SIRT1 is increased in affected brain regions and hypothalamic metabolic pathways are altered in Huntington disease.

AIMS: Metabolic dysfunction is involved in modulating the disease process in Huntington disease (HD) but the underlying mechanisms are not known. The aim of this study was to investigate if the metabolic regulators sirtuins are affected in HD. METHODS: Quantitative real-time polymerase chain reactions were used to assess levels of SIRT1-3 and downstream targets in post mortem brain tissue from HD patients and control cases as well as after selective hypothalamic expression of mutant huntingtin (HTT) using recombinant adeno-associated viral vectors in mice. RESULTS: We show that mRNA levels of the metabolic regulator SIRT1 are increased in the striatum and the cerebral cortex but not in the less affected cerebellum in post mortem HD brains. Levels of SIRT2 are only increased in the striatum and SIRT3 is not affected in HD. Interestingly, mRNA levels of SIRT1 are selectively increased in the lateral hypothalamic area (LHA) and ventromedial hypothalamus (VMH) in HD. Further analyses of the LHA and VMH confirmed pathological changes in these regions including effects on SIRT1 downstream targets and reduced mRNA levels of orexin (hypocretin), prodynorphin and melanin-concentrating hormone (MCH) in the LHA and of brain-derived neurotrophic factor (BDNF) in the VMH. Analyses after selective hypothalamic expression of mutant HTT suggest that effects on BDNF, orexin, dynorphin and MCH are early and direct, whereas changes in SIRT1 require more widespread expression of mutant HTT. CONCLUSIONS: We show that SIRT1 expression is increased in HD-affected brain regions and that metabolic pathways are altered in the HD hypothalamus.

Differences between pure desmoplastic melanoma and superficial spreading melanoma in terms of survival, distribution and other clinicopathologic features.

BACKGROUND: Pure desmoplastic melanoma (pDM) is an uncommon subtype of malignant melanoma with comparative high rates of local recurrence and low rates of sentinel lymph node positivity. The melanoma-specific survival (MSS) of pDM compared to other melanoma subtypes is unclear, with conflicting reports and lack of multivariable analyses. OBJECTIVES: We aimed to describe clinicopathological characteristics of a cohort of patients with pDM and to compare the MSS of pDM with superficial spreading melanoma (SSM). METHODS: A prospective cohort study was performed of all primary invasive cutaneous pDM with known tumour location and thickness reviewed at a tertiary referral centre over 21 years. RESULTS: A total of 119 primary cutaneous invasive pDMs from 3570 total invasive cutaneous melanomas were included. Compared to 2272 SSMs, and due largely to their greater average thickness, patients with pDM had worse MSS (unadjusted hazard ratio, HR, 2.56, 95% confidence interval, CI, 1.56-4.22). After adjustment for clinicopathologic factors (including thickness, ulceration, mitotic rate, age and sex), there was evidence that patients with pDM had an improved MSS (adjusted HR, 0.49; 95% CI, 0.28-0.87). Median thickness of head and neck pDM was greater than non-head and neck pDM (P < 0.001). There was reduced univariable MSS in head and neck pDM compared to the rest of the body. CONCLUSIONS: Decreased univariable MSS of patients with pDM compared to SSM was explained by the increased frequency of adverse clinicopathologic features at diagnosis, in particular the greater Breslow thickness of pDM. After adjustment, patients with pDM had half the chance of melanoma-specific death compared to SSM. Head and neck pDM were thicker at diagnosis compared to the rest of the body, which may account for its poorer survival compared to the rest of the body.

Piperacillin-tazobactam-induced linear IgA bullous dermatosis presenting clinically as Stevens-Johnson syndrome/toxic epidermal necrolysis overlap.

Linear IgA bullous dermatosis (LABD) is a subepidermal autoimmune bullous disease characterized by linear IgA deposition at the basement membrane zone, which is visualized by direct immunofluorescence. Patients with LABD typically present with widespread vesicles and bullae; however, this is not necessarily the case, as the clinical presentation of this disease is heterogeneous. LABD clinically presenting as Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) is an infrequent, yet well-described phenomenon. Most cases of LABD are idiopathic, but some cases are drug-induced. Multiple drugs have been implicated in the development of LABD. We report a case of piperacillin-tazobactam-induced LABD presenting clinically as SJS/TEN overlap. This is the first reported case of a strong causal association between piperacillin-tazobactam and the development of LABD.

