Robotic Pancreatoduodenectomy: Patient Selection, Volume Criteria, and Training Programs.

INTRODUCTION: There has been a rapid development in minimally invasive pancreas surgery in recent years. The most recent innovation is robotic pancreatoduodenectomy. Several studies have suggested benefits as compared to the open or laparoscopic approach. This review provides an overview of studies concerning patient selection, volume criteria, and training programs for robotic pancreatoduodenectomy and identified knowledge gaps regarding barriers for safe implementation of robotic pancreatoduodenectomy. MATERIALS AND METHODS: A Pubmed search was conducted concerning patient selection, volume criteria, and training programs in robotic pancreatoduodenectomy. RESULTS: A total of 20 studies were included. No contraindications were found in patient selection for robotic pancreatoduodenectomy. The consensus and the Miami guidelines advice is a minimum annual volume of 20 robotic pancreatoduodenectomy procedures per center, per year. One training program was identified which describes superior outcomes after the training program and shortening of the learning curve in robotic pancreatoduodenectomy. CONCLUSION: Robotic pancreatoduodenectomy is safe and feasable for all indications when performed by specifically trained surgeons working in centers who can maintain a minimum volume of 20 robotic pancreatoduodenectomy procedures per year. Large proficiency-based training program for robotic pancreatoduodenectomy seem essential to facilitate a safe implementation and future research on robotic pancreatoduodenectomy.

Development of a core outcome set for trials on induction of labour: an international multistakeholder Delphi study.

OBJECTIVE: To develop a set of core outcomes to be minimally reported in trials on induction of labour. DESIGN: Two-round Delphi survey and consensus meeting. POPULATION: Four stakeholder groups: midwives, obstetricians, neonatologists, and women's representatives. METHODS: Protocol registered with COMET (Registration Number: 695). Stakeholders rated reported outcomes for importance (1-limited to 9-critical). The median rating of each outcome was calculated. The consensus criteria to include outcomes were as follows: ≥70% participants rated outcomes as critical and <15% rated outcomes as limited importance. Outcomes that did not achieve consensus were taken to round two and, if there was still no consensus, to the final consensus meeting. MAIN OUTCOME MEASURES: Outcomes in trials of induction of labour. RESULTS: Of the 159 invited participants, 54% (86/159) completed the first round, and 83% completed the second round (71/86). The core outcome set included 28 core outcomes in four domains: Short-term maternal outcomes (n = 18)-cardiorespiratory arrest, damage to internal organs, death, haemorrhage, hysterectomy, infection, intensive care admission, length of hospital stay, mode of delivery, need for more than one induction agent, oxytocin augmentation, postnatal depression, pulmonary embolus, satisfaction with care, stroke, time from induction to delivery, uterine hyperstimulation, uterine scar dehiscence/rupture; short-term offspring outcomes (n = 8)-admission to the neonatal unit, birth trauma, death, hypoxic ischaemic encephalopathy/need for therapeutic hypothermia, meconium aspiration syndrome, need for respiratory support, infection, and seizures; long-term maternal outcomes (n = 1)-operative pelvic floor repair; long-term offspring outcomes (n = 1)-disability including neurodevelopmental delay. CONCLUSION: Trials on induction of labour should include this core outcome set to standardise reporting. TWEETABLE ABSTRACT: International multistakeholder Delphi study identifies a core outcome set for trials on induction of labour.

Oral health and dental morbidity in long-term allogeneic blood and marrow transplant survivors in Australia.

BACKGROUND: Oral and dental disease is a major cause of long-term morbidity following allogeneic blood and marrow transplantation (Allo-BMT). This study aimed to describe the extent and range of oral and dental complications in BMT recipients and to identify gaps in service provision provided to this high-risk group. METHODS: Participants were Allo-BMT recipients, aged >18 years, and received transplants between 2000 and 2012 in NSW. They completed seven surveys, the purpose-designed Sydney Post-BMT Study survey and six other validated instruments. RESULTS: Of 441 respondents, many reported dry mouth (45.1%), dental caries (36.7%), mouth ulcers (35.3%), oral GVHD (35.1%), gingivitis (16.2%), tooth abscess (6.1%) and oral cancer (1.5%). Regular dental visits were reported by 66.2% of survivors. Middle-high income, older age and geographic location showed a positive association with regular dental visits. Of those who did not visit the dentist regularly, 37% stated they did not feel it necessary, 36% reported cost and 20% stated it was not advised by the treating team. CONCLUSION: Despite oral complications commonly occurring after Allo-BMT, many survivors receive inadequate dental care. These results emphasize the need for improved oral health education, the importance of regular dental checks and improvement in the delivery of dental health services for BMT survivors.

