Type 3 Deiodinase and Consumptive Hypothyroidism: A Common Mechanism for a Rare Disease

The major product secreted by the thyroid is thyroxine (T4), whereas most of the biologically active triiodothyronine (T3) derives from the peripheral conversion of T4 into T3. The deiodinase enzymes are involved in activation and inactivation of thyroid hormones (THs). Type 1 and type 2 deiodinase (D1 and D2) convert T4 into T3 whereas D3 degrades T4 and T3 into inactive metabolites and is thus the major physiological TH inactivator. The hypothalamic-pituitary-thyroid axis maintains circulating TH levels constant, while the deiodinases tissue-specifically regulate intracellular thyroid status by controlling TH action in a precise spatio-temporal fashion. Here we review the data related to the recent identification of a paraneoplastic syndrome called “consumptive hypothyroidism,” which exemplifies how deiodinases alter substantially the concentration of TH in blood. This syndrome results from the aberrant uncontrolled expression of D3 that can induce a severe form of hypothyroidism by inactivating T4 and T3 in defined tumor tissue. This rare TH insufficiency generally affects patients in the first years of life, and has distinct features in terms of diagnosis, treatment, and prognosis with respect to other forms of hypothyroidism

Immunohistochemistry as an Important Tool in Biomarkers Detection and Clinical Practice

The immunohistochemistry technique is used in the search for cell or tissue antigens that range from amino acids and proteins to infectious agents and specific cellular populations. The technique comprises two phases: (1) slides preparation and stages involved for the reaction; (2) interpretation and quantification of the obtained expression. Immunohistochemistry is an important tool for scientific research and also a complementary technique for the elucidation of differential diagnoses which are not determinable by conventional analysis with hematoxylin and eosin. In the last couple of decades there has been an exponential increase in publications on immunohistochemistry and immunocytochemistry techniques. This review covers the immunohistochemistry technique; its history, applications, importance, limitations, difficulties, problems and some aspects related to results interpretation and quantification. Future developments on the immunohistochemistry technique and its expression quantification should not be disseminated in two languages—that of the pathologist and another of clinician or surgeon. The scientific, diagnostic and prognostic applications of this methodology must be explored in a bid to benefit of patient. In order to achieve this goal a collaboration and pooling of knowledge from both of these valuable medical areas is vita

management of one patient with oligoprogressive thyroid cancer during treatment with lenvatinib

Recent thyroid cancer guidelines found it reasonable to use local therapies during treatment with tyrosine kinase inhibitors (TKIs) in selected patients with oligoprogressive disease, namely, in the presence of a single progressing lesion in an otherwise TKI-responsive metastatic cancer. However, there is a lack of experience in the management of oligoprogressive thyroid cancers. This report illustrates the case of one patient with oligoprogressive thyroid cancer during therapy with lenvatinib. We found that the application of local ablative therapy in oligoprogressive disease prolonged the progression-free survival and thus extended the time to therapy interruption. However, the optimal care for TKI-treated oligoprogressive cancers remains unclear and needs to be investigated in prospective trials

Ultraviolet Germicidal Coil Cleaning: Impact on Heat Transfer Effectiveness and Static Pressure Drop

Cooling coil surfaces are ideal sites for biofilm formation due to the presence of adequate nutrients (deposited particles) and moisture (condensate), causing adverse impacts on heating, ventilation and air-conditioning (HVAC) energy usage and performance. In this study, an HVAC test apparatus was built in our laboratory to investigate the hypothesis that ultraviolet germicidal coil cleaning (UVG-CC) of heat exchanger surfaces improves heat transfer effectiveness and reduces the static pressure drop across the coil. The test apparatus consisted of two parallel ducts, each with its own cooling coil. One coil was treated with UVG-CC while the other was the control and left untreated. Thermodynamic properties of the air and water flowing through both heat exchangers were monitored over the course of two years with sensors and a data acquisition system. Differences in static pressure drop and coil effectiveness between the UV-treated and control coil were compared across multiple modes of coil operation (defined by presence of condensate). The effectiveness of UVG-CC was drastically affected by the presence of condensation on coil fins. We observed a statistically significant difference in the heat transfer effectiveness between the UV-treated and control coils in wetted conditions while no difference was observed in dry conditions. Sensor accuracy, however, contributed to large uncertainty in our result. The average heat transfer of the UV-treated coil was 3.0–6.4% higher compared to the control coil, with an uncertainty of ±2.7%. UVG-CC, however, did not significantly reduce static pressure drop

