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Background: Nicotine-containing electronic cigarette (EC) vaping has become popular worldwide, and our understanding of the effects of vaping on stroke outcomes is elusive. Using a rat model of transient middle cerebral artery occlusion, the current exploratory study aims to evaluate the sex-dependent effects of EC exposure on brain energy metabolism and stroke outcomes., Methods: Adult Sprague-Dawley rats of both sexes were randomly assigned to air/EC vapor (5% nicotine Juul pods) exposure for 16 nights, followed by randomization into 3 cohorts. The first cohort underwent exposure to air/EC preceding randomization to transient middle cerebral artery occlusion (90 minutes) or sham surgery, followed by survival for 21 days. During the survival period, rats underwent sensorimotor and Morris water maze testing. Subsequently, brains were collected for histopathology. A second cohort was exposed to air/EC after which brains were collected for unbiased metabolomics analysis. The third cohort of animals was exposed to air/EC and received transient middle cerebral artery occlusion/sham surgery, and brain tissue was collected 24 hours later for biochemical analysis., Results: In females, EC significantly increased ( P <0.05) infarct volumes by 94% as compared with air-exposed rats, 165±50 mm 3 in EC-exposed rats, and 85±29 mm 3 in air-exposed rats, respectively, while in males such a difference was not apparent. Morris water maze data showed significant deficits in spatial learning and working memory in the EC sham or transient middle cerebral artery occlusion groups compared with the respective air groups in rats of both sexes ( P <0.05). Thirty-two metabolites of carbohydrate, glycolysis, tricarboxylic acid cycle, and lipid metabolism were significantly altered ( P ≤0.05) due to EC, 23 of which were specific for females. Steady-state protein levels of hexokinase significantly decreased ( P <0.05) in EC-exposed females; however, these changes were not seen in males., Conclusions: Even brief EC exposure over 2 weeks impacts brain energy metabolism, exacerbates infarction, and worsens poststroke cognitive deficits in working memory more in female than male rats., Competing Interests: Disclosures Dr Raval reports employment by the American Heart Association. The other authors report no conflicts.

Objective: Identification of imaging prognostic parameters for early therapy personalisation to reduce treatment-related morbidity in paediatric Hodgkin lymphoma (HL). Our aim was to evaluate quantitative markers from baseline 2-[18F]fluoro-2-deoxy-d-glucose PET/CT as prognostic factors for treatment outcomes. Another goal was assessing the prognostic value of Deauville score at interim PET/CT., Methods: Twenty-one patients were prospectively enrolled. Median age was 12 years (range 6-17); 13 were female. Patients underwent PET/CT for disease staging (bPET), at the end of two cycles of chemotherapy (iPET) and after chemotherapy. A total of 173 lesions were segmented from bPET. We calculated 51 texture features for each lesion. Total metabolic tumour volume and total lesion glycolysis from bPET were calculated for response prediction at iPET. Univariate and multivariate analyses were used for optimal cut-off values to separate responders at iPET according to the Deauville score., Results: We identified four texture features as possible independent predictors of treatment outcomes at iPET. The areas under the ROC for univariate analysis were 0.89 (95% CI, 0.75-1), 0.82 (95% CI, 0.64-1), 0.79 (95% CI, 0.59-0.99) and 0.89 (95% CI, 0.75-1). The survival curves for patients assigned Deauville scores 1, 2, 3 and X were different from those assigned a score 4, with 4-year progression free-survival (PFS) rates of 85 versus 29%, respectively (P = 0.05)., Conclusions: We found four textural features as candidates for predicting early response to chemotherapy in paediatric patients with HL. The Deauville score at iPET was useful for differentiating PFS rates., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Adult-onset Still's disease (AOSD) is often refractory to standard therapy. Anakinra (ANK), an interleukin-1 receptor antagonist, has demonstrated efficacy in single cases and small series of AOSD. We assessed the efficacy of ANK in a series of AOSD patients. Multicenter retrospective open-label study. ANK was used due to lack of efficacy to standard synthetic immunosuppressive drugs and in some cases also to at least 1 biologic agent. Forty-one patients (26 women/15 men) were recruited. They had a mean age of 34.4 ± 14 years and a median [interquartile range (IQR)] AOSD duration of 3.5 [2-6] years before ANK onset. At that time the most common clinical features were joint manifestations 87.8%, fever 78%, and cutaneous rash 58.5%. ANK yielded rapid and maintained clinical and laboratory improvement. After 1 year of therapy, the frequency of joint and cutaneous manifestations had decreased to 41.5% and to 7.3% respectively, fever from 78% to 14.6%, anemia from 56.1% to 9.8%, and lymphadenopathy from 26.8% to 4.9%. A dramatic improvement of laboratory parameters was also achieved. The median [IQR] prednisone dose was also reduced from 20 [11.3-47.5] mg/day at ANK onset to 5 [0-10] at 12 months. After a median [IQR] follow-up of 16 [5-50] months, the most important side effects were cutaneous manifestations (n = 8), mild leukopenia (n = 3), myopathy (n = 1), and infections (n = 5). ANK is associated with rapid and maintained clinical and laboratory improvement, even in nonresponders to other biologic agents. However, joint manifestations are more refractory than the systemic manifestations.

