Recombinant human granulocyte- colony stimulating factor in women with unexplained recurrent pregnancy losses: a randomized clinical trial.

STUDY QUESTION: Does administration of recombinant human granulocyte colony stimulating factor (rhG-CSF) in the first trimester improve pregnancy outcomes, among women with a history of unexplained recurrent pregnancy loss? SUMMARY ANSWER: rhG-CSF administered in the first trimester of pregnancy did not improve outcomes among women with a history of unexplained recurrent pregnancy loss. WHAT IS KNOWN ALREADY: The only previous randomized controlled study of granulocyte colony stimulating factor in recurrent miscarriage in 68 women with unexplained primary recurrent miscarriage found a statistically significant reduction in miscarriage and improvement in live birth rates. A further four observational studies where G-CSF was used in a recurrent miscarriage population were identified in the literature, two of which confirmed statistically significant increase in clinical pregnancy and live birth rates. STUDY DESIGN, SIZE, DURATION: A randomized, double-blind, placebo controlled clinical trial involving 150 women with a history of unexplained recurrent pregnancy loss was conducted at 21 sites with established recurrent miscarriage clinics in the United Kingdom between 23 June 2014 and 05 June 2016. The study was coordinated by University of Birmingham, UK. PARTICIPANTS/MATERIALS, SETTING, METHODS: One hundred and fifty women with a history of unexplained recurrent pregnancy loss: 76 were randomized to rhG-CSF and 74 to placebo. Daily subcutaneous injections of recombinant human granulocyte - colony stimulating factor 130 µg or identical appearing placebo from as early as three to five weeks of gestation for a maximum of 9 weeks. The trial used central randomization with allocation concealment. The primary outcome was clinical pregnancy at 20 weeks of gestation, as demonstrated by an ultrasound scan. Secondary outcomes included miscarriages, livebirth, adverse events, stillbirth, neonatal birth weight, changes in clinical laboratory variables following study drug exposure, major congenital anomalies, preterm births and incidence of anti-drug antibody formation. Analysis was by intention to treat. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 340 participants were screened for eligibility of which 150 women were randomized. 76 women (median age, 32[IQR, 29-34] years; mean BMI, 26.3[SD, 4.2]) and 74 women (median age, 31[IQR, 26-33] years; mean BMI, 25.8[SD, 4.2]) were randomized to placebo. All women were followed-up to primary outcome, and beyond to live birth. The clinical pregnancy rate at 20 weeks, as well as the live birth rate, was 59.2% (45/76) in the rhG-CSF group, and 64.9% (48/74) in the placebo group, giving a relative risk of 0.9 (95% CI: 0.7-1.2; P = 0.48). There was no evidence of a significant difference between the groups for any of the secondary outcomes. Adverse events (AEs) occurred in 52 (68.4%) participants in rhG-CSF group and 43 (58.1%) participants in the placebo group. Neonatal congenital anomalies were observed in 1/46 (2.1%) of babies in the rhG-CSF group versus 1/49 (2.0%) in the placebo group (RR of 0.9; 95% CI: 0.1-13.4; P = 0.93). LIMITATIONS, REASONS FOR CAUTION: This trial was conducted in women diagnosed with unexplained recurrent pregnancy loss and therefore no screening tests (commercially available) were performed for immune dysfunction related pregnancy failure/s. WIDER IMPLICATIONS OF THE FINDINGS: To our knowledge, this is the first multicentre study and largest randomized clinical trial to investigate the efficacy and safety of granulocyte human colony stimulating factor in women with recurrent miscarriages. Unlike the only available single center RCT, our trial showed no significant increase in clinical pregnancy or live births with the use of rhG-CSF in the first trimester of pregnancy. STUDY FUNDING/COMPETING INTEREST(S): This study was sponsored and supported by Nora Therapeutics, Inc., 530 Lytton Avenue, 2nd Floor, Palo Alto, CA 94301, USA. Darryl Carter was the co-founder and VP of research, Nora Therapeutics, Inc. and held shares in the company. He holds a patent for the use of recombinant human granulocyte colony stimulating factor to reduce unexplained recurrent pregnancy loss. Mark Joing, Paul Kwon and Jeff Tong were or are employees of Nora Therapeutics, Inc. No other potential conflict of interest relevant to this article was reported. TRIAL REGISTRATION NUMBER: EUDRACT No: 2014-000084-40; ClinicalTrials.gov Identifier: NCT02156063. TRIAL REGISTRATION DATE: 31 Mar 2014. DATE OF FIRST PATIENT'S ENROLMENT: 23 Jun 2014.

