The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill.

Critical illness polyneuropathies (CIP) and myopathies (CIM) are common complications of critical illness. Several weakness syndromes are summarized under the term intensive care unit-acquired weakness (ICUAW). We propose a classification of different ICUAW forms (CIM, CIP, sepsis-induced, steroid-denervation myopathy) and pathophysiological mechanisms from clinical and animal model data. Triggers include sepsis, mechanical ventilation, muscle unloading, steroid treatment, or denervation. Some ICUAW forms require stringent diagnostic features; CIM is marked by membrane hypoexcitability, severe atrophy, preferential myosin loss, ultrastructural alterations, and inadequate autophagy activation while myopathies in pure sepsis do not reproduce marked myosin loss. Reduced membrane excitability results from depolarization and ion channel dysfunction. Mitochondrial dysfunction contributes to energy-dependent processes. Ubiquitin proteasome and calpain activation trigger muscle proteolysis and atrophy while protein synthesis is impaired. Myosin loss is more pronounced than actin loss in CIM. Protein quality control is altered by inadequate autophagy. Ca(2+) dysregulation is present through altered Ca(2+) homeostasis. We highlight clinical hallmarks, trigger factors, and potential mechanisms from human studies and animal models that allow separation of risk factors that may trigger distinct mechanisms contributing to weakness. During critical illness, altered inflammatory (cytokines) and metabolic pathways deteriorate muscle function. ICUAW prevention/treatment is limited, e.g., tight glycemic control, delaying nutrition, and early mobilization. Future challenges include identification of primary/secondary events during the time course of critical illness, the interplay between membrane excitability, bioenergetic failure and differential proteolysis, and finding new therapeutic targets by help of tailored animal models.

A mechanistic linkage between oral lichen planus and autoimmune thyroid disease.

OBJECTIVE: To determine the levels of antithyroid antibodies and thyroid hormones in the sera of patients with oral lichen planus (OLP), and to quantify the expression of thyroid proteins in OLP lesions. SUBJECTS AND METHODS: Venous blood samples were drawn from 110 patients with OLP who had no history of thyroid disease or levothyroxine supplementation (OLP+/LT4 -). A random population sample of 657 healthy subjects was used as the control group. Two additional groups were used as comparators. Immunohistochemical and qPCR analyses were performed on tissue specimens collected from the patients with OLP and thyroid disease and healthy subjects. RESULTS: No association was found between the presence of antithyroid antibodies and OLP. More patients in the OLP+/LT4 - group showed high levels of thyroid-stimulating hormone and low levels of free thyroxine than were seen in the control group. Thyroid-stimulating hormone receptor was more highly expressed in the OLP lesions of patients with thyroid disease than in the healthy oral mucosa. CONCLUSIONS: A significant number of patients with OLP who are not previously diagnosed with thyroid disease have thyroid parameters that are compatible with hypothyroidism. The expression of thyroid-stimulating hormone receptor in OLP lesions suggests that mechanisms related to autoimmune thyroid disease are involved in the aetiology of OLP.

Storage of red blood cells in a novel polyolefin blood container: a pilot in vitro study.

BACKGROUND AND OBJECTIVES: The present general plasticizer di-2-ethylhexyl-phthalate in polyvinylchloride (PVC) blood bags is only physically dispersed in PVC and will therefore leach into blood components. The objective of this study was to perform a first preliminary red blood cell (RBC) storage evaluation in a new blood bag manufactured of polyolefin without any inclusion of potentially migrating substances. STUDY DESIGN AND METHODS: This is a RBC storage study for 42 days. Blood collection was performed in a polyolefin-based PVC-free blood bag. RBCs were prepared within 8 h. Two different RBC additive solutions were used, either PAGGS-M or PAGGG-M. We weekly measured pH, K+ , glucose, lactate, haemolysis, red cell ATP and 2,3-DPG. RESULTS: RBC storage in PAGGS-M resulted in high haemolysis levels already after 21 days, exceeding the European maximum limit of 0·8%, and low ATP levels by the end of the storage period. With PAGGG-M, haemolysis exceeded 0·8% after 28 days of storage. For additional parameters, the results were comparable to those of previous studies in conventional blood bags. CONCLUSION: This is a first preliminary study of RBC storage in a new type of blood bags. PAGGG-M gave encouraging results except for its inability to prevent increased haemolysis. There will be room for further development of RBC additive solutions to address the haemolysis problems. Plasma should also be tested regarding the stability of coagulation and activation pathway variables. There may also be a potential for future use of the bag for preparation of pooled buffy-coat-derived platelets.

