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Zamrotul Izzah,1– 3,&ast; Tanja R Zijp,1,&ast; Christoffer Åberg,3 Daan J Touw,1,3,4 Job FM van Boven1,4 1Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; 2Department of Pharmacy Practice, Faculty of Pharmacy, Universitas Airlangga, Surabaya, Indonesia; 3Department of Pharmaceutical Analysis, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, the Netherlands; 4Medication Adherence Expertise Center of the Northern Netherlands (MAECON), Groningen, the Netherlands&ast;These authors contributed equally to this workCorrespondence: Job FM van Boven, Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, Hanzeplein 1 (Internal Postcode AP50), Groningen, 9713 GZ, the Netherlands, Tel +31 50 361 7893, Fax +31 50 361 4087, Email j.f.m.van.boven@umcg.nlPurpose: An electronic version of the Dosepak® (EDP) which records date and time of dosing events has been developed to monitor adherence to medication packaged in blisters. This study aimed to evaluate its usability and acceptance and to monitor dose-taking adherence for optimal implementation in future clinical trials and practice.Methods: Healthy volunteers aged over 18 years were asked to dispense placebo tablets twice daily from EDPs equipped with a re-usable electronic module for a total duration of four weeks. Afterwards, subjects were asked to complete an online questionnaire and partake in a short one-on-one interview. The usability of the EDP was assessed using the System Usability Scale (SUS), while dose-taking adherence was monitored by EDP records, pill counting, and self-report. The short interview explored user experiences in more detail.Results: Twenty subjects with median [IQR] age 41.5 [32– 49.8] years, 55% female, 45% healthcare professionals, and 20% chronic medication users completed the study and found the EDP easy to use, with a mean [SD] SUS score of 78.0 [11.2]. Median [IQR] dose-taking adherence was 89% [82– 95%] based on EDP records, 96.5% [89– 100%] based on pill counting, 92% [91– 96%] based on self-report, and the levels differed significantly (p < 0.05). Four themes emerged from the interviews: user preference, experience, patient burden, and ideas for improvement. Most participants preferred smaller sized blisters. They found the EDP simple to use and did not see any patient burden for its use in trials or clinical practice. Some reported forgetfulness and suggested reminders built into the blister or sent to their mobile phones. Adequate information or instruction should also be provided for older people and polypharmacy patients.Conclusion: EDP had good perceived usability, was well accepted, and differed significantly from other adherence measurement methods. This study provides input to further guide scale-up of the blister packages.Keywords: compliance, digital health, e-health, patient preference, real-time monitoring, smart packaging

Abstract Background Nanoparticles (NPs) are currently used in a wide variety of fields such as technology, medicine and industry. Due to the novelty of these applications and to ensure their success, a precise characterization of the interactions between NPs and cells is essential. Findings The current study explores the uptake of polystyrene NPs by 1321N1 human astrocytoma and A549 human lung carcinoma cell lines. In this work we show for the first time a comparison of the uptake rates of fluorescently labeled carboxylated polystyrene (PS) NPs of different sizes (20, 40 and 100 nm) in two different cell types, keeping the number of NPs per unit volume constant for all sizes. We propose a reliable methodology to control the dose of fluorescently labeled NPs, by counting individual NPs using automated particle detection from 3D confocal microscopy images. The possibility of detecting individual NPs also allowed us to calculate the size of each nanoparticle and compare the fluorescence of single NPs across different sizes, thereby providing a robust platform for normalization of NP internalization experiments as measured by flow cytometry. Conclusions Our findings show that 40 nm NPs are internalized faster than 20 nm or 100 nm particles in both cell lines studied, suggesting that there is a privileged size gap in which the internalization of NPs is higher.

Understanding nanoparticle interactions with the central nervous system, in particular the blood-brain barrier, is key to advances in therapeutics, as well as assessing the safety of nanoparticles. Challenges in achieving insights have been significant, even for relatively simple models. Here we use a combination of live cell imaging and computational analysis to directly study nanoparticle translocation across a human in vitro blood-brain barrier model. This approach allows us to identify and avoid problems in more conventional inferential in vitro measurements by identifying the catalogue of events of barrier internalization and translocation as they occur. Potentially this approach opens up the window of applicability of in vitro models, thereby enabling in depth mechanistic studies in the future. Model nanoparticles are used to illustrate the method. For those, we find that translocation, though rare, appears to take place. On the other hand, barrier uptake is efficient, and since barrier export is small, there is significant accumulation within the barrier.

