Rimantadine and 2‐adamantanamine elicit local anesthesia to cutaneous nociceptive stimuli in a rat model

The aim of this study was to investigate infiltrative cutaneous anesthesia of 2‐adamantanamine and rimantadine. After subcutaneous injections of drugs in rats, the blockade of cutaneous trunci muscle reflex by 2‐adamantanamine and rimantadine was evaluated. Lidocaine, a common local anesthetic, was used as control. We showed that rimantadine and 2‐adamantanamine as well as the local anesthetic lidocaine produced infiltrative anesthesia of skin in a dose‐dependent fashion. Saline (vehicle) group displayed no cutaneous anesthesia. The relative potency of these drugs was rimantadine [23.8 (21.1–26.8)] = lidocaine [26.4 (22.7–30.6)] > 2‐adamantanamine [64.6 (55.0–75.9)] (P < 0.01). On an equianesthetic basis [25% effective dose (ED₂₅), ED₅₀, and ED₇₅], rimantadine and 2‐adamantanamine had longer duration of action than lidocaine (P < 0.05). Neither local injection of saline nor intraperitoneal administration of a large dose of drugs elicited cutaneous anesthesia (data not shown). These data demonstrated for the first time that rimantadine had a similar potent and longer duration of skin infiltrative anesthesia than did lidocaine, whereas 2‐adamantanamine had a less potency but longer duration of cutaneous anesthesia than did lidocaine.     

Heparin‐induced non‐necrotizing skin lesions: rarely associated with heparin‐induced thrombocytopenia

See also Warkentin TE, Linkins L‐A. Non‐necrotizing heparin‐induced skin lesions and the 4T’s score. This issue, pp 1483–. Summary. Background: Recently, there has been an increasing number of reports regarding adverse skin reactions to subcutaneous heparin administration. Case series have implied that heparin‐induced skin lesions are predominantly associated with life‐threatening heparin‐induced thrombocytopenia (HIT) in at least 22% of patients. Skin lesions, therefore, have been included in clinical scores for HIT. Objectives: To determine the association of heparin‐induced skin lesions with HIT. This would have a pivotal impact on further anticoagulatory management in patients with heparin‐induced skin lesions. Patients/Methods: In our observational cohort study, 87 consecutive patients with heparin‐induced skin lesions (85 occurring during low‐molecular‐weight heparin administration) were evaluated using a standardized internal protocol, including HIT diagnostics (heparin‐platelet factor 4‐ELISA, heparin‐induced platelet activation assay), platelet count monitoring, clinical/sonographical screening for thrombosis, skin allergy testing and, if necessary, histology. Results: None of the observed heparin‐induced skin lesions was due to HIT; all lesions were caused by delayed‐type IV‐hypersensitivity reactions (DTH) instead. Even the cutaneous reaction in one patient with concomitant HIT could be classified histologically as DTH reaction, amounting to an association of heparin‐induced skin lesions and HIT in 1.2% (1/87; 95% confidence interval, 0.00–0.06). Conclusion: Heparin‐induced skin lesions associated with use of low‐molecular‐weight heparins do not seem to be strongly associated with a systemic immunologic reaction in terms of HIT and might rather be due to DTH reactions than due to microvascular thrombosis. Hence, we propose refining existing pretest probability scores for HIT, unless underlying causes have been clarified.     

An Anatomic‐Based Approach for the Placement of Implantable Loop Recorders

Introduction: Placement of the Reveal implantable loop recorder (ILR; Medtronic Inc., Minneapolis, MN, USA) has previously involved preoperative cutaneous mapping to determine the optimal location. We describe an anatomic‐based approach to ILR placement that does not require cutaneous mapping. Method: A total of 63 patients (40 women, 23 men, mean age 38 ± 15 years) were included in the study. Each underwent implantation of a Reveal ILR in the left upper chest area midway between the supraclavicular notch and the left breast area. Thirty‐two patients received a Medtronic Reveal DX ILR and 31 received Reveal XT device. Results: In all 62 patients, adequate electrocardiographic tracings were obtained at implant without the need for preoperative cutaneous mapping, and all were followed for a period of 10 ± 4 months afterwards. The mean P wave amplitude was 0.12 ± 0.20 mV at implant and at follow‐up (6–14 months postimplant); the amplitude was 0.11 ± 0.19 mV. The peak‐to‐peak QRS amplitude was 0.48 ± 0.15 mV at implant and 0.44 ± 0.16 mV at a follow‐up of 6–14 months. The P waves were not detected in two patients at follow‐up. In one patient, decreased amplitude of QRS complex resulted in the autoactivation of the device and in one other patient noise was inappropriately oversensed and recorded. Conclusion: A simple anatomic approach can be used for reveal ILR placement. (PACE 2010; 33:1149–1152)     