Climatic, Edaphic Factors and Cropping History Help Predict Click Beetle (Coleoptera: Elateridae) (Agriotes spp.) Abundance.

It is assumed that the abundance of Agriotes wireworms (Coleoptera: Elateridae) is affected by agro-ecological factors such as climatic and edaphic factors and the crop/previous crop grown at the sites investigated. The aim of this study, conducted in three different geographic counties in Croatia from 2007 to 2009, was to determine the factors that influence the abundance of adult click beetle of the species Agriotes brevis Cand., Agriotes lineatus (L.), Agriotes obscurus (L.), Agriotes sputator (L.), and Agriotes ustulatus Schall. The mean annual air temperature, total rainfall, percentage of coarse and fine sand, coarse and fine silt and clay, the soil pH, and humus were investigated as potential factors that may influence abundance. Adult click beetle emergence was monitored using sex pheromone traps (YATLORf and VARb3). Exploratory data analysis was preformed via regression tree models and regional differences in Agriotes species' abundance were predicted based on the agro-ecological factors measured. It was found that the best overall predictor of A. brevis abundance was the previous crop grown. Conversely, the best predictor of A. lineatus abundance was the current crop being grown and the percentage of humus. The best predictor of A. obscurus abundance was soil pH in KCl. The best predictor of A. sputator abundance was rainfall. Finally, the best predictors of A. ustulatus abundance were soil pH in KCl and humus. These results may be useful in regional pest control programs or for predicting future outbreaks of these species.

Phylogeographic structure, demographic history and morph composition in a colour polymorphic lizard.

In polymorphic species, population divergence in morph composition and frequency has the potential to promote speciation. We assessed the relationship between geographic variation in male throat colour polymorphism and phylogeographic structure in the tawny dragon lizard, Ctenophorus decresii. We identified four genetically distinct lineages, corresponding to two polymorphic lineages in the Northern Flinders Ranges and Southern Flinders Ranges/Olary Ranges regions respectively, and a monomorphic lineage in the Mt Lofty Ranges/Kangaroo Island region. The degree of divergence between these three lineages was consistent with isolation to multiple refugia during Pleistocene glacial cycles, whereas a fourth, deeply divergent (at the interspecific level) and monomorphic lineage was restricted to western New South Wales. The same four morphs occurred in both polymorphic lineages, although populations exhibited considerable variation in the frequency of morphs. By contrast, male throat coloration in the monomorphic lineages differed from each other and from the polymorphic lineages. Our results suggest that colour polymorphism has evolved once in the C. decresii species complex, with subsequent loss of polymorphism in the Mt Lofty Ranges/Kangaroo Island lineage. However, an equally parsimonious scenario, that polymorphism arose independently twice within C. decresii, could not be ruled out. We also detected evidence of a narrow contact zone with limited genotypic admixture between the polymorphic Olary Ranges and monomorphic Mt Lofty Ranges regions, yet no individuals of intermediate colour phenotype. Such genetic divergence and evidence for barriers to gene flow between lineages suggest incipient speciation between populations that differ in morph composition.

Local adaptation and divergence in colour signal conspicuousness between monomorphic and polymorphic lineages in a lizard.

Population differences in visual environment can lead to divergence in multiple components of animal coloration including signalling traits and colour patterns important for camouflage. Divergence may reflect selection imposed by different receivers (conspecifics, predators), which depends in turn on the location of the colour patch. We tested for local adaptation of two genetically and phenotypically divergent lineages of a rock-inhabiting lizard, Ctenophorus decresii, by comparing the visual contrast of colour patches to different receivers in native and non-native environments. The lineages differ most notably in male throat coloration, which is polymorphic in the northern lineage and monomorphic in the southern lineage, but also differ in dorsal and lateral coloration, which is visible to both conspecifics and potential predators. Using models of animal colour vision, we assessed whether lineage-specific throat, dorsal and lateral coloration enhanced conspicuousness to conspecifics, increased crypsis to birds or both, respectively, when viewed against the predominant backgrounds from each lineage. Throat colours were no more conspicuous against native than non-native rock but contrasted more strongly with native lichen, which occurs patchily on rocks inhabited by C. decresii. Conversely, neck coloration (lateral) more closely matched native lichen. Furthermore, although dorsal coloration of southern males was consistently more conspicuous to birds than that of northern males, both lineages had similar absolute conspicuousness against their native backgrounds. Combined, our results are consistent with local adaptation of multiple colour traits in relation to multiple receivers, suggesting that geographic variation in background colour has influenced the evolution of lineage-specific coloration in C. decresii.

