New compounds with bioisosteric replacement of classic choline kinase inhibitors show potent antiplasmodial activity.

In the fight against Malaria, new strategies need to be developed to avoid resistance of the parasite to pharmaceutics and other prevention barriers. Recently, a Host Directed Therapy approach based on the suppression of the starting materials uptake from the host by the parasite has provided excellent results. In this article, we propose the synthesis of bioisosteric compounds that are capable of inhibiting Plasmodium falciparum Choline Kinase and therefore to reduce choline uptake, which is essential for the development of the parasite. Of the 41 bioisosteric compounds reported herein, none showed any influence of the linker on the antimalarial and enzyme inhibitory activity, whereas an effect of the type of cationic heads used could be observed. SARs determined that the thienopyrimidine substituted in 4 by a pyrrolidine is the best scaffold, independently of the chosen linker. The decrease in lipophilicity seems to improve the antimalarial activity but to cause an opposite effect on the inhibition of the enzyme. While potent compounds with similar good inhibitory values have been related to the proposed mechanism of action, some of them still show discrepancies and further studies are needed to determine their specific molecular target.This research was funded by Convocatoria 2019 Proyectos de I + D + i - RTI Tipo B “Ministerio de Ciencia e Innovación” grant number PID2019–109294RB-I00, University of Granada, Cei-BioticProject grant number CEI2013-MP-1, the Instituto de Salud Carlos III Subdirección General de Redes y Centros de Investigación Cooperativa-Red de Investigación Cooperativa en Enfermedades Tropicales (RICET: RD16/0027/0014), the Plan Nacional (SAF PID2019-109623RB-I002016-79957-R) and the Junta de Andalucía (BIO-199)

Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy.

Sphingolipid imbalance is the culprit in a variety of neurological diseases, some affecting the myelin sheath. We have used whole-exome sequencing in patients with undetermined leukoencephalopathies to uncover the endoplasmic reticulum lipid desaturase DEGS1 as the causative gene in 19 patients from 13 unrelated families. Shared features among the cases include severe motor arrest, early nystagmus, dystonia, spasticity, and profound failure to thrive. MRI showed hypomyelination, thinning of the corpus callosum, and progressive thalamic and cerebellar atrophy, suggesting a critical role of DEGS1 in myelin development and maintenance. This enzyme converts dihydroceramide (DhCer) into ceramide (Cer) in the final step of the de novo biosynthesis pathway. We detected a marked increase of the substrate DhCer and DhCer/Cer ratios in patients' fibroblasts and muscle. Further, we used a knockdown approach for disease modeling in Danio rerio, followed by a preclinical test with the first-line treatment for multiple sclerosis, fingolimod (FTY720, Gilenya). The enzymatic inhibition of Cer synthase by fingolimod, 1 step prior to DEGS1 in the pathway, reduced the critical DhCer/Cer imbalance and the severe locomotor disability, increasing the number of myelinating oligodendrocytes in a zebrafish model. These proof-of-concept results pave the way to clinical translation

COVID-19 and the Global Impact on Colorectal Practice and Surgery

Background: The novel severe acute respiratory syndrome coronavirus 2 virus that emerged in December 2019 causing coronavirus disease 2019 (COVID-19) has led to the sudden national reorganization of health care systems and changes in the delivery of health care globally. The purpose of our study was to use a survey to assess the global effects of COVID-19 on colorectal practice and surgery. Materials and Methods: A panel of International Society of University Colon and Rectal Surgeons (ISUCRS) selected 22 questions, which were included in the questionnaire. The questionnaire was distributed electronically to ISUCRS fellows and other surgeons included in the ISUCRS database and was advertised on social media sites. The questionnaire remained open from April 16 to 28, 2020. Results: A total of 287 surgeons completed the survey. Of the 287 respondents, 90% were colorectal specialists or general surgeons with an interest in colorectal disease. COVID-19 had affected the practice of 96% of the surgeons, and 52% were now using telemedicine. Also, 66% reported that elective colorectal cancer surgery could proceed but with perioperative precautions. Of the 287 respondents, 19.5% reported that the use of personal protective equipment was the most important perioperative precaution. However, personal protective equipment was only provided by 9.1% of hospitals. In addition, 64% of surgeons were offering minimally invasive surgery. However, 44% reported that enough information was not available regarding the safety of the loss of intra-abdominal carbon dioxide gas during the COVID-19 pandemic. Finally, 61% of the surgeons were prepared to defer elective colorectal cancer surgery, with 29% willing to defer for ≤ 8 weeks. Conclusion: The results from our survey have demonstrated that, globally, COVID-19 has affected the ability of colorectal surgeons to offer care to their patients. We have also discussed suggestions for various practical adaptation strategies for use during the recovery period. We have presented the results of a survey used to assess the global impact of coronavirus disease 2019 (COVID-19) on the delivery of colorectal surgery. Despite accessible guidance information, our results have demonstrated that COVID-19 has significantly affected the ability of colorectal surgeons to offer care to patients. We have also discussed practical adaptation strategies for use during the recovery phase