Comparison of the CELLEX™ and UVAR‐XTS™ closed‐system extracorporeal photopheresis devices in the treatment of chronic graft‐versus‐host disease

Extracorporeal Photopheresis (ECP) is a cellular immunotherapy frequently used for steroid‐refractory graft‐versus‐host disease (GVHD). Chronic GVHD (cGVHD), response to ECP is associated with survival benefit. The UVAR‐XTS^TM system and the more recently developed CELLEX^TM device (both Therakos^TM) are the mainstay for ECP‐delivery in the UK and US. No comparison of treatment outcomes has been reported. We retrospectively compared cGVHD response and steroid reduction and withdrawal in patients treated exclusively over 12 months with either the XTS (n = 51) or CELLEX (n = 50). Our hypothesis was that there would be no difference in clinical outcome or steroid changes in the 2 matched cohorts. We also compared infection incidence, infection‐related death (IRD), and treatment time. Significant clinical improvement and regular capacity to reduce or cease steroids was encountered in both cohorts; at 6 months of ECP 70% of cutaneous cGvHD patients had partial or complete responses and 85% of patients receiving steroids pre‐ECP had reduced dosage. In the XTS group we unexpectedly encountered both superior steroid reduction (86% dose at least halved vs. 61% for CELLEX, P = 0.01) and withdrawal (15 vs. 5 CELLEX, P = 0.01) and a trend for superior skin disease response in the CELLEX‐treated cohort at 3 months. No inter‐relationship was evident. Halving or greater reduction of steroid dose by 3 or 6 months was associated with reduced risk of IRD in the XTS cohort as was withdrawal at 6 months for the combined cohorts. By 6 months, XTS‐treated patients had experienced fewer antibiotic‐requiring infections (mean 1.9 vs. 2.8, P = 0.025). Origins for the disparities are unclear and warrant investigation.     

MRI tumor characterization using Gd‐GlyMe‐DOTA‐perfluorooctyl‐mannose‐conjugate (Gadofluorine M™), a protein‐avid contrast agent

The rationale and objectives were to define the MRI tumor‐characterizing potential of a new protein‐avid contrast agent, Gd‐GlyMe‐DOTA‐perfluorooctyl‐mannose‐conjugate (Gadofluorine M?; Schering AG, Berlin, Germany) in a chemically induced tumor model of varying malignancy. Because of the tendency for this agent to form large micelles in water and to bind strongly to hydrophobic sites on proteins, it was hypothesized that patterns of dynamic tumor enhancement could be used to differentiate benign from malignant lesions, to grade the severity of malignancies and to define areas of tumor necrosis. Gadofluorine M, 0.05 mmol Gd kg^?1, was administered intravenously to 28 anesthetized rats that had developed over 10 months mammary tumors of varying degrees of malignancy as a consequence of intraperitoneal administration of N‐ethyl‐N‐nitrosourea (ENU), 45–250 mg kg^?1. These tumors ranged histologically from benign fibroadenomas to highly undifferentiated adenocarcinomas. Dynamic enhancement data were analyzed kinetically using a two‐compartment tumor model to generate estimates of fractional plasma volume (fPV), apparent fractional extracellular volume (fEV*) and an endothelial transfer coefficient (K^PS) for this contrast agent. Tumors were examined microscopically for tumor type, degree of malignancy (Scarff–Bloom–Richardson score) and location of necrosis. Eighteen tumor‐bearing rats were successfully imaged. MRI data showed an immediate strong and gradually increasing tumor enhancement. K^PS and fEV*, but not fPV obtained from tumors correlated significantly (p < 0.05) with the SBR tumor grade, r = 0.65 and 0.56, respectively. Estimates for K^PS and fEV* but not fPV were significantly lower in a group consisting of benign and low‐grade malignant tumors compared with the group of less‐differentiated high‐grade tumors (1.61 ± 0.64 vs 3.37 ± 1.49, p < 0.01; 0.45 ± 0.17 vs 0.78 ± 0.24, p < 0.01; and 0.076 ± 0.048 vs 0.121 ± 0.088, p = 0.24, respectively). It is concluded that the protein‐avid MRI contrast agent Gadofluorine M enhances tumors of varying malignancy depending on the tumor grade, higher contrast agent accumulation for more malignant lesions. The results show potential utility for differentiating benign and low‐grade malignant lesions from high‐grade cancers. Copyright © 2006 John Wiley & Sons, Ltd.     