Cellular composition of long-standing gingivitis and periodontitis lesions.

BACKGROUND AND OBJECTIVE: Insufficient information on the cellular composition of long-standing gingivitis lesions without signs of attachment loss makes an understanding of differences in cellular composition between "destructive" and "nondestructive" periodontal lesions difficult. The aim of the current study was to analyze differences in cell characteristics between lesions representing long-standing gingivitis and severe periodontitis. MATERIAL AND METHODS: Two groups of patients were recruited. One group consisted of 36 patients, 33-67 years of age, with severe generalized periodontitis (periodontitis group). The second group consisted of 28 patients, 41-70 years of age, with overt signs of gingival inflammation but no attachment loss (gingivitis group). From each patient a gingival biopsy was obtained from one selected diseased site and prepared for immunohistochemical analysis. RESULTS: Periodontitis lesions were twice as large and contained significantly larger proportions, numbers and densities of cells positive for CD138 (plasma cells) and CD68 (macrophages) than did gingivitis lesions. The proportion of B cells that expressed the additional CD5 marker (B-1a cells) was significantly larger in periodontitis lesions than in gingivitis lesions. The densities of T cells and B cells did not differ between periodontitis lesions and gingivitis lesions. T cells were not the dominating cell type in gingivitis lesions, as B cells together with their subset plasma cells comprised a larger number and proportion than T cells. CONCLUSION: Periodontitis lesions at teeth with advanced attachment and bone loss exhibit quantitative and qualitative differences in relation to gingivitis lesions at teeth with no attachment and bone loss. It is suggested that the large number and high density of plasma cells are the hallmarks of advanced periodontitis lesions and the most conspicuous difference in relation to long-standing gingivitis lesions.

Time course analysis of mechanical ventilation-induced diaphragm contractile muscle dysfunction in the rat.

Controlled mechanical ventilation (CMV) plays a key role in triggering the impaired diaphragm muscle function and the concomitant delayed weaning from the respirator in critically ill intensive care unit (ICU) patients. To date, experimental and clinical studies have primarily focused on early effects on the diaphragm by CMV, or at specific time points. To improve our understanding of the mechanisms underlying the impaired diaphragm muscle function in response to mechanical ventilation, we have performed time-resolved analyses between 6 h and 14 days using an experimental rat ICU model allowing detailed studies of the diaphragm in response to long-term CMV. A rapid and early decline in maximum muscle fibre force and preceding muscle fibre atrophy was observed in the diaphragm in response to CMV, resulting in an 85% reduction in residual diaphragm fibre function after 9-14 days of CMV. A modest loss of contractile proteins was observed and linked to an early activation of the ubiquitin proteasome pathway, myosin:actin ratios were not affected and the transcriptional regulation of myosin isoforms did not show any dramatic changes during the observation period. Furthermore, small angle X-ray diffraction analyses demonstrate that myosin can bind to actin in an ATP-dependent manner even after 9-14 days of exposure to CMV. Thus, quantitative changes in muscle fibre size and contractile proteins are not the dominating factors underlying the dramatic decline in diaphragm muscle function in response to CMV, in contrast to earlier observations in limb muscles. The observed early loss of subsarcolemmal neuronal nitric oxide synthase activity, onset of oxidative stress, intracellular lipid accumulation and post-translational protein modifications strongly argue for significant qualitative changes in contractile proteins causing the severely impaired residual function in diaphragm fibres after long-term mechanical ventilation. For the first time, the present study demonstrates novel changes in the diaphragm structure/function and underlying mechanisms at the gene, protein and cellular levels in response to CMV at a high temporal resolution ranging from 6 h to 14 days.