Evaluation of appendicitis risk prediction models in adults with suspected appendicitis

Background Appendicitis is the most common general surgical emergency worldwide, but its diagnosis remains challenging. The aim of this study was to determine whether existing risk prediction models can reliably identify patients presenting to hospital in the UK with acute right iliac fossa (RIF) pain who are at low risk of appendicitis. Methods A systematic search was completed to identify all existing appendicitis risk prediction models. Models were validated using UK data from an international prospective cohort study that captured consecutive patients aged 16–45 years presenting to hospital with acute RIF in March to June 2017. The main outcome was best achievable model specificity (proportion of patients who did not have appendicitis correctly classified as low risk) whilst maintaining a failure rate below 5 per cent (proportion of patients identified as low risk who actually had appendicitis). Results Some 5345 patients across 154 UK hospitals were identified, of which two‐thirds (3613 of 5345, 67·6 per cent) were women. Women were more than twice as likely to undergo surgery with removal of a histologically normal appendix (272 of 964, 28·2 per cent) than men (120 of 993, 12·1 per cent) (relative risk 2·33, 95 per cent c.i. 1·92 to 2·84; P < 0·001). Of 15 validated risk prediction models, the Adult Appendicitis Score performed best (cut‐off score 8 or less, specificity 63·1 per cent, failure rate 3·7 per cent). The Appendicitis Inflammatory Response Score performed best for men (cut‐off score 2 or less, specificity 24·7 per cent, failure rate 2·4 per cent). Conclusion Women in the UK had a disproportionate risk of admission without surgical intervention and had high rates of normal appendicectomy. Risk prediction models to support shared decision‐making by identifying adults in the UK at low risk of appendicitis were identified

Long term results of centralising intertrochanteric osteotomy in Legg Calve Perthes disease. (Report on 60 cases)

The writers propose a new classification of Legg-Calvé-Perthes' disease into three degrees of increasing gravity. Grade 1 includes hips with minimal or no flattening of the epiphysis, normal relations between the head of the femur and the acetabulum, and a normally orientated epiphyseal cartilage. Grade 2 comprises hips with slight epiphyseal flattening (one third or less), the epiphyseal growth cartilage is horizontal, the femoral head is partly uncovered due to epiphyseal subluxation, but becomes normal in the abduction test. Grade 3 hips show severe epiphyseal flattening (more than one third), the epiphyseal growth cartilage is horizontal, and the epiphyseal subluxation persists even in the abduction test. In our opinion, the advantage of this classification, which is not dependent on a determination of the extent of the necrosis, is that it is less subjective, and can be applied more easily and immediately, as compared with Catterall's classification. The results in sixty cases of intertrochanteric centralising osteotomy were constantly satisfactory in grades 1 and 2, but unsatisfactory in grade 3. The writers consider that surgical intervention is unnecessary in patients with hips in grade 1, while femoral osteotomy is contra-indicated in grade 3 cases. In the latter event, surgical intervention, if considered necessary, should be a pelvic osteotomy or cheiloplasty of the femoral epiphysis. Centralising osteotomy is the operation of choice in patients of grade 2. The results were better in patients who were less than six years of age at the time of operation

Risultati a distanza dell'osteotomia femorale di centrazione nella malattia di Legg-Calvé-Perthes

Gli autori propongono una nuova classificazione della malattia di Legg-Calvé-Perthes in tre gradi di gravità crescente, basati su determinati parametri di “testa a rischio” e specialmente sulla relazione tra la testa del femore e l’acetabolo. Sono presentati i risultati a lungo termine ottenuti in 60 pazienti trattati con osteotomia intertrocanterica centralizzante. Si suggerisce un modello di trattamento, basato sulla gravità iniziale della condizione

[Technical notes on the use of the circular mechanical stapler].

The Authors, in the light of their experience, study some technical aspects in the use of circular stapling devices (SPTU-EEA). After paying attention to the risks involved in the employment of such instruments, they explain the precautions they consider necessary to prevent the most common complications. As a conclusion, they confirm the safety of stapling devices, provided they are used with skilfulness and caution