Search

Refereed/Peer-reviewed Sudden infant death syndrome (SIDS) occurs more often in male than in female infants, suggesting involvement of the X-chromosome. Histopathological studies have suggested that altered expression of the Neurokinin-1 receptor may also play a role in the pathogenesis of SIDS. It was hypothesised that genetic variants in three X-chromosome-encoded microRNA (miRNA/miR), known to down-regulate expression of the Neurokinin-1 receptor, may contribute to SIDS. Aim: To identify sequence variants in the miRNAs within a study cohort (27 cases of SIDS and 28 controls) and determine if there was a difference in the frequencies in male and female SIDS infants. Methods: Genomic DNA prepared from stored blood spots was amplified and sequenced to identify genetic variants in miR500A, miR500B and miR320D2. Results: No novel variants in the miRNAs were identified in our study cohort. We identified one known single-nucleotide polymorphism (SNP) in miR320D2: rs5907732 G/T, in both cases and controls. No significant difference in the SNP frequency was observed between male and female SIDS cases. Conclusion: This pilot study suggests that sequence variants in three miRNAs do not contribute to the reported higher prevalence of SIDS in male infants and do not contribute to the pathogenesis of SIDS in our cohort.

This study was undertaken to review fatal cases of insulin overdose in South Australia (SA) over a 20-year period to assess rates and characteristics of insulin-related deaths among insulin-dependent diabetics and non-diabetics for all manners of death. Records from the National Coronial Information System (NCIS) and Forensic Science SA (FSSA) were searched for all cases of fatal insulin overdose in South Australia (SA) between 2000 and 2019. Collected variables included age, sex, cause of death, scene findings, manner of death, decedent medical and personal histories, biochemistry, toxicology, histopathology, and autopsy findings. Statistical analyses were performed using R (version 4.1.2). Forty cases of insulin overdose were identified in SA between 2000 and 2019. Twenty-nine cases (72.5%) were suicides, with the remaining cases classified as accidental or undetermined intent. Thirteen of the 22 insulin-dependent diabetics (59%) had a history of depression, 10 of whom had previously demonstrated suicidal ideation. The current study has shown that suicides using insulin among insulin-dependent diabetics are equally as prevalent, if not more so than fatal accidental insulin overdoses. This can largely be attributed to insulin-dependent diabetic access to a potentially lethal substance. Suicide prevention strategies should focus on insulin-dependent diabetics with a history of depression, particularly for those with access to rapid-acting insulin.

The spatial distribution of radiopharmaceuticals within multicellular clusters is known to have a significant effect on their biological response. Most therapeutic radiopharmaceuticals distribute nonuniformly in tissues which makes predicting responses of micrometastases challenging. The work presented here analyzes published temporally dependent nonuniform activity distributions within tumor spheroids treated with actinium-225-DOTA encapsulating liposomes (sup225/supAc-liposomes) and uses these data in MIRDcell V3.11 to calculate absorbed dose distributions and predict biological response. The predicted responses are compared with experimental responses.Four types of liposomes were prepared having membranes with different combinations of release (R) and adhesion (A) properties. The combinations were Rsup-/supAsup-/sup, Rsup-/supAsup+/sup, Rsup+/supAsup-/sup, and Rsup+/supAsup+/sup. These afford different penetrating properties into tissue. The liposomes were loaded with either carboxyfluorescein diacetate succinimidyl ester (CFDA-SE) orsup225/supAc. MDA-MB-231 spheroids were treated with the CFDA-SE-liposomes, harvested at different times, and the time-integrated CFDA-SE concentration at each radial position within the spheroid was determined. This was translated into meansup225/supAc decays/cell versus radial position, uploaded to MIRDcell, and the surviving fraction of cells in spherical multicellular clusters was simulated. The MIRDcell-predicted surviving fractions were compared with experimental fractional-outgrowths of the spheroids following treatment withsup225/supAc-liposomes.The biological responses of the multicellular clusters treated withsup225/supAc-liposomes with physicochemical properties Rsup+/supAsup+/sup, Rsup-/supAsup+/sup, and Rsup-/supAsup-/supwere predicted by MIRDcell with statistically significant accuracy. The prediction for Rsup+/supAsup-/supwas not predicted accurately.In most instances, MIRDcell predicts responses of spheroids treated withsup225/supAc-liposomes that result in different tissue-penetrating profiles of the delivered radionuclides.