Concentration‐independent MRI of pH with a dendrimer‐based pH‐responsive nanoprobe

The measurement of extracellular pH (pH_e) has significant clinical value for pathological diagnoses and for monitoring the effects of pH‐altering therapies. One of the major problems of measuring pH_e with a relaxation‐based MRI contrast agent is that the longitudinal relaxivity depends on both pH and the concentration of the agent, requiring the use of a second pH‐unresponsive agent to measure the concentration. Here we tested the feasibility of measuring pH with a relaxation‐based dendritic MRI contrast agent in a concentration‐independent manner at clinically relevant field strengths. The transverse and longitudinal relaxation times in solutions of the contrast agent (GdDOTA‐4AmP)₄₄‐G5, a G5–PAMAM dendrimer‐based MRI contrast agent in water, were measured at 3 T and 7 T magnetic field strengths as a function of pH. At 3 T, longitudinal relaxivity (r₁) increased from 7.91 to 9.65 mM^?1 s^?1 (on a per Gd³⁺ basis) on changing pH from 8.84 to 6.35. At 7 T, r₁ relaxivity showed pH response, albeit at lower mean values; transverse relaxivity (r₂) remained independent of pH and magnetic field strengths. The longitudinal relaxivity of (GdDOTA‐4AmP)₄₄‐G5 exhibited a strong and reversible pH dependence. The ratio of relaxation rates R₂/R₁ also showed a linear relationship in a pH‐responsive manner, and this pH response was independent of the absolute concentration of (GdDOTA‐4AmP)₄₄‐G5 agent. Importantly, the nanoprobe (GdDOTA‐4AmP)₄₄‐G5 shows pH response in the range commonly found in the microenvironment of solid tumors. Copyright © 2015 John Wiley & Sons, Ltd.     

The laminin‐211‐derived PPFEGCIWN motif accelerates wound reepithelialization and increases phospho‐FAK‐Tyr397 and Rac1‐GTP levels in a rat excisional wound splinting model

We previously reported that the PPFEGCIWN motif (Ln2‐LG3‐P2‐DN3), residues 2678–2686 of the human laminin α2 chain, promotes cell attachment of normal human epidermal keratinocytes (NHEKs) and dermal fibroblasts (NHDFs); however, its in vivo effects on cutaneous wound healing have not yet been examined. In this study, we sought to determine whether Ln2‐LG3‐P2‐DN3 could promote full‐thickness cutaneous wound healing by accelerating wound reepithelialization and wound closure in vivo. Ln2‐LG3‐P2‐DN3 had significantly higher cell attachment and spreading activities than vehicle or scrambled peptide control in both NHEKs and NHDFs in vitro. The wound area was significantly smaller in rats treated with Ln2‐LG3‐P2‐DN3 than in those treated with vehicle or scrambled peptide in the early phase of wound healing. Furthermore, Ln2‐LG3‐P2‐DN3 significantly accelerated wound reepithelialization relative to vehicle or scrambled peptide and promoted FAK‐Tyr397 phosphorylation and Rac1 activation. Collectively, our findings suggest that the PPFEGCIWN motif has potential as a therapeutic agent for cutaneous regeneration via the acceleration of wound reepithelization and wound closure.     

