ILEOSTIM trial: a study protocol to evaluate the effectiveness of efferent loop stimulation before ileostomy reversal.

PURPOSE: A protective loop ileostomy is the most useful method to reduce sequelae in the event of an anastomotic leakage (AL) after rectal cancer surgery. However, it requires an additional stoma reversal surgery with its own potential complications. Postoperative ileus (POI) remains the most common complication after ileostomy reversal, which leads to an increase in morbidity, length of hospital stay (LOS) and overall healthcare costs. Several retrospective studies carried out in this field have concluded that there are insufficient evidence-based recommendations about the routine application of preoperative bowel stimulation in clinical practice. Here we discuss whether stimulation of the efferent limb before ileostomy reversal might reduce POI and improve postoperative outcomes. METHODS: This is a multicentre randomised controlled trial to determine whether mechanical stimulation of the efferent limb during the 2 weeks before the ileostomy reversal would help to reduce the development of POI after surgery. This study was registered on Clinicaltrials.gov (NCT05302557). Stimulation will consist of infusing a solution of 500 ml of saline chloride solution mixed with a thickening agent (Resource©, Nestlé Health Science; 6.4 g sachet) into the distal limb of the ileostomy loop. This will be performed within the 2 weeks before ileostomy reversal, in an outpatient clinic under the supervision of a trained stoma nurse. CONCLUSION: The results of this study could provide some insights into the preoperative management of these patients.

EGFR mutation subtypes and response to immune checkpoint blockade treatment in non-small-cell lung cancer.

BACKGROUND: Although EGFR mutant tumors exhibit low response rates to immune checkpoint blockade overall, some EGFR mutant tumors do respond to these therapies; however, there is a lack of understanding of the characteristics of EGFR mutant lung tumors responsive to immune checkpoint blockade. PATIENTS AND METHODS: We retrospectively analyzed de-identified clinical and molecular data on 171 cases of EGFR mutant lung tumors treated with immune checkpoint inhibitors from the Yale Cancer Center, Memorial Sloan Kettering Cancer Center, University of California Los Angeles, and Dana Farber Cancer Institute. A separate cohort of 383 EGFR mutant lung cancer cases with sequencing data available from the Yale Cancer Center, Memorial Sloan Kettering Cancer Center, and The Cancer Genome Atlas was compiled to assess the relationship between tumor mutation burden and specific EGFR alterations. RESULTS: Compared with 212 EGFR wild-type lung cancers, outcomes with programmed cell death 1 or programmed death-ligand 1 (PD-(L)1) blockade were worse in patients with lung tumors harboring alterations in exon 19 of EGFR (EGFRΔ19) but similar for EGFRL858R lung tumors. EGFRT790M status and PD-L1 expression did not impact response or survival outcomes to immune checkpoint blockade. PD-L1 expression was similar across EGFR alleles. Lung tumors with EGFRΔ19 alterations harbored a lower tumor mutation burden compared with EGFRL858R lung tumors despite similar smoking history. CONCLUSIONS: EGFR mutant tumors have generally low response to immune checkpoint inhibitors, but outcomes vary by allele. Understanding the heterogeneity of EGFR mutant tumors may be informative for establishing the benefits and uses of PD-(L)1 therapies for patients with this disease.

Advances in the systemic treatment of melanoma brain metastases.

Of the solid tumor types that metastasize to the brain, melanoma has the highest propensity to form brain metastases. In addition, much remains unknown regarding the pathophysiology involved in melanoma cell extravasation through the blood-brain barrier, which enables interactions with the microenvironment, and melanoma cell transcriptomic responses to brain-specific cues. However, recent developments in targeted therapy and immunotherapy have generated considerable optimism regarding the treatment of metastatic melanoma. Although robust efficacy data exist on systemic therapy treatment of extracranial melanoma, data in the setting of melanoma brain metastases (MBM) are limited, primarily because patients with MBM are typically excluded from clinical trials. However, several clinical trials focusing on patients with MBM are now complete, and more are underway. Clinical evaluation of serine/threonine-protein kinase B-Raf inhibition in combination with MEK inhibition for MBM produced intracranial response rates of close to 60%, suggesting that inhibition of the mitogen-activated protein kinase pathway has the potential to further improve MBM outcomes. For immunotherapy, there is now increasing evidence that checkpoint inhibitors may also be effective in MBM with a high rate of durable intracranial responses observed with combination therapy. Furthermore, radiotherapy-particularly MBM treatment with mainstay stereotactic radiosurgery-appears to be safe and effective when combined with systemic therapy. Finally, evolving magnetic resonance imaging capabilities have inspired new approaches to the measurement of tumor burden and treatment responses. This review evaluates current published evidence describing MBM as a multifaceted disease and presents an overview of currently available and investigational treatments for patients with MBM.

