Results of TRIO-15, a multicenter, open-label, phase II study of the efficacy and safety of ganitumab in patients with recurrent platinum-sensitive ovarian cancer.

BACKGROUND: IGF signaling has been implicated in the pathogenesis and progression of ovarian carcinoma (OC). Single agent activity and safety of ganitumab (AMG 479), a fully human monoclonal antibody against IGF1R that blocks binding of IGF1 and IGF2, were evaluated in patients with platinum-sensitive recurrent OC. METHODS: Patients with CA125 progression (GCIG criteria) or measurable disease per RECIST following primary platinum-based therapy received 18 mg/kg of ganitumab q3w. The primary endpoint was objective response rate (ORR) assessed per RECIST 1.1 by an independent radiology review committee (IRC) and/or GCIG CA125 criteria. Secondary endpoints included clinical benefit rate (CBR), progression free survival (PFS) and overall survival (OS). RESULTS: 61 pts. were accrued. Objective responses were seen in 5/61 patients (ORR 8.2%, 95% CI, 3.1-18.8) with 1 partial response (PR) by RECIST and 2 complete responses (CR) as well as 2 PR by CA125 criteria. CBR was 80.3% (95% CI, 67.8-89.0%). The median PFS according to RECIST by IRC was 2.1 months (95% CI, 2.0-3.1). The median PFS per RECIST IRC and/or CA125 was 2.0 months (95% CI, 1.8-2.2). The median OS was 21 months (95% CI, 19.5-NA). The most common overall adverse events were fatigue (36.1%) and hypertension (34.4%). Grade 1/2 hyperglycemia occurred in 30.4% of patients. Hypertension (11.5%) and hypersensitivity (8.2%) were the most frequent grade 3 adverse events. CONCLUSIONS: IGF1R inhibition with ganitumab was well-tolerated, however, our results do not support further study of ganitumab as a single agent in unselected OC patients.

Association between changes in knee load and effusion-synovitis: evidence of mechano-inflammation in knee osteoarthritis using high tibial osteotomy as a model.

OBJECTIVE: Although mechanically-induced inflammation is an appealing explanation linking different etiologic factors in osteoarthritis (OA), clinical research investigating changes in both biomechanics and joint inflammation is limited. The purpose of this study was to evaluate the association between change in surrogate measures of knee load and knee effusion-synovitis in patients with medial compartment knee OA undergoing high tibial osteotomy (HTO). METHODS: Thirty-six patients with medial compartment knee OA and varus alignment underwent 3D gait analysis and 3T magnetic resonance imaging (MRI) preoperatively and 1 year after medial opening wedge HTO. Primary outcome measures were the change in the external knee adduction moment impulse during walking and change in knee suprapatellar effusion-synovitis volume manually segmented on MRI by one blinded assessor. RESULTS: Mean (SD) knee adduction moment impulse [24.0 (6.5) Nm•s] and knee effusion-synovitis volume [8976.7 (8016.9) mm3] suggested substantial preoperative medial knee load and inflammation. 1-year postoperative changes in knee adduction moment impulse [-10.1 Nm•s (95%CI: -12.7, -7.4)], and knee effusion-synovitis volume [-1856 mm3 (95%CI: -3830, 117)] were positively correlated [r = 0.60 (95% CI 0.34, 0.78)]. Simple linear regression suggested a 448 mm3 (95%CI: 241, 656) reduction in knee effusion-synovitis volume per 1 Nm•s reduction in knee adduction moment impulse. Change in knee adduction moment impulse explained 36% (R2 = 0.36) of the variance of change in knee effusion-synovitis volume. CONCLUSIONS: Reduction in medial knee load is positively associated with reduction in knee inflammation after HTO, suggesting the phenomenon of mechano-inflammation in patients with knee OA.

Early or delayed anterior cruciate ligament reconstruction: Is one superior? A systematic review and meta-analysis.

