A Painless Right Anterior Neck Mass.

A 58-year-old woman presents with a several-week history of a painless right-sided swelling on her anterior neck. What is your diagnosis?

An mTORC1 to HRI signaling axis promotes cytotoxicity of proteasome inhibitors in multiple myeloma.

Multiple myeloma (MM) causes approximately 20% of deaths from blood cancers. Notwithstanding significant therapeutic progress, such as with proteasome inhibitors (PIs), MM remains incurable due to the development of resistance. mTORC1 is a key metabolic regulator, which frequently becomes dysregulated in cancer. While mTORC1 inhibitors reduce MM viability and synergize with other therapies in vitro, clinically, mTORC1 inhibitors are not effective for MM. Here we show that the inactivation of mTORC1 is an intrinsic response of MM to PI treatment. Genetically enforced hyperactivation of mTORC1 in MM was sufficient to compromise tumorigenicity in mice. In vitro, mTORC1-hyperactivated MM cells gained sensitivity to PIs and hypoxia. This was accompanied by increased mitochondrial stress and activation of the eIF2α kinase HRI, which initiates the integrated stress response. Deletion of HRI elevated the toxicity of PIs in wt and mTORC1-activated MM. Finally, we identified the drug PMA as a robust inducer of mTORC1 activity, which synergized with PIs in inducing MM cell death. These results help explain the clinical inefficacy of mTORC1 inhibitors in MM. Our data implicate mTORC1 induction and/or HRI inhibition as pharmacological strategies to enhance MM therapy by PIs.

Surface treatment and adhesion approaches on polymer-infiltrated ceramic network: influence on the bond strength to resin cement

Aim: To evaluate the effect of different surface treatments and adhesive approaches on the microshear bond strength of resin cement to a polymer-infiltrated ceramic network (PICN). Methods: PICN blocks were randomly assigned into 9 groups (n=10): CTRL: no treatment; HF: 5% hydrofluoric acid etching; HF-S: HF + silane; HF-S-A: HF-S + adhesive (Adper Single Bond 2); HF-UA: HF + universal adhesive (Single Bond Universal); SB: sandblasting with 50 µm Al2O3 particles; SB-S: SB + silane; SB-S-A: SB-S + adhesive; SB-UA: SB + universal adhesive. Resin cement microcylinders (Ø = 0.96 mm; height = 1 mm) (RelyX Ultimate) were built upon the PICN surface after roughness and contact angle measurements. Next, microshear bonding tests (µSBS) were performed (0.5 mm/min) after water storage (37ºC, 90 days) and thermocycling (12,000 cycles; 5ºC-55ºC). Failure modes were observed under stereomicroscope. Bond strength data were analyzed by two-way ANOVA/Tukey's test and t-tests. Kruskal-Wallis/Dunn's tests were conducted for roughness and contact angle data (α = 0.05). Results: A rougher surface and lower contact angles were observed for Sandblasting. HF-S (18.54 ± 2.03 MPa), SB-S (19.00 ± 1.66 MPa) and SB-UA (18.07 ± 2.36 MPa) provided the highest bond strength values, followed by the other treated groups. The CTRL group resulted in lower bond strength (7.18 ± 2.34 MPa). Conclusion: Hydrofluoric acid etching followed by silane application and sandblasting followed by silane or universal adhesive are useful clinical steps to enhance bonding to PICN. Adhesive applications after HF etching have no advantages in bonding to PICN

Self-reported regular alcohol consumption in adolescents and emerging adults with type 1 diabetes: A neglected risk factor for diabetic ketoacidosis? Multicenter analysis of 29 630 patients from the DPV registry.