Residential culturable fungi, (1-3, 1-6)-ß-d-glucan, and ergosterol concentrations in dust are not associated with asthma, rhinitis, or eczema diagnoses in children.

Qualitative reporting of home indoor moisture problems predicts respiratory diseases. However, causal agents underlying such qualitative markers remain unknown. In the homes of 198 multiple allergic case children and 202 controls in Sweden, we cultivated culturable fungi by directly plating dust, and quantified (1-3, 1-6)-ß-D-glucan and ergosterol in dust samples from the child's bedroom. We examined the relationship between these fungal agents and degree of parent or inspector-reported home indoor dampness, and microbiological laboratory's mold index. We also compared the concentrations of these agents between multiple allergic cases and healthy controls, as well as IgE-sensitization among cases. The concentrations of culturable fungal agents were comparable between houses with parent and inspector-reported mold issues and those without. There were no differences in concentrations of the individual or the total summed culturable fungi, (1-3, 1-6)-ß-D-glucan, and ergosterol between the controls and the multiple allergic case children, or individual diagnosis of asthma, rhinitis, or eczema. Culturable fungi, (1-3, 1-6)-ß-D-glucan, and ergosterol in dust were not associated with qualitative markers of indoor dampness or mold or indoor humidity. Furthermore, these agents in dust samples were not associated with any health outcomes in the children.

Syncytin-1 and its receptor is present in human gametes.

MAIN PURPOSE AND RESEARCH QUESTION: To determine whether the true fusogen Syncytin-1 and its receptor (ASCT-2) is present in human gametes using qRT-PCR, immunoblotting and immunofluorescence. METHODS: Donated oocytes and spermatozoa, originating from a fertility center in tertiary referral university hospital, underwent qRT-PCR, immunoblotting and immunofluorescence analyzes. RESULTS: Quantitative RT-PCR of sperm samples from sperm donors showed that syncytin-1 is present in all samples, however, protein levels varied between donors. Syncytin-1 immunoreactivity predominates in the sperm head and around the equatorial segment. The receptor ASCT-2 is expressed in the acrosomal region and in the sperm tail. Moreover, ASCT-2, but not syncytin-1, is expressed in oocytes and the mRNA level increases with increasing maturity of the oocytes. CONCLUSIONS: Syncytin and its receptor are present in human gametes and localization and temporal appearance is consistent with a possible role in fusion between oocyte and sperm.

What determines myonuclear domain size?

The muscle cell is multinuclear and each nucleus controls transcriptional activity in the surrounding territory of cytoplasm called myonuclear domain (MND). MND size varies with the fiber type and is inversely proportional to the muscle fiber oxidative capacity. Change in MND size precedes change in myonuclei count during post-natal growth and most conditions of muscle fiber hypertrophy, suggesting that the myonuclei have the ability to enhance their synthetic capacity according to cell size, functional and metabolic needs. MND size has a "ceiling" limit during hypertrophic process beyond which extra myonuclei are donated by satellite cell to support further muscle growth. During ageing-related atrophy, myonuclei are not lost but an unequal distribution is reported. Ageing myonucleus still responds to resistant exercise and hormone replacement therapy (HRT) by enhancing its transcriptional capacity. Thus the MND size is far from constant and modulates itself to contribute to the muscle remodeling in various conditions.

The influence of epigenetics in relation to oral health.

The immune response is influenced by genetic and epigenetic factors, as well as disease and environmental factors. The term 'epigenetics' describes changes in the genome that influence the gene expression without altering the DNA sequence. In contrast to genetic changes in the DNA, epigenetic changes are reversible and are influenced by environmental factors. The aim of this study is to review the literature on epigenetic modifications with respect to oral health and inflammatory conditions in the oral cavity and to discuss the potential use of this new research field for the dental hygienists' and/or dentists' clinical work. Relevant publications were identified using the PubMed database without limits. The searches were conducted during January to March 2012 and resulted in articles published between 1912 and 2012. Key factors such as environment, diet, smoking, bacteria and inflammation were identified to be relevant to oral health. The result of this review article shows that there is a void in the research on epigenetics in relation to oral health. Identification of epigenetic modifications correlating with oral health may not only present a link between the influence of genetics and that of the environment on oral diseases but also provide new treatment models and tools for the dental professionals.