[Diabetic ketoacidosis with mild hyperglycemia associated with the use of canagliflozin. Report of one case with type 1 diabetes]. / Cetoacidosis diabética euglicémica asociada a inhibidor de cotransportador de sodio glucosa Tipo 2 en paciente con diabetes Mellitus Tipo 1.

Diabetic ketoacidosis with mild hyperglycemia is a major complication of sodium-glucose cotransporter 2 inhibitors. Although its use is not approved for patients with type 1 diabetes mellitus, the drug is often prescribed with the hope of optimizing metabolic control. We report a 20 years old female with hypothyroidism and type 1 diabetes consulting for vomiting and abdominal pain. The patient had used canagliflozin during the two previous months. Laboratory showed a blood glucose of 200 mg/dl, a severe metabolic acidosis (pH 7.1) and ketonemia. The patient was successfully treated in the intensive care unit.

Real-time random safety audits: A transforming tool adapted to new times. / Análisis aleatorios de seguridad en tiempo real, una herramienta transformadora adaptada a los nuevos tiempos.

Real-time random safety audits constitute a tool designed to transfer knowledge from the sources of scientific evidence to the patient bedside. It has proven useful in critically ill patients, improving safety in the process of critical patient care, turning unsafe situations into safe ones in daily practice, and ensuring adherence to scientific evidence. In parallel, the design and methodology involved affords process indicators that will make it possible to know how we provide care for our patients, evolution over time (with regular feedback for professionals), the impact of our interventions, and benchmarking.

Dopamine D(1) receptor deletion strongly reduces neurotoxic effects of methamphetamine.

Methamphetamine (METH) is a potent, highly addictive psychostimulant consumed worldwide. In humans and experimental animals, repeated exposure to this drug induces persistent neurodegenerative changes. Damage occurs primarily to dopaminergic neurons, accompanied by gliosis. The toxic effects of METH involve excessive dopamine (DA) release, thus DA receptors are highly likely to play a role in this process. To define the role of D(1) receptors in the neurotoxic effects of METH we used D(1) receptor knock-out mice (D(1)R(-/-)) and their WT littermates. Inactivation of D(1)R prevented METH-induced dopamine fibre loss and hyperthermia, and increases in gliosis and pro-inflammatory molecules such as iNOS in the striatum. In addition, D(1)R inactivation prevented METH-induced loss of dopaminergic neurons in the substantia nigra. To explore the relationship between hyperthermia and neurotoxicity, METH was given at high ambient temperature (29 °C). In this condition, D(1)R(-/-) mice developed hyperthermia following drug delivery and the neuroprotection provided by D(1)R inactivation at 23 °C was no longer observed. However, reserpine, which empties vesicular dopamine stores, blocked hyperthermia and strongly potentiated dopamine toxicity in D(1)R(-/-) mice, suggesting that the protection afforded by D(1)R inactivation is due to both hypothermia and higher stored vesicular dopamine. Moreover, electrical stimulation evoked higher DA overflow in D(1)R(-/-) mice as demonstrated by fast scan cyclic voltammetry despite their lower basal DA content, suggesting higher vesicular DA content in D(1)R(-/-) than in WT mice. Altogether, these results indicate that the D(1)R plays a significant role in METH-induced neurotoxicity by mediating drug-induced hyperthermia and increasing the releasable cytosolic DA pool.