Unexpected hepatic failure with liver necrosis is sometimes encountered during a forensic autopsy. Determining the etiology may sometimes be difficult, although increasingly herbal medicines are being implicated. To determine whether such effects might also be caused by foodstuffs, the following in vitro study was undertaken. Four formulations of traditional herbal soup advertised as bak kut teh were prepared and added to cultures of liver carcinoma cells (HepG2). Cell viability was assessed using an MTT colorimetric assay at 48 h demonstrating that all formulations had significant toxicity prior to dilution (p p = 0.023), Formulation #2 30% (p = 0.009), and Formulation #3 41% (p p > 0.05). Formulation 4 showed approximately 83% cell death before dilution (p p = 0.023) and 1:1000 (14% ± 3.8, p = 0.024). This study has shown that herbal foodstuffs such as bak kut teh may be responsible for variable degrees of in vitro hepatotoxicity, thus extending the range of herbal products that may be potentially injurious to the liver. If unexpected liver damage is encountered at autopsy, information on possible recent ingestion of herbal food preparations should be sought, as routine toxicology screening will not identify the active components. Liver damage may therefore be caused not only by herbal medicines but possibly by herbal products contained in food.

Ned Kelly, an iconic figure in contemporary Australian mythology, was a bushranger (outlaw) who was executed in 1880 for the murder of a serving police officer, Constable Thomas Lonigan. Kelly is often commemorated by tattoos which depict his armour and helmet or his alleged last words of “Such is life”. A study was undertaken from January 1, 2011, to December 31, 2020, at Forensic Science SA, Adelaide, South Australia, of all cases with such tattoos. De-identified case details included the year of death, age, sex and cause and manner of death. There were 38 cases consisting of 10 natural deaths (26.3%) and 28 unnatural (73.7%). The latter included 15 cases of suicide (39.5%), 9 accidents (23.7%) and 4 homicides (10.5%). Of the 19 suicides and homicides, there were 19 males and no females (age range 24–57 years; average 44 years). The number of suicides in the general South Australian forensic autopsy population in 2020 was 216/1492 (14.5%) which was significantly lower than in the study population in which 39.5% of cases were suicides (2.7 times higher; p p

The fear of being buried alive or taphophobia remains a significant concern for a number of individuals. In previous centuries however, reports of live burials were frequently promulgated in the media fostering an industry focused around the manufacturing and selling of security coffins which either facilitated egress or enabled the recently buried to alert those on the surface to their plight. Holding mortuaries with resuscitation facilities were also established mainly in Continental Europe to permit close observation of the recently deceased until definitive signs of putrefaction had developed. Underpinning much of this panic was the inability of medical practitioners to definitely diagnose death. Although still a rare possibility, mainly in situations where qualified medical personnel are not available, the likelihood of alive burial is nowadays fortunately rare.

Following a witnessed lethal lightning strike of an adult male who was standing outside in a storm, numerous Lichtenberg figures were identified upon external examination of the body. Sectioning across multiple areas of linear erythema in the figures showed no subcutaneous hemorrhage. This was later confirmed on histology which showed only subtle dermal capillary dilatation with no interstitial hemorrhage or inflammation in these areas. The only areas of interstitial hemorrhage were present in adjacent scattered punctate burns from arcing. The documented resolution of Lichtenberg figures within hours would be more in keeping with temporary functional capillary dilatation, shown in this case, rather than with tissue alteration by interstitial hemorrhage or inflammation.

A 39-year-old woman who had undergone an uncomplicated elective cesarean section for a low-lying placenta collapsed and died the following day. At autopsy, there was dissection of an aneurysmally-dilated thoracic aorta with 400 mls of fluid and clotted blood in the pericardial sac. There were no features of Marfan syndrome or other connective tissue disorders. Histology revealed thinning of the aortic wall with fragmentation of elastic fibers and no inflammation. Vessels elsewhere were normal. This case demonstrates a rare complication of pregnancy that may not present until after delivery with unexpected collapse and sudden death. Predisposing factors include an increased cardiac output, reduction in systemic vascular resistance, an increase in left ventricular muscle mass, and alterations in serum progesterone and estrogen levels which may cause structural changes to the aortic wall. The possibility of syndromic and familial connective tissue disorders should also be considered.

