Mutations in C8ORF37 cause Bardet Biedl syndrome (BBS21).

Bardet Biedl syndrome (BBS) is a multisystem genetically heterogeneous ciliopathy that most commonly leads to obesity, photoreceptor degeneration, digit anomalies, genito-urinary abnormalities, as well as cognitive impairment with autism, among other features. Sequencing of a DNA sample from a 17-year-old female affected with BBS did not identify any mutation in the known BBS genes. Whole-genome sequencing identified a novel loss-of-function disease-causing homozygous mutation (K102*) in C8ORF37, a gene coding for a cilia protein. The proband was overweight (body mass index 29.1) with a slowly progressive rod-cone dystrophy, a mild learning difficulty, high myopia, three limb post-axial polydactyly, horseshoe kidney, abnormally positioned uterus and elevated liver enzymes. Mutations in C8ORF37 were previously associated with severe autosomal recessive retinal dystrophies (retinitis pigmentosa RP64 and cone-rod dystrophy CORD16) but not BBS. To elucidate the functional role of C8ORF37 in a vertebrate system, we performed gene knockdown in Danio rerio and assessed the cardinal features of BBS and visual function. Knockdown of c8orf37 resulted in impaired visual behavior and BBS-related phenotypes, specifically, defects in the formation of Kupffer's vesicle and delays in retrograde transport. Specificity of these phenotypes to BBS knockdown was shown with rescue experiments. Over-expression of human missense mutations in zebrafish also resulted in impaired visual behavior and BBS-related phenotypes. This is the first functional validation and association of C8ORF37 mutations with the BBS phenotype, which identifies BBS21. The zebrafish studies hereby show that C8ORF37 variants underlie clinically diagnosed BBS-related phenotypes as well as isolated retinal degeneration.

The relationship between patient risk factors and early versus late postoperative emetic symptoms.

BACKGROUND: Postoperative nausea and vomiting (PONV) remain common complications after elective surgery. Prophylactic antiemetic drugs are frequently administered to patients with well known risk factors for developing PONV. We designed this prospective observational study to assess the relationship between common patient risk factors for developing PONV and the occurrence of early (0-24 h) versus late (24-72 h) emetic symptoms. METHODS: One hundred thirty patients undergoing elective laparoscopic (n = 88) or plastic (n = 42) surgery were assigned a risk score for developing PONV based on the Apfel risk scoring system, which assigns one point each for female gender, nonsmoking status, history of PONV or motion sickness, and postoperative opioid use. It was assumed that all patients would receive an opioid analgesic in the postoperative period. The patients received 0, 1, 2, or 3 antiemetic drugs for prophylaxis. The occurrence of nausea, vomiting, and need for rescue antiemetics was assessed at specific time intervals from 0 to 6, 6-24, and 24-72 h after surgery. In addition, the impact of PONV on recovery of normal activities of daily living was assessed using a standardized patient questionnaire. RESULTS: One or more prophylactic antiemetics were administered to 87%, 90%, and 95% of the patients in the two, three, and four Apfel risk-factor groups, respectively. In the presence of three or four risk factors, >/=2 antiemetics were administered to 56% and 75% of the patients, respectively. Vomiting was reported in 11% and 22% of patients in the three and four risk factor groups compared with 6% in the two risk factor group at 0-6 h, and 13% and 27% (vs 0%) at 6-24 h, respectively. However, in the 24-72 h postoperative period, the incidences of emesis were low and did not differ in the three risk groups (9%, 5%, and 11%, respectively). The occurrence of moderate-to-severe nausea was increased in the higher risk groups at 0-6 h and 6-24 h (19%-28% vs 6% and 20%-30% vs 9%, respectively). However, the incidences of nausea in the 24-72 h period in the three and four risk factor groups were not different from the two-risk factor group (5% and 8% vs 6%, respectively). The need for rescue antiemetics and interference of emetic symptoms with normal activities was greater in the four risk factor group compared with the two and three risk factor groups. CONCLUSION: Despite the frequent use of multiple antiemetic drugs for prophylaxis, an Apfel risk score of three or four (vs 2) was associated with a higher incidence of emetic sequelae in the first 24 h after surgery. However, the occurrence of late (24-72 h) emetic symptoms was low and appeared to be unrelated to the patient's Apfel risk score.

Doxylamine succinate-pyridoxine hydrochloride (Diclegis) for the management of nausea and vomiting in pregnancy: an overview.