BACKGROUND: The risk of hypoglycemia increases after alcohol consumption in patients with type 1 diabetes. This study aimed to investigate the association between metabolic control and self-reported alcohol consumption in young patients with type 1 diabetes. MATERIALS AND METHODS: N = 29 630 patients with type 1 diabetes aged 12 to <30 years (median age 17.0 [14.9, 18.3] years, duration of diabetes 6.8 [3.3, 10.9] years, 53% male) from the German/Austrian DPV registry were analyzed. Patients were categorized into abstainers, low-risk drinkers, and at-risk drinkers. BMI, HbA1c, and rates of severe hypoglycemia (SH) and diabetic ketoacidosis (DKA) were compared between alcohol consumption groups using multivariable hierarchical regression models. The association between alcohol use and smoking status was assessed using χ 2 test. RESULTS: Overall, 10.8% of the patients reported regular alcohol consumption. Proportion of alcohol use as well as the amount of alcohol consumed increased with age and were higher in males than in females (all P < .05). Patients with Turkish migration background reported less alcohol consumption. HbA1c, SH rate, and DKA rate (adjusted for age, gender, duration of diabetes, therapy) were significantly lower in abstainers than in patients drinking alcohol (all P < .05). Smoking status was significantly associated with alcohol consumption (P < .001). CONCLUSION: Self-reported alcohol consumption is likely to be underreported when collected in face-to-face settings such as doctors' visits. Nevertheless, our data revealed a significant association between higher alcohol consumption and worse glycemic control, in particular higher DKA rates. Information about alcohol-induced complications is of great importance in diabetes education in young people with type 1 diabetes.

Emergence and establishment of native and non-native species in soils of remnant and converted highland grasslands - southern Brazil / Emergência e estabelecimento de espécies nativas e exóticas em solos de campos convertidos e nativos remanescentes do Planalto - Sul do Brasil

Abstract Native grasslands in the Campos de Cima da Serra, Brazil, are being converted at speed for exotic tree plantations and cropland. The impact of modified and novel soil conditions on the establishment of native grassland species is unknown; establishment of non-native species, deliberately or accidentally introduced, could be favoured. In a common garden composed of fully randomized replicate samples of soils collected from remnant grassland, former cropland and pine plantations, we tested emergence and establishment of five cold-season species: Native low-tussock grass Piptochaetium montevidense (Spreng.) Parodi; native legume Trifolium riograndense Burkart; naturalized low-tussock grass Vulpia bromoides (L.) Gray; low-tussock grass Holcus lanatus L., cultivated and naturalized in Brazil; and a cultivar of non-native Trifolium repens. Other than expected, soil type and species*soil type interactions had no significant effect on seedling emergence after 132 days in the field. Species effect on seedling emergence, however, was highly significant. Vulpia bromoides emergence was significantly highest in all soil types. Holcus lanatus and Trifolium riograndense both achieved second highest emergence rates and did not differ significantly from each other. Lowest overall emergence rates were found in the non-native clover cultivar. Lab germination tests failed for Piptochaetium, although it showed reasonable emergence in the field. Good performance of the native clover is encouraging for future grassland restoration, but the value of highly germinable Vulpia as a forage remains to be tested. Holcus tolerates a wide range of soil conditions and its life history traits may promote naturalization, or even invasiveness. Native grasslands of the region should be monitored for this species. Studies like these, but set up on a larger geographical scale and with a wider array of native species, will be essential in developing ecological restoration methods for southern Brazilian grasslands.

Resumo Uma acelerada conversão do campo nativo em plantações de espécies florestais exóticas e lavouras tem ocorrido nos Campos de Cima da Serra, Sul do Brasil. Ainda é desconhecido o impacto que as condições edáficas, em solos alterados ou preservados, exercem no estabelecimento de espécies nativas do campo; as espécies exóticas, introduzidas deliberada ou acidentalmente, talvez sejam favorecidas. Em um common garden composto por repetições aleatórias de amostras de solo, coletadas em áreas de antigas plantações de pinus, de antigas lavouras ou em áreas com campo nativo preservado, foram testados a emergência e o estabelecimento de cinco espécies hibernais: Piptochaetium montevidense (Spreng.) Parodi, gramínea cespitosa nativa; Trifolium riograndense Burkart, leguminosa nativa; Vulpia bromoides (L.) Gray, gramínea cespitosa naturalizada no sul do Brasil; Holcus lanatus L., gramínea cespitosa exótica, cultivada e disseminada no Brasil; e um cultivar de Trifolium repens, leguminosa exótica largamente utilizada. Diferentemente do esperado, o tipo de solo e interações espécie*tipo de solo não tiveram efeito significativo na emergência de plântulas após 132 dias de teste a campo. O efeito da espécie na emergência das plântulas, entretanto, foi altamente significativo. A emergência de Vulpia bromoides foi significativamente superior em qualquer tipo de solo. Ambos Holcus lanatus e Trifolium riograndense apresentaram as segundas maiores taxas de emergência, não diferindo significativamente entre si; as taxas mais baixas foram apresentadas pelo cultivar de trevo não nativo. O Teste de Germinação em laboratório falhou para o Piptochaetium, apesar de este ter demonstrado razoável emergência a campo. O bom desempenho do trevo nativo é encorajador para futuras restaurações de pastagens nativas; o valor forrageiro de Vulpia, que apresentou alta germinação, ainda precisa ser testado. Holcus tolera uma ampla faixa de condições de solo, e suas características adaptativas podem vir a torná-lo naturalizado ou mesmo invasivo. Os campos da região devem ser monitorados em função dessa espécie. Estudos como esse, mas configurados em escala geográfica maior e com maior variedade de espécies nativas, serão essenciais no desenvolvimento de métodos de restauração para os Campos Sulinos Brasileiros.