BACKGROUND: Anterior cruciate ligament (ACL) reconstruction is a rapidly developing orthopaedic field and an area of notable clinical equipoise. The optimal timing of surgery in an acute (< 3 weeks) or delayed (≥ 3 weeks) time frame remains unresolved with a 2010 meta-analysis concluding no difference between these two groups across multiple outcomes. In an era of evidence-based medicine, surgeons are still basing their decisions on when to operate on little more than anecdotal evidence and personal preference. Clear guidance is required to determine whether the timing of surgery can optimise outcomes in this largely young and active patient cohort. METHODS: A systematic literature search was performed in January 2018 of Embase, Medline and OpenGrey in accordance with (PRISMA) guidelines. A total of 658 articles were retrieved, with 6 suitable for inclusion, covering 576 ACL reconstructions. Four meta-analyses were performed assessing subjective measures of Tegner activity scale and Lysholm score, and objective measures of arthroscopically identified meniscal and chondral injury. Additional relevant outcome measures underwent narrative review. Study bias was assessed and reported using the Downs and Black checklist. RESULTS: A statistically significant difference of 0.39 points was found on the Tegner activity scale in favour of early surgery within 3 weeks (RR 0.39, CI 0.10, 0.67, p = 0.008). No statistically difference was found between groups for the patient-reported Lysholm score (RR - 0.18, CI - 2.40, 2.05, p = 0.17). There was no statistically significant difference between groups for intra-operative findings of meniscal lesions (RR 0.84, CI 0.66, 1.08, p = 0.17). A trend towards significance was observed for the incidence of chondral lesions in the early surgery group (RR 0.56, CI 0.31, 1.02, p = 0.06). All the studies were rated either fair or good on the Downs and Black checklist with no study excluded due to bias. CONCLUSIONS: Although there was a statistically significant result for the Tegner activity scale in favour of early surgery, the magnitude of the effect is unlikely to translate into any clinically meaningful difference. At present, there remains no clear evidence to determine superiority of acute/early or delayed reconstruction of a ruptured anterior cruciate ligament. Further research through methodologically robust randomised controlled trials or through the UK National Ligament Registry  may help to provide clearer guidance.

Nematode 18S rRNA gene is a reliable tool for environmental biosafety assessment of transgenic banana in confined field trials.

Information on relatedness in nematodes is commonly obtained by DNA sequencing of the ribosomal internal transcribed spacer region. However, the level of diversity at this locus is often insufficient for reliable species differentiation. Recent findings suggest that the sequences of a fragment of the small subunit nuclear ribosomal DNA (18S rRNA or SSU), identify genera of soil nematodes and can also distinguish between species in some cases. A database of soil nematode genera in a Ugandan soil was developed using 18S rRNA sequences of individual nematodes from a GM banana confined field trial site at the National Agricultural Research Laboratories, Kawanda in Uganda. The trial was planted to evaluate transgenic bananas for resistance to black Sigatoka disease. Search for relatedness of the sequences gained with entries in a public genomic database identified a range of 20 different genera and sometimes distinguished species. Molecular markers were designed from the sequence information to underpin nematode faunal analysis. This approach provides bio-indicators for disturbance of the soil environment and the condition of the soil food web. It is being developed to support environmental biosafety analysis by detecting any perturbance by transgenic banana or other GM crops on the soil environment.

Presentation of laryngeal papilloma in childhood: the Leeds experience.

INTRODUCTION: The human papilloma virus (HPV) can cause laryngeal papillomatosis in childhood. The aetiology is thought to be vertical transmission. Clinically these children are usually asymptomatic for the first 6 months of life. As the papillomas develop locally, symptoms begin to develop. The symptoms range from voice change to frank hoarseness, and 'noisy' breathing, most commonly inspiratory stridor. METHOD: Clinical images from microlaryngoscopy and bronchoscopy over a 12-year period were assessed for laryngeal papilloma. RESULTS: In Leeds seven cases presented to the specialist centre over the past 12 years, the average age at presentation was 6.8 years and duration of onset of symptoms to specialist review was 21 months. Five of the children had been treated for asthma and two presented in extremis. CONCLUSION: The take home message for clinicians is hoarse voice associated with shortness of breath needs specialist referral.

Clinical, ultrasound and biochemical features of polycystic ovary syndrome in adolescents: implications for diagnosis.

