A phase I, dose escalation, pharmacodynamic, pharmacokinetic, and food-effect study of α2 integrin inhibitor E7820 in patients with advanced solid tumors.

UNLABELLED: Introduction E7820 is an orally administered sulfonamide that inhibits alfa-2-integrin mRNA expression. Pre-clinically E7820 showed tumor anti-angiogenic effects in various tumor cell lines and xenograft mouse models. Human daily dosing of 100 mg QD had previously been shown to be safe and tolerable. Methods The study consisted of two parts: Part A (food effect) and Part B (determination of maximum tolerated dose (MTD) for bi-daily (BID) dosing). E7820 dosing started at 50 mg BID with planned escalation to 60, 80 and 100 mg BID every 28 days. Results Fifteen patients were enrolled in Part A and 26 in Part B. The most frequent adverse events of all grades were constipation, diarrhea, nausea, and fatigue while anemia, neutropenia, and fatigue were most frequent grade ≥3 toxicities. At dose-level 60 mg BID, two patients experienced dose-limiting toxicities (grade 3 neutropenic sepsis and grade 4 neutropenia). Therefore the recommended dose (RD) was 50 mg BID. Food had no effect on E7820 exposure. E7820 exposure following twice daily administration was dose-proportional. Expression of platelet integrin-α2 measured as a response biomarker in Part B, generally decreased by a median 7.7 % from baseline following treatment with 50 mg BID E7820. Reduction was most pronounced within 1-week post treatment. The median duration of treatment was median 54, range 20-111 days. The best overall response in any treatment group was stable disease (SD): 23.1 % in Part A (100 mg QD); at the RD 66.7 % (12 of 18 patients) and 40 % in the 60 mg BID group in Part B. CONCLUSIONS: Food had no effect on E7820 exposure. A dose of 50 mg BID was considered the MTD. Treatment with E7820 is safe and tolerable with 2/3 of patients (66.7 %) at MTD having SD as their best response.

Strategies for engaging with future radiation protection professionals: a public outreach case study.

It is evident that there is a nuclear skills shortage within the UK, and logically it can be assumed that the shortfall extends to the radiation protection arena. Plans for nuclear new-build and the decommissioning of existing nuclear sites will require many more people with radiological knowledge and practical competencies. This converts to a nuclear industry requirement in the order of 1000 new recruits per year over at least the next ten years, mainly as new apprentices and graduates. At the same time, the strong demand for persons with radiation protection know-how in the non-nuclear and health care sectors is unlikely to diminish. The task of filling this skills gap is a significant one and it will require a determined effort from many UK stakeholders. The Society for Radiological Protection (SRP) has adopted a strategy in recent years to help address this skills gap. The aim is to engage the interest of secondary school students in the science of radiation and inspire them to follow a career in radiation protection. This paper presents the reasoning behind this strategy and, in an 'outreach case study', describes the establishment of the annual SRP Schools Event. This event is becoming an important addition to the national efforts aimed at increasing the numbers of skilled UK radiation protection professionals over the forthcoming decades.

Phase II trial of domatinostat (4SC-202) in combination with avelumab in patients with previously treated advanced mismatch repair proficient oesophagogastric and colorectal adenocarcinoma: EMERGE.

BACKGROUND: Most oesophagogastric adenocarcinomas (OGAs) and colorectal cancers (CRCs) are mismatch repair proficient (MMRp), responding poorly to immune checkpoint inhibition. We evaluated the safety and efficacy of domatinostat (histone deacetylase inhibitor) plus avelumab (anti-PD-L1 antibody) in patients with previously treated inoperable, advanced/metastatic MMRp OGA and CRC. PATIENTS AND METHODS: Eligible patients were evaluated in a multicentre, open-label dose escalation/dose expansion phase II trial. In the escalation phase, patients received escalating doses of domatinostat [100 mg once daily (OD), 200 mg OD, 200 mg twice daily (BD)] orally for 14 days followed by continuous dosing plus avelumab 10 mg/kg administered intravenously 2-weekly (2qw) to determine the recommended phase II dose (RP2D). The trial expansion phase evaluated the best objective response rate (ORR) during 6 months by RECIST version 1.1 using a Simon two-stage optimal design with 2/9 and 1/10 responses required to proceed to stage 2 in the OGA and CRC cohorts, respectively. RESULTS: Patients (n = 40) were registered between February 2019 and October 2021. Patients in the dose escalation phase (n = 12) were evaluated to confirm the RP2D of domatinostat 200 mg BD plus avelumab 10 mg/kg. No dose-limiting toxicities were observed. Twenty-one patients were treated at the RP2D, 19 (9 OGA and 10 CRC) were assessable for the best ORR; 2 patients with CRC did not receive combination treatment and were not assessable for the primary endpoint analysis. Six patients were evaluated in the dose escalation and expansion phases. In the OGA cohort, the best ORR was 22.2% (95% one-sided confidence interval lower bound 4.1) and the median duration of disease control was 11.3 months (range 9.9-12.7 months). No responses were observed in the CRC cohort. No treatment-related grade 3-4 adverse events were reported at the RP2D. CONCLUSIONS: Responses in the OGA cohort met the criteria to expand to stage 2 of recruitment with an acceptable safety profile. There was insufficient signal in the CRC cohort to progress to stage 2. TRIAL REGISTRATION: NCT03812796 (registered 23rd January 2019).