At the interface between two regions, for example the air-liquid interface of a lipid solution, there can arise non-equilibrium situations. The water chemical potential corresponding to the ambient RH will, in general, not match the water chemical potential of the solution, and the gradients in chemical potential cause diffusional flows. If the bulk water chemical potential is close to a phase transition, there is the possibility of forming an interfacial phase with structures qualitatively different from those found in the bulk. Based on a previous analysis of this phenomenon in two component systems (C. Aberg, E. Sparr, K. J. Edler and H. Wennerström, Langmuir, 2009, 25, 12177), we here analyse the henomenon for three-component systems. The relevant transport equations are erived, and explicit results are given for some limiting cases. Then the formalism s applied conceptually to four different aqueous lipid systems, which in addition to water and a phospholipid contain (i) octyl glucoside, (ii) urea, (iii) heavy water, and (iv) sodium cholate as the third component. These four cases are chosen to illustrate (i) a method to use a micelle former to transport lipid to the interface where a multi-lamellar structure can form; (ii) to use a co-solvent to inhibit the formation of a gel phase at the interface; (iii) a method to form pure phospholipid multi-lamellar structures at the interface; (iv) a method to form a sequence of phases in the interfacial region. These four cases all have the character of theoretically based conjectures and it remains to investigate experimentally whether or not the conditions can be realized in practice.

The search for understanding the interactions of nanosized materials with living organisms is leading to the rapid development of key applications, including improved drug delivery by targeting nanoparticles, and resolution of the potential threat of nanotechnological devices to organisms and the environment. Unless they are specifically designed to avoid it, nanoparticles in contact with biological fluids are rapidly covered by a selected group of biomolecules to form a corona that interacts with biological systems. Here we review the basic concept of the nanoparticle corona and its structure and composition, and highlight how the properties of the corona may be linked to its biological impacts. We conclude with a critical assessment of the key problems that need to be resolved in the near future.

A model membrane system based on lipid lyotropic phases confined inside the pores of a well-defined scaffold membrane, thereby forming a double-porous membrane structure, is described. The model membrane system is characterized with regard to lipid structure, lipid location, and phase transitions, using small-angle X-ray scattering, differential scanning calorimetry, and confocal microscopy. The system enables studies of transport across oriented lipid bilayers as well as of lipids in confinement. The lipids are shown to be located inside the membrane pores, and the effect of confinement on lipid structure is shown to be small, although dependent on the surface properties of the scaffold membrane. For transport studies, Franz diffusion cells and different types of drugs/dyes are used, and the transport studies are complemented with theoretical modeling. Lipids investigated include monoolein, dioleoyl phosphatidylcholine, dimyristoyl phosphatidylcholine, and E. coli total lipid extract. In the case of monoolein, the lipid structure can be changed from a bicontinuous cubic Ia3d phase to a liquid crystalline lamellar phase, by controlling the osmotic pressure of the surrounding solution through addition of water-soluble polymer. The osmotic pressure can thereby be used as a switch, changing the permeability of the lipid phase up to 100-fold, depending on the properties of the diffusing substance. The large effect of changing the structure implies an alignment of the lamellar phase inside the pores.

Central to understanding how nanoscale objects interact with living matter is the need for reproducible and verifiable data that can be interpreted with confidence. Likely this will be the basis of durable advances in nanomedicine and nanomedical safety. To develop these fields, there is also considerable interest in advancing the first generation of theoretical models of nanoparticle (NP) uptake into cells, and NP biodistribution in general. Here we present an uptake study comparing the outcomes for free molecular dye and NPs labeled with the same dye. A simple flux-based approach is presented to model NP uptake. We find that the intracellular NP concentration grows linearly in time, and that the uptake is essentially irreversible, with the particles accumulating in lysosomes. A wide range of practical challenges, from labile dye release to NP aggregation and the need to account for cell division, are addressed to ensure that these studies yield meaningful kinetic information., From the Clinical Editor: The authors present an uptake study comparing the outcomes for free molecular dye and NPs labeled with the same dye. A wide range of practical challenges are addressed including labile dye release, NP aggregation and the need to account for cell division with the goal that these studies yield meaningful kinetic information., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: carriers of the JP2 clone of Aggregatibacter actinomycetemcomitans exhibit an enhanced risk for developing aggressive periodontitis compared with individuals carrying non-JP2 clones. While the JP2 clone is almost exclusively detected among adolescents of African descent, reports on Caucasians colonized with the JP2 clone are remarkably few., Objective: the aim of this paper is to report on the history of periodontal disease and microbiological findings in a Caucasian family., Material and Methods: a. actinomycetemcomitans and other periodontitis-associated bacterial species in subgingival plaque samples were quantified by conventional culture technique. Leucotoxin promoter typing, serotyping and further characterizations of A. actinomycetemcomitans isolates were performed by PCR. DNA sequencing of the pseudogene, hbpA was performed to determine the origin of the detected JP2 clones. Further, genetically ancestry testing of family members was carried out., Results: the JP2 clone was detected in samples from two of the family members, a 33-year-old daughter and her 62-year-old mother. Relationship of their JP2 clones with JP2 clone strains from the Mediterranean area of Africa was indicated. Genotyping confirmed the Caucasian origin of all family members., Conclusions: Caucasian JP2 carriers exist and older subjects can carry the JP2 clone of A. actinomycetemcomitans.