Nausea and vomiting in pregnancy (NVP) is common and often undertreated, in part due to fears of adverse effects of medications on the fetus during early pregnancy. In April 2013, the US Food and Drug Administration (FDA) approved doxylamine succinate 10 mg and pyridoxine hydrochloride (a vitamin B6 analog) 10 mg as a delayed-release combination pill called Diclegis for the treatment of NVP. Diclegis is currently the only medication that is FDA-approved for the indication of NVP. This review addresses the historical context, safety, efficacy, pharmacology, and practical role of doxylamine and pyridoxine for the management of NVP. The reintroduction of this doxylamine-pyridoxine combination pill into the American market fills a therapeutic gap in the management of NVP left by the removal of the same active drugs marketed over 30 years ago in the form of Bendectin. The substantial amount of safety data accumulated over the years makes it one of the few drugs that qualify for FDA Pregnancy Category A status. In the hierarchical approach to pharmacological treatment of NVP, the combination of doxylamine and pyridoxine should thus be first-tier.

Neonatal survival after prolonged preterm premature rupture of membranes before 24 weeks of gestation.

OBJECTIVE: To evaluate neonatal survival after prolonged preterm premature rupture of membranes (PROM) in the era of antenatal corticosteroids, surfactant, and inhaled nitric oxide. METHODS: A single-center retrospective cohort study of neonates born from 2002-2011 after prolonged (1 week or more) preterm (less than 24 weeks of gestation) rupture of membranes was performed. The primary outcome was survival to discharge. Neonates whose membranes ruptured less than 24 hours before delivery (n=116) were matched (2:1) on gestational age at birth, sex, and antenatal corticosteroid exposure with neonates whose membranes ruptured 1 week or more before delivery (n=58). Analysis used conditional logistic regression for categorical data and Wilcoxon signed rank test for continuous data. RESULTS: The prolonged preterm PROM exposed and unexposed cohorts had survival rates of 90% and 95%, respectively, although underpowered to assess the statistical significance (P=.313). Exposed neonates were more likely have pulmonary hypoplasia (26/58 exposed, 1/114 unexposed, P<.001), pulmonary hypertension (21/56 exposed, 10/112 unexposed, P<.001), and pulmonary air leak (21/58 exposed, 14/114 unexposed, P<.001). Gestational age at rupture (20.4 weeks exposed, 22.3 weeks unexposed, P=.189), length of rupture (3.7 weeks exposed, 6.4 weeks unexposed, P=.717), and lowest maximal vertical pocket before 24 weeks of gestation (0 cm exposed, 1.4 cm unexposed, P=.114) did not discriminate between survivors and nonsurvivors after exposure to prolonged preterm PROM. CONCLUSION: With antenatal steroid exposure and aggressive pulmonary management, survival to discharge after prolonged preterm PROM was 90%. Pulmonary morbidities were common. Of note, the data were limited to women who remained pregnant 1 week or longer after rupture of membranes.

Placental and uterine pathology in women undergoing peripartum hysterectomy.

OBJECTIVE: To estimate if peripartum hysterectomies performed for intractable uterine atony have pathologic findings consistent with infection more often than those hysterectomies performed for other indications. METHODS: This is a retrospective cohort study of all consecutive peripartum hysterectomies at our institution from 1988 to 2009. Scheduled cesarean hysterectomies were excluded. Maternal, fetal, and pathologic data were obtained by medical record review. Pathologic evaluation was performed for each specimen per a standardized protocol. Patients undergoing hysterectomy for uterine atony were compared with those requiring hysterectomy for another indication. Pearson's χ and Student's t test were used for analysis. RESULTS: Of 324,654 deliveries during the study period, 558 (1.7%) women underwent emergent peripartum hysterectomies; 190 (34%) were for intractable uterine atony. Those requiring hysterectomy for uterine atony were more likely to be at term (87% compared with 62%), have clinical chorioamnionitis (19% compared with 6%), and have longer labors (8 hours compared with 2.5 hours). Certain placental pathologic findings were significantly more common in the atony group, including chorioamnionitis, umbilical vasculitis, chorionic plate vasculitis, and funisitis. Acute endometritis and cervicitis were also more common in the atony group. Conversely, abnormal placental implantation (37% compared with 8%) and leiomyomas (21% compared with 8%) were significantly more common in the group requiring hysterectomy for other indications. CONCLUSION: Patients requiring emergent peripartum hysterectomies as a result of intractable uterine atony are more likely to have clinical and pathologic findings consistent with acute inflammation and infection. LEVEL OF EVIDENCE: II.

FGF acts as a co-transmitter through adenosine A(2A) receptor to regulate synaptic plasticity.