The effect of a perioperative ketamine infusion on the incidence of chronic postsurgical pain-a pilot study.

Chronic postsurgical pain (CPSP) is a common and debilitating complication of major surgery. We undertook a pilot study at three hospitals to assess the feasibility of a proposed large multicentre placebo-controlled randomised trial of intravenous perioperative ketamine to reduce the incidence of CPSP. Ketamine, 0.5 mg/kg pre-incision, 0.25 mg/kg/hour intraoperatively and 0.1 mg/kg/hour for 24 hours, or placebo, was administered to 80 patients, recruited over a 15-month period, undergoing abdominal or thoracic surgery under general anaesthesia. The primary endpoint was CPSP in the area of the surgery reported at six-month telephone follow-up using a structured questionnaire. Fourteen patients (17.5%) reported CPSP (relative risk [95% confidence interval] if received ketamine 1.18 [0.70 to 1.98], P=0.56). Four patients in the treatment group and three in the control group reported ongoing analgesic use to treat CPSP and two patients in each group reported their worst pain in the previous 24 hours at ≥3/10 at six months. There were no significant differences in adverse event rates, quality of recovery scores, or cumulative morphine equivalents consumption in the first 72 hours. Numeric Rating Scale pain scores (median [interquartile range, IQR]) for average pain in the previous 24 hours among those patients reporting CPSP were 17.5 [0 to 40] /100 with no difference between treatment groups. A large (n=4,000 to 5,000) adequately powered multicentre trial is feasible using this population and methodology.

Effects of feeding two RRR-α-tocopherol formulations on serum, cerebrospinal fluid and muscle α-tocopherol concentrations in horses with subclinical vitamin E deficiency.

BACKGROUND: Alpha-tocopherol (α-TP) supplementation is recommended for the prevention of various equine neuromuscular disorders. Formulations available include RRR-α-TP acetate powder and a more expensive but rapidly water-dispersible liquid RRR-α-TP (WD RRR-α-TP). No cost-effective means of rapidly increasing serum and cerebrospinal fluid (CSF) α-TP with WD RRR-α-TP and then sustaining concentrations with RRR-α-TP acetate has yet been reported. OBJECTIVES: To evaluate serum, CSF and muscle α-TP concentrations in an 8-week dosing regimen in which horses were transitioned from WD RRR-α-TP to RRR-α-TP acetate. STUDY DESIGN: Non-randomised controlled trial. METHODS: Healthy horses with serum α-TP of <2 µg/mL were divided into three groups and followed for 8 weeks. In the control group (n = 5), no α-TP was administered. In the second group (Group A; n = 7), 5000 IU/day RRR-α-TP acetate was administered. In the third group (Group WD-A; n = 7), doses of 5000 IU/day of WD RRR-α-TP were administered over 3 weeks, followed by a 4-week transition from WD RRR-α-TP to RRR-α-TP acetate, and a final 1 week of treatment with RRR-α-TP acetate. Serum samples were obtained weekly; muscle biopsies were obtained before, at 2.5 weeks and after supplementation. CSF samples were obtained before and after the 8-week period of supplementation. RESULTS: Serum α-TP increased significantly in Group WD-A at week 1 and remained significantly higher than in Group A and the control group throughout the transition, with inter-individual variation in response. Serum α-TP increased significantly by week 7 in Group A. CSF α-TP increased significantly in Group WD-A only. Muscle α-TP concentrations did not differ significantly across groups. Serum and CSF α-TP were closely correlated (r = 0.675), whereas serum and muscle-α-TP concentrations were not correlated. MAIN LIMITATIONS: The study duration was short and data on pre-transition CSF was lacking. CONCLUSIONS: The administration of 5000 IU/day of water-dispersible RRR-α-TP rapidly increases serum α-TP. Serum and CSF α-TP concentrations are sustained with a gradual transition to 5000 IU/day of RRR-α-TP acetate. Periodic evaluation of serum α-TP concentrations is recommended because responses vary among individuals.