Objective Sustaining concussions has been linked to health issues later in life, yet evidence for associations between contact sports exposure and long-term cognitive performance is mixed. This cross-sectional study of former professional American-style football players tested the association of several measures of football exposure with later life cognitive performance, while also comparing the cognitive performance of former players to nonplayers. Methods In total, 353 former professional football players (Mage = 54.3) completed both (1) an online cognitive test battery measuring objective cognitive performance and (2) a survey querying demographic information, current health conditions, and measures of past football exposure, including recollected concussion symptoms playing professional football, diagnosed concussions, years of professional play, and age of first football exposure. Testing occurred an average of 29 years after former players’ final season of professional play. In addition, a comparison sample of 5,086 male participants (nonplayers) completed one or more cognitive tests. Results Former players’ cognitive performance was associated with retrospectively reported football concussion symptoms (rp = −0.19, 95% CI −0.09 to −0.29; p Conclusions Future investigations of the long-term outcomes of contact sports exposure should include measures of sports-related concussion symptoms, which were more sensitive to objective cognitive performance than other football exposure measures, including self-reported diagnosed concussions.

An 86-year-old woman with Alzheimer disease collapsed in her nursing home and was not able to be resuscitated. At autopsy, the major findings were in the larynx where a pedunculated oncocytic cystadenoma had occluded the glottis. Oncocytic cysts or cystadenomas of the larynx are rare histologically benign lesions that account for only 0.1–1% of laryngeal lesions. While the usual presentation is of a sensation of a mass in the throat, hoarseness, or stridor, very occasionally, there may be acute airway compromise and sudden death. Oncocytic cystadenoma should, therefore, be included in the differential diagnosis of potentially lethal obstructive laryngeal lesions.

To determine the role of cardiac disease in driver fatalities, a retrospective review of autopsy files at Forensic Science SA in Adelaide, Australia, was undertaken over a 13-year-period January 2005-December 2017 for individuals aged ≥ 40 years who had died while driving a motor vehicle. The incidence of significant coronary artery atherosclerosis (CAA) and cardiomegaly was evaluated with comparisons between drivers and a control group of passengers. Autopsy examinations were performed on 303 drivers and 72 passengers who died of trauma and on 63 drivers who died of a cardiac event while driving. The average age for drivers dying of trauma was 58.5 years (range 40-93 years) with 48 (15.8%) having CAA and 31 (10.2%) having cardiomegaly. This was not statistically different to passengers (aged 63.3 years; range 40-93 years; 20.8% having CAA; 11 (15.2%) cardiomegaly; (p 0.2). Drivers with significant cardiac disease did not, therefore, have increased rates of death in crashes, although a distinct subgroup of drivers consisted of those who had died from cardiac events and not trauma, while driving. The latter may be increasing in number given the aging population.

Sodium nitrite (NaNO2) is a compound with broad practical applications in food preservation, automotive maintenance, and animal control. Sodium nitrite is also potentially fatal when ingested, as it interferes with the ability of red blood cells to transport oxygen. While incidents of accidental consumption have been reported in the literature, case reports of sodium nitrite being used as a pharmacological suicide agent are becoming more frequent. Therefore, a study was undertaken to evaluate trends in sodium nitrite deaths in South Australia between 2000 and 2019. All cases of fatal sodium nitrite ingestion were identified in the Toxicology database and autopsy reports at Forensic Science SA (FSSA). Ten cases of fatal sodium nitrite ingestion were identified, with the rate of cases increasing significantly over the study period (p > .001). Of the ten deaths attributed to sodium nitrite toxicity, eight were male, and two were female. The age range of decedents was 22–74 years (mean 51.9, SD 21.1), 22–74 years for males (mean 58.4, SD 18.2) and 23–29 years for females (mean 26.0, SD 4.2). Males (80%) and those with a history of depression and/or suicidal ideation (70%) were over-represented within the study population. While autopsy findings were generally consistent with the literature, scene findings emphasized the accessibility of sodium nitrite to the general public. This study highlights both a significant increasing trend in the use of sodium nitrite in suicides and important analytical limitations in the evaluation of suspected cases.

Three morbidly obese men aged 69, 49 and 45 years with respective BMIs of 46.3, 49.1 and 59.3 died suddenly from underlying cardiovascular disease. At autopsy all were found to have marked penile shortening typical of an entity known as “buried penis.” This condition arises in adulthood most commonly from morbid obesity as the penile shaft becomes enveloped by encroaching suprapubic adipose tissue. It is associated with infective, obstructive and malignant complications. Histology will be required to identify less-common causative conditions or any inflammatory or premalignant/malignant changes.

