Mouse TIGIT inhibits NK‐cell cytotoxicity upon interaction with PVR

The activity of natural killer (NK) cells is controlled by a balance of signals derived from inhibitory and activating receptors. TIGIT is a novel inhibitory receptor, recently shown in humans to interact with two ligands: PVR and Nectin2 and to inhibit human NK‐cell cytotoxicity. Whether mouse TIGIT (mTIGIT) inhibits mouse NK‐cell cytotoxicity is unknown. Here we show that mTIGIT is expressed by mouse NK cells and interacts with mouse PVR. Using mouse and human Ig fusion proteins we show that while the human TIGIT (hTIGIT) cross‐reacts with mouse PVR (mPVR), the binding of mTIGIT is restricted to mPVR. We further demonstrate using surface plasmon resonance (SPR) and staining with Ig fusion proteins that mTIGIT binds to mPVR with higher affinity than the co‐stimulatory PVR‐binding receptor mouse DNAM1 (mDNAM1). Functionally, we show that triggering of mTIGIT leads to the inhibition of NK‐cell cytotoxicity, that IFN‐γ secretion is enhanced when mTIGIT is blocked and that the TIGIT‐mediated inhibition is dominant over the signals delivered by the PVR‐binding co‐stimulatory receptors. Additionally, we identify the inhibitory motif responsible for mTIGIT inhibition. In conclusion, we show that TIGIT is a powerful inhibitory receptor for mouse NK cells.     

Dynamic assays of inhibin B, anti-Mullerian hormone and estradiol following FSH stimulation and ovarian ultrasonography as predictors of IVF outcome

BACKGROUND: We evaluated basal and dynamic hormonal markers [(FSH, inhibin B, estradiol and anti-Mullerian hormone (AMH)] during the follicular phase and luteal phase of the menstrual cycle and ultrasonic ovarian morphology as predictors of IVF outcome. METHODS: Fifty-six women, aged <38 years, with normal day 3 FSH levels were included prospectively. Serum estradiol, inhibin B and AMH were measured before and 24 h after administration of 300 IU of recombinant FSH on cycle day 3-4 and during the luteal phase. Ovarian volume and antral follicle count (AFC) were evaluated on cycle day 3-4. The predictive value of oocyte number and pregnancy were assessed using uni- and multivariate analysis. RESULTS:Poor responders (<6 oocytes) had significantly lower luteal AMH levels, while high responders (>20 oocytes) had significantly higher AFC, AMH and luteal stimulated inhibin B and estradiol than normal responders. Multivariate regression analyses showed that the best models for predicting oocyte number included AFC, follicular phase AMH and stimulated inhibin B. Only AMH showed a significant difference between pregnant and non-pregnant women at both cycle phases. CONCLUSIONS: In young women (<38 years), AFC or basal AMH and stimulated inhibin B predict ovarian response for IVF. The only predictor for pregnancy is follicular or luteal phase AMH.     

Does optimal follicular size in IUI cycles vary between clomiphene citrate and gonadotrophins treatments?

Objective: To evaluate pregnancy-related leading follicles during ovulation induction and superovulation with clomiphene citrate (CC) or gonadotropin.

Design: Retrospective cohort.

Patients: Five hundred and forty-two women who underwent a total of 615 treatment cycles with CC or gonadotropin.

Intervention: We evaluated the effects of CC and gonadotropin on the leading follicles, clinical pregnancy rates and miscarriage rate.

Results: The number of follicles larger than 15?mm in the different protocols was comparable. In those treated with CC, the diameter of the dominant follicles before human chorionic gonadotropins (hCG) trigger in the conception cycles (20.4?±?1.2?mm) was significantly larger than in the non-conception cycles (18.8?±?1.9?mm). In women treated with gonadotropin, the diameter of the leading follicle in the conception cycles (18.5?±?1.7?mm) was comparable to that in the non-conception cycles (18.2?±?1.7?mm). The pregnancy-related diameter of the leading follicle in CC cycles (20.4?±?1.2?mm) was significantly larger than that in gonadotropin cycles (18.8?±?1.9?mm; p?=?0.001; 95% CI, ?2.2 to ?0.9).