A laminin‐2‐derived peptide promotes early‐stage peripheral nerve regeneration in a dual‐component artificial nerve graft

The DLTIDDSYWYRI motif (Ln2‐P3) of human laminin‐2 has been reported to promote PC12 cell attachment through syndecan‐1; however, the in vivo effects of Ln2‐P3 have not been studied. In Schwann cells differentiated from skin‐derived precursors, the peptide was effective in promoting cell attachment and spreading in vitro. To examine the effects of Ln2‐P3 in peripheral nerve regeneration in vivo, we developed a dual‐component poly(p‐dioxanone) (PPD)/poly(lactic‐co‐glycolic acid) (PLGA) artificial nerve graft. The novel graft was coated with scrambled peptide or Ln2‐P3 and used to bridge a 10 mm defect in rat sciatic nerves. The dual‐component nerve grafts provided tensile strength comparable to that of a real rat nerve trunk. The Ln2‐P3‐treated grafts promoted early‐stage peripheral nerve regeneration by enhancing the nerve regeneration rate and significantly increased the myelinated fibre density compared with scrambled peptide‐treated controls. These findings indicate that Ln2‐P3, combined with tissue‐engineering scaffolds, has potential biomedical applications in peripheral nerve injury repair. Copyright © 2012 John Wiley & Sons, Ltd.     

The importance of medical and nursing care of the open prostatectomy‐related vesico‐cutaneous fistula

Obstruction of the Foley catheter following open prostatectomy occurs frequently and can lead to the development of vesiculo‐cutaneous fistula unless recognized and managed effectively. Vesico‐cutaneous fistula reduces the patient's quality of life and increases overall health care costs. In this case report, we explore how ineffective medical and nursing care could lead to the development of vesico‐cutaneous fistula and outline what good medical and nursing care should consist of in order to prevent this condition. As far as we know, there is no case report of open prostatectomy‐related vesico‐cutaneous fistula in the literature to date.     

Clinical Results of Far‐Field R‐Wave Reduction with a Short Tip‐Ring Electrode

Background: Far‐field R‐wave (FFRW) sensing of the atrial lead of AAI or DDD pacemakers causes incorrect mode switches and remains a problem in patients with atrial arrhythmias in whom low voltage sensing is essential. We studied a pacing electrode with a short tip‐ring distance (1.1 mm). We compared our findings with recordings from a conventional electrode with a larger tip‐ring distance (10 mm). Methods: Thirty‐six consecutive patients with an indication for DDD pacing were implanted with the short tip‐ring electrode. Another 23 patients received the conventional electrode. FFRW and P‐wave amplitudes during pacing and intrinsic ventricular depolarization were measured at implantation. Measurements were repeated before hospital discharge and at follow‐up between 10 and 14 days after implantation. Results: P‐wave amplitude was slightly smaller in the short tip‐ring group (2.71 ± 1.04 vs 3.17 ± 1.30 mV in the conventional group, respectively, P = NS). All P‐waves exceeded 1.2 mV. FFRW during pacing was 0.07 ± 0.05 in the short tip‐ring group and 0.54 ± 0.32 mV in the conventional group (P < 0.001). FFRW during intrinsic rhythm was 0.08 ± 0.04 and 0.55 ± 0.31 mV, respectively (P < 0.001). The ratio between P‐wave and FFRW was 48.6 ± 27.2 in the short tip‐ring group and 7.3 ± 4.4 in the conventional group (P < 0.001). FFRW and P‐wave amplitudes did not change at hospital discharge or during follow‐up. Conclusion: FFRW can be suppressed without compromising P‐wave sensing by using a pacing electrode with a short tip‐ring distance. Whether reduced FFRW amplitude results in clinical endpoints remains to be determined.     

Sonography for Locoregional Staging and Follow‐up of Cutaneous Melanoma

Objective. Sonography is being used with increasing frequency in the assessment of locoregional tumor spread in patients with melanoma. Nevertheless, to maximize its practical impact, sonography should be performed with state‐of‐the‐art equipment, by specifically trained operators, and using a careful exploration technique and well‐defined diagnostic criteria. In this “how I do it”–type article, we illustrate our practical approach to sonography of cutaneous melanoma. Methods. We first illustrate the basic and advanced technical requirements; then we describe our exploration methods and our image interpretation approach; and finally, we report on our use of sonography as a guidance tool for interventional procedures. Special emphasis is given to methodological and interpretative clues, tricks, and pitfalls. Results. Sonography can be used in the initial staging of patients with melanoma, particularly in the screening of patients scheduled for a sentinel lymph node biopsy procedure. Additionally, sonography can be used during patient follow‐up to detect locoregional recurrence earlier than palpation. Conclusions. Sonography plays a growing role in the assessment of the superficial spread of melanoma. Nevertheless, state‐of‐the‐art equipment and careful exploration by trained operators are necessary.     