Postexcisional melanocytic regrowth extending beyond the initial scar: a novel clinical sign of melanoma.

BACKGROUND: Recurrent naevi are widely recognized to occur commonly following incomplete removal of melanocytic lesions. These lesions have been generally understood as representing benign imitators of melanoma. OBJECTIVES: To provide a formal description of the clinical findings of postexcisional melanocytic regrowth. METHODS: We examined all cases of recurrent pigmentation adjacent to scars from previous excisional biopsies of melanocytic naevi treated at a private dermatology practice from 1995 to 2012. RESULTS: We report nine cases of recurrence of melanocytic lesions that were melanomas. The most suspicious clinical feature for melanoma in these cases was the growth of the lesion beyond the confines of the initial scar, into the surrounding normal skin. CONCLUSIONS: This pattern of recurrence of a melanocytic lesion represents a little recognized and distinctive clinical presenting sign of melanoma.

The provision of a trauma bed in theatre recovery and its impact on trauma theatre efficiency: experience from a high-volume trauma unit.

INTRODUCTION: Inefficiencies in the trauma setting are well known and have been further exacerbated by the COVID-19 pandemic among other factors, resulting in national guidance to aid improvements in resource utilisation. This study introduced a novel surgeon-led intervention, a trauma bed in recovery, with the aim of improving trauma theatre efficiency. METHODS: This quality improvement project was conducted using a Plan Do Study Act (PDSA) methodology and comprised multiple cycles to assess theatre performance. A multidisciplinary team (MDT) approach with relevant stakeholder input enabled intervention implementation, aimed at facilitating 'golden patient' arrival in the anaesthetic room as early as possible. The primary outcome was the time at which the first patient entered the anaesthetic room, and the secondary outcome was the number of cases performed each day. RESULTS: The study period was 1 year and encompassed three PDSA cycles. The intervention achieved its primary outcome by PDSA cycle 1 and its secondary outcome by PDSA cycle 2, demonstrating statistically significantly improved results (p < 0.001). A subanalysis assessed the specific impact of the intervention, and demonstrated a significant improvement in both outcomes when the intervention was used as intended (p < 0.0005). CONCLUSIONS: A ringfenced trauma bed significantly improved theatre start times and thereby theatre efficiency. This is a simple, pragmatic intervention that benefitted the MDT trauma team while also demonstrating a sustained impact. Given that National Health Service efficiency is at the forefront of national healthcare discourse, we recommend that this intervention is implemented in other trauma units to help provide a solution to this longstanding issue.

Registry-derived stage (RD-Stage) for capturing stage at diagnosis for pancreatic carcinoma in Australia.

INTRODUCTION: Stage of pancreatic carcinoma at diagnosis is a strong prognostic indicator of morbidity and mortality, yet is poorly notified to population-based cancer registries ("cancer registries"). Registry-derived stage (RD-Stage) provides a method for cancer registries to use available data sources to compile and record stage in a consistent way. This project describes the development and validation of rules to capture RD-Stage (pancreatic carcinoma) and applies the rules to data currently captured in each Australian cancer registry. MATERIALS AND METHODS: Rules for deriving RD-stage (pancreatic carcinoma) were developed using the American Joint Commission on Cancer (AJCC) Staging Manual 8th edition and endorsed by an Expert Working Group comprising specialists responsible for delivering care to patients diagnosed with pancreatic carcinoma, cancer registry epidemiologists and medical coders. Completeness of data fields required to calculate RD-Stage (pancreatic carcinoma) and an overall proportion of cases for whom RD stage could be assigned was assessed using data collected by each Australian cancer registry, for period 2018-2019. A validation study compared RD-Stage (pancreatic carcinoma) calculated by the Victorian Cancer Registry with clinical stage captured by the Upper Gastro-intestinal Cancer Registry (UGICR). RESULTS: RD-Stage (pancreatic carcinoma) could not be calculated in 4/8 (50%) of cancer registries; one did not collect the required data elements while three used a staging system not compatible with RD-Stage requirements. Of the four cancer registries able to calculate RD-Stage, baseline completeness ranged from 9% to 76%. Validation of RD-Stage (pancreatic carcinoma) with UGICR data indicated that there was insufficient data available in VCR to stage 174/457 (38%) cases and that stage was unknown in 189/457 (41%) cases in the UGICR. Yet, where it could be derived, there was very good concordance at stage level (I, II, III, IV) between the two datasets. (95.2% concordance], Kendall's coefficient = 0.92). CONCLUSION: There is a lack of standardisation of data elements and data sources available to cancer registries at a national level, resulting in poor capacity to currently capture RD-Stage (pancreatic carcinoma). RD-Stage provides an excellent tool to cancer registries to capture stage when data elements required to calculate it are available to cancer registries.