Pilot study of high-performance air filtration for classroom applications.

UNLABELLED: A study was conducted to investigate the effectiveness of three air purification systems in reducing the exposure of children to air contaminants inside nine classrooms of three Southern California schools. Continuous and integrated measurements were conducted to monitor the indoor and outdoor concentrations of ultrafine particles (UFPs), fine and coarse particulate matter (PM2.5 and PM10 , respectively), black carbon (BC), and volatile organic compounds. An heating, ventilating, and air conditioning (HVAC)-based high-performance panel filter (HP-PF), a register-based air purifier (RS), and a stand-alone air cleaning system (SA) were tested alone and in different combinations for their ability to remove the monitored pollutants. The combination of a RS and a HP-PF was the most effective solution for lowering the indoor concentrations of BC, UFPs, and PM2.5 , with study average reductions between 87% and 96%. When using the HP-PF alone, reductions close to 90% were also achieved. In all cases, air quality conditions were improved substantially with respect to the corresponding baseline (preexisting) conditions. Data on the performance of the gas-absorbing media included in the RS and SA unit were inconclusive, and their effectiveness, lifetime, costs, and benefits must be further assessed before conclusions and recommendations can be made. PRACTICAL IMPLICATIONS: The installation of effective air filtration devices in classrooms may be an important mitigation measure to help reduce the exposure of school children to indoor pollutants of outdoor origin including ultrafine particles and diesel particulate matter, especially at schools located near highly trafficked freeways, refineries, and other important sources of air toxics.

Phase I trial on the safety of topical rhVEGF on chronic neuropathic diabetic foot ulcers.

OBJECTIVE: To assess the safety/tolerability and perform a preliminary efficacy evaluation of a multiple-dosing regimen of recombinant human vascular endothelial growth factor (VEGF165 or rhVEGF; telbermin) applied topically to chronic diabetic neuropathic foot ulcers. METHOD: Subjects with type 1 or 2 diabetes mellitus were randomised to receive either topical applied telbermin (72 microg/cm2) (n=29) or placebo (n=26) treatment to the foot ulcer surface in conjunction with standard ulcer care. Subjects received treatment every 48 hours (maximum three doses per week) for up to six weeks. Weekly 35mm photography, quantitative planimetry and physical examinations documented the ulcer appearance, surface area and stage. Safety endpoints included incidence of clinically significant hypotension, adverse events and ulcer infection. Exploratory efficacy endpoints included percentage reduction in total ulcer surface area, incidence of complete ulcer healing and time to complete ulcer healing. RESULTS: Incidence of adverse events was comparable in the two treatment groups. None of the adverse events were attributed to study drug, and no hypotension was observed as a result of telbermin treatment. Occurrence of infected study ulcers appeared to be balanced between the treatment groups. Positive trends suggestive of potential signals of biological activity were observed for incidence of complete ulcer healing (41.4% telbermin versus 26.9% placebo at day 43 [P=0.39]) and time to complete ulcer healing (25th percentile of 32.5 days telbermin versus 43.0 days placebo [log-rank P=0.13]). CONCLUSION: The topical application of telbermin 72 microg/cm2 three times a week for up to six weeks appeared to be well tolerated. Further studies are required to characterise the safety/efficacy of telbermin more completely.

Comparative tolerance of adolescents of differing ethic backgrounds to lactose-containing and lactose-free dairy drinks. I. Initial experience with a double-blind procedure.

A lactose-free (LF) chocolate dairy drink and one containing 4.5% lactose (LC) were administered randomly in 240- and 480-ml volumes on 4 consecutive mornings under double-blind conditions to 110 healthy teenagers (14 to 19 years old) of differing ethnic backgrounds. Capillary blood glucose analysis after 50 g of oral lactose identified 67 of them as lactose malabsorbers. Neither absorbers nor malabsorbers reported significantly different gastrointestinal symptoms after 240 ml of LC compared with the same amount of LF. However, 17 absorbers and 21 malabsorbers reported symptoms inconsistent with intolerance due to lactose. These subjects had symptoms after LF only, after both LF and LC, or after 240 ml but not 480 ml of LC. After 480 ml of LC, 26 malabsorbers had symptoms, compared to 15 after 480 ml of LF. The prevalence of symptoms after 480 ml of LC, but not after 480 ml of LF, was 7% for absorbers, and 24% for malabsorbers. The results indicate that most of the individuals who reported gastrointestinal symptoms after ingestion of the two beverages did so for reasons other than their lactose content.