Epidemiology and patient-reported measurement outcome of pelvic fractures in children and adolescents - A population-based cohort study from the Swedish fracture register.

BACKGROUND AND PURPOSE: Pediatric pelvic fractures are uncommon, representing 0.2-3% of total pediatric fractures. The long-term patient-reported outcome in the pediatric population has not been evaluated yet. The purpose of the study was to describe the epidemiology of pelvic and acetabular fractures in pediatric patients including long-term patient-reported outcomes. PATIENTS AND METHODS: The Swedish Fracture Register (SFR) was used to identify all patients aged 6-17 years at injury with a pelvic fracture between 2015 and 2021. All patients were invited to answer Patient-Reported measurement instruments in 2021. RESULTS: The study cohort consisted of 223 patients with a median age at fracture of 15 years and with 62 % boys. 201 sustained a pelvic and 22 acetabular fractures. Falls were the leading cause of fracture, followed by transport accidents. Most fractures (both pelvis and acetabulum) were type A (73 %), and 21 fractures (9 %) could not be classified according to AO. 85 % of fractures were treated non-surgically. All Type C fractures were treated surgically. Seven PROMIS® profile domains were completed by 31 % of the sample at a mean follow-up time of 3.5 years after pelvic/acetabular fracture. Most patients had "no concern" or "mild concern" but those who had surgery had an inferior t-score in most domains. CONCLUSION: Most fractures occurred in older individuals, with falls during sports activities being the most common cause. This raises important questions about prevention strategies. The PROMIS-Pain-Interference scale indicated that the younger the age at fracture, the more pain was reported at follow-up.

Whole-genome sequencing drug susceptibility testing is associated with positive MDR-TB treatment response.

Until recently, multidrug-resistant TB (MDR-TB) was treated with lengthy and toxic regimens. New three-drug anti-TB regimens raise the question of whether they are sufficiently active for MDR-TB in Central Asia, an MDR-TB hotspot region.In a cohort of rifampicin-resistant (RR) and MDR-TB patients in the Kyrgyz Republic, we investigated the impact of the number of drugs that were tested susceptible by whole-genome sequencing (WGS) and conventional drug susceptibility testing (DST) and used for treatment on the treatment response, defined as 'matches'. Logistic regressions were performed to assess the effect of having ≥ 4 susceptible drugs in a regimen at baseline and at Month 2 on the treatment response.The study included 227 participants with RR/MDR-TB (30.8% female; median age 30.4 years). The age- and sex-adjusted analysis showed an association between a regimen with ≥ 4 WGS matches at baseline (adjusted odds ratio [aOR] 2.10, 95% CI 1.00-4.41). No association was found when using conventional DST to define matches.Our study confirms that the inclusion of four efficacious anti-TB drugs in an MDR-TB regimen increases the chances of a positive treatment response. Susceptibility of at least four drugs in WGS-DST predicts a positive treatment response..

Detection of an aging-related increase in advanced glycation end products in fast- and slow-twitch skeletal muscles in the rat.

Glycation, a non-enzymatic addition of reducing sugars to ε-amino groups of proteins, is a post-translational modification that results in the formation of irreversible advanced glycation end products (AGEs). Ageing related decline in myofibrillar protein function is effected by a number of structural and functional modifications including glycation. Functional properties of skeletal muscles, such as maximum velocity of unloaded shortening, are known to be profoundly affected by ageing at the motor unit, cellular and tissue levels. However, the contribution of protein modifications to a decline in muscle function is not well understood. In this study we measured AGEs of intracellular and sarcolemmal proteins, using an anti-AGE antibody in soleus (SOL) and extensor digiotorum longus (EDL) muscles of male and female rats of five different age groups. Using a fluorescent secondary antibody to visualize AGEs in the confocal microscope, we found that myosin is glycated in both fiber types in all age groups; an ageing related increase in AGEs was observed in both intracellular and sarcolemmal regions in all age groups, with the exception of sarcolemma of SOL (unchanged) and EDL (reduced) in female rats; the greatest concentration of AGEs was found intracellularly in the SOL of the oldest age group (27-30) of females. While an ageing related decline in motor properties can be partially attributed to the observed increase in myofibrillar protein glycation, our results also indicate that intracellular and the less well studied sarcolemmal protein modification likely contribute to an aging-related decline in muscle function. Further studies are required to establish a link between the observed ageing related increase in glycation and muscle function at the motor unit, cellular and tissue levels.