Bevacizumab with peri-operative epirubicin, cisplatin and capecitabine (ECX) in localised gastro-oesophageal adenocarcinoma: a safety report.

BACKGROUND: Peri-operative chemotherapy and surgery is a standard treatment of localised oesophagogastric adenocarcinoma; however, the outcomes remain poor. PATIENTS AND METHODS: ST03 is a multicentre, randomised, phase II/III study comparing peri-operative ECX with or without bevacizumab (ECX-B). The primary outcome measure of phase II (n = 200) was safety, specifically gastrointestinal (GI) perforation rates and cardiotoxicity. RESULTS: Two hundred patients were randomised between October 2007 and April 2010. Ninety-one/101 (90%) ECX and 86/99 (87%) ECX-B patients completed pre-operative chemotherapy; 7 ECX and 9 ECX-B patients stopped due to toxicity. Gastrointestinal perforations (3 ECX, 1 ECX-B), cardiac events (1 ECX, 4 ECX-B) and venous thromboembolic events (VTEs, 8 ECX, 7 ECX-B) were uncommon. Arterial thromboembolic events (ATEs, myocardial infarction (MI) or cerebrovascular accident) were more frequent with ECX-B (5 versus 1 with ECX). Delayed wound healing, anastomotic leaks and GI bleeding rates were similar. More asymptomatic left ventricular ejection fraction (LVEF) falls (≥15% and/or to <50%) occurred with ECX-B (21.2% versus 11.1% with ECX). Clinically significant falls (≥10% to below lower limit of normal, LLN) occurred in (15.3%) and (8.9%) respectively, with no associated cardiac failure (median 22 months follow-up). CONCLUSIONS: Addition of bevacizumab to peri-operative ECX chemotherapy is feasible with acceptable toxicity and no negative impact on surgical outcomes.

Pathological and epidemiological factors associated with advanced stage at diagnosis of breast cancer.

BACKGROUND: Breast cancer is a highly heterogeneous disease, but the stage at presentation significantly influences outcome. It is important to dissect the pathobiological and epidemiological factors that influence the stage at presentation in order to develop effective strategies to improve clinical outcome. SOURCES OF DATA: PubMed references relating to breast cancer subtypes, molecular classification of breast cancer, genetic susceptibility, young women and breast cancer. AREAS OF AGREEMENT: HER-2 positive, basal-like tumours and inflammatory breast cancers (IBC) more frequently present as late stage disease. Socioeconomic, cultural and ethnic background also influence stage at presentation. AREAS OF CONTROVERSY: The biology of IBC is poorly understood. Relative contribution of social and genetic factors in certain ethnic groups. GROWING POINTS Molecular determinants of breast cancer behaviour. Genetic and biological factors influencing disease phenotype in different ethnic groups. AREAS TIMELY FOR DEVELOPING RESEARCH: Biology of basal-like tumours and IBC. Role of predisposition of genetic variants in determining breast cancer phenotypes. Biological differences in breast cancer from different ethnic groups.

Identification and characterization of a null-activity mutant containing a cryptic pre-mRNA splice site for cytosolic fructose-1,6-bisphosphatase in Flaveria linearis.