BACKGROUND: Diagnosing polycystic ovary syndrome (PCOS) in adolescence is clinically challenging. The prevalence of clinical, ultrasound and biochemical features of PCOS in a community-based adolescent population using current diagnostic criteria has not previously been described. METHODS: This was a prospective cohort study with 244 unselected post-menarchal girls, mean age 15.2 years, of whom 91% were Caucasian. Subjects were recruited from a large population-based birth cohort (the Raine cohort). Clinical hyperandrogenism (HA) was quantified using Ferriman-Gallwey scores. In the early follicular phase (Day 2-6), we measured circulating androgens and sex hormone-binding globulin by immunoassay, and ovarian morphology was assessed by transabdominal ultrasound examination. BMI and waist-hip ratio were measured. RESULTS: Normal ranges for early follicular phase androgens in adolescence were derived for this population. The top 5 and 10% of circulating free testosterone levels were 45.6 and 34.5 pmol/l, respectively. Fifty-one percent of girls reported menstrual irregularity. Clinical HA was uncommon, being observed in only 3.5% of girls. Mean ovarian volume was greater than that reported by others in adult women and 35% of girls had polycystic ovary morphology on transabdominal ultrasound. Taking the upper 5% of free testosterone as HA, 42 girls (18.5%) would have met the Rotterdam criteria for PCOS, 11 girls (5%) the Androgen Excess Society criteria and 7 girls (3.1%) the National Institutes of Health criteria. CONCLUSIONS: Menstrual irregularity is common in adolescence and does not relate to clinical or biochemical HA. Diagnostic criteria for PCOS which include ovarian volume and morphology may be of limited use in adolescence.

Organizational role for pubertal androgens on adult hypothalamic-pituitary-adrenal sensitivity to testosterone in the male rat.

The inhibitory effect of androgens on the hypothalamic-pituitary-adrenal (HPA) axis in basal and stress conditions in adult male rats is well documented. Major sex-related neuroendocrine changes take place during puberty. There is a robust rise in production and secretion of gonadal steroids, which is thought to underlie numerous neural and behavioural changes brought on after puberty. The present study investigated the effect of the pubertal rise in gonadal steroid levels on the subsequent adult corticosterone profile, particularly the sensitivity of the adult HPA axis to testosterone. Animals were castrated either prepubertally (28 days) or in adulthood (11 weeks) and adult animals were subsequently treated with subcutaneous implants containing either testosterone or cholesterol. Using an automated blood sampling system, blood was collected from each freely moving, conscious rat every 10 min (i) over a 24 h period; (ii) in response to 10 min of noise stress, and (iii) following an immunological challenge with lipopolysaccharide (LPS). Analysis revealed that testosterone treatment did not significantly affect overall corticosterone release over the 24 h period in adult animals castrated before puberty in contrast to animals castrated in adulthood in which testosterone significantly suppressed corticosterone secretion. Following either a noise stress or LPS injection, testosterone treatment did not affect the hypothalamic or adrenal stress response in animals castrated prepubertally. Testosterone significantly suppressed the corticotrophin-releasing hormone and arginine vasopressin mRNA as well as the corticosterone response to LPS in castrated animals that had had their testes intact over puberty. These data provide evidence that puberty is a critical organizational period during which rising levels of gonadal steroids programme the sensitivity of the adult HPA axis to gonadal steroids in adulthood.

Postoperative fall after the use of the 3-in-1 femoral nerve block for knee surgery: a report of four cases.

We present a serious postoperative complication related to the use of femoral nerve block in 4 patients, each of whom fell and sustained further injury. Preoperatively, all patients underwent a 3-in-1 femoral nerve block with 30 to 35 ml of 0.25% levobupivacaine with 1:200,000 epinephrine, with guidance by a nerve stimulator. After the falls, neurological examination of the operated legs revealed reduced 2-point discrimination, pain, and/or light touch sensation. All patients underwent further operation for the fall injury and had delayed full weight bearing. We recommend that, after having a femoral nerve block, patients should undergo enhanced postoperative evaluation of blockade and proprioceptive function to ensure safe neurological function before mobilisation.

Verrucous carcinoma of the foot: a case report.