In this communication, we analyse the passage of oxygen and carbon dioxide over the respiratory membrane. The lung surfactant membrane at the alveolar interface can have a very special arrangement, which affects the diffusional transport. We present a theoretical model for the diffusion of small molecules in membranes with a complex structure, and we specifically compare a membrane composed of a tubular bilayer network with a membrane consisting of a stack of bilayers. Oxygen and carbon dioxide differ in terms of their solubility in the aqueous and the lipid regions of the membrane, and we show that this difference clearly influences their transport properties in the different membrane structures. During normal respiration, the rate-limiting step for carbon dioxide transport is in the gas phase of the different compartments in the lung. For oxygen, on the other hand, the rate is limited by the transport between alveoli and the capillary blood vessels, including the lung surfactant membrane. In a membrane with a structure of a continuous tubular lipid network, oxygen transport is facilitated to a significant extent compared with the structure of aligned lipid bilayers. The model calculations in the present study show that transport of oxygen through the tubular structure is indeed ca 30 per cent faster than transport through a membrane composed of stacked bilayers. The tubular network will also facilitate the transport of apolar substances between the gas phase and the blood. Important examples are ethanol and other volatile liquids that can leave the blood through the lungs, and gaseous anaesthetics or volatile solvents that are inhaled. This exemplifies a new physiological role of a tubular lipid network in the lung surfactant membrane.

We present a theoretical study of two coupled diffusion processes through a membrane which is able to respond to the presence of the diffusing substances with a phase change. The case we consider is when the direct driving force for one of the processes vanishes, i.e. when the chemical potential of one of the components, or some other intensive variable, is kept equal in the two reservoirs surrounding the membrane. The coupling of the two transport processes results in non-zero gradients inside the membrane also for the variable that is equal in the two reservoirs. There is a concomitant change in the phase coexistence compared to the behaviour expected if only considering the external conditions. The transport properties of the two phases within the membrane have to be different for this effect to occur, but otherwise the prerequisites are rather general. An analogous effect is expected for the case of coupled diffusion and heat conduction. Amphiphilic systems or biological membranes often show large changes in structure and transport properties due to small variations in thermodynamic variables such as temperature, the osmotic pressure of the solvent or the presence of cosolvents and cosolutes. The effects we find are therefore particularly relevant to these systems.

A theoretical model is presented for the formation of an ordered phase close to the air-liquid interface of an open binary aqueous solution. The chemical potential of water in the liquid phase is, in general, not equal to the chemical potential of water in the ambient atmosphere. There are therefore nonequilibrium conditions close to the air-liquid interface. There is also a gradient in the chemical potential of water, which could lead to the formation of a new interfacial phase. The formation of an interfacial phase is analyzed in terms of the equilibrium phase behavior corresponding to the local water chemical potential. The possibility of forming an interfacial phase is strongly dependent on the ambient conditions, bulk composition, and diffusive transport properties of the phases in question. Explicit calculations are presented for the formation of a lamellar liquid-crystalline phase close to the air-liquid interface of an isotropic surfactant solution with parameters chosen from the sodium bis(2-ethylhexyl)sulfosuccinate (AOT)/water system. We consider the relevance of the model to neutron reflectivity studies of the interface between air and surfactant/water systems, as well as to surfactant/polymer/water systems.