To evaluate the use of the three standard definitions of sudden infant death syndrome (SIDS) in the contemporary literature.A search was undertaken of the US National Library of Medicine 'PubMed' database for all research articles listed under 'sudden infant death syndrome' or 'SIDS', from 2019 to 2021 accessible through the University of Adelaide library.564 papers had keywords 'sudden infant death syndrome' or 'SIDS'. 300 papers were not included in the study as they were not written in English, SIDS was not the primary focus, publishing was in predatory journals, or they were Letters to the Editor, commentaries, technical reports, reviews or editorials. The remaining 264 papers consisted of 172 papers without a standard definition, including reports without definitions, with idiosyncratic or incorrectly quoted definitions or with incorrect referencing (65%), and 92 with one of the three standard definitions either quoted in full in the text or correctly referenced (35%).Nearly two-thirds of peer-reviewed publications on SIDS listed on PubMed over the past three years have not quoted or referenced accepted definitions. Interpreting research conclusions and monitoring trends in SIDS mortality will be extremely difficult if different population subgroups are being targeted by different research groups.

To determine how well definitions of SIDS in the literature are being cited and referenced.The "PubMed" database was searched for "sudden infant death syndrome" from 2020 to 2021. Of 421 original papers, 50 were randomly selected and checked to determine whether one of the three internationally accepted definitions of SIDS: Seattle, NICHD and San Diego definitions had been cited/quoted in the text and correctly referenced. Papers that incorrectly cited or did not cite one standard definitions were assigned into: (i) those that used mis-cited, idiosyncratic or other (alternative, non-standard) definitions and, (ii) those where there was no definition.Fifty-six per cent of papers correctly cited standard definitions, a 12% decrease from the 68% in a similar study in 2012. Of those only 22% both correctly cited/referenced one of the standard definitions. Major issues in 78% of papers involved citing one and referencing another standard definition (N = 7, 14%), citing or referencing alternative, non-standard definitions (N = 8, 16%) or not citing or referencing any definition (N = 24, 48%).There is an increasing trend to not follow standard definitions of SIDS. This may hinder data interpretation where cases have not been appropriately defined and negatively impact upon the validity of SIDS research.

A 26-year-old man who suddenly collapsed and died was found at autopsy to have a ruptured aortic aneurysm which had the classic "tree bark" appearance of tertiary syphilis. Tracking of blood into the pericardial sac had resulted in sudden death from cardiac tamponade. Serological results were consistent with syphilis and HIV was excluded. Sudden death in a young HIV-negative man from the effects of syphilis is exceedingly rare nowadays.

A 35-year-old man with schizophrenia died from an overdose of propranolol (blood level = 60 mg/L). Post mortem CT scanning showed marked distension of the esophagus by granular material with a bolus of similar material within the stomach. At autopsy 62 g of lime green pharmacobezoar was present within the esophagus with an additional 130gm mass of similar material within the stomach, both of which contained propranolol. The rest of the gastrointestinal tract was unremarkable. The mouth, pharynx, glottis, larynx, trachea and bronchi were all structurally normal with no obstructive material. Thus, there was no evidence of airway compromise to suggest that the bezoar had mechanically contributed to death. Rather, elution of the drug had resulted in lethal blood levels. The color of the pharmacobezoar derived from the green color of certain propranolol tablets. Death was therefore attributed to propranolol toxicity with an associated finding of a massive gastro-esophageal pharmacobezoar.

Cryptococcosis is a fungal disease caused predominantly by Cryptococcus neoformans and Cryptococcus gatti. It is most often found in immunocompromised individuals and has quite protean and chronic manifestations affecting all body systems. The unexpected death of a 22-year-old man with cryptococcal meningoencephalitis demonstrates, however, that it may have a fulminant course in previously well individuals. Also present at autopsy was a toruloma of the upper lobe of the right lung. Delays in clinical diagnoses, confusion with tuberculosis and precipitate clinical deterioration may mean that cases will be encountered unexpectedly during medicolegal autopsies.

Although the overall suicide rate worldwide has changed minimally over the past 100 years, different trends have been observed over time in the USA, Australia, and New Zealand (NZ). However, few studies have focused on suicides in children ( 80% of cases in South Australia and Auckland and 56% in Hennepin County. Hennepin County had a greater proportion of suicides using firearms (28%), compared to 1.9% in Auckland and 5.1% in South Australia. Unusual means of suicide were used less frequently by youth than previously.