Signalling pathways regulating muscle mass in ageing skeletal muscle: the role of the IGF1-Akt-mTOR-FoxO pathway.

During ageing skeletal muscles undergo a process of structural and functional remodelling that leads to sarcopenia, a syndrome characterized by loss of muscle mass and force and a major cause of physical frailty. To determine the causes of sarcopenia and identify potential targets for interventions aimed at mitigating ageing-dependent muscle wasting, we focussed on the main signalling pathway known to control protein turnover in skeletal muscle, consisting of the insulin-like growth factor 1 (IGF1), the kinase Akt and its downstream effectors, the mammalian target of rapamycin (mTOR) and the transcription factor FoxO. Expression analyses at the transcript and protein level, carried out on well-characterized cohorts of young, old sedentary and old active individuals and on mice aged 200, 500 and 800 days, revealed only modest age-related differences in this pathway. Our findings suggest that during ageing there is no downregulation of IGF1/Akt pathway and that sarcopenia is not due to FoxO activation and upregulation of the proteolytic systems. A potentially interesting result was the increased phosphorylation of the ribosomal protein S6, indicative of increased activation of mTOR complex1 (mTORC1), in aged mice. This result may provide the rationale why rapamycin treatment and caloric restriction promote longevity, since both interventions blunt activation of mTORC1; however, this change was not statistically significant in humans. Finally, genetic perturbation of these pathways in old mice aimed at promoting muscle hypertrophy via Akt overexpression or preventing muscle loss through inactivation of the ubiquitin ligase atrogin1 were found to paradoxically cause muscle pathology and reduce lifespan, suggesting that drastic activation of the IGF1-Akt pathway may be counterproductive, and that sarcopenia is accelerated, not delayed, when protein degradation pathways are impaired.

Apoptosis of mouse mast cells is reciprocally regulated by the IgG receptors FcγRIIB and FcγRIIIA.

BACKGROUND: Mast cells are important effector cells in allergy. They usually have a long life span and resist cell death induction. Fcγ receptor- and IgG immune complex-mediated apoptosis has been demonstrated in B-lineage cells, but not in mast cells. The aim of the current study was to investigate whether mast cells could respond to apoptosis induction by IgG immune complex aggregation of Fcγ receptors. It is known that mouse mast cells express the low-affinity Fcγ receptors FcγRIIB and FcγRIIIA, which bind IgG especially in the form of antigen-IgG immune complexes. METHODS: Mouse bone marrow-derived cultured mast cells were examined for surface expression of FcγRIIB and FcγRIIIA. Apoptosis of such cells from wild-type, FcγRIIB(-/-) or FcγRIIIA(-/-) mice was measured following receptor aggregation by IgG immune complexes. RESULTS: Our data demonstrate that aggregation of either FcγRIIB or FcγRIIIA by IgG immune complexes induced apoptosis of mouse bone marrow-derived cultured mast cells. However, mast cells expressing both FcγRIIB and FcγRIIIA were able to resist cell death induction by IgG immune complexes. CONCLUSION: Our findings reveal a fine-tuning system for regulating mast cell apoptosis through aggregating Fcγ receptors by IgG immune complexes. Such apoptosis regulation may have a substantial impact on mast cell homeostasis during allergic inflammation.

Detecting population structure in a high gene-flow species, Atlantic herring (Clupea harengus): direct, simultaneous evaluation of neutral vs putatively selected loci.