Background: The Swedish quality improvement initiative Quality Improvement in Coronary Care previously demonstrated significant improvements in caregiver adherence to national guidelines for acute myocardial infarction. The associated impact on 1-year clinical outcome is presented here., Methods and Results: During the baseline period July 2001 to June 2002, 6878 consecutive acute myocardial infarction patients <80 years were included at the 19 intervention and 19 control hospitals and followed for a mean of 12 months. During the postintervention period of May 2003 to April 2004, 6484 patients were included and followed in the same way. From baseline to postintervention, improvements in mortality and cardiovascular readmission rates (events per 100 patient-years) were significant in the intervention group (-2.82, 95% CI -5.26 to -0.39; -9.31, 95% CI -15.48 to -3.14, respectively). However, in the control hospitals, there were no significant improvements (0.04, 95% CI -2.40 to 2.47; -4.93, 95% CI -11.10 to 1.24, respectively). Bleedings in the control group increased in incidence (0.92, 95% CI 0.41 to 1.43), whereas the incidence remained unchanged in the intervention group (0.07, 95% CI -0.44 to 0.58). When the difference of changes between the study groups were evaluated, the results still were in favor of the intervention group, albeit significant only for bleeding complications (mortality: -2.70, 95% CI -6.37 to 0.97; cardiovascular readmissions: -6.85, 95% CI -16.62 to 2.93; bleeding complications: -0.82, 95% CI -1.66 to 0.01)., Conclusions: With a systematic quality improvement initiative aiming to increase the adherence to acute myocardial infarction guidelines, it is possible to achieve long-term positive effects on clinical outcome.

The "acidic mantle" of the skin surface has been related to several essential functions of the skin, although the origin of the acidity is still obscure. In this paper, we investigate how different transport processes can influence the local proton concentration inside a membrane consisting of oriented lipid bilayers. This system is chosen as a simple model of the extracellular lipids in the upper layer of the skin, the stratum corneum. We present a theoretical model for diffusional transport over the membrane in the presence of an osmotic gradient and a gradient in CO(2), taking into account the influence of these gradients on the lipid structure and the local electrostatics. We are also discussing the complications in applying the concept of pH to the stratum corneum. From this, we make the following conclusions: (i) The definition of pH in the stratum corneum is ambiguous, and thus, all statements regarding pH should always be related to a clear definition. (ii) A natural definition of pH in the stratum corneum can be proposed which takes into account local heterogeneity, local charges, and the fact that the stratum corneum is not in thermodynamical equilibrium. (iii) Diffusive transport across an oriented bilayer stack in the presence of an osmotic gradient and/or a gradient in CO(2) can give rise to a substantial gradient in pH. (iv) The results from the simplified model can be correlated to experimental observations of pH in the stratum corneum.

The large osmotic gradient over the outermost layer of human skin implies major structural changes along the gradient, which in turn affects transport. In particular, the possibility of phase changes introduces a non-linear element to the transport behaviour. We present a novel model membrane system to be used for studying these transport mechanisms, where we use a hydrophobic porous polymer membrane as a scaffold for lipid lyotropic phases. The polymer membrane provides mechanical robustness, but also prevents defects of the lipid lyotropic phases, and it can induce an orientation of anisotropic phases. We study the location, structure and phase behaviour of the confined phases. It is shown that this model membrane system allow for accurate measurements of transport through lipid membranes in the presence of different osmotic gradients. A theoretical description is evaluated and shows that this phenomenon can be understood in terms of the proposed mechanism of phase changes. The novel double-porous lipid membrane constitutes a mechanically robust system for studies in aligned systems, which is generally very difficult to achieve. This could have large implications for studies of transport processes in, e.g. skin and other biomembrane model systems.

Objective: Data from the Swedish National Register in Cardiac Care have shown over the last 10 years an enduring gap between optimal treatment of acute myocardial infarction (AMI) according to current guidelines and the treatment actually given. We performed a controlled, prospective study in order to evaluate the effects of applying a multidisciplinary team-based improvement methodology to the use of evidence-based treatments in AMI, together with the use of a modified National Quality Register. The project engaged 25% of the Swedish hospitals., Method: Multidisciplinary teams from 20 hospitals participating in the National Register in Cardiac Care, ranging from small to large hospitals, were trained in continuous quality improvement methodology. Twenty matched hospitals served as controls. Our efforts were focused on finding and applying tools and methods to increase adherence to the national guidelines for 5 different treatments for AMI. For measurement, specially designed quality control charts were made available in the National Register for Cardiac Care., Results: To close the gap, an important issue for the teams was to get all 5 treatments in place. Ten of the hospitals in the study group reduced the gap in 5 of 5 treatments by 50%, while none of the control hospitals did so., Conclusions: This first, controlled prospective study of a registry supported by multidisciplinary team-based improvement methodology showed that this approach led to rapidly improved adherence to AMI guidelines in a broad spectrum of hospitals and that National Quality Registers can be helpful tools.