In Vitro and In Vivo Effects of Melatonin-Containing Combinations in Human Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) has poor prognosis and high mortality rates. Therefore, it is necessary to identify new targets and therapeutic strategies to improve the prognosis of patients with PDAC. Integrative therapies are increasingly being used to boost the efficacy of the known anticancer therapeutic approaches. Hence, this study aimed to evaluate the effects of a novel combination of different potential anticancer molecules, melatonin (MLT), cannabidiol (CBD), and oxygen-ozone (O2/O3) to treat PDAC using in vitro and in vivo models of human PDAC. The effect of this combination was investigated in combination with gemcitabine (GEM), the most common chemotherapeutic drug used for PDAC treatment. The combination of MLT + CBD + O2/O3 was more effective than the individual treatments in inhibiting PDAC cell viability and proliferation, inducing cell death, and modulating the RAS pathway protein levels. Moreover, different combinations of treatments reduced tumor mass in the PDAC mouse model, thus promoting the effect of GEM. In conclusion, a mixture of MLT + CBD + O2/O3 could serve as a potential adjuvant therapeutic strategy for PDAC

Adjuvant treatment delay in breast cancer patients

Background: to evaluate if time between surgery and the first adjuvant treatment (chemotherapy, radiotherapy or hormone therapy) in patients with breast cancer is a risk factor for lower overall survival (OS). Method: data from a five-year retrospective cohort study of all women diagnosed with invasive breast cancer at an academic oncology service were collected and analyzed. Results: three hundred forty-eight consecutive women were included. Time between surgery and the first adjuvant treatment was a risk factor for shorter overall survival (HR=1.3, 95CI 1.06-1.71, p=0.015), along with negative estrogen receptor, the presence of lymphovascular invasion and greater tumor size. A delay longer than 4 months between surgery and the first adjuvant treatment was also associated with shorter overall survival (cumulative survival of 80.9% for delays ≤ 4 months vs. 72.6% for delays > 4 months; p=0.041, log rank test). Conclusion: each month of delay between surgery and the first adjuvant treatment in women with invasive breast cancer increases the risk of death in 1.3-fold, and this effect is independent of all other well-established risk factors. Based on these results, we recommend further public strategies to decrease this interval

Biometric measurements involving the terminal portion of the thoracic duct on left level IV: an anatomic study