The experience of survival following allogeneic haematopoietic stem cell transplantation in New South Wales, Australia.

Allogeneic haematopoietic stem cell transplantation (allo-HSCT) entails long-term morbidities that impair survivors' quality of life through broad physical and psychosocial sequelae. Current data and survival measurements may be inadequate for contemporary Australian allo-HSCT recipients. This study sought to comprehensively describe survivorship in an up-to-date, local setting through validated measurements and a novel questionnaire designed to complement and address limitations of current instruments. All adults who received an allo-HSCT between 2000 and 2012 in New South Wales were eligible and included, if alive, those literate and consenting to the study, which encompassed seven survey instruments. Four hundred and forty-three survivors participated, which is 76% of contactable (n=583) and 66% of eligible survivors (n= 669). Chronic GVHD (cGVHD) and co-morbidity rates were similar to published data. Noteworthy results include prevalent sexual dysfunction (66% females, 52% males), loss of income (low income increased from 21 to 36%, P<0.001) and employment (full-time employment fell from 64 to 33%, P<0.001), suboptimal vaccination (31% complete), and health screening (≈50%). Risk factors for poor vaccination and health screening were cGVHD, younger age, less education, rural/regional residence and transplantation <2 years. This study suggests that improvement in survivorship may necessitate structural changes in the current delivery of health services.

Aspergillus arachnoiditis post intrathecal baclofen pump insertion.

This report describes an unusual fungal infection of an intrathecal baclofen pump which, to our knowledge, has not been reported previously. We describe a 39-year-old man with severe lower limb spasticity due to secondary progressive multiple sclerosis that was managed with insertion of an intrathecal baclofen pump. He subsequently presented with distinct neurological decline secondary to an intrathecal baclofen pump infection with Aspergillus terreus.

Acidotoxicity and acid-sensing ion channels contribute to motoneuron degeneration.

Amyotrophic lateral sclerosis (ALS) is a fatal neurological condition with no cure. Mitochondrial dysfunction, Ca(2+) overloading and local hypoxic/ischemic environments have been implicated in the pathophysiology of ALS and are conditions that may initiate metabolic acidosis in the affected tissue. We tested the hypothesis that acidotoxicity and acid-sensing ion channels (ASICs) are involved in the pathophysiology of ALS. We found that motoneurons were selectively vulnerable to acidotoxicity in vitro, and that acidotoxicity was partially reduced in asic1a-deficient motoneuron cultures. Cross-breeding of SOD1(G93A) ALS mice with asic1a-deficient mice delayed the onset and progression of motor dysfunction in SOD1 mice. Interestingly, we also noted a strong increase in ASIC2 expression in motoneurons of SOD1 mice and sporadic ALS patients during disease progression. Pharmacological pan-inhibition of ASIC channels with the lipophilic amiloride derivative, 5-(N,N-dimethyl)-amiloride hydrochloride, potently protected cultured motoneurons against acidotoxicity, and, given post-symptom onset, significantly improved lifespan, motor performance and motoneuron survival in SOD1 mice. Together, our data provide strong evidence for the involvement of acidotoxicity and ASIC channels in motoneuron degeneration, and highlight the potential of ASIC inhibitors as a new treatment approach for ALS.

A multicenter, randomized trial of flat dosing versus intrapatient dose escalation of single-agent carboplatin as first-line chemotherapy for advanced ovarian cancer: an SGCTG (SCOTROC 4) and ANZGOG study on behalf of GCIG.