Background: The adherence to evidence-based treatment guidelines for acute myocardial infarction (AMI) is still suboptimal. Therefore, we designed a study to evaluate the effects of a collaborative quality improvement (QI) intervention on the adherence to AMI guidelines. The intervention used a national web-based quality registry to generate local and regular real-time performance feedback., Methods: A 12-month baseline measurement of the adherence rates was retrospectively collected, comprising the period July 1, 2001, through June 30, 2002. During the intervention period of November 1, 2002, through April 30, 2003, multidisciplinary teams from 19 nonrandomized intervention hospitals were subjected to a multifaceted QI-oriented intervention. Another 19 hospitals, unaware of their status as controls, were matched to the intervention hospitals. During the postintervention measurement period of May 1, 2003, through April 30, 2004, a total of 6726 consecutive patients were included at the intervention (n = 3786) and control (n = 2940) hospitals. The outcome measures comprised 5 Swedish national guideline-derived quality indicators, compared between baseline and postintervention levels in the control and QUICC intervention hospitals., Results: In the control and QI intervention hospitals, the mean absolute increase of patients receiving angiotensin-converting enzyme inhibitors was 1.4% vs 12.6% (P = .002), lipid-lowering therapy 2.3% vs 7.2% (P = .065), clopidogrel 26.3% vs 41.2% (P = .010), heparin/low-molecular weight heparin 5.3% vs 16.3% (P = .010), and coronary angiography 6.2% vs 16.8% (P = .027), respectively. The number of QI intervention hospitals reaching a treatment level of at least 70% in 4 or 5 of the 5 indicators was 15 and 5, respectively. In the control group, no hospital reached 70% or more in just 4 of the 5 indicators., Conclusions: By combining a systematic and multidisciplinary QI collaborative with a web-based national quality registry with functionality allowing real-time performance feedback, major improvements in the adherence to national AMI guidelines can be achieved.

The intestinal epithelium is unique in that it harbors auto-reactive T cells largely absent from the peripheral TCR repertoire in normal mice. Intestinal intraepithelial lymphocytes (IEL) expressing self-reactive TCR are mostly CD8alphaalpha+ cells in adult H-Y TCR RAG(-/-) male mice homozygous for the restricting MHC I allele, H-2D(b). By contrast, in male mice heterozygous for the restricting and non-restricting MHC I allele, H-2D(d) (MHC F(1), H-2D(b/d)), IEL are composed of CD8alphabeta and CD8alphaalpha+ T cells. Here we demonstrate that IEL in the immediate postnatal period of MHC homozygous male mice were mostly CD8(-) T cells, while IEL in MHC F(1) male mice were CD8(-) and CD8alphabeta+ T cells. Regardless of the MHC I configuration and the ability to support positive selection of CD8alphabeta+ cells in the thymus, the expansion of CD8alphaalpha+ IEL was a late postnatal event that followed a reduction in CD8(-) IEL. Furthermore, although in vivo treatment with the specific peptide antigen resulted in an earlier accumulation of activated IEL, the expansion of CD8alphaalpha+ IEL remained inefficient until late in postnatal life. Finally, as CD8(-) IEL stimulated with TCR agonists in vitro, acquired expression of CD8alphaalpha, we propose that CD8alphaalpha+ IEL derive from CD8(-) IEL intermediates. Whether CD8(-) IEL are CD8alphabeta-lineage cells that escape deletion in the thymus or are T cells targeted to the intestine from the thymus because of the early and high level TCR transgene expression in this model, is not clear. The signals required for the expansion of CD8alphaalpha+ IEL are however, incomplete in the immediate postnatal intestine. Determining the factors required for the expansion or retention of CD8alphaalpha+ IEL bearing high affinity, self-specific TCR will further elucidate the in vivo role of these T cells in intestinal homeostasis and perhaps, autoimmunity.

It has been demonstrated experimentally that recognition of novel items is more accurate than recognition of previously familiarized items. Tulving and Kroll (1995) proposed that this effect is due to novelty detectors in the brain giving processing priority to novel information. Recently, Dobbins et al. (1998) suggested that the effect is due to source discrimination problems. In the present two experiments attempts were made to facilitate source discrimination by having different orienting tasks and materials in the familiarization and in the critical presentations. Degree of familiarization was manipulated by varying number of presentations one, two or three times. The results in Experiment 1 showed that the novelty effect increased linearly as a function of presentations in the familiarization phase. In the second experiment the difference between familiar and novel items was even more pronounced. Enactment at encoding was added as a manipulation during familiarization. The results of Experiment 2 showed that the novelty effect did increase linearly for items with nonenacted encoding (in which the familiarization and the critical phase were more similar) but not for enacted encoding. All subjects reported experiencing source discrimination difficulties in both experiments despite the measures taken to diminish them. It seems safe to conclude that source discrimination difficulties are a part of the novelty effect.

