctive clinical and radiological features in patients with CD73 deficiency.

OBJECTIVES: Arterial calcification due to deficiency of CD73 (ACDC) is a hereditary autosomal recessive ectopic mineralization syndrome caused by loss-of-function mutations in the ecto-5'-nucleotidase gene. Periarticular calcification has been reported but the clinical characterization of arthritis as well as the microstructure and chemical composition of periarticular calcifications and SF crystals has not been systematically investigated. METHODS: Eight ACDC patients underwent extensive rheumatological and radiological evaluation over a period of 11 years. Periarticular and synovial biopsies were obtained from four patients. Characterization of crystal composition was evaluated by compensated polarized light microscopy, Alizarin Red staining for synovial fluid along with X-ray diffraction and X-ray micro tomosynthesis scanner for periarticular calcification. RESULTS: Arthritis in ACDC patients has a clinical presentation of mixed erosive-degenerative joint changes with a median onset of articular symptoms at 17 years of age and progresses over time to the development of fixed deformities and functional limitations of small peripheral joints with, eventually, larger joint and distinct axial involvement later in life. We have identified calcium pyrophosphate and calcium hydroxyapatite (CHA) crystals in SF specimens and determined that CHA crystals are the principal component of periarticular calcifications. CONCLUSION: This is the largest study in ACDC patients to describe erosive peripheral arthropathy and axial enthesopathic calcifications over a period of 11 years and the first to identify the composition of periarticular calcifications and SF crystals. ACDC should be considered among the genetic causes of early-onset OA, as musculoskeletal disease signs may often precede vascular symptoms.

Patient powered prophylaxis: A 12-month study of individualized prophylaxis in adults with severe haemophilia A.

INTRODUCTION: Adults with severe haemophilia A (SHA) may experience breakthrough bleeds despite standard weight-based FVIII prophylaxis three times weekly. Individualized prophylaxis has evolved to optimize patient outcomes. AIMS: This study aimed to evaluate the impact of a standardized approach to individualized prophylaxis on annualized bleeding rates (ABR), factor utilization, physical activity and quality of life in adults with SHA. METHODS: In this prospective cohort study, patients with baseline FVIII:C <2% and ABR >3 on weight-based prophylaxis received a standardized approach to individualized prophylaxis. Changes in ABR, annualized FVIII consumption and adherence from the 12-month prestudy and 12-month intervention period were compared. Changes in Haemo-QoL-A total score, Physical Functioning (PF) subscale and physical activity level measured by accelerometry were also examined. RESULTS: Eighteen patients participated (median age 26 years). Individualized prophylaxis decreased total bleeds in the population by 69% and traumatic bleeds by 73%. The median ABR decreased from 7.5 to 2 (P<.001). Annualized factor consumption increased by 7.3%, as a result of 66% reduction in factor utilization for treatment of bleeds and 25% increase in factor utilization for prophylaxis. Adherence scores for frequency and dosing did not change. There was a significant increase in the Haemo-QoL-A total score (P=.02) and PF score (P=.01) from baseline to 4 months but no change in physical activity. CONCLUSION: Patients with SHA who switched from standard to individualized prophylaxis show reduced ABR and increased FVIII consumption, and also improved their health-related quality of life. The mechanism is independent of adherence to prescribed prophylactic regimen.

Autoimmune Neutropenia Updates: Etiology, Pathology, and Treatment.

Autoimmune neutropenia (AIN) is defined as a neutrophil count <1.5 × 109/L caused by increased peripheral destruction of neutrophils from an underlying autoimmune mechanism in which autoantibodies are directed against a patient's own neutrophils. AIN has a multifactorial etiology ranging from an idiopathic primary phenomenon to secondary disorders associated with established autoimmune diseases. Primary AIN is more prevalent in children, generally self-limited, and typically manifests as a sole hematologic abnormality. Secondary AIN is more common in adults and often occurs in the setting of concurrent autoimmune diseases, infections, malignancies, or medications. It may be seen posttransplantation or occasionally with neurological diseases. Various laboratory modalities are used to detect anti-neutrophil antibodies. Although biologic agents such as rituximab and alemtuzumab (Campath-1H) have been used in the management of AIN, granulocyte colony-stimulating factor remains the first-line therapy. In this article we provide a review of the pathogenesis of AIN, its clinical presentation, and the current treatment options.

Landau-Zener-Stückelberg Interferometry in Quantum Dots with Fast Rise Times: Evidence for Coherent Phonon Driving.

Manipulating qubits via electrical pulses in a piezoelectric material such as GaAs can be expected to generate incidental acoustic phonons. In this Letter we determine theoretically and experimentally the consequences of these phonons for semiconductor spin qubits using Landau-Zener-Stückelberg interferometry. Theoretical calculations predict that phonons in the presence of the spin-orbit interaction produce both phonon-Rabi fringes and accelerated evolution at the singlet-triplet anticrossing. Observed features confirm the influence of these mechanisms. Additionally, evidence is found that the pulsed gates themselves act as phonon cavities increasing the influence of phonons under specific resonant conditions.

Comparing the effectiveness of nasal dilator strips: does race play a role?