Preliminary evaluation of novel 68Ga‐DOTAVAP‐PEG‐P2 peptide targeting vascular adhesion protein‐1

Introduction: Expression of vascular adhesion protein‐1 (VAP‐1) is induced at the sites of inflammation where extravasation of leukocytes from blood to the peripheral tissue occurs. VAP‐1 is a potential target for anti‐inflammatory therapy and for in vivo imaging of inflammation. Purpose of this study was to preliminarily evaluate a novel VAP‐1‐targeting peptide as a potential PET imaging agent. Methods: Cyclic 17‐amino‐acid peptide selected from phage display libraries was 1,4,7,10‐tetraazacyclododecane‐N,N′,N′′,N′′′‐tetraacetic acid (DOTA) conjugated via 8‐amino‐3,6‐diooxaoctanoyl linker (polyethylene glycol, PEG derivative) and labelled with ⁶⁸Ga (⁶⁸Ga‐DOTAVAP‐PEG‐P2). In vitro stability of ⁶⁸Ga‐DOTAVAP‐PEG‐P2 was determined in saline, rat plasma and human plasma by radio‐HLPC. Lipophilicity was measured by calculating octanol‐water partition coefficient (logP). Whole‐body distribution kinetics and stability after intravenous injection in healthy rats was studied in vivo by PET imaging, ex vivo by measuring radioactivity of excised tissues, and by radio‐HPLC. Results: In vitro the ⁶⁸Ga‐DOTAVAP‐PEG‐P2 remained stable >4 h in saline and rat plasma, but degraded slowly in human plasma after 2 h of incubation. The logP value of ⁶⁸Ga‐DOTAVAP‐PEG‐P2 was ?1·3. In rats, ⁶⁸Ga‐radioactivity cleared rapidly from blood circulation and excreted quickly in urine. At 120 min after injection the fraction of intact ⁶⁸Ga‐DOTAVAP‐PEG‐P2 were 77 ± 6·0% and 99 ± 1·0% in rat plasma and urine, respectively. Conclusions: These basic and essential in vitro and in vivo studies of the new VAP‐1 targeting peptide revealed promising properties for an imaging agent. Further investigations to clarify in vivo VAP‐1 targeting are warranted.     

Development and validation of a smoothing‐splines‐based correction method for improving the analysis of CEST‐MR images

Chemical exchange saturation transfer (CEST) imaging is an emerging MRI technique relying on the use of endogenous or exogenous molecules containing exchangeable proton pools. The heterogeneity of the water resonance frequency offset plays a key role in the occurrence of artifacts in CEST‐MR images. To limit this drawback, a new smoothing‐splines‐based method for fitting and correcting Z‐spectra in order to compensate for low signal‐to‐noise ratio (SNR) without any a priori model was developed. Global and local voxel‐by‐voxel Z‐spectra were interpolated by smoothing splines with smoothing terms aimed at suppressing noise. Thus, a map of the water frequency offset (‘zero’ map) was used to correctly calculate the saturation transfer (ST) for each voxel. Simulations were performed to compare the method to polynomials and zero‐only‐corrected splines on the basis of SNR improvement. In vitro acquisitions of capillaries containing solutions of LIPOCEST agents at different concentrations were performed to experimentally validate the results from simulations. Additionally, ex vivo investigations of bovine muscle mass injected with LIPOCEST agents were performed as a function of increasing pulse power. The results from simulations and experiments highlighted the importance of a proper ‘zero’ correction (15% decrease of fictitious CEST signal in phantoms and ex vivo preparations) and proved the method to be more accurate compared with the previously published ones, often providing a SNR higher than 5 in different simulated and experimentally noisy conditions. In conclusion, the proposed method offers an accurate tool in CEST investigation. Copyright © 2008 John Wiley & Sons, Ltd.     