Comparative tolerance of adolescents of differing ethnic backgrounds to lactose-containing and lactose-free dairy drinks. II. Improvement of a double-blind test.

Using an improved double-blind test procedure, the relationship between lactose malabsorption and lactose intolerance was investigated in 87 healthy teenagers (14--19 years old) of differing ethnic backgrounds. Capillary blood glucose analysis after an oral dose of 50 g of lactose identified 45 lactose malabsorbers. A lactose-free (LF) chocolate dairy drink and one containing 4.5% lactose (LC) were administered under double-blind conditions on 4 consecutive mornings. As in a similar prior study, no statistically significant differences were found in the incidence of symptoms reported by malabsorbers and absorbers after drinking 240 ml of either the LF or the LC preparation. However, 12 lactose absorbers reported symptoms apparently not due to lactose, i.e., after 240 ml of LF, after this amount of both LF and LC, or after 240 ml (but not 480 ml) of LC. Such false-positive results would only be identified by the double-blind approach. It did not appear that any of the malabsorbers had symptoms due to the lactose in 240 ml of LC. However, 16% of the malabsorbers apparently reacted to the lactose in 480 ml of LC. Well designed, double-blind clinical trials are essential for evaluation of gastrointestinal responses to lactose or other ingredients in milk.

Dissociation of microglial activation and neuropathic pain behaviors following peripheral nerve injury in the rat.

Peripheral nerve injury commonly leads to neuropathic pain states fostered, in part, by neuroimmunologic events. We used two models of neuropathic pain (L5 spinal nerve cryoneurolysis (SPCN) and chronic constriction injury (CCI)) to assess the role of spinal glial activation responses in producing pain behaviors. Scoring of glial responses subjectively encompassed changes in cell morphology, cell density and intensity of immunoreactivity with specific activation markers (OX-42 and anti-glial fibrillary acidic protein (GFAP) for microglia and astrocytes, respectively). Glial responses were compared with tactile sensitivity (mechanical allodynia) at 1, 3 or 10 days following SPCN and with thermal hyperalgesia at 10 days in the CCI group. Neuropathic pain behaviors preceded and did not closely correlate with microglial responses in either model. Perineural application of bupivacaine prior to SPCN prevented spinal microglial responses but not pain behaviors. Spinal astrocytic responses to SPCN were early, robust and not altered by bupivacaine. The current findings support the use of bupivacaine as a tool to suppress microglial activation and challenge the putative role of microglia in initiating or potentiating pain behaviors which result from nerve injury.

Life stress and dysphoria: the role of self-esteem and hopelessness.

This study evaluated the hypotheses that the relation between life stress (life events and daily hassles) and longitudinal change in dysphoria would be (a) moderated by self-esteem and (b) mediated by longitudinal change in hopelessness. Eighty undergraduates were first assessed on self-esteem, hopelessness, and dysphoria and then reassessed 3 months later on life events, daily hassles, hopelessness, and dysphoria. Residual change in dysphoria was significantly associated with self-esteem, life stress, and a Self-Esteem X Life Stress interaction. However, inconsonant with predictions, the moderating impact of self-esteem was greatest under conditions of low (vs. high) life stress. Moreover, residual change in hopelessness mediated the relations between residual change in dysphoria and both self-esteem and life stress.

Aspirin enhances multidrug resistance gene 1 expression in human Molt-4 T lymphoma cells.