BACKGROUND: Nasal dilator strips are thought to widen and stiffen the anterior nasal cavity, and thus improve symptoms of nasal obstruction. It is postulated that anthropomorphic differences in external nasal proportions between races may influence the effectiveness of such dilator strips. METHODS: Caucasian and Asian subjects were compared. Nasal peak inspiratory flow, nasal airway resistance, minimum cross-sectional area and visual analogue scale measurements of nasal obstruction were recorded at baseline and following the application of two different dilator strips. RESULTS: Nine Caucasian and six Asian subjects were recruited (n = 15). There was a significant difference between races in terms of nasal peak inspiratory flow improvements following nasal strip application (mean of 29.4 litres per minute in Caucasians vs 14.6 litres per minute in Asians; p = 0.04). Only Caucasians experienced a significant decrease in nasal airway resistance (median of 0.12 Pa/cm3/s; p < 0.01). CONCLUSION: Nasal peak inspiratory flow, minimum cross-sectional area and visual analogue scale values improved from baseline with strip application in both populations. Only Caucasians experienced significant nasal airway resistance improvement with strip application. Both cohorts experienced nasal peak inspiratory flow improvement, with Caucasians experiencing a significantly larger improvement.

Fibres found in the eye during and after phacoemulsification cataract surgery.

PURPOSE: Fibres are regularly found within the delivery cartridge (DC) and in the anterior chamber (AC) during phacoemulsification cataract surgery (PCS) and postoperatively. The purpose of this study was to identify their frequency and possible significance. SETTING: Dedicated ophthalmic day surgery. DESIGN: Prospective, consecutive, single-surgeon, cohort study. METHODS: In 639 eyes undergoing PCS, the presence of fibres was documented in or on both the DC and in the AC intraoperatively, and in the AC postoperatively. The intraoperative method of fibre removal was documented. Corrected distance visual acuity (CDVA) was recorded preoperatively, and at day 1, week 1, and week 4 postoperatively. The incidence of clinical cystoid macular oedema (CMO) and endophthalmitis in the retained fibre subcohort was compared with that of the non-fibre subcohort. RESULTS: A total of 5.2% of the operated eyes had a fibre or fibres in or on the DC, which in all cases was removed with forceps intraoperatively. A total of 14.6% of operated eyes had a fibre or fibres in the AC intraoperatively; these were removed by irrigation/aspiration. Postoperatively, five eyes (0.78%) had a fibre in the AC. There was no significant difference in postoperative CDVA between the fibre and non-fibre subcohorts (P=0.26), and no clinically significant CMO or endophthalmitis in either subcohort. CONCLUSIONS: Most fibres seen on the DC or in the eye are sterile and non-inflammatory. However, there have been reports of endophthalmitis attributed to retained fibres. In this study, there were no complications attributable to the fibres, but their removal may minimise any adverse potential.

Long-range spin transfer in triple quantum dots.

Tunneling in a quantum coherent structure is not restricted to only nearest neighbors. Hopping between distant sites is possible via the virtual occupation of otherwise avoided intermediate states. Here we report the observation of long-range transitions in the transport through three quantum dots coupled in series. A single electron is delocalized between the left and right quantum dots, while the center one remains always empty. Superpositions are formed, and both charge and spin are exchanged between the outermost dots. The delocalized electron acts as a quantum bus transferring the spin state from one end to the other. Spin selection is enabled by spin correlations. The process is detected via the observation of narrow resonances which are insensitive to Pauli spin blockade.

Bipolar spin blockade and coherent state superpositions in a triple quantum dot.

Spin qubits based on interacting spins in double quantum dots have been demonstrated successfully. Readout of the qubit state involves a conversion of spin to charge information, which is universally achieved by taking advantage of a spin blockade phenomenon resulting from Pauli's exclusion principle. The archetypal spin blockade transport signature in double quantum dots takes the form of a rectified current. At present, more complex spin qubit circuits including triple quantum dots are being developed. Here we show, both experimentally and theoretically, that in a linear triple quantum dot circuit the spin blockade becomes bipolar with current strongly suppressed in both bias directions and also that a new quantum coherent mechanism becomes relevant. In this mechanism, charge is transferred non-intuitively via coherent states from one end of the linear triple dot circuit to the other, without involving the centre site. Our results have implications for future complex nanospintronic circuits.

The pentacyclic triterpenoids in herbal medicines and their pharmacological activities in diabetes and diabetic complications.

Pentacyclic triterpenoids including the oleanane, ursane and lupane groups are widely distributed in many medicinal plants, such as Glycyrrhiza species, Gymnema species, Centella asiatica, Camellia sinensis, Crataegus species and Olea europaea, which are commonly used in traditional medicine for the treatment of diabetes and diabetic complications. A large number of bioactive pentacyclic triterpenoids, such as oleanolic acid, glycyrrhizin, glycyrrhetinic acid, ursolic acid, betulin, betulinic acid and lupeol have shown multiple biological activities with apparent effects on glucose absorption, glucose uptake, insulin secretion, diabetic vascular dysfunction, retinopathy and nephropathy. The versatility of the pentacyclic triterpenes provides a promising approach for diabetes management.

Quantum interference between three two-spin states in a double quantum dot.

Qubits based on the singlet (S) and the triplet (T(0), T(+)) states in double quantum dots have been demonstrated in separate experiments. It has been recently proposed theoretically that under certain conditions a quantum interference could occur from the interplay between these two qubit species. Here we report experiments and modeling that confirm these theoretical predictions and identify the conditions under which this interference occurs. Density matrix calculations show that the interference pattern manifests primarily via the occupation of the common singlet state. The S/T(0) qubit is found to have a much longer coherence time as compared to the S/T(+) qubit.