Improvement of cognitive function in wild-type and Alzheimer´s disease mouse models by the immunomodulatory properties of menthol inhalation or by depletion of T regulatory cells.

A complex network of interactions exists between the olfactory, immune and central nervous systems. In this work we intend to investigate this connection through the use of an immunostimulatory odorant like menthol, analyzing its impact on the immune system and the cognitive capacity in healthy and Alzheimer's Disease Mouse Models. We first found that repeated short exposures to menthol odor enhanced the immune response against ovalbumin immunization. Menthol inhalation also improved the cognitive capacity of immunocompetent mice but not in immunodeficient NSG mice, which exhibited very poor fear-conditioning. This improvement was associated with a downregulation of IL-1ß and IL-6 mRNA in the brain´s prefrontal cortex, and it was impaired by anosmia induction with methimazole. Exposure to menthol for 6 months (1 week per month) prevented the cognitive impairment observed in the APP/PS1 mouse model of Alzheimer. Besides, this improvement was also observed by the depletion or inhibition of T regulatory cells. Treg depletion also improved the cognitive capacity of the APPNL-G-F/NL-G-F Alzheimer´s mouse model. In all cases, the improvement in learning capacity was associated with a downregulation of IL-1ß mRNA. Blockade of the IL-1 receptor with anakinra resulted in a significant increase in cognitive capacity in healthy mice as well as in the APP/PS1 model of Alzheimer´s disease. These data suggest an association between the immunomodulatory capacity of smells and their impact on the cognitive functions of the animals, highlighting the potential of odors and immune modulators as therapeutic agents for CNS-related diseases.

[Irreversible electroporation: present and future in the treatment of hepatocellular carcinoma].

Currently, among the possible treatments for hepatocellular carcinoma there is group of minimally invasive ablation techniques with wide clinical acceptance due to their greater efficacy and safety in comparison to traditional therapies, low cost, and no need of being admitted to hospital (outpatient treatment program). Irreversible electroporation is a non-thermal ablation technique in which electrical fields are used to create nanopores in the cell membrane that induce tumor cell death. Irreversible electroporation has shown promising results in numerous clinical trials; however, its control on long-term tumor growth and recurrence is inferior in comparison to that of radiofrequency. Combining irreversible electroporation with immunological agents may increase its efficacy in the treatment of focal lesions and metastases. In this work, we present an update on IRE including procedure, mechanism of action, application as a treatment for HCC, and the improvements that have been made in the past few years.

Electroporación irreversible: presente y futuro en el tratamiento del carcinoma hepatocelular / Irreversible electroporation: present and future in the treatment of hepatocellular carcinoma

Entre los tratamientos actuales para el carcinoma hepatocelular se encuentra un grupo de técnicas de ablación mínimamente invasivas con gran aceptación clínica por su mayor eficacia y seguridad respecto a las terapias tradicionales, bajo coste económico y aplicación ambulatoria. La electroporación irreversible es una técnica de ablación no térmica que crea nanoporos en la membrana celular mediante administración de campos eléctricos, induciendo la muerte de las células tumorales. Aunque la electroporación irreversible presenta resultados prometedores en numerosos ensayos clínicos, su control a largo plazo del crecimiento y de las recidivas tumorales es inferior al de la radiofrecuencia. La combinación de electroporación irreversible con agentes inmunológicos podría aumentar su eficacia tanto en el tratamiento de lesiones focales como de metástasis. Esta revisión realiza una actualización sobre la electroporación irreversible: procedimiento, mecanismo de acción, aplicación como tratamiento del carcinoma hepatocelular y alternativas de mejora que están aflorando en los últimos años.(AU)

Currently, among the possible treatments for hepatocellular carcinoma there is group of minimally invasive ablation techniques with wide clinical acceptance due to their greater efficacy and safety in comparison to traditional therapies, low cost, and no need of being admitted to hospital (outpatient treatment program). Irreversible electroporation is a non-thermal ablation technique in which electrical fields are used to create nanopores in the cell membrane that induce tumor cell death. Irreversible electroporation has shown promising results in numerous clinical trials; however, its control on long-term tumor growth and recurrence is inferior in comparison to that of radiofrequency. Combining irreversible electroporation with immunological agents may increase its efficacy in the treatment of focal lesions and metastases. In this work, we present an update on IRE including procedure, mechanism of action, application as a treatment for HCC, and the improvements that have been made in the past few years.(AU)

Testicular Pain as A Warning Symptom of a Symptomatic Abdominal Aortic Aneurysm: Case Report and Review of The Literature.

BACKGROUND: Isolated testicular pain is an unusual clinical presentation of symptomatic abdominal aortic aneurysms (AAA). We present two patients hemodynamically stable with an isolated acute testicular pain related to an AAA and a review of the published literature up to present. METHODS: Two adult-old males with an acute isolated testicular pain presented to the emergency department. Although both cases had their symptoms for more than 24 hours and were hemodynamically stable, the misdiagnosis of a urological condition in one case and a delay of the intervention in the second resulted in a sudden drop of vital signs and the need of an urgent open surgery. RESULTS: A bibliographic review of the 15 published cases is presented. Most cases occurred without a previous diagnosis of AAA. Aneurysms were characteristically very large (mean 10 cm). The initial diagnosis was frequently wrong, attributing the pain mostly to genito-urinary conditions. The testicular pain presented days and even weeks before rupture, which may offer a convenient window of hemodynamic stability for repair. CONCLUSIONS: Acute testicular pain in adult-old patients with aneurysm risk factors and specially with a first urological evaluation discarding a genitourinary disorder should alert clinicians to consider the diagnosis of a symptomatic abdominal aortic aneurysm. The early and accurate recognition of these cases may increase the survival.