Cytosolic fructose-1,6-bisphosphatase (cytFBPase) (E.C. 3.1.3.11) catalyzes the first irreversible reaction of daytime sucrose synthesis. A Flaveria linearis (F. linearis) mutant (line 84-9) previously shown to have ~10% wildtype cytFBPase activity contains no cytFBPase activity based on enzymatic and immunoprecipitation analysis. Genetic segregation and Southern analysis of an F2 population shows one gene copy of cytFBPase in F. linearis and linkage of null cytFBPase activity to the cytFBPase structural gene. A point mutation is present in the structural gene coding for cytFBPase in the mutant, causing a cryptic pre-mRNA splice site and a corresponding 24 amino acid deletion spanning the active site of the enzyme. Collectively, these data support the identification of a null-activity mutant for cytFBPase in F. linearis. This is the first report of a null mutant in the daytime sucrose synthesis pathway confirmed by both enzymatic and molecular analysis. Null cytFBPase in F. linearis does not predispose all lines to high starch accumulation due to an epistatic gene interaction; low starch accumulation in null cytFBPase lines segregates with elevated pyrophosphate-dependent phosphofructokinase (PFP) activity when grown in a 16 h photoperiod. Surprisingly, growth of parental lines and F2 progeny having null cytFBPase in continuous light rescued the wildtype growth phenotype. All null cytFBPase lines showed CO(2)-insensitivity/reversed sensitivity of photosynthesis, indicating that null cytFBPase causes a reduced total capacity for both photosynthesis and end-product synthesis regardless of starch and PFP phenotype. Collectively, the data indicate that F. linearis, a C3-C4 photosynthetic intermediate, has alternative cytFBPase-independent pathways for daytime sucrose synthesis.

The utility of assessing the gross appearances of FNA specimens.

OBJECTIVE: Ideally, fine needle aspiration (FNA) cytology should be performed with near-patient assessment of the adequacy of the specimen by a cytopathologist. However, this is often not feasible. A cruder alternative is for the FNA practitioner to examine the gross appearances of the specimen and to try to predict the its quality. This study set out to determine the value of this approach. METHODS: The study was conducted in tertiary public hospitals in New Zealand and the UK. FNA gross material grading was performed by a variety of pathologists on FNA samples taken using manual guidance and image guidance. The FNA gross material grade was compared with the findings on microscopic examination. RESULTS: Nine out of 123 FNA samples were assessed as Grade 1 (unlikely to contain diagnostic material). All were subsequently reported as having insufficient diagnostic tissue on microscopic examination. Forty-two of the FNA samples were assessed as Grade 2 (possibly contains diagnostic material) and 46 as Grade 3 (probably contains diagnostic material). None from either of these grades was reported as showing insufficient diagnostic material on microscopic examination. Twenty-six cases were reported as Grade 4 (material suggesting a specific diagnosis). None of these was reported as showing insufficient diagnostic material on microscopic examination. The most common Grade 4 provisional diagnosis was that of a colloid cyst or colloid nodule of the thyroid (seven cases). Only two cases had misleading Grade 4 provisional diagnoses. Both were thought to be pus on gross examination but showed necrotic carcinoma on microscopic examination. CONCLUSIONS: The gross appearances of FNA samples can usually predict the adequacy of the samples and sometimes predict the final microscopic diagnosis. However, near-patient microscopic assessment of FNA specimens is preferable if available.

A molecular mechanism of integrin crosstalk: alphavbeta3 suppression of calcium/calmodulin-dependent protein kinase II regulates alpha5beta1 function.

Many cells express more than one integrin receptor for extracellular matrix, and in vivo these receptors may be simultaneously engaged. Ligation of one integrin may influence the behavior of others on the cell, a phenomenon we have called integrin crosstalk. Ligation of the integrin alphavbeta3 inhibits both phagocytosis and migration mediated by alpha5beta1 on the same cell, and the beta3 cytoplasmic tail is necessary and sufficient for this regulation of alpha5beta1. Ligation of alpha5beta1 activates the calcium- and calmodulin-dependent protein kinase II (CamKII). This activation is required for alpha5beta1-mediated phagocytosis and migration. Simultaneous ligation of alphavbeta3 or expression of a chimeric molecule with a free beta3 cytoplasmic tail prevents alpha5beta1-mediated activation of CamKII. Expression of a constitutively active CamKII restores alpha5beta1 functions blocked by alphavbeta3-initiated integrin crosstalk. Thus, alphavbeta3 inhibition of alpha5beta1 activation of CamKII is required for its role in integrin crosstalk. Structure-function analysis of the beta3 cytoplasmic tail demonstrates a requirement for Ser752 in beta3-mediated suppression of CamKII activation, while crosstalk is independent of Tyr747 and Tyr759, implicating Ser752, but not beta3 tyrosine phosphorylation in initiation of the alphavbeta3 signal for integrin crosstalk.