Type 1 diabetes in older adults: Comparing treatments and chronic complications in the United States T1D Exchange and the German/Austrian DPV registries.

AIMS: Compare characteristics, therapies and clinical outcomes in older adults with type 1 diabetes in the United States T1D Exchange (T1DX) and German/Austrian Diabetes Patienten Verlaufsdokumentation (DPV) registries. METHODS: Cross-sectional study of adults ≥60years old with type 1 diabetes seen in 2011-2012 in the T1DX (n=1283) and DPV (n=2014) registries. Wilcoxon rank-sum test was used for continuous variables and chi-square test for categorical variables. Adjusted analyses used generalized linear models. RESULTS: Individuals in both registries were similar in body mass index (mean 27kg/m2), percent with obesity (25%) and gender (48% male). In T1DX there was longer diabetes duration (32.3 vs. 28.8years), greater use of antihypertensive medications (including ACE-I and ARBs; 85% vs. 62%), statins (68% vs. 40%), aspirin (77% vs. 21%), insulin pumps (58% vs. 18%), and less smoking (7% vs. 10%); lower adjusted mean LDL-cholesterol (84 vs. 109mg/dL), and lower adjusted mean systolic and diastolic blood pressures (128 vs. 136 and 68 vs. 74mmHg); fewer myocardial infarctions (6% vs. 9% [99% CI of difference, 1% to 5%]), strokes (2% vs. 8% [3% to 7%]), microvascular complications including microalbuminuria (17% vs. 44% [22% to 32%]) but increased depression (16.1% vs. 8.7%). Adjusted mean HbA1c levels were similar (7.5%, 58mmol/mol). CONCLUSIONS: Differences between the registries included greater use of antihypertensives, statins and insulin pumps, and fewer chronic complications in the T1DX. Further research is needed to better understand the role of intensive therapy in improving outcomes in older adults with type 1 diabetes.

High variability in oral glucose tolerance among 1,128 patients with cystic fibrosis: a multicenter screening study.

BACKGROUND: In cystic fibrosis, highly variable glucose tolerance is suspected. However, no study provided within-patient coefficients of variation. The main objective of this short report was to evaluate within-patient variability of oral glucose tolerance. METHODS: In total, 4,643 standardized oral glucose tolerance tests of 1,128 cystic fibrosis patients (median age at first test: 15.5 [11.5; 21.5] years, 48.8% females) were studied. Patients included were clinically stable, non-pregnant, and had at least two oral glucose tolerance tests, with no prior lung transplantation or systemic steroid therapy. Transition frequency from any one test to the subsequent test was analyzed and within-patient coefficients of variation were calculated for fasting and two hour blood glucose values. All statistical analysis was implemented with SAS 9.4. RESULTS: A diabetic glucose tolerance was confirmed in 41.2% by the subsequent test. A regression to normal glucose tolerance at the subsequent test was observed in 21.7% and to impaired fasting glucose, impaired glucose tolerance or both in 15.2%, 12.0% or 9.9%. The average within-patient coefficient of variation for fasting blood glucose was 11.1% and for two hour blood glucose 25.3%. CONCLUSION: In the cystic fibrosis patients studied, a highly variable glucose tolerance was observed. Compared to the general population, variability of two hour blood glucose was 1.5 to 1.8-fold higher.

Aryl piperazine melanocortin MC4 receptor agonists.

Incorporation of substituted phenyl piperazine privileged structures into a known MC4 specific dipeptoid consensus sequence resulted in a series of potent (EC(50)=24 nM) and selective MC4-R agonists. We report the SAR of this series of compounds using in vitro cAMP functional assays in cells transfected with the MC4 or other melancortin receptors.