Combined pulmonary fibrosis and emphysema syndrome: a radiologic perspective.

Chronic obstructive pulmonary disease (that includes emphysema) results in significant morbidity and mortality worldwide. Idiopathic pulmonary fibrosis (IPF) is also a chronic and progressive parenchymal lung disease with an average survival of less than 5 years after diagnosis. Combined pulmonary fibrosis and emphysema (CPFE) is an important but still underdiagnosed syndrome. Its diagnosis is based on the radiological findings at computed tomography which consists of emphysema of the upper lung zones and fibrosis of the lower lung zones. Since this syndrome has a very bad prognosis, even worse than isolated finding of emphysema or fibrosis alone, early recognition and rapid treatment are important. In this article we will review and elucidate the radiologic appearance of this syndrome and highlight its clinical importance.

[Emotional support and Bach Flower Therapy]. / Apoyo emocional y terapia con flores de Bach.

Bach Flower Therapy is a method to cure and prevent physical and/or emotional disorders by means of treating our emotional unbalances. Primary Health Care Centers are an excellent site to apply this therapy since their main working instrument is an interview focused on patients. Over a 14 month period, a group of patients received this type of treatment in a Primary Health Care Center in Catalonia from a nurse at the center prepared to apply this therapy. The objective of this study is to describe the patients who received it, the identified nursing diagnoses, and the evolution of the physical and/or emotional disorders after treatment has been applied. Patients were enrolled in this therapy Project based on a request by the medical/nursing consultants treating patients or by a patient's own request to participate. 119 persons, of whom 78.15% were female, received personalized therapy until their health condition improved; seven patients had been excluded from this therapy since they only received a rescue remedy. The time period between the first and the last visit varied according to each case and the individual's personality 405 visits took place, an average of 3.4 per patient. Improvement was measured on the EVA scale: 87.4% of those patients who received treatment reported good or very good evolution/results. Bach Therapy appears to be a good alternative to psycho-pharmaceuticals, shows itself to be very effective, with fewer secondary effects, and less than 2% of patients evidencing gastric intolerance to this preparation.

Attitudes towards Oral Health in Patients with Rheumatoid Arthritis: A Qualitative Study Nested within a Randomized Controlled Trial.

INTRODUCTION: Patients with rheumatoid arthritis (RA) present a higher incidence and severity of periodontitis than the general population. Our study, Outcomes of Periodontal Treatment in Patients with Rheumatoid Arthritis (OPERA), was a randomized waiting-list controlled trial using mixed methods. Patients randomized to the intervention arm received intensive periodontal treatment, and those in the control arm received the same treatment with a 6-mo delay. AIM: The nested qualitative component aimed to explore patients' experiences and priorities concerning oral health and barriers and facilitators for trial participation. METHODS: Using purposive sampling until thematic saturation was reached, we conducted 21 one-to-one semistructured interviews with randomized patients in either of the 2 treatment arms as well as with patients who did not consent for trial participation. RESULTS: The patients described their experiences about RA, oral health, and study participation. Previous experiences with dental care professionals shaped patients' current perceptions about oral health and the place of oral health on their list of priorities compared with other conditions. Patients also highlighted some of the barriers and facilitators for study participation and for compliance with oral health maintenance. The patients, in the control arm, presented their views regarding the acceptable length of waiting time for the intervention. CONCLUSION: The associations between periodontal and systemic health are increasingly recognized by the literature. Our study provided an insight into RA patients' experiences and perceptions about oral health. It also highlighted some of the barriers and facilitators for participating in a periodontal interventional study for this group. We hope that our findings will support the design of larger interventional periodontal studies in patients with RA. The complex challenges faced by the burden of RA and the associated multimorbidities in this patient group might highlight opportunities to improve access to oral health services in this patient population. KNOWLEDGE TRANSFER STATEMENT: This article provided insights into the experiences and perceptions of rheumatoid arthritis patients about their oral health to improve patient participation in a definitive clinical trial.

Chemical characterization with XPS of the surface of polymer microparticles loaded with morphine.