We present a case of verrucous carcinoma of the foot in a 34-year-old man. This is a rare, locally invasive, well-differentiated, low-grade squamous cell carcinoma, with human papilloma virus as a possible causative agent. It follows a chronic course and mimics a variety of skin lesions, delaying diagnosis by up to 15 years. The definitive diagnosis is made histologically, and treatment by wide local excision is recommended. Our patient underwent wide local excision and partial 5th metatarsal amputation because of invasive disease, local infection, and peripheral vascular disease. There were no postoperative complications. At the 10-year follow-up, there were no signs of tumour recurrence.

Constant Isothiocyanate-Release Potentials across Biofumigant Seeding Rates.

Biofumigation is an integrated pest-management method involving the mulching of a glucosinolate-containing cover crop into a field in order to generate toxic isothiocyanates (ITCs), which are effective soil-borne-pest-control compounds. Variation in biofumigation efficacy demonstrates a need to better understand the factors affecting pest-control outcomes and develop best practices for choosing biofumigants, growth conditions, and mulching methods that allow the greatest potential isothiocyanate release. We measured the glucosinolate concentrations of six different commercial varieties of three biofumigant plant species: Brassica juncea (ISCI99, Vitasso, and Scala) Raphanus sativus (Diablo and Bento), and Sinapis alba (Ida Gold). The plants were grown in the range of commercially appropriate seeding rates and sampled at three growth stages (early development, mature, and 50% flowering). Within biofumigant species, the highest ITC-release potentials were achieved with B. juncea cv. ISCI99 and R. sativus cv. Bento. The highest ITC-release potential occurred at the 50% flowering growth stage across the species. The seeding rate had a minor impact on the ITC-release potential of R. sativus but had no significant effects on the ITC-release potentials of the B. juncea or S. alba cultivars.

QPCR analysis and RNAi define pharyngeal gland cell-expressed genes of Heterodera glycines required for initial interactions with the host.

Changes in transcript abundance of genes expressed in the three pharyngeal gland cells of Heterodera glycines after host invasion were monitored by quantitative polymerase chain reaction (qPCR) and the consequences of disrupting their expression studied by RNAi treatment prior to invasion. Two transcripts were known to be expressed in the two subventral gland cells (hg-pel and hg-eng-1), a further two in the single dorsal gland cell only (hg-gp and hg-syv46), and a fifth transcript (hg-cm) was expressed by both gland cell types. The qPCR study established that transcripts of hg-syv46 and hg-gp increased in abundance by 2 days postinfection (dpi), with the former remaining the most abundant. The hg-cm transcript level showed minor changes from 0 to 14 dpi but did fall by 21 dpi. In contrast, hg-eng-1 and hg-eng-2 messenger (m)RNA declined by 7 dpi and hg-pel by 14 dpi before it increased at 21 dpi. RNAi-targeting of hg-eng-1 reduced the number of females present on the plants at 10 days. Targeting of hg-gp, hg-cm, and hg-pel caused a change in sexual fate favoring male development on roots. Both effects were evident after targeting hg-syv46. Suppression of hg-eng-1 mRNA levels in second-stage juveniles (J2i) by RNAi was transient, with a recovery by 15 days of incubation in water after treatment. Presoaking H. glycines J2 with double-stranded RNA has value for studying gene function during the nematode's early interaction with a plant.

Effect of the glucocorticoid receptor antagonist Org 34850 on basal and stress-induced corticosterone secretion.