The development of TCR alphabeta(+), CD8alphabeta(+) intestinal intraepithelial lymphocytes (IEL) is dependent on MHC class I molecules expressed in the thymus, while some CD8alphaalpha(+) IEL may arise independently of MHC class I. We examined the influence of MHC I allele dosage on the development CD8(+) T cells in RAG 2(-/-) mice expressing the H-2D(b)-restricted transgenic TCR specific for the male, Smcy-derived H-Y Ag (H-Y TCR). IEL in male mice heterozygous for the restricting (H-2D(b)) and nonrestricting (H-2D(d)) MHC class I alleles (MHC F(1)) were composed of a mixture of CD8alphabeta(+) and CD8alphaalpha(+) T cells, while T cells in the spleen were mostly CD8alphabeta(+). This was unlike IEL in male mice homozygous for H-2D(b), which had predominantly CD8alphaalpha(+) IEL and few mostly CD8(-) T cells in the spleen. Our results demonstrate that deletion of CD8alphabeta(+) cells in H-Y TCR male mice is dependent on two copies of H-2D(b), whereas the generation of CD8alphaalpha(+) IEL requires only one copy. The existence of CD8alphabeta(+) and CD8alphaalpha(+) IEL in MHC F(1) mice suggests that their generation is not mutually exclusive in cells with identical TCR. Furthermore, our data imply that the level of the restricting MHC class I allele determines a threshold for conventional CD8alphabeta(+) T cell selection in the thymus of H-Y TCR-transgenic mice, whereas the development of CD8alphaalpha(+) IEL is dependent on, but less sensitive to, this MHC class I allele.

Recent functional brain imaging studies have shown that sensory-specific brain regions that are activated during perception/encoding of sensory-specific information are reactivated during memory retrieval of the same information. Here we used PET to examine whether verbal retrieval of action phrases is associated with reactivation of motor brain regions if the actions were overtly or covertly performed during encoding. Compared to a verbal condition, encoding by means of overt as well as covert activity was associated with differential activity in regions in contralateral somatosensory and motor cortex. Several of these regions were reactivated during retrieval. Common to both the overt and covert conditions was reactivation of regions in left ventral motor cortex and left inferior parietal cortex. A direct comparison of the overt and covert activity conditions showed that activation and reactivation of left dorsal parietal cortex and right cerebellum was specific to the overt condition. These results support the reactivation hypothesis by showing that verbal-explicit memory of actions involves areas that are engaged during overt and covert motor activity., (Copyright 2001 Academic Press.)

Background: Surgery for rectal cancer is associated with high morbidity and mortality rates. The reason for this has been much debated. This population-based study reports the findings on postoperative morbidity and mortality after rectal cancer surgery following the introduction of a centralized colorectal unit in a county central hospital, supervised by a colorectal surgeon using the most recent techniques., Methods: All consecutive patients with rectal cancer who underwent surgery at four county hospitals in the Västmanland county in Sweden during 1993-1996 (n = 133) were compared with patients who underwent surgery at the new colorectal unit in the county central hospital from 1996 to 1999 (n = 144)., Results: The number of operating surgeons was reduced from 26 to four. The postoperative mortality rate decreased from 8 to 1 per cent (P = 0.002) and the total postoperative complication rate was reduced from 57 to 24 per cent (P < 0.001). Surgical complications dropped from 37 to 11 per cent (P < 0.001). The relaparotomy rate fell from 11 to 4 per cent (P < 0.05). Postoperative stay in hospital was reduced from a median of 13 to 9 days (P < 0.001)., Conclusion: The new organization, with centralized rectal cancer surgery using modern techniques, reduced postoperative mortality and overall morbidity rates to less than half.

Episodic memory for simple commands is better following enacted than verbal encoding. This has been proposed to be due to the possibility to base retrieval on motor information. Here we used PET to test the hypothesis that motor brain areas show increased retrieval-related activity following enacted compared to verbal encoding. Brain activity was also monitored during retrieval after imaginary enactment during encoding. It was found that activity in the right motor cortex was maximal following encoding enactment, intermediate following imaginary encoding enactment, and lowest following verbal encoding. These findings provide support that one basis for the facilitating effect on memory performance of overt, and to a lesser degree covert, encoding enactment is the possibility to base retrieval on motor information.