Abnormalities of striatal function have been implicated in several major neurological and psychiatric disorders, including Parkinson's disease, schizophrenia and depression. Adenosine, via activation of A(2A) receptors, antagonizes dopamine signaling at D2 receptors and A(2A) receptor antagonists have been tested as therapeutic agents for Parkinson's disease. We found a direct physical interaction between the G protein-coupled A(2A) receptor (A(2A)R) and the receptor tyrosine kinase fibroblast growth factor receptor (FGFR). Concomitant activation of these two classes of receptors, but not individual activation of either one alone, caused a robust activation of the MAPK/ERK pathway, differentiation and neurite extension of PC12 cells, spine morphogenesis in primary neuronal cultures, and cortico-striatal plasticity that was induced by a previously unknown A(2A)R/FGFR-dependent mechanism. The discovery of a direct physical interaction between the A(2A) and FGF receptors and the robust physiological consequences of this association shed light on the mechanism underlying FGF functions as a co-transmitter and open new avenues for therapeutic interventions.

Effect of short-term postoperative celecoxib administration on patient outcome after outpatient laparoscopic surgery.

PURPOSE: Non-opioid analgesics are increasingly used as part of a multimodal regimen for pain management. This prospective, randomized, double-blinded, placebo-controlled study was designed to evaluate the effect of short-term postoperative administration of celecoxib on pain management and recovery outcomes following laparoscopic surgery. METHODS: Eighty consenting ASA I-III outpatients undergoing laparoscopic surgery were randomly assigned to one of two treatment groups: Control (placebo) or Celecoxib (celecoxib, 400 mg x day(-1)). The initial dose (celecoxib 400 mg or placebo po) was administered in the recovery room, and celecoxib 200 mg (or a placebo) po bid was continued for three additional days after surgery. Postoperative pain scores and the need for opioid- containing analgesics were recorded at specific intervals in the recovery room. Follow-up evaluations were performed at 24 hr, 48 hr, 72 hr and seven days and one month after surgery to assess post-discharge pain, analgesic requirements, complications, quality of recovery, and resumption of normal activities, as well as patient satisfaction with their pain management. RESULTS: Celecoxib reduced mean pain scores and the need for analgesics at 24 hr and 48 hr postoperatively. Patient satisfaction with their postoperative pain management was also higher in the Celecoxib group (94 +/- 8 vs 80 +/- 25, P<0.05). Quality of recovery scores were significantly higher in the Celecoxib group on the first and second postoperative days (17 +/- 1 vs 15 +/- 2, and 18 +/- 1 vs 16 +/- 2, respectively). Finally, bowel function recovered an average of one day earlier and patients resumed activities of daily living two days earlier in the Celecoxib group (P<0.05). CONCLUSION: Short-term administration of celecoxib, 400 mg x day(-1) po, decreased postoperative pain and the need for opioid-containing analgesic medication, leading to an improved quality of recovery after outpatient laparoscopic surgery.

Protein phosphatase 2C binds selectively to and dephosphorylates metabotropic glutamate receptor 3.

Cell surface receptor membrane localization is strongly dependent on protein-protein interactions often involving regulation by phosphorylation/dephosphorylation of the intracellular domains of membrane proteins. The present study was carried out to identify metabotropic glutamate receptor (mGluR) 3 regulatory binding proteins. Using the yeast two-hybrid technique, we found that the 50-aa C-terminal cytoplasmic tail of mGluR3 interacts specifically with protein phosphatase 2Calpha (PP2Calpha). This interaction was confirmed by GST pull-down and coimmunoprecipitation assays. mGluR3 interacts with PP2Calpha, beta, gamma, and delta isoforms; however, among the mGluR family only mGluR3 interacted with PP2C. The minimal interacting domain of mGluR3 comprised residues 836-855. Alignment between mGluR3 and mGluR2, a closely related group II receptor, indicated that this domain is not conserved between the two receptors. The mGluR3 cytoplasmic C-terminal tail contains one phosphorylation site for protein kinase A (Ser-845), but the phosphatase that dephosphorylates this site has not been previously identified. We find that PP2C, but not PP1, PP2A, or PP2B, dephosphorylates the mGluR3 cytoplasmic tail in vitro. The dephosphorylated form of the mGluR3 cytoplasmic tail, but not the equivalent region of mGluR2, inhibited PP2C assayed by using [32P]casein as a substrate. However, phosphorylation of the mGluR3 cytoplasmic tail at Ser-845 inhibits the interaction with PP2C. These results indicate distinct functions for mGluR2 and mGluR3 and suggest a dynamic regulation of mGluR3 by PP2C.