The activity of the hypothalamic-pituitary-adrenal (HPA) axis is characterised both by an ultradian pulsatile pattern of glucocorticoid secretion and an endogenous diurnal rhythm. Glucocorticoid feedback plays a major role in regulating HPA axis activity and this mechanism occurs via two different receptors: mineralocorticoid (MR) and glucocorticoid receptors (GR). In the present study, the effects of both acute and subchronic treatment with the GR antagonist Org 34850 on basal and stress-induced HPA axis activity in male rats were evaluated. To investigate the effect of Org 34850 on basal diurnal corticosterone rhythm over the 24-h cycle, an automated blood sampling system collected samples every 10 min. Acute injection of Org 34850 (10 mg/kg, s.c.) did not affect basal or stress-induced corticosterone secretion, but was able to antagonise the inhibitory effect of the glucocorticoid agonist methylprednisolone on stress-induced corticosterone secretion. However, 5 days of treatment with Org 34850 (10 mg/kg, s.c., two times a day), compared to rats treated with vehicle (5% mulgofen in 0.9% saline, 1 ml/kg, s.c.), increased corticosterone secretion over the 24-h cycle and resulted in changes in the pulsatile pattern of hormone release, but had no significant effect on adrenocorticotrophic hormone secretion or on stress-induced corticosterone secretion. Subchronic treatment with Org 34850 did not alter GR mRNA expression in the hippocampus, paraventricular nucleus of the hypothalamus or anterior-pituitary, or MR mRNA expression in the hippocampus. Our data suggest that a prolonged blockade of GRs is required to increase basal HPA axis activity. The changes observed here with ORG 34850 are consistent with inhibition of GR-mediated negative feedback of the HPA axis. In light of the evidence showing an involvement of dysfunctional HPA axis in the pathophysiology of depression, Org 34850 could be a potential treatment for mood disorders.

Diurnal variation in the responsiveness of the hypothalamic-pituitary-adrenal axis of the male rat to noise stress.

Basal activity of the rat hypothalamic-pituitary-adrenal (HPA) axis is highly dynamic and displays both circadian and ultradian rhythmicity in corticosterone secretion. This study investigated the relationship between basal corticosterone pulsatility and the corticosterone response to noise during the early light phase when there are no endogenous corticosterone pulses and during the early dark phase when there are hourly pulses of corticosterone. An automated blood sampling system was used to collect blood in conscious male rats at 5-min intervals before, during and after exposure to 10-min periods of white noise (104 dB). Behavioural responses to noise were also monitored during these periods. During the early light phase (morning), there was a consistent corticosteroid response to noise with corticosterone concentrations rising rapidly and reaching peak values 10-15 min after the noise had ceased, following which circulating concentrations declined at a rate comparable to the hormones half-life. A second noise stress, 80 min later, resulted in adaptation of the corticosterone response. During the early dark phase (evening), the corticosterone response to the noise was similar to that seen in the morning, although there was no adaptation to a second stimulus. During the evening, the inhibition of endogenous HPA activity after the sound was limited to 40 min following stress.

Malignant intraosseous peripheral nerve sheath tumour of the proximal femur: a case report.

We report a rare case of an intraosseous malignant peripheral nerve sheath tumour of the femoral head and neck. The tumour presented as a well-defined radiolucent lesion on plain radiography. Computed tomography showed aggressive destruction of the bone with no involvement of the adjacent soft tissues. Magnetic resonance imaging revealed an isointense signal intensity on T1-weighted images, hyperintensity on T2-weighted images, and non-homogeneously increased signal intensity after administration of contrast media. The final diagnosis was based on pathohistologic analyses due to the non-specific nature of the lesion.

Parental pre-pregnancy BMI is a dominant early-life risk factor influencing BMI of offspring in adulthood.

OBJECTIVE: We examined parental and early-life variables in order to identify risk factors for adulthood overweight and obesity in offspring. We report here on the longitudinal prevalence of overweight and obesity in Australian children born between 1989 and 1991 and followed from birth to age 22. METHODS: Data were analysed on 1355 participants from the Western Australian Pregnancy Cohort (Raine) Study, with anthropometry collected during pregnancy, at birth, one year and at three yearly intervals thereafter. Multivariate analyses and cross-sectional logistic regression quantified the timing and contribution of early-life risk factors for overweight and obesity in young-adulthood. RESULTS: At five years of age 12.6% of children were overweight and 5.2% were obese. By early adulthood, the prevalence of obesity had increased to 12.8%, whilst overweight remained relatively stable at 14.2% (range from early childhood to adulthood 11-16%). Parental pre-pregnancy body mass index (BMI) was the strongest determinant of adult offspring BMI. Although rapid first year weight gain was associated with increased offspring BMI, the impact of first year weight-gain diminished over childhood, whilst the impact of parental BMI increased over time. CONCLUSIONS: Parental pre-pregnancy BMI and rapid early-life weight gain predispose offspring to obesity in adulthood.

Organizational role for testosterone and estrogen on adult hypothalamic-pituitary-adrenal axis activity in the male rat.