In many marine fish species, genetic population structure is typically weak because populations are large, evolutionarily young and have a high potential for gene flow. We tested whether genetic markers influenced by natural selection are more efficient than the presumed neutral genetic markers to detect population structure in Atlantic herring (Clupea harengus), a migratory pelagic species with large effective population sizes. We compared the spatial and temporal patterns of divergence and statistical power of three traditional genetic marker types, microsatellites, allozymes and mitochondrial DNA, with one microsatellite locus, Cpa112, previously shown to be influenced by divergent selection associated with salinity, and one locus located in the major histocompatibility complex class IIA (MHC-IIA) gene, using the same individuals across analyses. Samples were collected in 2002 and 2003 at two locations in the North Sea, one location in the Skagerrak and one location in the low-saline Baltic Sea. Levels of divergence for putatively neutral markers were generally low, with the exception of single outlier locus/sample combinations; microsatellites were the most statistically powerful markers under neutral expectations. We found no evidence of selection acting on the MHC locus. Cpa112, however, was highly divergent in the Baltic samples. Simulations addressing the statistical power for detecting population divergence showed that when using Cpa112 alone, compared with using eight presumed neutral microsatellite loci, sample sizes could be reduced by up to a tenth while still retaining high statistical power. Our results show that the loci influenced by selection can serve as powerful markers for detecting population structure in high gene-flow marine fish species.

Co-occurrence of toxic bacterial and fungal secondary metabolites in moisture-damaged indoor environments.

UNLABELLED: Toxic microbial secondary metabolites have been proposed to be related to adverse health effects observed in moisture-damaged buildings. Initial steps in assessing the actual risk include the characterization of the exposure. In our study, we applied a multi-analyte tandem mass spectrometry-based methodology on sample materials of severely moisture-damaged homes, aiming to qualitatively and quantitatively describe the variety of microbial metabolites occurring in building materials and different dust sample types. From 69 indoor samples, all were positive for at least one of the 186 analytes targeted and as many as 33 different microbial metabolites were found. For the first time, the presence of toxic bacterial metabolites and their co-occurrence with mycotoxins were shown for indoor samples. The bacterial compounds monactin, nonactin, staurosporin and valinomycin were exclusively detected in building materials from moist structures, while chloramphenicol was particularly prevalent in house dusts, including settled airborne dust. These bacterial metabolites are highly bioactive compounds produced by Streptomyces spp., a group of microbes that is considered a moisture damage indicator in indoor environments. We show that toxic bacterial metabolites need to be considered as being part of very complex and diverse microbial exposures in 'moldy' buildings. PRACTICAL IMPLICATIONS: Bacterial toxins co-occur with mycotoxins in moisture-damaged indoor environments. These compounds are measurable also in settled airborne dust, indicating that inhalation exposure takes place. In attempts to characterize exposures to microbial metabolites not only mycotoxins but also bacterial metabolites have to be targeted by the analytical methods applied. We recommend including analysis of samples of outdoor air in the course of future indoor assessments, in an effort to better understand the outdoor contribution to the indoor presence of microbial toxins. There is a need for a sound risk assessment concerning the exposure to indoor microbial toxins at concentrations detectable in moisture-damaged indoor environments.

Sp1 binds to the G allele of the-1087 polymorphism in the IL-10 promoter and promotes IL-10 mRNA transcription and protein production.

Interleukin (IL)-10 is an important cytokine in immune regulation and promotes B-cell proliferation and antibody production. High levels of IL-10 were found in subjects with autoimmune diseases. The A to G single nucleotide polymorphism at -1087 of the IL-10 promoter is associated with differences in promoter activity and IL-10 production. The objectives of this study were to analyze differences in the transcription factor binding to the -1087 IL-10 gene polymorphism in B-cells, the influence of the A to G transition on the IL-10 and Sp1 gene expression in B-cells after lipopolysaccharide (LPS) stimulation and the effect of knockdown of Sp1 on IL-10 gene expression. Using B-cell lines obtained from subjects with GG and AA genotypes for the -1087 polymorphism and chromatin immunoprecipitation assay, we showed that the transcription factors PU.1 and Spi-B bound to both G and A alleles, whereas the transcription factor Sp1 only bound to the G allele. LPS stimulation of the B-cells resulted in a larger increase in IL-10 and Sp1 gene expression for GG genotypes than AA genotypes and knockdown of Sp1 gene expression resulted in a decrease in IL-10 mRNA transcription. IL-10 production was higher for the GG genotype than for the AA genotype.