Injuries from motor vehicle collisions are frequently encountered in routine forensic practice. While the most common lethal events involve blunt force trauma with injuries to the head and neck, chest, abdomen, pelvis and limbs, review of the literature and case files shows that a wide variety of other fatal situations can occur that may involve sharp force and penetrating trauma, incineration, drowning, asphyxia, organic diseases and combinations of these. The following overview details potential factors that may contribute to death following vehicle crashes.

Sight is arguably the most important sense in human. Being constantly exposed to the environmental stress, irritants and pathogens, the ocular surface – a specialized functional and anatomical unit composed of tear film, conjunctival and corneal epithelium, lacrimal glands, meibomian glands, and nasolacrimal drainage apparatus – serves as a crucial front-line defense of the eye. Host defense peptides (HDPs), also known as antimicrobial peptides, are evolutionarily conserved molecular components of innate immunity that are found in all classes of life. Since the first discovery of lysozyme in 1922, a wide range of HDPs have been identified at the ocular surface. In addition to their antimicrobial activity, HDPs are increasingly recognized for their wide array of biological functions, including anti-biofilm, immunomodulation, wound healing, and anti-cancer properties. In this review, we provide an updated review on: (1) spectrum and expression of HDPs at the ocular surface; (2) participation of HDPs in ocular surface diseases/conditions such as infectious keratitis, conjunctivitis, dry eye disease, keratoconus, allergic eye disease, rosacea keratitis, and post-ocular surgery; (3) HDPs that are currently in the development pipeline for treatment of ocular diseases and infections; and (4) future potential of HDP-based clinical pharmacotherapy for ocular diseases.

The aporias of time that Paul Ricœur identifies in the conclusion to his three-volume Time and Narrative offer a fecund starting-point from which to consider how the poetics of narrativity figures in a philosophy of the will. By setting the poetics of narrativity against the aporetics of temporality, Ricoeur highlights the narrative art’s operative power in drawing together incidents and events in answer to time’s dispersion across the present, the past, and the future. In turn, the confession of the limits of narrative opens the way to a broader consideration of the idea of the unity of history in the absence of a meta-historical plot. This idea calls for a reflection on the ethical and political imperative of making freedom a reality for all. By taking the theory of freedom’s actualization as a touchstone, I argue that the vision of a reconciled humanity that for Ricœur is the intended object of the poetics of the will acquires the force of a directive idea. The capacity to refashion the real from within thus proves to be decisive for drawing out the connection between the aporetics of temporality, the poetics of narrativity, and Ricœur’s philosophical anthropology.

An 89-year-old man involved in a vehicle crash was found at autopsy to have a linear seat belt mark on the right side of his neck associated with extensive injuries of the right paraspinal muscles with fracture-dislocation and separation of cervical vertebrae 5 and 6. There was also fracture of the right facet joint between cervical vertebrae 5 and 6 and laceration of the right vertebral artery. Death was due to a cervical seat belt injury with spinal fracture and laceration of the right vertebral artery. The presence of extensive injuries to the right paraspinal muscles and cervical vertebra 5-6 fact joint beneath the seat belt mark would be in keeping with trauma due to the belt webbing, rather than mere hyperextension/flexion of the cervical spine. This report demonstrates a rare form of seat belt injury, transection of the vertebral artery, and suggests that the finding of seat belt markings on the lateral aspect of the neck should prompt examination for this type of lethal vascular injury at autopsy.

A 27-year-old man presented to hospital with neck swelling and difficulty breathing following a recent tooth extraction. He underwent uncomplicated surgical drainage of the submandibular region after which he became acutely short of breath and collapsed and was not able to be resuscitated. At autopsy the major findings were swelling of the neck due to diffuse cellulitis with edema and neutrophil infiltrates within connective tissue and marked submucosal edema of the epiglottis, glottic inlet and tonsils sufficient to cause airway obstruction. Cultures from the site of surgical intervention showed a mixed growth of Gram positive and negative bacilli and Gram positive cocci. Death was due to airway obstruction resulting from marked submucosal edema of the glottic inlet associated with submandibular cellulitis (Ludwig's angina) following extraction of a right lower first molar tooth. Lethal Lugwig angina, although rare in current forensic practice, may still present as a cause of acute upper airway occlusion and must be considered in the differential diagnosis of significant upper airway compromise.