Thrombospondin-1 (TSP-1) is an extracellular matrix protein produced by astrocytes, which can promote synaptogenesis. The regulation of astrocytic TSP-1 involves extracellular ATP through the activation of P2Y receptors coupled to various protein kinase signaling pathways. However, not much is known about the mechanisms regulating TSP-1 expression in primary cortical astrocytes after a traumatic brain injury. Using an in-vitro model of central nervous system trauma that stimulates the release of ATP, we found that trauma-induced expression and release of TSP-1 involved purinergic signaling as both expression and release were significantly attenuated by pyridoxalphosphate-6-azophenyl-2'-4'-disulfonic acid, a P2 receptor antagonist. Further antagonist studies with reactive blue 2 point to a role for P2Y4, as reactive blue 2 is a potent antagonist for rat P2Y4 receptors. In addition, the injury-induced expression of TSP-1 was significantly attenuated by the inhibition of extracellular signal-regulated kinase and p38/mitogen-activated protein kinase, whereas injury-induced release of TSP-1 was significantly blocked by the inhibition of extracellular signal-regulated kinase and Akt. Using an in-vivo model of a moderate parasagittal fluid-percussion brain injury, we found that TSP-1 levels were increased when compared with those in sham animals in the cortex, thalamus, and hippocampus. We conclude that TSP-1 expression after injury can be regulated by the activation of P2 receptors coupled with protein kinase signaling pathways and suggest that purinergic signaling, by regulating TSP expression, may play an important role in cell-matrix and cell-cell interactions such as those occurring during central nervous system repair.

Resistance to doxorubicin based chemotherapy is a major therapeutic problem limiting advanced breast cancer treatment. 99mTc hexakis-2-methoxyisobutylisonitrile ((99m)Tc-MIBI) has been reported to be extruded from tumour cells by the P-glycoprotein and multidrug resistance protein encoded by MDR1 and MRP1 genes, respectively. These proteins are involved in the cellular efflux of several chemotherapeutic agents including doxorubicin. The aim of this study was to investigate the clinical value of a standard (99m)Tc-MIBI scintimammography technique in the prediction of response to chemotherapy in advanced breast cancer patients. Fifty-six lesions from 33 female patients with locally advanced (n=27) or recurrent breast cancer (n=6) were included in the study. MIBI scintigraphy was performed 2-8 days prior to chemotherapy (FAC regimen). Images were acquired 10 min and 1 h post-injection of 740-1110 MBq of (99m)Tc-MIBI. Tumour-to-normal background tissue uptake ratios were calculated on each lesion in the early (T/B(e)) and delayed phase of the study (T/B(d)). Both T/B(e) and T/B(d) ratios were significantly higher (P<0.0001) in responders (n=43) than nonresponders (n=13). Diagnostic values of (99m)Tc-MIBI in the prediction of chemotherapy response were evaluated using the arbitrary cut-off values of 1.5 for T/B(e) and 1.4 forT/B(d). Sensitivity, specificity, positive and negative predictive values were 88.4%, 92.3%, 97.4%, 70.6%; and 90.7%, 100.0%, 100.0%, 76.6%, for T/B(e) and T/B(d), respectively. We conclude that (99m)Tc-MIBI scintigraphy may be a clinically valuable tool for guiding chemotherapy in advanced breast cancer patients.

