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.

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.

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.

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.

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.

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.

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.

Pancreatic beta cell function persists in many patients with chronic type 1 diabetes, but is not dramatically improved by prolonged immunosuppression and euglycaemia from a beta cell allograft.

AIMS/HYPOTHESIS: We measured serum C-peptide (at least 0.167 nmol/l) in 54 of 141 (38%) patients with chronic type 1 diabetes and sought factors that might differentiate those with detectable C-peptide from those without it. Finding no differences, and in view of the persistent anti-beta cell autoimmunity in such patients, we speculated that the immunosuppression (to weaken autoimmune attack) and euglycaemia accompanying transplant-based treatments of type 1 diabetes might promote recovery of native pancreatic beta cell function. METHODS: We performed arginine stimulation tests in three islet transplant and four whole-pancreas transplant recipients, and measured stimulated C-peptide in select venous sampling sites. On the basis of each sampling site's C-peptide concentration and kinetics, we differentiated insulin secreted from the individual's native pancreatic beta cells and that secreted from allografted beta cells. RESULTS: Selective venous sampling demonstrated that despite long-standing type 1 diabetes, all seven beta cell allograft recipients displayed evidence that their native pancreas secreted C-peptide. Yet even if chronic immunosuppression coupled with near normal glycaemia did improve native pancreatic C-peptide production, the magnitude of the effect was quite small. CONCLUSIONS/INTERPRETATION: Some native pancreatic beta cell function persists even years after disease onset in most type 1 diabetic patients. However, if prolonged euglycaemia plus anti-rejection immunosuppressive therapy improves native pancreatic insulin production, the effect in our participants was small. We may have underestimated pancreatic regenerative capacity by studying only a limited number of participants or by creating conditions (e.g. high circulating insulin concentrations or immunosuppressive agents toxic to beta cells) that impair beta cell function.

Psychometric properties of the Chinese (Cantonese) Tinnitus Handicap Inventory.

OBJECTIVES: To establish the reliability and validity of the Chinese (Cantonese) version of the Tinnitus Handicap Inventory to measure the self-perceived handicapping effect and severity of the condition in patients with chronic tinnitus. DESIGN: Cross-sectional psychometric validation study. SETTING: Audiology clinics in a hospital setting. PARTICIPANTS: Subjects were 114 adult Chinese who attended the audiology clinics with a complaint of tinnitus. MAIN OUTCOME MEASURES: Test-retest and internal consistency reliability; construct validity. RESULTS: The Chinese version of the Tinnitus Handicap Inventory and its subscales showed good internal consistency reliabilities (alpha = 0.72-0.94) that are comparable to those of the original version. High correlations were observed between the Tinnitus Handicap Inventory and psychological distress, tinnitus-related problem ratings and severity ratings. Factor analysis showed that the Chinese version of the Tinnitus Handicap Inventory has a unifactorial structure. A high degree of test-retest reliability was observed (intraclass correlation coefficient = 0.88). CONCLUSIONS: The results suggest that the Chinese (Cantonese) version of the Tinnitus Handicap Inventory is a reliable and valid measure of general tinnitus-related distress that can be used in clinical settings to quantify the impact of tinnitus on daily life.

Oral rehabilitation of a patient with scleroderma associated with systematic lupus erythematosus: a case report.

This case report presents a patient who had a limited oral opening due to systematic lupus erythematosus (SLE) and describes how oral rehabilitation was achieved with a removable partial denture. Various techniques for the delivery of oral health care have been reported for patients who have limited mouth openings as a result of SLE and scleroderma. After a review of the literature, a new approach was required for this patient with SLE who had a very limited mouth opening. The retention for the removable partial denture (RPD) used the undercut in the abutment teeth and a magnet-retained sectional RPD. A set of tweezers was modified to help with the insertion and removal of the sectional RPD by the patient. This paper reports a new clinical and laboratory technique of fabricating a sectional RPD using magnets and customized tweezers for this patient.