Regeneration of dental pulp/dentine complex with a three‐dimensional and scaffold‐free stem‐cell sheet‐derived pellet

Dental pulp/dentine complex regeneration is indispensable to the construction of biotissue‐engineered tooth roots and represents a promising approach to therapy for irreversible pulpitis. We used a tissue‐engineering method based on odontogenic stem cells to design a three‐dimensional (3D) and scaffold‐free stem‐cell sheet‐derived pellet (CSDP) with the necessary physical and biological properties. Stem cells were isolated and identified and stem cells from root apical papilla (SCAPs)‐based CSDPs were then fabricated and examined. Compact cell aggregates containing a high proportion of extracellular matrix (ECM) components were observed, and the CSDP culture time was prolonged. The expression of alkaline phosphatase (ALP), dentine sialoprotein (DSPP), bone sialoprotein (BSP) and runt‐related gene 2 (RUNX2) mRNA was higher in CSDPs than in cell sheets (CSs), indicating that CSDPs have greater odonto/osteogenic potential. To further investigate this hypothesis, CSDPs and CSs were inserted into human treated dentine matrix fragments (hTDMFs) and transplanted into the subcutaneous space in the backs of immunodeficient mice, where they were cultured in vivo for 6 weeks. The root space with CSDPs was filled entirely with a dental pulp‐like tissue with well‐established vascularity, and a continuous layer of dentine‐like tissue was deposited onto the existing dentine. A layer of odontoblast‐like cells was found to express DSPP, ALP and BSP, and human mitochondria lined the surface of the newly formed dentine‐like tissue. These results clearly indicate that SCAP‐CSDPs with a mount of endogenous ECM have a strong capacity to form a heterotopic dental pulp/dentine complex in empty root canals; this method can be used in the fabrication of bioengineered dental roots and also provides an alternative treatment approach for pulp disease. Copyright © 2013 John Wiley & Sons, Ltd.     

Promising effects of exosomes isolated from menstrual blood‐derived mesenchymal stem cell on wound‐healing process in diabetic mouse model

Wound healing is a complicated process that contains a number of overlapping and consecutive phases, disruption in each of which can cause chronic nonhealing wounds. In the current study, we investigated the effects of exosomes as paracrine factors released from menstrual blood‐derived mesenchymal stem cells (MenSCs) on wound‐healing process in diabetic mice. The exosomes were isolated from MenSCs conditioned media using ultracentrifugation and were characterized by scanning electron microscope and western blotting assay. A full thickness excisional wound was created on the dorsal skin of each streptozotocin‐induced diabetic mouse. The mice were divided into three groups as follows: phosphate buffered saline, exosomes, and MenSC groups. We found that MenSC‐derived exosomes can resolve inflammation via induced M1–M2 macrophage polarization. It was observed that exosomes enhance neoangiogenesis through vascular endothelial growth factor A upregulation. Re‐epithelialization accelerated in the exosome‐treated mice, most likely through NF‐κB p65 subunit upregulation and activation of the NF‐κB signaling pathway. The results demonstrated that exosomes possibly cause less scar formation through decreased Col1:Col3 ratio. These notable results showed that the MenSC‐derived exosomes effectively ameliorated cutaneous nonhealing wounds. We suggest that exosomes can be employed in regenerative medicine for skin repair in difficult‐to‐heal conditions such as diabetic foot ulcer.     

Association of Crown‐Rump Length at 11 to 14 Weeks' Gestation and Risk of a Large‐for‐Gestational‐Age Neonate