Temporally stable genetic structure of heavily exploited Atlantic herring (Clupea harengus) in Swedish waters.

Information on the temporal stability of genetic structures is important to permit detection of changes that can constitute threats to biological resources. Large-scale harvesting operations are known to potentially alter the composition and reduce the variability of populations, and Atlantic herring (Clupea harengus) has a long history of heavy exploitation. In the Baltic Sea and Skagerrak waters, the census population sizes have declined by 35-50% over the last three decades. We compared the genetic structure of Atlantic herring in these waters sampled at least two different times between 1979 and 2003 by assaying 11 allozyme and nine microsatellite loci. We cannot detect any changes in the amount of genetic variation or spatial structure, and differentiation is weak with overall F(ST)=0.003 among localities for the older samples and F(ST)=0.002 for the newer ones. There are indications of temporal allele frequency changes, particularly in one of five sampling localities that is reflected in a relatively small local N(e) estimate of c. 400. The previously identified influence of selection at the microsatellite locus Cpa112 remains stable over the 24-year period studied here. Despite little genetic differentiation, migration among localities appears small enough to permit demographic independence between populations.

Clinical assessment of a new anaesthetic drug administration system: a prospective, controlled, longitudinal incident monitoring study.

A safety-orientated system of delivering parenteral anaesthetic drugs was assessed in a prospective incident monitoring study at two hospitals. Anaesthetists completed an incident form for every anaesthetic, indicating if an incident occurred. Case mix data were collected and the number of drug administrations made during procedures estimated. From February 1998 at Hospital A and from June 1999 at Hospital B, until November 2003, 74,478 anaesthetics were included, for which 59,273 incident forms were returned (a 79.6% response rate). Fewer parenteral drug errors occurred with the new system than with conventional methods (58 errors in an estimated 183,852 drug administrations (0.032%, 95% CI 0.024-0.041%) vs 268 in 550,105 (0.049%, 95% CI 0.043-0.055%) respectively, p = 0.002), a relative reduction of 35% (difference 0.017%, 95% CI 0.006-0.028%). No major adverse outcomes from these errors were reported with the new system while 11 (0.002%) were reported with conventional methods (p = 0.055). We conclude that targeted system re-design can reduce medical error.

Maresin 1 Promotes Wound Healing and Socket Bone Regeneration for Alveolar Ridge Preservation.

Tooth extraction results in alveolar bone resorption and is accompanied by postoperative swelling and pain. Maresin 1 (MaR1) is a proresolving lipid mediator produced by macrophages during the resolution phase of inflammation, bridging healing and tissue regeneration. The aim of this study was to examine the effects of MaR1 on tooth extraction socket wound healing in a preclinical rat model. The maxillary right first molars of Sprague-Dawley rats were extracted, and gelatin scaffolds were placed into the sockets with or without MaR1. Topical application was also given twice a week until complete socket wound closure up to 14 d. Immediate postoperative pain was assessed by 3 scores. Histology and microcomputed tomography were used to assess socket bone fill and alveolar ridge dimensional changes at selected dates. The assessments of coded specimens were performed by masked, calibrated examiners. Local application of MaR1 potently accelerated extraction socket healing. Macroscopic and histologic analysis revealed a reduced soft tissue wound opening and more rapid re-epithelialization with MaR1 delivery versus vehicle on socket healing. Under micro-computed tomography analysis, MaR1 (especially at 0.05 µg/µL) stimulated greater socket bone fill at day 10 as compared with the vehicle-treated animals, resulting in less buccal plate resorption and a wider alveolar ridge by day 21. Interestingly, an increased ratio of CD206+:CD68+ macrophages was identified in the sockets with MaR1 application under immunohistochemistry and immunofluorescence analysis. As compared with the vehicle therapy, local delivery of MaR1 reduced immediate postoperative surrogate pain score panels. In summary, MaR1 accelerated extraction wound healing, promoted socket bone fill, preserved alveolar ridge bone, and reduced postoperative pain in vivo with a rodent preclinical model. Local administration of MaR1 offers clinical potential to accelerate extraction socket wound healing for more predictable dental implant reconstruction.