BACKGROUND: We recently found that aspirin induces the expression of P-glycoprotein (P-gp), a protein mediating drug resistance, in human prostate cancer cells. The purpose of this study was to evaluate the effect of aspirin on the expression of P-gp in a different human cancer type, i.e., T lymphoma. Furthermore, we analyzed this effect at the level of the gene encoding P-gp, MDR1, and of the transcription factor (NF-IL6), regulating this gene. MATERIALS AND METHODS: NF-IL6 was assayed by the electrophoretic mobility shift assay, MDR1 mRNA was assayed by the reverse transcriptase polymerase chain reaction (RT-PCR), and P-gp was assayed by Western blotting. RESULTS: aspirin, at plasma attainable levels, induced NF-IL6 DNA-binding activity, and increased MDR1 mRNA expression (by up to 140%), as well as the expression of P-gp, in Molt-4 cells. CONCLUSIONS: This study suggests that treatment with aspirin induces a cellular signal culminating in the enhancement of P-gp expression in T lymphoma Molt-4 cells.

Mucoepidermoid odontogenic cyst.

This unusual cystic lesion was previously described as a lesion that has features of both botryoid odontogenic cyst and mucoepidermoid tumor and later was named as glandular odontogenic cyst. An additional case is reported and its clinicopathologic features described. The name "mucoepidermoid odontogenic cyst" is proposed.

The intramandibular sliding myo-osseous graft for delayed reconstruction of selected mandibular defects. A preliminary report.

A technique for re-establishing continuity of the mandibular bone using an intramandibular sliding myo-osseous graft is presented. The usefulness and the simplicity of this modified pedicled bone graft is shown and additional experience with the technique is now justified to give a full assessment of the procedure.

Hope and dysphoria: the moderating role of defense mechanisms.

It was hypothesized that the adaptive value of hope cognitions would be dependent upon the quality of an individual's defense style. Undergraduate students completed measures of hope, defense mechanisms, and dysphoria in two studies. As predicted, defense mechanisms significantly moderated the relation between hope and dysphoria. In addition, both hope and defense mechanisms predicted dysphoria as main effects. Individuals who had low hope and an immature defense style had particularly high levels of dysphoria. Low hope was not maladaptive for individuals with a mature defense style, suggesting that a subtype of low hope ("defensive hopelessness") may exist that is analogous to defensive pessimism. Individuals with high hope had low levels of dysphoria regardless of defense style. Overall, the present study suggests that an integration of psychodynamic and cognitive perspectives on hope may be productive.

Attributional style and psychodynamic defense mechanisms: toward an integrative model of depression.

The present study examined the influences of cognitive style and psychodynamic defense mechanisms in accounting for levels of dysphoria. Measures of dysphoria, defense mechanisms, and attributional style were completed by 147 undergraduate students. Consistent with the hypothesis, both attributional style and principalization were independently associated with dysphoria. Moreover, principalization moderated the influence of attributional style on levels of dysphoria. In addition, attributional style and turning against self were independently associated with dysphoria. Turning against other, projection, and reversal were not associated with dysphoria. The results provide partial support for the notion that the applicability and validity of the hopelessness theory of depression are bolstered by a consideration of psychodynamic phenomena. Potential implications of this line of research for the movement toward psychotherapy integration are discussed.

Attributional style and defense mechanisms: a synthesis of cognitive and psychodynamic factors in depression.

In a study involving 160 undergraduates, we tested the hypothesis that attributional style and defense style would have interactive effects on depressive symptoms. Consistent with this hypothesis, both negative attributional style and low defense maturity were associated with depressive symptoms, both as main effects and in interaction. Negative attributional style was associated with depressive symptoms primarily when accompanied by low defense maturity. The presence of a positive attributional style reduced the relation between low defense maturity and depressive symptoms, and the presence of high defense maturity reduced the relation between a negative attributional style and depressive symptoms. In addition, high defense immaturity was shown to be a possible mediator of the relation between negative attributional style and depressive symptoms. Clinical implications for psychotherapy integration are discussed.

The effect of therapeutic radiation on canine alveolar ridges augmented with hydroxylapatite.

The purpose of this investigation was to evaluate the effect of radiation on hydroxylapatite (HA) implanted subperiosteally for alveolar ridge augmentation in dogs. All bicuspids and molars were extracted from 16 dogs. After 6 weeks, nonporous HA granules were implanted subperiosteally on the alveolar ridge. Following 4 months of healing, 12 dogs (experimental group) underwent therapeutic radiation therapy (Co60, 4,000 rad [40 Gy]) to the head and neck region. Four dogs were not irradiated and served as controls. Four animals (three experimental and one control) were killed at 5,6,7, and 8 months after HA augmentation. Light microscopic evaluation showed that approximately 25% of HA granules were encased by bone while the others were surrounded by fibrous connective tissue. Dissolution of the HA was observed. Microparticles of HA were phagocytized as part of a granulomatous inflammatory reaction. This reaction decreased significantly as time elapsed after implantation. Osteoclastic activity was seen at the junction of HA and periosteum and as part of bone remodeling. Dissolution of the HA granules and the granulomatous inflammatory reaction were not significantly increased by therapeutic radiation. The radiation did not cause development of dehiscence or osteonecrosis.