Clinical and dermoscopic characteristics of Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive cutaneous malignancy with a high mortality rate. Diagnosis is often delayed. OBJECTIVES: To characterize the dermoscopic features of MCC. METHODS: Clinical and dermoscopic images of 12 biopsy-proven MCCs were analysed in a retrospective manner, with existing dermoscopic criteria being scored independently by three dermatologists. RESULTS: The four most frequent clinical features were cherry red colour, shiny surface, sharp circumscription and nodular morphology. Significant dermoscopic features included linear irregular and polymorphous vessels, poorly focused vessels, milky pink areas, white areas, structureless areas and architectural disorder. Pigmented structures were absent from all lesions. CONCLUSIONS: The dermoscopic features described herein help the clinician to distinguish MCC from other benign and malignant red nodules. Increasing recognition of the presenting features will facilitate earlier diagnosis of MCC and reduced mortality.

Size at birth and adult fat mass in twin sheep are determined in early gestation.

Size at birth is related to adult health outcomes. Twins are born smaller than singletons; this has been assumed to be secondary to limited nutrient supply in late gestation.We hypothesised that growth trajectory in twins, and the adult consequences of being conceived a twin, are determined in early gestation. Twin pregnancies in sheep were randomised to reduction of one twin on day 42 of a 148 day pregnancy by intra-thoracic KCl (Reductions, n =46) or a sham procedure (Twins, n =22). Singleton-bearing ewes also underwent a sham procedure (n =27). Ewes lambed spontaneously. Linear measures of size at birth were similar in Twins and Reductions, and significantly less than in Singletons. Birthweight was lower in Twins and Reductions than in Singletons, and less in Twins than in Reductions (means (SEM): Singletons, liveborn n =23: 6.59 (0.17) kg; Twins, liveborn n =36: 5.23 (0.16) kg; Reductions, liveborn n =27: 5.76 (0.15) kg; all comparisons P <0.05). Reductions grew most rapidly between birth and weaning (Singletons, 20.0 (0.4) g kg⁻¹ day⁻¹; Twins, 20.0 (0.3) g kg⁻¹ day⁻¹; Reductions, 21.0 (0.3) g kg⁻¹ day⁻¹, P <0.05) and were of similar weight as Singletons by weaning; Twins remained smaller by weaning but grew most rapidly thereafter (Singletons, 1.6 (0.1) g kg⁻¹ day⁻¹; Twins, 2.1 (0.1) g kg⁻¹ day⁻¹; Reductions, 1.6 (0.1) g kg⁻¹ day⁻¹, P <0.01), so that all groups had similar weight at 2 years. However, Twins and Reductions had greater percentage fat mass than Singletons at 2 years (Singletons, 11.1 (1.1)%; Twins, 14.8 (1.2)%; Reductions, 15.5 (1.1)%, P <0.05). Thus, in twins, fetal growth trajectory, linear size at birth and adult fat mass are largely determined in early gestation. If this is also true in humans, there are important implications for interventions aimed at optimising fetal growth and pregnancy outcome.

Second to fourth digit ratio (2D:4D), breast cancer risk factors, and breast cancer risk: a prospective cohort study.

BACKGROUND: We aimed to assess whether 2D:4D measures are associated with breast cancer risk. METHODS: We derived the ratio of the lengths of the index and ring fingers (2D:4D), and right minus left 2D:4D (Δ(r-l)) from digit lengths measured from photocopies of participants' hands collected during a recent follow-up of the Melbourne Collaborative Cohort Study, a prospective study including 24 469 women. Of the 9044 women with available data, we identified 573 incident breast cancer cases. Hazard ratios (HR) and 95% confidence intervals (CI) for a one standard deviation difference in 2D:4D measures were obtained from Weibull survival models, and linear regression models were used to examine potential associations between 2D:4D measures and age at menarche and menopause. RESULTS: We found a direct association between left 2D:4D and breast cancer risk, an inverse association between Δ(r-l) and risk of breast cancer, but no association between right 2D:4D and breast cancer risk. Among breast cancer cases, both right 2D:4D and Δ(r-l) were inversely associated with age at diagnosis. We also observed associations between both right 2D:4D and Δ(r-l) and age at menopause, with increasing digit ratio measures related to earlier mean age at menopause. CONCLUSION: Digit ratio measures might be associated with breast cancer risk and age at onset of breast cancer. If confirmed in other studies, this suggests that lower exposure or sensitivity to prenatal testosterone might be associated with lower risk of breast cancer.