Hydrophilic matrices are a potentially useful option for the development of oral controlled-release formulations. The porous surface of these particles makes it possible to control or modify release of the active principle after administration. As a result, such formulations can be used in liquid controlled-release pharmaceutical formulations. We investigated a method of spontaneous drug encapsulation to prepare ethylcellulose polymer microparticles (since the polymer is synthetic rather than natural the final suspension is called pseudolatex) filled with morphine hydrochloride. Morphine is incorporated to water during the synthesis process and thus it is microencapsulated inside the micelles that give rise to the final microparticles. X-ray photoelectron spectroscopy (XPS), a technique that can identify elements in a sample without destroying it, was used for the chemical analysis of the surface of these microspheres. The results demonstrated the complete absence of morphine from the microsphere surface, which was taken as evidence that the drug had been completely encapsulated.

E-selectin ligands recognised by HECA452 induce drug resistance in myeloma, which is overcome by the E-selectin antagonist, GMI-1271.

Multiple myeloma (MM) is characterized by the clonal expansion and metastatic spread of malignant plasma cells to multiple sites in the bone marrow (BM). Recently, we implicated the sialyltransferase ST3Gal-6, an enzyme critical to the generation of E-selectin ligands, in MM BM homing and resistance to therapy. Since E-selectin is constitutively expressed in the BM microvasculature, we wished to establish the contribution of E-selectin ligands to MM biology. We report that functional E-selectin ligands are restricted to a minor subpopulation of MM cell lines which, upon expansion, demonstrate specific and robust interaction with recombinant E-selectin in vitro. Moreover, an increase in the mRNA levels of genes involved in the generation of E-selectin ligands was associated with inferior progression-free survival in the CoMMpass study. In vivo, E-selectin ligand-enriched cells induced a more aggressive disease and were completely insensitive to Bortezomib. Importantly, this resistance could be reverted by co-administration of GMI-1271, a specific glycomimetic antagonist of E-selectin. Finally, we report that E-selectin ligand-bearing cells are present in primary MM samples from BM and peripheral blood with a higher proportion seen in relapsed patients. This study provides a rationale for targeting E-selectin receptor/ligand interactions to overcome MM metastasis and chemoresistance.

Cnr interferes with dimerization of the replication protein alpha in phage-plasmid P4.

DNA replication of phage-plasmid P4 in its host Escherichia coli depends on its replication protein alpha. In the plasmid state, P4 copy number is controlled by the regulator protein Cnr (copy number regulation). Mutations in alpha (alpha(cr)) that prevent regulation by Cnr cause P4 over-replication and cell death. Using the two-hybrid system in Saccharomyces cerevisiae and a system based on lambda immunity in E.coli for in vivo detection of protein-protein interactions, we found that (i) alpha protein interacts with Cnr, whereas alpha(cr) proteins do not; (ii) both alpha-alpha and alpha(cr)-alpha(cr) interactions occur and the interaction domain is located within the C-terminal of alpha; (iii) Cnr-Cnr interaction also occurs. Using an in vivo competition assay, we found that Cnr interferes with both alpha-alpha and alpha(cr)-alpha(cr) dimerization. Our data suggest that Cnr and alpha interact in at least two ways, which may have different functional roles in P4 replication control.

Sequential atomic force microscopy imaging of a spontaneous nanoencapsulation process.

Since hydrophilic matrices were proposed for controlled drug delivery, many polymeric excipients have been studied in order to make drug release fit the desired profiles. It has been pointed out that lambda-carrageenan, a sulphated polymer from algae, can suitably control the release rate of basic drugs from hydrophilic matrices with no need for complex technological processes. In this work, we propose a method to monitor morphologically the interaction between lambda-carrageenan and dexchlorpheniramine maleate (D-CPM), in order to find out how the release profiles can be so easily controlled. To this end, solutions of both polymer and drug were prepared at very low concentration. Solutions were mixed and samples were taken every hour over a period of 20 h. The characterization technique employed, atomic force microscopy (AFM), provides a high resolution, allowing to show the three-dimensional morphology of the samples within the nanometric scale. The results demonstrate that lambda-carrageenan is able to nanoencapsulate spontaneously D-CPM molecules, which offers the possibility to easily control the release rate of the drug. This work has moreover demonstrated the suitability of AFM for the specific case of the on-time monitoring of interaction processes that happen in pharmaceutical systems.