We tested the hypothesis that a transient non-lethal ischemic insult lasting 2 min would protect against subsequent moderate traumatic brain injury. Sprague-Dawley rats were randomized into three experimental groups, including sham ischemia procedures and ischemic preconditioning (IPC) followed 48 h later by moderate traumatic brain injury (TBI) provoked by parasagittal fluid percussion injury (1.8-2.1 atm) and IPC followed by 48 h sham TBI. Seven days after the secondary insult, animals were perfusion-fixed for quantitative histopathological analysis. The CA3 necrotic cell count was decreased by 63% in TBI animals that had undergone IPC as compared to TBI animals that underwent sham IPC. TBI animals that had undergone IPC demonstrated significantly smaller contusion volumes than the TBI alone group (6.44 +/- 1.51 vs 1.37 +/- 0.63 mm3, mean +/- s.e.m.) These data indicate that IPC applied 2 days before moderate fluid percussion brain injury increases the brain resistance to traumatic brain damage.

Initial reports suggest that 99mTc-methoxyisobutylisonitrile (MIBI) scanning may be of clinical value in staging patients with malignant melanoma. We carried out a study to evaluate the potential of this technique in the detection of recurrent disease. Whole-body 99mTC-MIBI scans were performed in 81 patients with a history of a surgically excised MM: 28 with known recurrent lesions and 53 during follow-up without evidence of disease. Images started 10 min post-injection, using a dose of 740 MBq. Diagnoses were confirmed by cytological/histological examination or at least one conventional imaging modality. Blinded interpretations of the MIBI scans were performed. Whole-body MIBI scanning correctly detected 68 (92%) of 74 metastatic lesions in the following sites: regional lymph nodes (n=23), non-regional lymph nodes (n=10), skin (n=16), brain/cerebellum (n=6), lung (n=8), bone (n=4) and breast (n=1). The technique failed to detect three subcutaneous regressive lesions (< 1 cm), one liver metastasis, one spleen metastasis and a case of multiple small lesions of the duodenal mucous membrane. In 14 patients the procedure detected previously unknown metastatic lesions. These results suggest that 99mTc-MIBI scanning is an effective imaging modality for whole-body screening of metastatic disease in malignant melanoma patients with the potential to influence treatment planning.

Diffusely reduced 99Tc(m)-pertechnetate uptake is a relatively infrequent but annoying finding that impairs evaluation of the thyroid gland. We studied 32 female patients aged 19-85 years with markedly reduced pertechnetate uptake. The following causes of reduced pertechnetate uptake were recognized: treatment with iodinated pharmaceuticals (n = 15), suppression therapy with T4 (n = 11), subacute thyroiditis (n = 5) and massive tumour replacement (n = 1). 99Tc(m)-MIBI thyroid scintigraphy was performed within 24 h of the pertechnetate study. The results were correlated with neck ultrasound, serum TSH (n = 25) and surgical findings in patients who had been operated on. The technique identified the following conditions: normally sized thyroids (n = 4), diffuse goitres (n = 8), multinodular goitres (n = 17) and solitary thyroid nodules (n = 3). Moreover, substernal goitres were identified in nine patients. This condition was confirmed at surgery in seven patients. Ultrasonography was concordant in 29 of 32 patients in terms of thyroid size and structure, but failed to demonstrate substernal thyroid tissue. Our results suggest that 99Tc(m)-MIBI scintigraphy may contribute to the diagnosis of thyroid pathology and treatment planning in patients with diffusely decreased 99Tc(m)-pertechnetate uptake.

The purpose of this study was to determine whether transient unilateral (2 h) middle cerebral artery occlusion (MCAo) is capable of inducing bilateral ischemic tolerance in hippocampal CA1 neurons when temporary bilateral forebrain ischemia by two-vessel occlusion (2VO) is carried out 3 days later, and to explore the relationship of this tolerance to the regional expression of c-fos and hsp-70 mRNA. Rats were sacrificed 4 days after 2VO, and normal-appearing neurons in CA1 subregions were counted. Rats subjected to MCAo and 2VO showed significant protection of CA1 neurons in both hippocampi, whereas rats which underwent sham MCAo and 2VO typically had severe bilateral destruction of CA1 neurons (normal neuron counts, ipsilateral medial CA1: 59.8 +/- 7.2 vs 16.6 +/- 7.8 (mean +/- s.e.m.); middle CA1: 50.0 +/- 4.7 vs 16.0 +/- 8.8; lateral CA1: 43.5 +/- 5.7 vs 13.8 +/- 6.3; contralateral, medial CA1: 52.3 +/- 6.3 vs 17.0 +/- 6.4; middle CA1: 43.3 +/- 4.7 vs 19.8 +/- 8.1; lateral CA1: 45.5 +/- 4.6 vs 26.0 +/- 10.3, respectively). This neuronal tolerance was preceded by the early bilateral induction of c-fos mRNA, which may in turn lead to expression of critical target genes that promote cell recovery.