Conclusion: Pregnancy-related diameter of the leading follicle in CC cycles is significantly larger than that in gonadotropin cycles and the best time for hCG trigger in the CC cycle is when the leading follicle reaches 20?mm.     

Corrected-QT intervals as related to methadone dose and serum level in methadone maintenance treatment (MMT) patients: a cross-sectional study

AIMS: To determine and evaluate QTc intervals in electrocardiograms (ECGs) of former heroin addicts, currently in methadone maintenance treatment (MMT), as previous reports suggest that methadone may prolong QTc intervals, thus possibly increasing the risk for Torsade de pointes (TdP). DESIGN: Cross-sectional study. SETTING: Between January 2003 and September 2004, patients on a steady dose of methadone for at least 2 weeks were studied. PARTICIPANTS: This study is a subset of 153 patients, of whom 151 patients participated in a study of high methadone doses and serum levels. A total of 138 patients in MMT for a minimum of 100 days up to 10.7 years, receiving 40-290 mg/day methadone dose, participated. MEASUREMENTS: Patients had an ECG at the time when blood was drawn for determination of serum methadone levels at around 24 hours after the last oral methadone dose. Corrected-QT intervals (QTc) were calculated using the Bazett formula. FINDINGS: Of 138 patients studied, 98 (71%) were male. Mean QTc interval was 418.3 +/- 32.8 milliseconds (ms). Mean methadone dose was 170.9 +/- 50.3 mg/day and mean serum methadone level was 708.2 +/- 363.1 ng/ml. Methadone dose and serum levels did not correlate with QTc. Three patients had QTc intervals above 500 ms ('prolonged'). After 2 +/- 0.4 years of follow-up, two patients died; they were two of three patients with very prolonged QTc. Causes of death were not attributed to cardiac origin. An additional 19 patients had QTc intervals of between 450 and 499 ms ('possibly prolonged'). None of these QTc > or = 450 ms patients had any cardiac problems. Methadone doses of all 22 patients were > 120 mg/day. CONCLUSIONS: Methadone maintenance is generally safe; however, the possible toxicity of high dose (> 120 mg/day) should be monitored for QTc.     

Stent implantation for coarctation of aorta caused by a Rashkind patent ductus arteriosus umbrella.

This case demonstrates a novel use of stent implantation for relief of coarctation of the aorta caused by protrusion of a Rashkind patent ductus arteriosus umbrella. Follow-up 3 years after stent implantation shows complete relief of obstruction.     

Transcatheter closure of large congenital coronary‐cameral fistulae with Amplatzer devices

Objectives : To report on the methods and results of treatment of large congenital coronary‐cameral fistulae by transcatheter closure with Amplatzer devices. Background : Large coronary‐cameral fistulae cause a steal phenomenon from the normal coronary circulation. Surgical closure is an option. However, transcatheter methods allow for temporary occlusion, definition of anatomy, and online assessment of successful closure. Amplatzer devices are compact occluders that can be fully delivered, collapsed, and repositioned until a satisfactory position is attained. Methods : Coronary and fistula anatomy were defined by selective coronary angiography with or without temporary occlusion. Device closure of the fistula was performed at the most distal point accessible, often from the cameral side using an arteriovenous loop method. Results : Ten patients of median age 2.6 years (0.5–52.2) and weight 14.4 kg (6.1–67) underwent an attempt at transcatheter closure of a large fistula. In nine patients, the fistula was closed successfully with a device. There were no complications. Conclusions : Transcatheter closure of coronary‐cameral fistula with Amplatzer devices is safe and effective. © 2009 Wiley‐Liss, Inc.     

Locked-in your heart-shaped box: Familial-role and attachment orientation as predictors of grief in prolonged disorders of consciousness vs. death

Abstract

Death or prolonged disorders of consciousness (DOC) of a loved one are both considered relational-losses that severely disrupt attachment-bonds. Grief in both conditions was compared by exploring the impact of familial-role and attachment-orientation. In DOC, caregivers’ grief was found significantly intensified relative to Death. Familial-role impacted grief in both conditions alike, with partners' heightened grief in DOC reflecting the complexity of their stagnant bonds. In Death, avoidance-attachment mitigated grief, while in DOC anxiety-attachment accentuated grief, we suggest that while physical-separation in death facilitates the modification of continuing attachment-schema, in DOC, modification may be required while the patient is still alive.