Genome sequence of the plant pathogen and biotechnology agent Agrobacterium tumefaciens C58.

Agrobacterium tumefaciens is a plant pathogen capable of transferring a defined segment of DNA to a host plant, generating a gall tumor. Replacing the transferred tumor-inducing genes with exogenous DNA allows the introduction of any desired gene into the plant. Thus, A. tumefaciens has been critical for the development of modern plant genetics and agricultural biotechnology. Here we describe the genome of A. tumefaciens strain C58, which has an unusual structure consisting of one circular and one linear chromosome. We discuss genome architecture and evolution and additional genes potentially involved in virulence and metabolic parasitism of host plants.

Effects of gender and age on paediatric headache.

The aim of this study was to evaluate the impact of gender and age on headache characteristics and disability. Headache characteristics were assessed at an initial visit to a paediatric specialty care centre and five follow-up visits. A total number of 4121 patients were evaluated. Fifty-eight per cent of the sample was female. Boys were younger at their first headache and initial visit. They more frequently described headache pain as squeezing and location as top of the head. Girls reported more frequent and longer headaches. Girls more often described headache pain as sharp and location as back of the head. Age accounted for more variance than gender in headache severity, duration, frequency and disability. Gender differences exist in headache characteristics. Age is also an important factor in the variability in characteristics and disability. Longitudinal studies are needed to describe further the natural history of headaches in childhood and compare outcome between genders.

CD45 regulates Src family member kinase activity associated with macrophage integrin-mediated adhesion.

BACKGROUND: Adhesion of leukocytes to the extracellular matrix and to other cells is mediated by members of the integrin family of adhesion molecules. Src family kinases are activated upon integrin-mediated adhesion. In lymphocytes, CD45 is a leukocyte-specific transmembrane protein tyrosine phosphatase that activates Src family kinases associated with B-cell and T-cell antigen receptor signaling by constitutive dephosphorylation of the inhibitory carboxy-terminal tyrosine phosphorylation site. Here, we show that CD45 is also important in downregulating the kinase activity of Src family members during integrin-mediated adhesion in macrophages. RESULTS: We found that CD45 colocalized with beta2 integrin and the Src family kinase p53/56(lyn) to adhesion sites in bone marrow-derived macrophages. Macrophages from CD45(-/-) mice were unable to maintain integrin-mediated adhesion. In adherent macrophages, absence of CD45 led to the hyperphosphorylation and hyperactivation of p56/59(hck) and p53/56(lyn), but not of p58(c-fgr). CD45 directly inactivated p59(hck) but not p56(lck) in transient transfection assays. Furthermore, coexpression of CD45 with p59(hck) or p56(lyn) containing a tyrosine to phenylalanine mutation at the carboxy-terminal negative regulatory site resulted in decreased tyrosine phosphorylation of the Src family member kinases due to dephosphorylation of the potentiating tyrosine phosphorylation site within the kinase domain. CONCLUSIONS: Using primary bone marrow macrophages, these studies demonstrate that CD45 regulates Src family kinases and is required to maintain macrophage adhesion. CD45 decreases Src family kinase activity by dephosphorylating the tyrosine residue located within the kinase domain.

The protein tyrosine phosphatase SHP-1 regulates integrin-mediated adhesion of macrophages.

The Src homology 2 domain phosphatase-1 (SHP-1) is a tyrosine phosphatase containing two amino-terminal SH2 domains and is expressed primarily by hematopoietic-derived cells [1]. The viable motheaten (Hcphme-v) mutant mice (mev) suffer from progressive inflammation due to a deficiency of SHP-1 enzyme activity [2,3] and die at 3-4 months of age from macrophage and neutrophil accumulation in the lung [4]. The mechanism by which SHP-1 deficiency leads to inflammation is unknown. We found that macrophages from mev mice adhered and spread to a greater extent than normal macrophages through alpha m beta 2 integrin-mediated contacts. Whereas macrophages deficient in the transmembrane tyrosine phosphatase CD45 (CD45-/-) spontaneously detached from alpha m beta 2 integrin contacts [5], cells deficient in both CD45 and SHP-1 did not. In SHP-1 deficient macrophages there was a 10-15-fold increase in D-3 phospholipid products of phosphatidylinositol (PI) 3-kinase. Concomitantly, there was a 2-5-fold increase in membrane-associated PI 3-kinase activity in mev macrophages relative to normal macrophages. Treatment of macrophages with the PI 3-kinase inhibitors wortmannin or LY294002 resulted in a dramatic detachment of cells, indicating that PI 3-kinase activity is required for adhesion. These data demonstrate that SHP-1 is necessary for detachment from alpha m beta 2 integrin-mediated contacts in primary macrophages and suggest that a defect in this pathway may contribute to inflammatory disease.

