Altered peripheral immune profiles in treatment-resistant depression: response to ketamine and prediction of treatment outcome.

A subset of patients with depression have elevated levels of inflammatory cytokines, and some studies demonstrate interaction between inflammatory factors and treatment outcome. However, most studies focus on only a narrow subset of factors in a patient sample. In the current study, we analyzed broad immune profiles in blood from patients with treatment-resistant depression (TRD) at baseline and following treatment with the glutamate modulator ketamine. Serum was analyzed from 26 healthy control and 33 actively depressed TRD patients free of antidepressant medication, and matched for age, sex and body mass index. All subjects provided baseline blood samples, and TRD subjects had additional blood draw at 4 and 24 h following intravenous infusion of ketamine (0.5 mg kg-1). Samples underwent multiplex analysis of 41 cytokines, chemokines and growth factors using quantitative immunoassay technology. Our a priori hypothesis was that TRD patients would show elevations in canonical pro-inflammatory cytokines; analyses demonstrated significant elevation of the pro-inflammatory cytokine interleukin-6. Further exploratory analyses revealed significant regulation of four additional soluble factors in patients with TRD. Several cytokines showed transient changes in level after ketamine, but none correlated with treatment response. Low pretreatment levels of fibroblast growth factor 2 were associated with ketamine treatment response. In sum, we found that patients with TRD demonstrate a unique pattern of increased inflammatory mediators, chemokines and colony-stimulating factors, providing support for the immune hypothesis of TRD. These patterns suggest novel treatment targets for the subset of patients with TRD who evidence dysregulated immune functioning.

The deubiquitinating enzyme DUBAI stabilizes DIAP1 to suppress Drosophila apoptosis.

Deubiquitinating enzymes (DUBs) counteract ubiquitin ligases to modulate the ubiquitination and stability of target signaling molecules. In Drosophila, the ubiquitin-proteasome system has a key role in the regulation of apoptosis, most notably, by controlling the abundance of the central apoptotic regulator DIAP1. Although the mechanism underlying DIAP1 ubiquitination has been extensively studied, the precise role of DUB(s) in controlling DIAP1 activity has not been fully investigated. Here we report the identification of a DIAP1-directed DUB using two complementary approaches. First, a panel of putative Drosophila DUBs was expressed in S2 cells to determine whether DIAP1 could be stabilized, despite treatment with death-inducing stimuli that would induce DIAP1 degradation. In addition, RNAi fly lines were used to detect modifiers of DIAP1 antagonist-induced cell death in the developing eye. Together, these approaches identified a previously uncharacterized protein encoded by CG8830, which we named DeUBiquitinating-Apoptotic-Inhibitor (DUBAI), as a novel DUB capable of preserving DIAP1 to dampen Drosophila apoptosis. DUBAI interacts with DIAP1 in S2 cells, and the putative active site of its DUB domain (C367) is required to rescue DIAP1 levels following apoptotic stimuli. DUBAI, therefore, represents a novel locus of apoptotic regulation in Drosophila, antagonizing cell death signals that would otherwise result in DIAP1 degradation.

A controlled study for gender selection using swim-up separation.

OBJECTIVE: To evaluate the success for gender selection using a sample of semen separated by a modified swim-up technique. DESIGN: We retrospectively compared the gender outcome of two treatments (A and B) for either a male or female offspring with those who conceived spontaneously. SETTING: Private practice of one author (M. A.K.). PATIENTS, PARTICIPANTS: The treatment groups consisted of 52 total pregnancies for couples who conceived by the separation technique. Of these 52 participants, 15 desired a female offspring and were placed into treatment A and 37 desired a male offspring and were placed into treatment B. The control groups consisted of 162 women who were presented with initial consultation for gender selection and conceived spontaneously. Control group A consisted of 80 women who initially chose a female offspring, and control group B consisted of 82 participants who initially chose a male. INTERVENTIONS: In treatment group A, one timed intrauterine insemination (IUI) was carried out with the bottom 0.5 ml of the separated semen on cycle days 12-14, when the follicle was 18-22 mm. Patients in this group were also administered clomiphene citrate and human chorionic gonadotropin. In treatment group B, one timed IUI was done with the top 0.5 ml of the separated semen, when the follicle was 18-22 mm. MAIN OUTCOME MEASURE: The gender outcome of the pregnancies of two treatment and control groups was evaluated based on the known desired gender. RESULTS: The success rate for conceiving a female child after intervention (treatment group A) was 86.7% effective (p = 0.002) as compared to the control group A. Couples seeking a male child (treatment group B) were 89.2% effective (p = 0.0002) as compared to the control group B. CONCLUSIONS: This study reveals that the modified swim-up method with additional monitoring results in statistically significant gender preselection.