Objective. The purpose of this study was to evaluate the association between crown‐rump length (CRL) and the risk of a large‐for‐gestational‐age (LGA) neonate. Methods. Data were retrospectively collected on consecutive women with a healthy singleton pregnancy followed to delivery at our center from 2003 to 2006 who underwent nuchal translucency, pregnancy‐associated plasma protein‐A, and free β‐human chorionic gonadotropin screening at 11 to 14 weeks' gestation. Pregnancies were dated by the last menstrual period (LMP) confirmed by CRL at 6 to 10 weeks or the known time of fertilization. The fetal CRL at 11 to 14 weeks was obtained from frozen sonographic images. The measured CRL was converted to gestational weeks using the method of Hadlock et al (Radiology 1992; 182:501–505). The expected gestational age (GA) by the LMP was subtracted from the measured GA to yield the ΔCRL. The association between the ΔCRL and birth weight was statistically analyzed. Results. The sample included 521 women. Fifty neonates (9.6%) were LGA (≥90th percentile), 38 (7.3%) small for gestational age, and 433 (83.1%) appropriate for gestational age. The LGA group was characterized by significantly larger‐than‐expected CRL measurements (P = .033). The birth weight percentile and rate of LGA neonates were significantly higher in pregnancies in which the ΔCRL was ½ week or greater (P = .007 and .033, respectively). There was a significant linear correlation between the ΔCRL and birth weight percentile (P = .001). On multivariate logistic regression analysis, the ΔCRL was the only significant predictor of an LGA neonate (odds ratio, 1.6; 95% confidence interval, 1.07–2.4; P = .023). Conclusions. Pregnancies with LGA neonates are characterized by larger‐than‐expected CRL measurements at 11 to 14 weeks' gestation.     

Factors influencing 133‐xenon washout in a nose‐sinus model

The 133‐xenon washout technique is a non‐invasive method for the evaluation of ventilation of the paranasal sinuses. The half‐time of 133‐xenon washout (T½) is considered to reflect sinus ostial function and sinus ventilation. However, it is not known how morphological and physiological factors affect the washout from the paranasal sinuses. The aim of the present study was to evaluate how sinus volume, ostial diameter and nasal ventilation influence 133‐xenon washout in a nose‐sinus model. This is important for the interpretation of measurements of 133‐xenon washout from paranasal sinuses in healthy subjects and in subjects with sinus disease. The 133‐xenon washout was measured with a scintillation camera. The statistical analysis of the results showed that the logarithm (to the base 10) of the half‐time of 133‐xenon washout is linearly related to the ostial diameter, the sinus volume and the nasal ventilation in the model. In a multiple linear regression model, the most important factor contributing to 133‐xenon washout was found to be the ostial diameter, which explained 76% of the variation in log T½. In the same statistical model the sinus volume explained 7·5% and the ventilation 5·3% of the variation in log T½. Calculations of the functional ostial diameter in healthy subjects were made, based on the results of the model study. The mean functional ostial diameter was found to be 3·5 mm (range 0·5–7·5 mm). The results obtained with the present model experiments may be of importance for the correct interpretation of the results of measurements of 133‐xenon washout in healthy subjects and patients.     

Microdose study of a P‐glycoprotein substrate,fexofenadine, using a non‐radioisotope‐labelled drug and LC/MS/MS

Objective: Fexofenadine is a P‐glycoprotein substrate of low bioavailability. It is primarily excreted into faeces as a parent drug via biliary excretion. The predictability from microdose data for the drug absorbed via transporters such as P‐glycoprotein is not known. Therefore, this study assessed the predictability of therapeutic‐dose pharmacokinetics of fexofenadine from microdosing data using non‐radioisotope‐labelled drug and liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI‐MS/MS). Method: In a single dose, randomized, two‐way crossover study, eight subjects received a microdose (100 μg) or a therapeutic dose (60 mg) of fexofenadine. Blood samples were collected until 12 h after dosing, and assayed using LC/MS/MS. Results: Plasma concentration–time curves of fexofenadine between microdose and therapeutic dose were similar. The mean ± SD of C_max normalized to 60 mg dose after microdose and therapeutic dose were 379 ± 147 and 275 ± 145 ng/mL respectively. The mean AUC_last normalized to 60 mg dose after microdose and therapeutic dose were 1914 ± 738 and 1431 ± 432 ng/h/mL respectively. The mean dose‐adjusted C_max and AUC_last after microdose were higher compared with those after therapeutic dose. Individual plots of C_max and AUC_last normalized to 60 mg dose, were similar for microdose and therapeutic dose. None of the pharmacokinetic parameters were statistically different using anova . Overall, the microdose pharmacokinetics profile was similar to, and hence predictive of, that of the therapeutic dose. Conclusion: For the P‐glycoprotein substrate fexofenadine, the predictability of therapeutic‐dose pharmacokinetics from microdose data was good. A microdose study using a non‐radioisotope‐labelled drug and LC/MS/MS is convenient, and has the potential to aid the early selection of drug candidates.