We report unexpected death of a 72-year-old man due to a hemoperitoneum (1.9 L of blood in the abdominal cavity). Postmortem examination revealed that the cause of the hemorrhage was an arterial aneurysmal lesion in the greater omentum. The lesion measured 4 × 4 × 6 cm with a generally smooth wall, but with a focal area of rupture within a hemorrhagic region measuring 1 × 2 cm. There was a substantial feeding artery. Histological examination revealed features in keeping with a pseudoaneurysm, but also with some features of a true aneurysm. There was no history of trauma and the rupture of the aneurysmal lesion that had caused the hematoperitoneum was considered to be spontaneous. Prior to his death the deceased had attended hospital for epigastric pain, which was attributed to dyspepsia, but otherwise he had not had symptoms prior to his death.

A recent series of deaths in previously healthy dogs in Victoria, Australia associated with the ingestion of raw meat contaminated by indospicine derived from native Australian plants of the Indigofera species draws attention to the potential that exists for herbal toxicity in domestic animals. Although the efficacy of herbal remedies generally remains unproven in domestic animals, herbal preparations are being increasingly used as supplements and treatments. Issues with incorrect ingredients, inadequate processing, faulty, incomplete or inaccurate product labelling, contamination with toxins, adulteration with undeclared pharmaceutical agents and herb-herb interactions are well recognized as causes of adverse effects in humans. However, apart from of the effects of noxious weed species, the literature on herbal toxicity in domestic animals is sparse. Thus, the forensic evaluation of cases of suspected poisoning in domestic animals should also encompass an accurate description the type and dose of any herbal preparations that may have been recently administered.

Reactive oxygen species (ROS) within the cell are rapidly detoxified by antioxidants such as glutathione. Depletion of glutathione will therefore increase levels of intracellular ROS, which can lead to oxidative DNA damage and the induction of apoptosis. The working hypothesis was that Ogg1 null mouse embryonic fibroblasts (mOgg1(-/-) MEFs) would be more sensitive in response to GSH depletion due to their deficiency in the removal of the oxidative DNA modification, 8-oxo-7,8-dihydroguanine (8-oxoG). Following GSH depletion, an increase in intracellular ROS and a subsequent induction of apoptosis was measured in mOgg1(-/-) MEFs; as expected. Unexpectedly, an elevated basal level of ROS was identified in mOgg1(-/-) MEFs compared to wild type MEFs; which we suggest is partly due to the differential expression of key anti-oxidant genes. The elevated basal ROS levels in mOgg1(-/-) MEFs were not accompanied by a deficiency in ATP production or a large increase in 8-oxoG levels. Although 8-oxoG levels did increase following GSH depletion in mOgg1(-/-) MEFs; this increase was significantly lower than observed following treatment with a non-toxic dose of hydrogen peroxide. Reconstitution of Ogg1 into mOgg1(-/-) MEFs resulted in an increased viability following glutathione depletion, however this rescue did not differ between a repair-proficient and a repair-impaired variant of Ogg1. The data indicates that induction of apoptosis in response to oxidative stress in mOgg1(-/-) MEFs is independent of DNA damage and OGG1-initiated DNA repair.

The synthetically versatile pinacol boronic ester group (Bpin) is generally thought of as a bulky moiety because of the two adjacent quaternary sp3 -hydribized carbon atoms in its diol backbone. However, recent diastereoselective reactions reported in the literature have cast doubt on this perception. Reported herein is a detailed experimental and computational analysis of Bpin and structurally related boronic esters which allows determination of three different steric parameters for the Bpin group: the A-value, ligand cone angle, and percent buried volume. All three parameters suggest that the Bpin moiety is remarkably small, with the planarity of the oxygen-boron-oxygen motif playing an important role in minimising steric interactions. Of the three steric parameters, percent buried volume provides the best correlation between steric size and diastereoselectivity in a Diels-Alder reaction.

A 69-year-old man was found lying on the floor at his home address. According to the police report every room was filled with refuse and "thirty or so cats" were resident in the house. The body showed signs of extensive post mortem animal predation with opening of the chest and abdominal cavities, loss of soft tissues of the face, loss of soft tissues and organs of the neck, loss of the lungs and heart, and injuries to the liver, right kidney, stomach, transverse colon and cecum. The cause of death could not be determined from the autopsy given the absence of certain vital organs such as the heart and lungs, and the presence of early putrefaction. The case shows that considerable soft tissue, bone and organ loss may occur when a number of animals work in concert. The collective term for such a group of cats is a clowder. The extent of post-mortem damage from animal activity therefore relies not only on the species involved, but also the numbers of participating animals.