INTRODUÇÃO: No esvaziamento cervical do nível IV à esquerda, a porção final do ducto torácico (DT) pode ser lesada, aumentando significativamente a morbimortalidade pós-operatória. O melhor tratamento é a prevenção. Contudo, não há disponível na literatura medidas biométricas que auxiliem a identificação da desembocadura do DT. MATERIAIS E MÉTODOS: a desembocadura do DT foi identificada e distâncias úteis foram medidas em 25 cadáveres não-formolizados. Análise estatística foi realizada para verificar associações. RESULTADOS: a desembocadura do DT ocorreu na confluência jugulo-subclávia (CJS – 60%), na veia jugular interna esquerda (VJIE – 36%) e na veia braquiocefálica esquerda (4%). Uma associação estatisticamente significante foi encontrada entre a desembocadura na confluência jugulo-subclávia e a distância entre a VJIE e o músculo omo-hioide (Medida #1). Indivíduos cujo DT desemboca na CJS apresentaram a Medida #1 com mediana de 34.5±12.0mm, já os com desembocadura na VJIE apresentaram mediana de 22.3±8.7mm (p=0.015 – Student´s t-test). A regressão logística demonstrou que para cada aumento de 10mm na Medida #1 há uma chance de 1.12x de encontrar a desembocadura do DT na CJS (OR=1.12; CI95%:1,01-1,25; p=0.032). Para essa Medida #1 estabeleceu-se um cut-off de 19mm como teste diagnóstico para prever a desembocadura do DT na CJS, com sensibilidade de 86.7% (CI95%:59.5-98.3%), especificidade de 55.6% (CI95%:21.2-86.3%), PPV de 76.5% (CI95%:50.1-93.2%), NPV de 71.4% (CI95%:25.8-97.2%) e ROC AUC de 79.3% (CI95%: 58.0-92.9%). CONCLUSÃO: este estudo anatômico demonstrou que o local de desembocadura do DT mais frequente é a CJS e que a Medida #1 é capaz de prever o local de desembocadura do DT.BACKGROUND: During a neck dissection involving the left IV level, the final segment of the thoracic duct (TD) may be injured, significantly increasing postoperative morbi-mortality. The best treatment is its prevention. However, there is a lack of helpful biometric measurements focusing on the TD termination in the literature. MATERIALS AND METHODS: The TD termination was identified and some helpful biometric measurements were obtained on 25 non-preserved cadavers. Statistical analysis was performed to analyze correlations. RESULTS: TD termination was found on the jugulo-subclavian junction (JSJ - 60%), on the left internal jugular vein (LIJV - 36%), and on the left brachiocephalic vein in 4%. A statistically significant association was found between TD termination on the JSJ and the distance between LIJV and omohyoid muscle (Measurement #1). Individuals with TD termination on the JSJ had median Measurement #1 of 34.5±12.0mm, compared with median Measurement #1 of 22.3±8.7mm among individuals with TD termination on LIJV (p=0.015 – Student´s t-test). The logistic regression showed for every 10mm increment of Measurement #1 there was 1.12x chance to find the TD termination on the JSJ (OR=1.12; CI95%:1,01-1,25; p=0.032). A 19mm cut-off was established for this distance as a diagnostic test to predict the TD termination on the JSJ, with sensitivity of 86.7% (CI95%:59.5-98.3%), specificity of 55.6% (CI95%:21.2-86.3%), PPV of 76.5% (CI95%:50.1-93.2%), NPV of 71.4% (CI95%:25.8-97.2%) and ROC AUC of 79.3% (CI95%: 58.0-92.9%). CONCLUSION: This anatomic study demonstrated the most frequent TD termination was on JSJ and Measurement #1 is able to predict the localization of TD termination

Combination Drug Therapy for the Management of Chronic Neuropathic Pain

Chronic neuropathic pain (NP) is an increasingly prevalent disease and leading cause of disability which is challenging to treat. Several distinct classes of drugs are currently used for the treatment of chronic NP, but each drug targets only narrow components of the underlying pathophysiological mechanisms, bears limited efficacy, and comes with dose-limiting side effects. Multimodal therapies have been increasingly proposed as potential therapeutic approaches to target the multiple mechanisms underlying nociceptive transmission and modulation. However, while preclinical studies with combination therapies showed promise to improve efficacy over monotherapy, clinical trial data on their efficacy in specific populations are lacking and increased risk for adverse effects should be carefully considered. Drug-drug co-crystallization has emerged as an innovative pharmacological approach which can combine two or more different active pharmaceutical ingredients in a single crystal, optimizing pharmacokinetic and physicochemical characteristics of the native molecules, thus potentially capitalizing on the synergistic efficacy between classes of drugs while simplifying adherence and minimizing the risk of side effects by reducing the doses. In this work, we review the current pharmacological options for the treatment of chronic NP, focusing on combination therapies and their ongoing developing programs and highlighting the potential of co-crystals as novel approaches to chronic NP management

Oral Cannabidiol Prevents Allodynia and Neurological Dysfunctions in a Mouse Model of Mild Traumatic Brain Injury

Neurological dysfunctions are the most impactful and persistent consequences of traumatic brain injury (TBI). Indeed, previous reports suggest that an association between TBI and chronic pain syndromes, as well anxio-depressive behaviors, tends to be more common in patients with mild forms of TBI. At present, no effective treatment options are available for these symptoms. In the present study, we used a weight drop mild TBI mouse model to investigate the effect of a commercially available 10% Cannabidiol (CBD) oil on both the sensorial and neuropsychiatric dysfunctions associated with mild TBI through behavioral and biomolecular approaches. TBI mice developed chronic pain associated with anxious and aggressive behavior, followed by a late depressive-like behavior and impaired social interaction. Such behaviors were related with specific changes in neurotransmitters release at cortical levels. CBD oral treatment restored the behavioral alterations and partially normalized the cortical biochemical changes. In conclusion, our data show some of the brain modifications probably responsible for the behavioral phenotype associated with TBI and suggest the CBD as a pharmacological tool to improve neurological dysfunctions caused by the trauma