Metabolic engineering of Arabidopsis and Brassica for poly(3-hydroxybutyrate-co-3-hydroxyvalerate) copolymer production.

Poly(hydroxyalkanoates) are natural polymers with thermoplastic properties. One polymer of this class with commercial applicability, poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) can be produced by bacterial fermentation, but the process is not economically competitive with polymer production from petrochemicals. Poly(hydroxyalkanoate) production in green plants promises much lower costs, but producing copolymer with the appropriate monomer composition is problematic. In this study, we have engineered Arabidopsis and Brassica to produce PHBV in leaves and seeds, respectively, by redirecting the metabolic flow of intermediates from fatty acid and amino acid biosynthesis. We present a pathway for the biosynthesis of PHBV in plant plastids, and also report copolymer production, metabolic intermediate analyses, and pathway dynamics.

Design, fabrication and perivascular implantation of bioactive scaffolds engineered with human adventitial progenitor cells for stimulation of arteriogenesis in peripheral ischemia.

Cell therapy represents a promising option for revascularization of ischemic tissues. However, injection of dispersed cells is not optimal to ensure precise homing into the recipient's vasculature. Implantation of cell-engineered scaffolds around the occluded artery may obviate these limitations. Here, we employed the synthetic polymer polycaprolactone for fabrication of 3D woodpile- or channel-shaped scaffolds by a computer-assisted writing system (pressure assisted micro-syringe square), followed by deposition of gelatin (GL) nanofibers by electro-spinning. Scaffolds were then cross-linked with natural (genipin, GP) or synthetic (3-glycidyloxy-propyl-trimethoxy-silane, GPTMS) agents to improve mechanical properties and durability in vivo. The composite scaffolds were next fixed by crown inserts in each well of a multi-well plate and seeded with adventitial progenitor cells (APCs, 3 cell lines in duplicate), which were isolated/expanded from human saphenous vein surgical leftovers. Cell density, alignment, proliferation and viability were assessed 1 week later. Data from in vitro assays showed channel-shaped/GPTMS-crosslinked scaffolds confer APCs with best alignment and survival/growth characteristics. Based on these results, channel-shaped/GPTMS-crosslinked scaffolds with or without APCs were implanted around the femoral artery of mice with unilateral limb ischemia. Perivascular implantation of scaffolds accelerated limb blood flow recovery, as assessed by laser Doppler or fluorescent microspheres, and increased arterial collaterals around the femoral artery and in limb muscles compared with non-implanted controls. Blood flow recovery and perivascular arteriogenesis were additionally incremented by APC-engineered scaffolds. In conclusion, perivascular application of human APC-engineered scaffolds may represent a novel option for targeted delivery of therapeutic cells in patients with critical limb ischemia.

Effects of ethanol on protein kinase C activity induced by filamentous actin.

Protein kinase C (PKC) can be activated by interaction with filamentous actin (F-actin) in the absence of membrane lipids (S.J. Slater, S.K. Milano, B.A. Stagliano, K.J. Gergich, J.P. Curry, F.J. Taddeo and C.D. Stubbs, Biochemistry 39 (2000) 271-280). Here, the effects of ethanol on the F-actin-induced activities of a panel of PKC isoforms consisting of 'conventional' (cPKC) alpha, betaI, gamma, 'novel' (nPKC) delta, epsilon and 'atypical' (aPKC) zeta were investigated using purified PKC and F-actin. Ethanol was found to inhibit the Ca2+- and phorbol ester-dependent activities of cPKCalpha and betaI, and the Ca2+- and phorbol ester-independent activity of cPKCgamma, whereas the activities of nPKCdelta, epsilon and aPKCzeta were unaffected. Although the activities of cPKCalpha and betaI induced by saturating levels of phorbol ester were inhibited by ethanol, the binding of these isozymes to F-actin was unaffected within the same phorbol ester concentration range. Conversely, within submaximal levels of phorbol ester, cPKCalpha and betaI activities were unaffected by ethanol whereas binding to F-actin was inhibited. The potency of the inhibition of F-actin-induced cPKCbetaI activity increased with n-alkanol chain length up to n-hexanol, after which it declined. The results indicate that PKC activities associated with F-actin, and therefore cellular processes involving the actin cytoskeleton, are potential targets for ethanol action. The effects of ethanol on these processes may differ according to the particular regulating PKC isoform, its intracellular localization and the presence of activators and cofactors.