BACKGROUND: The aim of the study is to demonstrate that intrapatient dose escalation of carboplatin would improve the outcome in ovarian cancer compared with flat dosing. PATIENTS AND METHODS: Patients with untreated stage IC-IV ovarian cancer received six cycles of carboplatin area under the curve 6 (AUC 6) 3 weekly either with no dose modification except for toxicity (Arm A) or with dose escalations in cycles 2-6 based on nadir neutrophil and platelet counts (Arm B). The primary end-point was progression-free survival (PFS). RESULTS: Nine hundred and sixty-four patients were recruited from 71 centers. Dose escalation was achieved in 77% of patients who had ≥1 cycle. The median AUCs (cycle 2-6) received were 6.0 (Arm A) and 7.2 (Arm B) (P < 0.001). Grade 3/4 non-hematological toxicity was higher in Arm B (31% versus 22% P = 0.001). The median PFS was 12.1 months in Arm A and B [hazard ratio (HR) 0.99; 95% confidence interval (CI) 0.85-1.15; P = 0.93]. The median overall survival (OS) was 34.1 and 30.7 months in Arms A and B, respectively (HR 0.98; 95% CI 0.81-1.18, P = 0.82). In multivariate analysis, baseline neutrophil (P < 0.001), baseline platelet counts (P < 0.001) and the difference between white blood cell (WBC) and neutrophil count (P = 0.009) had a significant adverse prognostic value. CONCLUSIONS: Intrapatient dose escalation of carboplatin based on nadir blood counts is feasible and safe. However, it provided no improvement in PFS or OS compared with flat dosing. Baseline neutrophils over-ride nadir counts in prognostic significance. These data may have wider implications particularly in respect of the management of chemotherapy-induced neutropenia.

D-dimer threshold increase with pretest probability unlikely for pulmonary embolism to decrease unnecessary computerized tomographic pulmonary angiography.

BACKGROUND: Increasing the threshold to define a positive D-dimer could reduce unnecessary computed tomographic pulmonary angiography (CTPA) for a suspected pulmonary embolism (PE) but might increase rates of a missed PE and missed pneumonia, the most common non-thromboembolic diagnosis seen on CTPA. OBJECTIVE: Measure the effect of doubling the standard D-dimer threshold for 'PE unlikely' Revised Geneva (RGS) or Wells' scores on the exclusion rate, frequency and size of a missed PE and missed pneumonia. METHODS: Patients evaluated for a suspected PE with 64-channel CTPA were prospectively enrolled from emergency departments (EDs) and inpatient units of four hospitals. Pretest probability data were collected in real time and the D-dimer was measured in a central laboratory. Criterion standard was CPTA interpretation by two independent radiologists combined with clinical outcome at 30 days. RESULTS: Of 678 patients enrolled, 126 (19%) were PE+ and 93 (14%) had pneumonia. Use of either Wells' ≤ 4 or RGS ≤ 6 produced similar results. For example, with RGS ≤ 6 and standard threshold (< 500 ng mL(-1)), D-dimer was negative in 110/678 (16%), and 4/110 were PE+ (posterior probability 3.8%) and 9/110 (8.2%) had pneumonia. With RGS ≤ 6 and a threshold < 1000 ng mL(-1) , D-dimer was negative in 208/678 (31%) and 11/208 (5.3%) were PE+, but 10/11 missed PEs were subsegmental and none had concomitant DVT. Pneumonia was found in 12/208 (5.4%) with RGS ≤ 6 and D-dimer < 1000 ng mL(-1). CONCLUSIONS: Doubling the threshold for a positive D-dimer with a PE unlikely pretest probability could reduce CTPA scanning with a slightly increased risk of missed isolated subsegmental PE, and no increase in rate of missed pneumonia.

Primary and long-term stability of a short-stem hip implant.

The new generation short-stem hip implants are designed to encourage physiological-like loading, to minimize stress-strain shielding and therefore implant loosening in the long term. As yet there are no long-term clinical studies available to prove the benefits of these short-stem implants. Owing to this lack of clinical data, numerical simulation may be used as a predictor of longer term behaviour. This finite element study predicted both the primary stability and long-term stability of a short-stem implant. The primary implant stability was evaluated in terms of interface micromotion. This study found primary stability to fall within the critical threshold for osseointegration to occur. Longer term stability was evaluated using a strain-adaptive bone remodelling algorithm to predict the long-term behaviour of the bone in terms of bone mineral density (BMD) changes. No BMD loss was observed in the classical Gruen zones 1 and 7 and bone remodelling patterns were comparable with hip resurfacing results in the literature.