Leukaemia cutis in chronic lymphocytic leukaemia following varicella zoster virus reactivation.

We report a case of a 75-year-old male with indolent chronic lymphocytic leukaemia (CLL) for 8 years, who presented with a 6-month history of a painful, zosteriform eruption in a T3-4 distribution that evolved into an unusual crop of papular nodules. Upon biopsy and immunostaining of these lesions CLL was proven consistent with leukaemia cutis related to varicella-zoster virus reactivation. In the absence of other treatment indices, he was commenced on chlorambucil with successful resolution of both his pain and the lesions.

The impact of the healthcare system in Barbados (provision of health insurance and the benefit service scheme) on the use of herbal remedies by Christian churchgoers.

AIM: To determine the impact of health insurance and the government's Benefit Service Scheme, a system that provides free drugs to treat mostly chronic illnesses to persons aged 16 to 65 years, on the use of herbal remedies by Christian churchgoers in Barbados. METHODS: The eleven parishes of Barbados were sampled over a six-week period using a survey instrument developed and tested over a four-week period prior to administration. Persons were asked to participate and after written informed consent, they were interviewed by the research team. The data were analysed by the use of IBM SPSS version 19. The data were all nominal, so descriptive statistics including counts, the frequencies, odds ratios and percentages were calculated. RESULTS: More than half of the participants (59.2%) were female, a little less than a third (29.9%) were male, and one tenth of the participants (10.9%) did not indicate their gender The majority of the participants were between the ages of 41 and 70 years, with the age range of 51-60 years comprising 26.1% of the sample interviewed. Almost all of the participants were born in Barbados (92.5%). Approximately 33% of the respondents indicated that they used herbal remedies to treat various ailments including chronic conditions. The odds ratio of persons using herbal remedies and having health insurance to persons not using herbal remedies and having health insurance is 1.01 (95% CI 0.621, 1.632). There was an increase in the numbers of respondents using herbal remedies as age increased. This trend continued until the age group 71-80 years which showed a reduction in the use of herbal remedies, 32.6% of respondents compared with 38.3% of respondents in the 61-70-year category. CONCLUSIONS: The data demonstrated that only a third of the study population is using herbal remedies for ailments. Health insurance was not an indicator neither did it influence the use of herbal remedies by respondents. The use of herbal remedies may not be associated with affluence. The reduction in the use of herbal remedies in the age group 71-80 years could be due to primarily a lower response rate from this age group, and secondarily due to the Benefit Service Scheme offering free medication to persons who have passed the age of 65 years.

Dietary patterns and risk of breast cancer.

BACKGROUND: Evidence is emerging that prudent/healthy dietary patterns might be associated with a reduced risk of breast cancer. METHODS: Using data from the prospective Melbourne Collaborative Cohort Study, we applied principal factor analysis to 124 foods and beverages to identify dietary patterns and estimated their association with breast cancer risk overall and by tumour characteristics using Cox regression. RESULTS: During an average of 14.1 years of follow-up of 20 967 women participants, 815 invasive breast cancers were diagnosed. Among the four dietary factors that we identified, only that characterised by high consumption of fruit and salad was associated with a reduced risk, with stronger associations observed for tumours not expressing oestrogen (ER) and progesterone receptors (PR). Compared with women in the lowest quintile of the factor score, the hazard ratio for women in the highest quintile was 0.92 (95% confidence interval (CI)=0.70-1.21; test for trend, P=0.5) for ER-positive or PR-positive tumours and 0.48 (95% CI=0.26-0.86; test for trend, P=0.002) for ER-negative and PR-negative tumours (test for homogeneity, P=0.01). CONCLUSION: Our study provides additional support for the hypothesis that a dietary pattern rich in fruit and salad might protect against invasive breast cancer and that the effect might be stronger for ER- and PR-negative tumours.