Ceramic inlays offer a good alternative to posterior composites, which still show a high polymerization shrinkage. The thin cement layer will reduce the total amount of shrinkage and probably result in a better marginal adaptation and decreased marginal leakage. Fired feldspathic ceramic inlays cemented with either a glass ionomer cement or a dual-cured composite resin luting cement were compared intraindividually. During a 3-year period 118 inlays, 59 in each group, were examined. Eleven inlays were evaluated as non-acceptable during the period: two (3.4%) in the composite resin group and nine (15.3%) in the glass ionomer cement group. In the composite group one inlay fractured partially and one inlay was replaced because of postoperative sensitivity. In the glass ionomer group four inlays were totally lost, and partial fractures occurred in five inlays. In the fractured glass ionomer cemented inlays the cement was still in place in the cavities. Eight patients reported post-operative sensitivity. No secondary caries was detected around the inlays even though 46% of the patients were considered high caries risk patients.

By comparative studies of sampling methods it was shown that specimens should be obtained preferably by aspiration in order to avoid contamination by anaerobic flora. Anaerobic transport systems are recommended, though some anaerobic strains tolerate exposure to air surprisingly well. A gassed-out tube or vial is the method of choice for transporting fluid specimens for anaerobic culture.

Eighteen patients with benign tumour or cyst of the oesophagus were operated on over a 26-year period at the Department of Thoracic and Cardiovascular Surgery of Uppsala University Hospital. The series comprised 11 cysts and 7 benign tumours, including one case of the rare myoblastoma. The incidence of operations was 0.33 per million population. There was no operative mortality and no subsequent morbidity from the oesophageal disease. The follow-up is complete. A review of the literature confirms that these lesions are rare and that they usually are submucosal. Many are asymptomatic (in our series only about 1/3 caused symptoms). The most common symptoms are those resulting from compression of the oesophagus, which can lead to obstruction and pulmonary complications. It may therefore be warrantable to operate on benign oesophageal tumours and cysts even in the absence of symptoms, thereby also confirming the diagnosis.

The strength of tissue against individual sutures in structures used in the repair of inguinal hernia was tested in situ in 19 cadavers. Altogether 465 measurements were made. Three different layers were investigated, and the mean tissue strength to a single suture was recorded as the mean of all means for each preparation and aspect as follows. (1) The superficial layer (external oblique aponeurosis). Superior aspect 5.3 kp, inferior aspect 5.5 kp. (2) Middle layer. Superior aspect (internal abdominal oblique), 5.9 kp; inferior aspect (inferior border of the inguinal ligament), 6.8 kp. (3) Deep layer. Superior aspect (transversalis fascia), 5.3 kp; inferior aspect (ilio-pubic tract), 6.9 kp. In Cooper's ligament the mean holding power of the tissue against a single suture was found to be 9.1 kp. The site of the most medial of the sutures in the superior aspect of the middle layer corresponds to the conjoined tendon, and the mean tissue strength to this suture was 11.0 kp. The findings thus suggest that the strengths of the tissues of the anterior and posterior walls of the inguinal canal are roughly equal. The structures making up the conjoined tendon and Cooper's ligament were strongest, however, and showed tissue strengths nearly twice those of other structures.

The strength of knotted thread for 12 different types of suture knot in combination with 11 types of suture material used in surgery was investigated one week after insertion in subcutaneous tissue in rabbits. The results were compared with similar investigations on knot strength carried out with 'dry knots'. The thread dimension used in both experiments was 000 (USP). As in vitro, the weakest point of a suture loop subjected to traction was the knot. The incidence of thread rupture within the loop but outside the knot was 1.4% in vitro and 5.9% in vivo, and was commonest with plain catgut. With one exception, however, thread breakage occurred at greater strain than the average required to produce knot failure with the material in question. A greater proportion of knots slipped in vivo then in vitro (72% and 35% respectively), with reduction of the strength of the suture loop as result. There was also greater scatter of measured values under in vivo conditions (standard deviation: 11% in vitro, 23% in vivo). For 7 of 11 suture materials the results indicated a reduction in knot-holding power after one week in situ in the living animal compared with in vivo conditions. This was naturally enough most marked with the two types of catgut (chrome 48%, plain 57%). In contrast, Dexon apparently remained unchanged after one week in vivo. The non-absorbable materials tested showed an estimated average fall in knot-holding power from 100% to 88% (range 109-65%), viz, an average of 12% units. The loss of holding power in vivo was, however, apparently never greater than 1/3 compared with 'dry knots' and calculated on average for all types of knot with non-absorbable materials.