Prospective multicenter assessment of interobserver agreement for radiologist interpretation of multidetector computerized tomographic angiography for pulmonary embolism.

BACKGROUND: Emergency physicians rely on the interpretation of radiologists to diagnose and exclude pulmonary embolism (PE) on the basis of computerized tomographic pulmonary angiography (CTPA). Few data exist regarding the interobserver reliability of this endpoint. OBJECTIVE: To quantify the degree of agreement in CTPA interpretation between four academic hospitals and an independent reference reading (IRR) laboratory. METHODS: Hospitalized and emergency department patients who had one predefined symptom and sign of PE and underwent 64-slice CTPA were enrolled from four academic hospitals. CTPA results as interpreted by board-certified radiologists from the hospitals were compared against those from the IRR laboratory. CTPAs were read as indeterminate, PE(-) or PE(+), and percentage obstruction was computed by the IRR laboratory, using a published method. Agreement was calculated with weighted Cohen's kappa. RESULTS: We enrolled 492 subjects (63% female, age 54 +/- 1 years, and 16.7% PE(+) at the site hospitals). Overall agreement was 429/492 (87.2%; 95% confidence interval 83.9-90.0). We observed 13 cases (2.6%) of complete discordance, where one reading was PE(+) and the other reading was PE(-). Weighted agreement was 92.3%, with kappa = 0.75. The median percentage obstruction for all patients was 9% (25th-75th percentile interquartile range: 5% to -30%). For CTPAs interpreted at the site hospitals as PE(-) or indeterminate but read as PE(+) by the IRR laboratory, the median of percentage obstruction was 6% (4-7%). CONCLUSION: We found in this sample a good level of agreement, with a weighted kappa of 0.75, but with 2.6% of patients having total discordance. Overall, a large proportion of clots were distal or minimally occlusive clots.

Genetic variation in RYR1 and malignant hyperthermia phenotypes.

BACKGROUND: Malignant hyperthermia (MH) is associated, in the majority of cases, with mutations in RYR1, the gene encoding the skeletal muscle ryanodine receptor. Our primary aim was to assess whether different RYR1 variants are associated with quantitative differences in MH phenotype. METHODS: The degree of in vitro pharmacological muscle contracture response and the baseline serum creatine kinase (CK) concentration were used to generate a series of quantitative phenotypes for MH. We then undertook the most extensive RYR1 genotype-phenotype correlation in MH to date using 504 individuals from 204 MH families and 23 RYR1 variants. We also determined the association between a clinical phenotype and both the laboratory phenotype and RYR1 genotype. RESULTS: We report a novel correlation between the degree of in vitro pharmacological muscle contracture responses and the onset time of the clinical MH response in index cases (P<0.05). There was also a significant correlation between baseline CK concentration and clinical onset time (P=0.039). The specific RYR1 variant was a significant determinant of the severity of each laboratory phenotype (P<0.0001). CONCLUSIONS: The MH phenotype differs significantly with different RYR1 variants. Variants leading to more severe MH phenotype are distributed throughout the gene and tend to lie at relatively conserved sites in the protein. Differences in phenotype severity between RYR1 variants may explain the variability in clinical penetrance of MH during anaesthesia and why some variants have been associated with exercise-induced rhabdomyolysis and heat stroke. They may also inform a mutation screening strategy in cases of idiopathic hyperCKaemia.

A modified lateral approach to parastomal hernia repair.

AIM: Parastomal hernia commonly occurs following the formation of a stoma. This is a review of parastomal hernia repair using a modified lateral approach to access the defect. PATIENTS/METHODS: A case series of 17 patients, with a median age of 65, who underwent parastomal hernia repair via a lateral approach over a five year period, is presented. RESULTS: Of the 17 repairs, there were four minor complications in the form of a superficial cellulitis and conservatively managed ileus. In total there were four recurrences, though only one recurrence occurred in 11 cases after slight modification of the technique. The period of follow-up ranged from 6 to 60 months. DISCUSSION: The lateral approach is a viable option for repair of parastomal hernia. It does not necessitate a laparotomy or relocation of the stoma.