Organizational effects of testosterone during a critical period of neonatal life have major irreversible effects on adult sexual behavior. We have investigated whether perinatal androgen changes also affect another major sexually differentiated system, the hypothalamo-pituitary-adrenal axis. This was assessed in male rats who had been exposed to perinatal flutamide or 1,4,6-androstatriene-3,17-dione (ATD). Once the animals reached adulthood, an automated sampling system was used to collect blood from freely moving animals at 10-min intervals over 24 h, followed by a noise stress and then the administration of lipopolysaccharide (LPS). Perinatal flutamide- and ATD-treated rats not only had higher mean corticosterone levels and increased frequency and amplitude of corticosterone pulses over the 24 h compared with vehicle-injected controls, but they also showed markedly increased corticosterone responses to both noise and LPS. All parameters of increased hypothalamo-pituitary-adrenal activity resembled the normal physiological state of the intact adult female rather than that of the intact adult male rat. Furthermore, 3 h after LPS administration, both flutamide- and ATD-treated animals had markedly higher levels of corticotropin-releasing factor mRNA in the parvocellular paraventricular nucleus (PVN) and proopiomelanocortin mRNA in the adenohypophysis. Flutamide-treated rats also had a greater level of PVN arginine vasopressin mRNA. PVN glucocorticoid receptor mRNA levels were significantly lower in both the flutamide- and the ATD-treated male rats. These data highlight the importance of perinatal exposure to both testosterone and estrogen(s) on the development of a masculinized circadian corticosterone profile and stress-induced hypothalamo-pituitary-adrenal axis activity in the adult male rat.

Modelling of the passage of drugs into milk.

Pharmacokinetic modelling of plasma to milk transfer of drugs has assisted our understanding of the milk to plasma ratio (M/P) and pitfalls associated with it. The most useful way of measuring M/P ratios is, however, by model independent analysis. Physiological models have been proposed to enable the prediction of M/P ratios. The most accurate in prospective performance is the log-transformed phase distribution model. This model, developed by stepwise multiple linear regression analysis, also assists in the understanding of the relative contribution of the various physiological factors involved in the distribution of drugs into milk.

The case for genetically modified crops with a poverty focus.

Recently seven National Academies of Science produced a report on transgenic plants and world agriculture. The report provides scientific perspectives to the ongoing public debate about the potential role for transgenic technology in world agriculture. In this article, we develop the themes of the report and emphasize the potential for future genetically modified (GM) crops with a poverty focus, emphasizing the potential of GM resistance to plant parasitic nematodes for subsistence potato farmers in Bolivia. We judge that a range of incremental gains to crop yields from many transgenes are valuable for future world security. We advocate the establishment of a standard that GM crops must achieve before they are both biosafe and appropriate for resource-poor farmers and we believe that the best interests of the poor require biotechnologists to work towards that objective.

Continual green-fluorescent protein monitoring of cauliflower mosaic virus 35S promoter activity in nematode-induced feeding cells in Arabidopsis thaliana.

The responsiveness of the cauliflower mosaic virus 35S promoter in feeding sites developed by both sexes of Heterodera schachtii and female Meloidogyne incognita has been studied. The objective was to establish the value of green-fluorescent protein (GFP) as a nondestructive reporter gene system for characterizing promoter activity at nematode feeding sites in vivo. Growth units were devised that allowed individual feeding sites in roots of Arabidopsis thaliana to be observed by both bright-field and epifluorescent illumination. Changes in GFP expression were visually observed under experimental conditions that resulted in chloroplast formation in syncytia but not other root cells. Changes in GFP levels altered the extent of quenching, by this protein, of red light emitted by chlorophyll within the chloroplasts under violet excitation. Image analysis provided a semiquantitative basis for simultaneous measurement of changes in GFP fluorescence and the unquenched emission by chlorophyll. GFP levels were constant in cells surrounding the syncytium induced by H. schachtii, but they fell progressive from 10 to 35 days postinfection within this structure. Significant reduction in GFP levels was not limited to the early part of the time course but also occurred between 27 and 35 days postinfection. GFP was detected by immunoblotting in females of M. incognita but not in H. schachtii parasitizing similar GFP-expressing roots.