Figures for tissue strength are reported from an investigation on the tissue holding power to a single suture in 8 parts of the gut between oesophagus and rectum in 71 preparations from 44 individuals. 1749 experiments were done. Three layers were tested in each part of the gut. The mean holding power of sutures in the mucosa was 0.26-0.83 kp, for those in the seromuscular coat 1.03-2.24 kp, and for through-and-through sutures, 1.02-2.54 kp. Appreciable differences in tissue strength appear to exist between different parts of the alimentary tract. The lowest values were noted in the oesophagus and sigmoid, and the highest in the stomach and colon. Sutures through the whole gut wall were hardly any stronger than sutures in the sero-muscular coat. There was a significant difference in holding power in cancer compared with non-cancer cases. The holding power was considerably reduced in subjects with cancer in the alimentary tract. Knowledge of tissue strength in the gut may help to explain why anastomoses break down, and will provide a firmer basis for the choice of sufficiently strong suture material and knots with a view to preventing this complication.

A review of the literature covering c. 158,000 laparotomies shows that acute relaparotomy has an incidence of 1.0% and a mortality rate of 43%. Over and above this, rupture of the abdominal wound, which illogically is often considered separately, occurs in 0.6% of all laparotomies and carries a mortality of 34% in the 179,000 laparotomies reviewed in this article. Our own series of 121 relaparotomies in 16,719 cases of laparotomy (an incidence of 0.72%, including burst abdomen) with a 28.1% mortality is discussed. Indications for relaparotomy have included haemorrhage (19%), ileus (25%), peritonitis (32%), wound rupture (22%), and other causes (2%).

In order to ascertain whether tissue in which suture thread is inserted undergoes weakening, the strength against sutures in healing aponeurotic layer was determined in rabbits. The dorsal aponeurosis was used as test tissue. A paravertebral incision 10 cm long was made in it, and this was sutured with 00 (USP) multifil steel thread. The strength measured as holding strength against a single suture was noted 3, 5, 7, 10, and 14 days after the procedure. The contralateral aponeurosis was used as control in each animal, and was tested in identical fashion. Two series of experiments were carried out, one with loosely tensed thread (Series I) and one with tightly pulled sutures (Series II). In series I the strength on the experimental side was reduced by 10 percent (average) on the 3rd, 5th, and 7th days compared to the controls. Increase in strength was seen, however, from the 3rd to 14th days, and was significant (p less than 0.05). In series II the measured values showed significantly (p less than 0.05) lower strength on the experimental side compared with the controls throughout the 14-day period of the experiment. Moderate reduction in the strength of healing aponeurosis was thus recorded. The duration of this weakening depended on how tightly the suture loops were tied.

The Department of Surgery at the University Hospital, Linköping has 133 beds and serves a population of 130000. During the 10-year period 1962-1971 35039 in-patient operations were performed, of which 16719 (48%) were laparotomies. If fracture surgery and urological operations are excluded (during the relevant period these specialties were included under General Surgery) the proportion of laparotomies becomes 67%. Of patients subjected to this procedure 431 (2.58%) died. The mortality for appendicectomy was 0.2%, for gall-bladder surgery 1.3%, for gastric surgery 8.1%, for colon surgery 11.9% for small-gut surgery (including ileus) 15.2%, and for pancreatic surgery 22.2%. Over and above the target organ, malignancy and age exceeding 50 years appear to have contributed greatly to a lethal outcome.

A case of fistula between false aneurysm (localized to the anastomosis of a dacron graft and the left iliac artery) and the sigmoid described, and its treatment is discussed.

In a series of 157 patients undergoing elective colorectal surgery, metronidazole or doxycycline was given to prevent infectious complications. The prophylaxis was started just before the operation and was administered for a total of three days. Excluding mild, negligible infections, 39 (25%) of the 157 patients had infectious complications, 23 from the metronidazole group (28%) and 16 from the doxycycline group (21%). The type of infection varied according to the medication. In four cases of the metronidazole group and 16 of the doxycycline group, anaerobic bacteria were found. The corresponding figures for aerobes were 36 and 20. Doxycycline thus was significantly more effective in preventing complications in general, but metronidazole gave superior protection against anaerobes.