Triple bone labeling of canine mandibles.

Fluorescence microscopy was used for evaluation of new bone formation in 16 canine mandibles augmented with hydroxylapatite (HA) granules. Three fluorochromes were injected at different time intervals during therapeutic radiation treatment. Oxytetracycline, DCAF, and alizarin-complexone were given intravenously to mark the bone level at these times, respectively. Oxytetracycline, which defined the baseline of bone at implantation of HA, was detectable in 42% of animals that were irradiated and in no animal of the nonirradiated control group. The marker DCAF, designating levels of bone at the start of radiation, was demonstrated in 92% of irradiated animals, and in 75% of animals in the control group. The uptake of alizarin-complexone determined the level of bone found at the end of irradiation. This marker was demonstrated in 50% of the dogs irradiated and in 75% of the control dogs. Bony trabeculae were found between and at the surface of the HA granules. New generation of bone directly on the HA granule and in the surrounding haversian systems as part of normal bone turnover was demonstrated to take place more than 5 months after implantation of HA.

Desmoplastic fibroma of the jaws: surgical management and review of the literature.

Desmoplastic fibroma of the jaws is a rare and locally aggressive tumor that has a high rate of recurrence. The cellularity, extent of the tumor, and completeness of the local excision may be factors in its tendency to recur. We reviewed the literature in an attempt to determine if there was any correlation between the histologic features of a desmoplastic fibroma, or the surgical procedure utilized, and the tumor's recurrence. From the information gathered, it was found that a more cellular desmoplastic fibroma or inadequate surgical procedure may be factors that contribute to the recurrence of the tumor. A case report of desmoplastic fibroma of the mandible in a 9-year-old child is presented. The tumor, which displayed areas of moderate cellularity, was resected via a partial hemimandibulectomy. There has been no recurrence to date (46 months).

Sociotropy and autonomy: preliminary evidence for construct validity using TAT narratives.

In this investigation, we evaluated the construct validity of sociotropy and autonomy as assessed by the revised Personal Style Inventory (PSI; Robins et al., 1994). Stories given to 6 cards of the Thematic Apperception Test (Murray, 1943) were coded for need for Achievement (McClelland, Atkinson, Clark, & Lowell, 1953) and need for Affiliation (Heyns, Veroff, & Atkinson, 1958). These scores were correlated with PSI Sociotropy and Autonomy, along with their component subscales. The construct validity of Sociotropy, Autonomy, and 5 of 6 component subscales were supported as hypoth sized. Consistent with past research, there was no support for the construct validity of the Perfectionism/Self-Criticism subscale of Autonomy. In addition, separate analyses by gender suggested that the construct validity of sociotropy may be greater for women than for men. The results represent an important finding in that nonquestionnaire measures of interpersonal and achievement-related concerns were found to support the validity of the PSI, a need identified by the questionnaire's authors.

Developmental changes in memory source monitoring.

Previous research suggests that children are more likely than adults to confuse memories of actions they imagined themselves performing with memories of actions they actually performed (Realization Judgments), but are not more likely to confuse memories of actions they had imagined performing with memories of actions they saw another person perform (Reality Monitoring). We approach these findings in terms of a theory about the processes by which people identify the sources of their recollections (Source Monitoring). This approach suggests that children may be more likely than adults to confuse memories from different sources whenever the sources are highly similar to one another. Experiments 1 and 2 tested this hypothesis by manipulating the perceptual and semantic similarity of two sources of information and testing 4- and 6-year-old and adult subjects' recollection of the sources of particular pieces of information. Experiment 3 tested the hypothesis that children are more likely than adults to mistakenly identify memories of things they imagined another person doing as memories of things they witnessed that person doing. The findings indicate that (a) people are more likely to confuse memories from similar than dissimilar sources, (b) source monitoring improves during the preschool and childhood years, and (c) children may be especially vulnerable to the effects of source similarity.