Interactions between multiple phosphorylation sites in the inactivation particle of a K+ channel. Insights into the molecular mechanism of protein kinase C action.

Protein kinase C inhibits inactivation gating of Kv3.4 K+ channels, and at least two NH2-terminal serines (S15 and S21) appeared involved in this interaction (. Neuron. 13:1403-1412). Here we have investigated the molecular mechanism of this regulatory process. Site-directed mutagenesis (serine --> alanine) revealed two additional sites at S8 and S9. The mutation S9A inhibited the action of PKC by approximately 85%, whereas S8A, S15A, and S21A exhibited smaller reductions (41, 35, and 50%, respectively). In spite of the relatively large effects of individual S --> A mutations, simultaneous mutation of the four sites was necessary to completely abolish inhibition of inactivation by PKC. Accordingly, a peptide corresponding to the inactivation domain of Kv3.4 was phosphorylated by specific PKC isoforms, but the mutant peptide (S[8,9,15,21]A) was not. Substitutions of negatively charged aspartate (D) for serine at positions 8, 9, 15, and 21 closely mimicked the effect of phosphorylation on channel inactivation. S --> D mutations slowed the rate of inactivation and accelerated the rate of recovery from inactivation. Thus, the negative charge of the phosphoserines is an important incentive to inhibit inactivation. Consistent with this interpretation, the effects of S8D and S8E (E = Glu) were very similar, yet S8N (N = Asn) had little effect on the onset of inactivation but accelerated the recovery from inactivation. Interestingly, the effects of single S --> D mutations were unequal and the effects of combined mutations were greater than expected assuming a simple additive effect of the free energies that the single mutations contribute to impair inactivation. These observations demonstrate that the inactivation particle of Kv3.4 does not behave as a point charge and suggest that the NH2-terminal phosphoserines interact in a cooperative manner to disrupt inactivation. Inspection of the tertiary structure of the inactivation domain of Kv3.4 revealed the topography of the phosphorylation sites and possible interactions that can explain the action of PKC on inactivation gating.

Bacterial contaminants and antibiotic prophylaxis in total hip arthroplasty.

We have investigated the contaminating bacteria in primary hip arthroplasty and their sensitivity to the prophylactic antibiotics currently in use. Impressions (627) of the gloved hands of the surgical team in 50 total hip arthroplasties were obtained on blood agar. The gloves were changed after draping, at intervals of 20 minutes thereafter, and before using cement. Changes were also undertaken whenever a visible puncture was detected. The culture plates were incubated at 37 degrees C for 48 hours. Isolates were identified and tested for sensitivity to flucloxacillin, which is a recognised indicator of sensitivity to cefuroxime. They were also tested against other agents depending upon their appearance on Gram staining. We found contamination in 57 (9%) impressions and 106 bacterial isolates. Coagulase-negative staphylococci were seen most frequently (68.9%), but we also isolated Micrococcus (12.3%), diphtheroids (9.4%), Staphylococcus aureus (6.6%) and Escherichia coli (0.9%). Of the coagulase-negative staphylococci, only 52.1% were sensitive to flucloxacillin and therefore to cefuroxime. We believe that it is now appropriate to review the relevance of prophylaxis with cefuroxime and to consider the use of other agents.

The effect of growth hormone administration on human sleep: a dose-response study.

Human growth hormone and saline were administered for one night each to normal volunteers in a cross-over study. A dose of 2 units im given 15 min before bedtime had no effect on sleep EEG parameters. In contrast, 5 units resulted in a 19% decrease in slow-wave sleep (p < 0.01) and a 13% increase in REM sleep (p < 0.05). Neither doe, when given during daytime, affected tests of affect or serial learning.

Reduction in plasma norepinephrine during fenfluramine treatment.

Plasma norepinephrine levels were reduced to 30% of placebo levels during the administration of fenfluramine, 120 mg/day, for 10 or more days. There was also a significant reduction in plasma dopamine beta-hydroxylase activity during fenfluramine treatment, suggesting that chronic administration may induce antiadrenergic effects which may be useful in the treatment of disorders affected by circulating catecholamines.