Toe pulse wave analysis in obliterating atherosclerosis.

photoplethysmographic measurements were carried out in 61 limbs with angiographically documented obliterating atherosclerosis (OA) and in 72 limbs with OA. The distance P was measured between the ascending and descending limbs of the pulse wave at the border of the upper and middle thirds of the amplitude. To standardize the measurements the P value was divided by the length L of the pulse wave (P/L ratio). Using 95% confidence limit in the group of healthy young individuals, 80.8% of the lower limbs with obliterating atherosclerosis without occlusion (OAWO) and 100% of those with complete occlusion (OAWCO) were revealed. In the group of healthy individuals (average age 50 years), 69.8% of lower limbs with OAWO and 100% of those with OAWCO were found. This method showed the higher number of detected OAWO when compared with peripheral systolic pressure measurements.

Multiseptate gallbladder.

Nine cases of multiseptate gallbladder have been reported in the English literature. Another case is presented. We consider cholecystectomy the treatment of choice because it relieves the symptoms and avoids chronic infection and stone formation.

[Comparison of humeral blood flow during rewarming and recooling of the hand in normal subjects or presenting Raynaud's phenomenon]. / Comparaison des débits sanguins huméraux lors du réchauffement et du refroidissement de la main chez des sujets sains ou présentant un phénomène de Raynaud.

Vascular reactivity to heat and cold was studied in 11 normal subjects without vascular disease and in 23 patients with Raynaud's phenomenon (etiologies: Raynaud's disease, scleroderma, thoracic outlet syndrome). The study of hand and digital temperatures and brachial artery blood flow was performed in ambiant conditions (room temperature 23.5 +/- 1 degree C) and after thermal (cold or warm exposure: 10, 33 and 40 degrees C), mechanical and metabolic modifications (with a wrist tourniquet). In these conditions, blood flow was studied at each temperature, before, during and after 3 minutes ischemia of the hand. Analysis of results showed that vasomotricity possibilities were preserved but that responses were not identical. Patients with primary Raynaud's phenomenon, and even more those with scleroderma as well, had reduced brachial artery blood flow after cooling (10 degrees C). After ischemia, maximal blood flow was also reduced. The microcirculatory disease existing in Raynaud's phenomenon limits the vasodilator capacity of hand vessels, but probably more in tissues with vascular lesions. Vasodilation seems to be limited during exposure to low well as high temperatures, but vasoconstriction capacity is not disturbed.

[Fibrinolytic activity of gingival fluid in hemophiliac patients]. / Actividad fibrinolítica del fluído gingival en pacientes hemofílicos.

The purpose of this investigation is to compare the fibrinolytic activity in the gingival fluid, of 32 hemophilic patients with 36 normal subjects. Oral examination was carried out in both groups in order to determine the extent of periodontal disease, using the Ramfjord Periodontal Index. The disease was classified in three grades according to the depth of the gingival crevices: grade I: 0 to 3 mm (Normal Deepness); grade II: from 3 to 6 mm; grade III higher than 6 mm. The fibrinolytic activity was measured in fibrin plates, prepared with thrombin and fibrinogen with and without plasminogen. It was found that the fibrinolytic activity was similar in the groups studied and related to the depth of the gingival crevices, with the exception of hemophilic patients with grade I disease, who showed higher fibrinolytic activity in the fibrin plates with plasminogen, than in the corresponding controls (p less than 0.001). This result could possibly be due to mucosal traumatism during the withdrawal of the sample, which permitted the release of plasminogen activators from the damaged vessels. It is important to mention the absence of grade III periodontal disease in the hemophilic group. The reason for this result could be due to the important bleeding occurring in grade II, which induces the patient to seek immediate professional attention. The above mentioned results suggest that the fibrinolytic activity of the gingival fluid in hemophilic and control patients is directly related to the degree of periodontal disease.