In May 1845 HMS Terror and HMS Erebus left England under the command of Sir John Franklin to find the Northwest Passage linking the north Atlantic and Pacific Oceans. The ships had been specially equipped for arctic conditions with central heating, auxiliary steam engines and reinforced steel bows to cut through the ice, however, despite these modern additions neither the vessels nor any of the 129 crew members would ever return. Recently the wrecks of the ships have been located in the waters around King William Island, Nunavut, Canada. Numerous theories have been advanced to explain the deaths that involve lead poisoning, scurvy and zinc deficiency. It is most likely, however, that the deaths were the result of multiple factors such as starvation, hypothermia, infection and general physical and mental decline. Cannibalism occurred but whether this involved the use of already dead sailors or the culling of the weak for food is not determinable. The essential point is that the crews were trapped in the Arctic, many thousands of miles from their homes and families, with dwindling food supplies and minimal chances of rescue.

The Arabidopsis resistance protein RPS5 is activated by proteolytic cleavage of the protein kinase PBS1 by the Pseudomonas syringae effector protease AvrPphB. We have previously shown that replacing seven amino acids at the cleavage site of PBS1 with a motif cleaved by the NIa protease of turnip mosaic virus (TuMV) enables RPS5 activation upon TuMV infection. However, this engineered resistance conferred a trailing necrosis phenotype indicative of a cell-death response too slow to contain the virus. We theorized this could result from a positional mismatch within the cell between PBS1TuMV, RPS5, and the NIa protease. To test this, we relocalized PBS1TuMV and RPS5 to cellular sites of NIa accumulation. These experiments revealed that relocation of RPS5 away from the plasma membrane compromised RPS5-dependent cell death in Nicotiana benthamiana, even though PBS1 was efficiently cleaved. As an alternative approach, we tested whether overexpression of plasma membrane–localized PBS1TuMV could enhance RPS5 activation by TuMV. Significantly, overexpressing the PBS1TuMV decoy protein conferred complete resistance to TuMV when delivered by either agrobacterium or by aphid transmission, showing that RPS5-mediated defense responses are effective against bacterial and viral pathogens. Lastly, we have now extended this PBS1 decoy approach to soybean by modifying a soybean PBS1 ortholog to be cleaved by the NIa protease of soybean mosaic virus (SMV). Transgenic overexpression of this soybean PBS1 decoy conferred immunity to SMV, demonstrating that we can use endogenous PBS1 proteins in crop plants to engineer economically relevant disease resistant traits.

Primary sclerosing cholangitis (PSC) is a chronic progressive liver disease. Sub-types of PSC have been described, most recently PSC with elevated serum and/or tissue IgG4 subclass. We aim to summarise the clinical phenotype, disease associations, differential diagnosis, response to therapy and pathogenic mechanisms underlying PSC-high IgG4 subtype. We reviewed PubMed, MEDLINE and Embase with the search terms "primary sclerosing cholangitis", "IgG4", and "IgG4-related sclerosing cholangitis (IgG4-SC)". Elevated serum IgG4 are found in up-to one-quarter, and abundant IgG4-plasma cell infiltrates in the liver and bile ducts are found in up-to one-fifth of PSC patients. This group have a distinct clinical phenotype, with some studies reporting a more aggressive course of liver and associated inflammatory bowel disease, compared to PSC-normal IgG4 and the disease mimic IgG4-SC. Distinguishing PSC-high IgG4 from IgG4-SC remains challenging, requiring careful assessment of clinical features, organ involvement and tissue morphology. Calculation of serum IgG4:IgG1 ratios and use of a novel IgG4:IgG RNA ratio have been reported to have excellent specificity to distinguish IgG4-SC and PSC-high IgG4 but require validation in larger cohorts. A role for corticosteroid therapy in PSC-high IgG4 remains unanswered, with concerns of increased toxicity and lack of outcome data. The immunological drivers underlying prominent IgG4 antibodies in PSC are incompletely defined. An association with PSC-high IgG4 and HLA class-II haplotypes (B*07, DRB1*15), T-helper2 and T-regulatory cytokines (IL4, IL10, IL13) and chemokines (CCL1, CCR8) have been described. PSC-high IgG4 have a distinct clinical phenotype and need careful discrimination from IgG4-SC, although response to immunosuppressive treatments and long-term outcome remains unresolved. The presence of IgG4 likely represents chronic activation to persistent antigenic exposure in genetically predisposed individuals.