Phase I dose-escalation trial of irinotecan with continuous infusion 5-FU first line, in metastatic colorectal cancer.

This single-centre phase I trial was designed to determine the maximum tolerated dose of irinotecan and the recommended dose to use in combination with a fixed dose of 5-fluorouracil (5-FU) administered as a protracted venous infusion, for the first-line treatment of metastatic colorectal cancer (CRC). Tolerability and efficacy were secondary end points. In all, 22 patients, median age 57 years, were treated with escalating, weekly doses of irinotecan (50, 75, 100 and 85 mg m(-2)) in combination with 250 mg m(-2) 5-FU administered as a continuous infusion. All patients had measurable disease. The combination was well tolerated up to an irinotecan dose of 75 mg m(-2). However, three out of five patients at the 100 mg m(-2) irinotecan dose level had their dose reduced due to multiple grade 2 toxicities, and eventually one patient stopped treatment due to grade 3 diarrhoea and multiple grade 2 toxicities. Subsequent patients were recruited at an irinotecan dose level of 85 mg m(-2). The overall response rate was 55%, comprising one complete and 11 partial responses (PRs). Six patients also achieved sustained stable disease (SD), giving a clinical benefit (complete response/PR/SD) response of 82%. The median duration of response was 238 days (8.5 months) and median time to progression was 224 days (8.0 months). Two patients who achieved PRs underwent partial hepatectomies. Thus, irinotecan (85 mg m(-2)) combined with a continuous infusion of 5-FU (250 mg m(-2)) is an active and well-tolerated regimen for the treatment of metastatic CRC. It represents an effective treatment for patients who require close supervision and support, throughout their initial exposure to chemotherapy for this disease, and this dose combination was recommended for an ongoing phase II study.

Patient characteristics and quality of life among a sample of Australian chronic pain clinic attendees.

BACKGROUND: Multidisciplinary chronic pain management programs have proliferated widely in recent decades. The clinical characteristics of patients attending these clinics are becoming the subject of increased research. Recent European data suggests that patients attending these clinics report very low quality of life. AIMS: The present study profiles an Australian population in terms of demographics, clinical characteristics and quality of life, as measured by the Short Form 36 Quality of Life Questionnaire (SF-36). METHODS: Data were collected prospectively from consecutive patients presenting to a multidisciplinary chronic pain clinic at a major Sydney metropolitan teaching-hospital. Cross-sectional analysis of demographic and clinical characteristics and quality of life were then undertaken. RESULTS: Descriptive analysis of demographics and clinical characteristics suggest a patient population group reporting significant pain severity and reduced quality of life. The comparison of SF-36 domain scores between clinic patients and Australian norm values indicates a greatly reduced score on all SF-36 domains for clinic patients. Pain clinic patients reported the most profound effect upon quality of life in the role physical, physical function and social function domains of the SF-36. Stepwise multiple regression indicated impaired coping ability and depressive disability as the most significant correlates of low quality of life. CONCLUSION: Patients who attend chronic pain clinics are likely to report low quality of life with an inability to cope. These findings suggest that future intervention research should explore the impacts of behavioural and self-management interventions. Psychological distress and ability to cope could be used as indices of improvement.

Likelihood ratio for trisomy 21 in fetuses with absent nasal bone at the 11-14-week scan.