Critical stenosis of the celiac trunk by the arcuate ligament, successfully treated by a laparoscopic approach.

A 56-year-old female was referred to our department with a five-month history of progressive abdominal pain related to physical exertion and copious meals. The pain was located in the mesogastric region and the right flank and remitted when the patient lay in the recumbent position with the knees bent. The patient reported nausea and a weight loss of 12 kg over the previous ten years. She had been diagnosed 18 years previously with hereditary leiomyomatosis and renal cancer and had undergone a hysterectomy and partial nephrectomy.

A proof-of-concept study of the in-vivo validation of a computational fluid dynamics model of personalized radioembolization.

Radioembolization (RE) with yttrium-90 (90Y) microspheres, a transcatheter intraarterial therapy for patients with liver cancer, can be modeled computationally. The purpose of this work was to correlate the results obtained with this methodology using in vivo data, so that this computational tool could be used for the optimization of the RE procedure. The hepatic artery three-dimensional (3D) hemodynamics and microsphere distribution during RE were modeled for six 90Y-loaded microsphere infusions in three patients with hepatocellular carcinoma using a commercially available computational fluid dynamics (CFD) software package. The model was built based on in vivo data acquired during the pretreatment stage. The results of the simulations were compared with the in vivo distribution assessed by 90Y PET/CT. Specifically, the microsphere distribution predicted was compared with the actual 90Y activity per liver segment with a commercially available 3D-voxel dosimetry software (PLANET Dose, DOSIsoft). The average difference between the CFD-based and the PET/CT-based activity distribution was 2.36 percentage points for Patient 1, 3.51 percentage points for Patient 2 and 2.02 percentage points for Patient 3. These results suggest that CFD simulations may help to predict 90Y-microsphere distribution after RE and could be used to optimize the RE procedure on a patient-specific basis.

Intratumoral STING Agonist Injection Combined with Irreversible Electroporation Delays Tumor Growth in a Model of Hepatocarcinoma.

BACKGROUND/AIM: Irreversible electroporation (IRE) showed promising results for small-size tumors and very early cancers. However, further development is needed to evolve this procedure into a more efficient ablation technique for long-term control of tumor growth. In this work, we show that it is possible to increase the antitumor efficiency of IRE by simmultaneously injecting c-di-GMP, a STING agonist, intratumorally. MATERIALS AND METHODS: Intratumoral administration of c-di-GMP simultaneously to IRE was evaluated in murine models of melanona (B16.OVA) and hepatocellular carcinoma (PM299L). RESULTS: The combined therapy increased the number of tumor-infiltrating IFN-γ/TNF-α-producing CD4 and CD8 T cells and delayed tumor growth, as compared to the effect observed in groups treated with c-di-GMP or IRE alone. CONCLUSION: These results can lead to the development of a new therapeutic strategy for the treatment of cancer patients refractory to other therapies.

Minimally Invasive Surgical Approach for the Treatment of Superior Mesenteric Artery Syndrome: Long-Term Outcomes.

BACKGROUND: Latero-lateral duodenojejunostomy is the treatment of choice for superior mesenteric artery syndrome (SMAS). The present study analyzes the long-term outcomes in 13 patients undergoing laparoscopic surgery for SMAS. MATERIALS AND METHODS: A retrospective study of 10 females and three males undergoing surgery between 2001 and 2013 was performed. Demographic, clinical and radiologic data and long-term surgical outcomes were recorded. In 12 patients latero-lateral duodenojejunostomy and in one patient distal laparoscopic gastrectomy with Roux-en-Y reconstruction were performed. The median age was 24 years (20-28), and the median duration of symptoms was 24 months (5-24). The most frequent symptoms were abdominal pain (n = 11; 92.3%), nausea and vomiting (n = 10; 77%) and weight loss (n = 9; 69.2%). The median operating time was 98 min (86-138) and hospital stay was 3 days (1-14). RESULTS: No reconversions occurred, and one patient experienced gastric emptying delay in the immediate postoperative period with spontaneous resolution. In four patients, SMAS was associated with severe stenosis of the celiac trunk which was treated in the same operation, and four patients presented stenosis of the left renal vein (the "nutcracker" phenomenon). With a median follow-up of 94 months (SD 65.3), eight patients (61.5%) had excellent results. One patient had a relapse of symptoms 4 years after surgery requiring distal gastrectomy, two patients presented delay in gastric emptying following temporary improvement and one patient experienced no improvement. CONCLUSIONS: Latero-lateral duodenojejunostomy yields good results in SMAS although it requires other gastric motility disorders to be ruled out for appropriate treatment to be established.