MYB–bHLH–WDR (MBW) transcription factor (TF) complexes regulate Arabidopsis seed coat development including mucilage and tannin biosynthesis. The R2R3 MYBs MYB5, MYB23 and TRANSPARENT TESTA2 (TT2) participate in the MBW complexes with the WD-repeat protein TRANSPARENT TESTA GLABRA1 (TTG1). These complexes regulate GLABRA2 (GL2) and TTG2 expression in developing seeds. Microarray transcriptome analysis of ttg1-1- and wild-type (Ler) developing seeds identified 246 TTG1-regulated genes, which include all known metabolic genes of the tannin biosynthetic pathway. The first detailed TTG1-dependent metabolic pathways could be proposed for the biosynthesis of mucilage, jasmonic acid (JA) and cuticle including wax ester in developing seeds. We also assigned many known and previously uncharacterized genes to the activation/inactivation of hormones, plant immunity and nutrient transport. The promoters of six cuticle pathway genes were active in developing seeds. Expression of 11 genes was determined in the developing seeds of the combinatorial mutants of MYB5, MYB23 and TT2, and in the combinatorial mutants of GL2, HOMEODOMAIN GLABROUS2 (HDG2) and TTG2. These six TFs positively co-regulated the expression of four repressor genes while three of the six TFs repressed the wax biosynthesis genes examined, suggesting that the three TFs upregulate the expression of these repressor genes, which, in turn, repress the wax biosynthesis genes. Chromatin immunoprecipitation analysis identified 21 genes directly regulated by MYB5 including GL2, HDG2, TTG2, four repressor genes and various metabolic genes. We propose a multi-tiered regulatory mechanism by which MBWs regulate tannin, mucilage, JA and cuticle biosynthetic pathways.

Introduction Obeticholic acid (OCA) is a semi-synthetic hydrophobic bile acid (BA) analogue that is highly selective agonist of farnesoid X receptor (FXR), a key nuclear BA receptor, which induces expression of gut-derived hormones, in particular fibroblast growth factor 19. The resulting beneficial effects of OCA on glucose and lipid metabolism and particularly hepatic inflammation make it a candidate for the treatment of a variety of conditions including primary biliary cholangitis (PBC) and nonalcoholic steatohepatitis (NASH). Sources of data In PBC patients who have not initially responded to ursodeoxycholic acid, OCA has been shown in double-blind controlled clinical trials to significantly reduce serum alkaline phosphatase. To date, OCA is the only therapy licensed by the FDA, EMA and endorsed by NICE as second line therapy for PBC. No medications are currently approved in Europe or the USA for the treatment of NASH. In recent clinical trials, OCA has been shown encouraging results by improving liver blood tests and reducing liver fibrosis with no worsening of NASH. Areas of agreement OCA is the established second line therapy for PBC in those patients who fail to adequately respond to ursodeoxycholic acid. Areas of controversy The main side effects of OCA treatment in both PBC and NASH is that of dose-dependent pruritis which can lead to treatment discontinuation in ~1–10% of patients. In addition, OCA-treated patients may also exhibit (reversible) alterations in serum lipid levels; most notably a small decrease in high density lipoprotein cholesterol. It is not yet known whether these changes carry a long-term cardiovascular risk in NASH. In addition, the relatively high cost of OCA may limit its use in cash-limited health systems. Growing Points Additional clinical trials are in progress to ascertain the long-term effects of OCA on survival in PBC and NASH. Areas timely for developing research New FXR agonists with a lower rate of side effects are being developed and trialed. Combination therapy with other agents may offer increased efficacy.

The brutal execution of Tsar Nicholas II, his wife and five children at Yekaterinberg in July 1918 was followed by apparently inept attempts to conceal the bodies. Despite this, the skeletons remained undiscovered until 1979. Even after anthropological and DNA analyses, the absence of two of the children in the grave raised doubts as to the identity of the remains. The discovery of the skeletal fragments of a young woman aged between 18 to 25 years and a boy aged between 10 to 14 years in a shallow grave near the primary burial site in 2007 enabled full DNA investigations of the remains to be undertaken in association with analyses of living Romanov descendants. Autosomal short tandem repeat (STR) testing revealed the sex and familial relationships within the group, and mitochondrial DNA (mtDNA) testing of the two hypervariable regions (HVI and HVII) showed links between the Tsar and Tsarina and living maternal relatives. The same point heteroplasmy in both the Tsar and his brother, Georgii provided further supportive evidence. There appears little doubt that the skeletal remains in the two graves outside Yekaterinburg are those of Tsar Nicholas, his wife and their five children. The genetic analyses and the features of the fragmented remains are all very consistent with the tragic story of the last days of the Romanov family and with the subsequent desecration and destruction of their bodies.