OBJECTIVE: To update the likelihood ratio for trisomy 21 in fetuses with absent nasal bone at the 11-14-week scan. METHODS: Ultrasound examination of the fetal profile was carried out and the presence or absence of the nasal bone was noted immediately before karyotyping in 5918 fetuses at 11 to 13+6 weeks. Logistic regression analysis was used to examine the effect of maternal ethnic origin and fetal crown-rump length (CRL) and nuchal translucency (NT) on the incidence of absent nasal bone in the chromosomally normal and trisomy 21 fetuses. RESULTS: The fetal profile was successfully examined in 5851 (98.9%) cases. In 5223/5851 cases the fetal karyotype was normal and in 628 cases it was abnormal. In the chromosomally normal group the incidence of absent nasal bone was related first to the ethnic origin of the mother, being 2.2% for Caucasians, 9.0% for Afro-Caribbeans and 5.0% for Asians; second to fetal CRL, being 4.7% for CRL of 45-54 mm, 3.4% for CRL of 55-64 mm, 1.4% for CRL of 65-74 mm and 1% for CRL of 75-84 mm; and third to NT, being 1.6% for NT < or = 95th centile, 2.7% for NT > 95th centile-3.4 mm, 5.4% for NT 3.5-4.4 mm, 6% for NT 4.5-5.4 mm and 15% for NT > or = 5.5 mm. In the chromosomally abnormal group there was absent nasal bone in 229/333 (68.8%) cases with trisomy 21 and in 95/295 (32.2%) cases with other chromosomal defects. Logistic regression analysis demonstrated that in the chromosomally normal fetuses significant independent prediction of the likelihood of absent nasal bone was provided by CRL, NT and Afro-Caribbean ethnic group, and in the trisomy 21 fetuses by CRL and NT. The likelihood ratio for trisomy 21 for absent nasal bone was derived by dividing the likelihood in trisomy 21 by that in normal fetuses. CONCLUSION: At the 11-14-week scan the incidence of absent nasal bone is related to the presence or absence of chromosomal defects, CRL, NT and ethnic origin.

Critical current of YBa(2)Cu(3)O(7-delta) low-angle grain boundaries.

Transport critical current measurements have been performed on 5 degrees [001]-tilt thin film YBa(2)Cu(3)O(7-delta) single grain boundaries with the magnetic field rotated in the plane of the film, phi. The variation of the critical current has been determined as a function of the angle between the magnetic field and the grain boundary plane. In applied fields above 1 T the critical current j(c) is found to be strongly suppressed only when the magnetic field is within an angle phi(k) of the grain boundary. Outside this angular range the behavior of the artificial grain boundary is dominated by the critical current of the grains. We show that the phi dependence of j(c) in the suppressed region is well described by a flux cutting model.

Hyaluronan enters keratinocytes by a novel endocytic route for catabolism.

Hyaluronan synthesized in the epidermis has an exceptionally short half-life, indicative of its catabolism by epidermal keratinocytes. An intracellular pool of endogenously synthesized hyaluronan, from 1 to 20 fg/cell, inversely related to cell density, was observed in cultured rat epidermal keratinocytes. More than 80% of the intracellular hyaluronan was small (<90 kDa). Approximately 25% of newly synthesized hyaluronan was endocytosed by the keratinocytes and had a half-life of 2-3 h. A biotinylated aggrecan G(1) domain/link protein probe demonstrated hyaluronan in small vesicles of approximately 100 nm diameter close to the plasma membrane, and in large vesicles and multivesicular bodies up to 1300 nm diameter around the nucleus. Hyaluronan did not co-localize with markers of lysosomes. However, inhibition of lysosomal acidification with NH(4)Cl or chloroquine, or treating the cells with the hyaluronidase inhibitor apigenin increased intracellular hyaluronan staining, suggesting that it resided in prelysosomal endosomes. Competitive displacement of hyaluronan from surface receptors using hyaluronan decasaccharides, resulted in a rapid disappearance of this endosomal hyaluronan (t(12) approximately 5 min), indicating its transitory nature. The ultrastructure of the hyaluronan-containing vesicles, co-localization with marker proteins for different vesicle types, and application of specific uptake inhibitors demonstrated that the formation of hyaluronan-containing vesicles did not involve clathrin-coated pits or caveolae. Treatment of rat epidermal keratinocytes with the OX50 monoclonal antibody against the hyaluronan receptor CD44 increased endosomal hyaluronan. However, no CD44-hyaluronan co-localization was observed intracellularly unless endosomal trafficking was retarded by monensin, or cultivation at 20 degrees C, suggesting CD44 recycling. Rat epidermal keratinocytes thus internalize a large proportion of their newly synthesized hyaluronan into non-clathrin-coated endosomes in a receptor mediated way, and rapidly transport it to slower degradation in the endosomal/lysosomal system.