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

Health Challenges and Perspectives for Sub-saharan Africa

the article is related to the partnership between University of Ferrara , Italy and Namibia University of Science and Technology in performing a new Bechelor's Degree for Nurses and Midwifer

Pre- and postsynaptic effects of glutamate in the frog labyrinth

The role of glutamate in quantal release at the cytoneural junction was examined by measuring mEPSPs and afferent spikes at the posterior canal in the intact frog labyrinth. Release was enhanced by exogenous glutamate, or dl-TBOA, a blocker of glutamate reuptake. Conversely, drugs acting on ionotropic glutamate receptors did not affect release; the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-R) blocker CNQX decreased mEPSP size in a dose-dependent manner; the NMDA-R blocker d-AP5 at concentrations <200 M did not affect mEPSP size, either in the presence or absence of Mg and glycine. In isolated hair cells, glutamate did not modify Ca currents. Instead, it systematically reduced the compound delayed potassium current, IKD, whereas the metabotropic glutamate receptor (mGluR)-II inverse agonist, (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl)propanoic acid (LY341495), increased it. Given mGluR-II decrease cAMP production, these finding are consistent with the reported sensitivity of IKD to protein kinase A (PKA)-mediated phosphorylation. LY341495 also enhanced transmitter release, presumably through phosphorylation-mediated facilitation of the release machinery. The observed enhancement of release by glutamate confirms previous literature data, and can be attributed to activation of mGluR-I that promotes Ca release from intracellular stores. Glutamate-induced reduction in the repolarizing IKD may contribute to facilitation of release. Overall, glutamate exerts both a positive feedback action on mGluR-I, through activation of the phospholipase C (PLC)/IP3 path, and the negative feedback, by interfering with substrate phosphorylation through Gi/0-coupled mGluRs-II/III. The positive feedback prevails, which may explain the increase in overall rates of release observed during mechanical stimulation (symmetrical in the excitatory and inhibitory directions). The negative feedback may protect the junction from over-activation

GATING AND SELECTIVITY OF CA-PERMEABLE CHANNELS OF SENSORY CELLS

Ca-permeable channels are ubiquitous and are gated by the binding of a ligand to a specific site or by a change in the membrane potential. In the present work, the cGMP gated channels of the vertebrate photoreceptors and the voltage gated Ca-channels of the hair cells of the frog semicircular canal are analyzed. The rod cGMP channel is a symmetric heterotetramer composed of two alfa and two beta subunits, all having binding sites for cGMP, (gating by cGMP <1 msec, Hll coefficient about 1.5-3, Kd about 5-50 microM). The channel is weakly voltage-dependent, and the current-voltage relations (I/V) can be fitted by the Goldman-Hodgkin-Katz equation only if a single ionic species carried the current, but not under bi-ionic conditions. The pore discriminates poorly among monovalent cations, whereas it is very permeable to Ca. However, Ca (and Mg) blocks the pore while permeating through it, thus Ca carries a smaller portion of the current with respect to Na ( about 15% vs. about 85% in physiological conditions) and reduces the channel conductance from about 25-60 pS to about 100 fS. Preliminary results indicate that the Ca permeability is modulated by the intracellular guanosine level. The Ca-channels of the hair cells of the semicircular canals are poorly known from an electrophysiological and a molecular point of view. As many other Ca-channels, the largest current (up to 300 pA) is attained at -20 mV, the reversal potential is smaller (about +20 mV) than the one predicted by the Nernst equation, and the current inactivates to some extent during depolarizing steps (10-280 ms duration). With time, the current becomes progressively smaller and the gating kinetics progressively slower (run-down), up to a point that no more functional channels are present. Previous data suggest that a single L-type Ca-channel exists in the hair celi membrane. This view is challenged by the following evidences: only in few of the cells Ca-free, 4 mM Ba solutions produce a two fold increase in the inward current, and 5 pM Bay K 8644, applied either extra- or intracellularly, increases the Ca-current with small changes in the I-V curve

GATING PROPERTIES OF HAIR CELLS CALCIUM CHANNELS IN THE FROG SEMICIRCULAR CANAL

Three distinct components of Ca current were recently demonstrated in hair cells mechanically isolated from the semicircular canals of the frog, using the whole-cell configuration of the patch-clamp recording technique. The L and R components were isolated on the basis of specific voltage dependencies, the differential sensitivities to drugs and toxins, and the fast run-down observed for one current component but not for the others. The L current increases in size during repetitive stimulation (run-up) and is carried by a non-inactivating, nifedipine-sensitive channel type; the second channel carries an R2, mibefradil-sensitive current; the third channel, which is present in 40% of the cells studied, carries an inactivating R1 current, also sensitive to mibefradil, which runs down first. The inactivation of the R1 component is Ca-dependent (mean time constanti about 6.7 ms in 4 mM external Ca); it is slowed down on decreasing extracellular Ca and disappears upon substituting an equiosmolar amount of Ba for external Ca. To further investigate whether modifications in intracellular Ca concentration ([Ca]i) at the cytoplasmic side of the channel affect the inactivation of the R1 component and in general the gating of all channel types, Ca currents were recorded in the presence of increasing amounts of BAPTA in the patch pipette. BAPTA is indeed expected to clamp [Ca]i more efficiently and rapidly than EGTA. Since K currents heavily contaminate recordings obtained using high concentrations of BAPTA in its commercially available K salt form, in the present experiments custom-synthesized tetracesium salt of BAPTA was employed. It resulted that even the highest concentrations of BAPTA used (50 mM) did not preverit Ca channel inactivation (and therefore [Ca]i rise), although, as expected, the kinetics of R1-channel inactivation was progressively slowed down upon increasing BAPTA concentration (up to tenfold in 25 mM BAPTA). Surprisingly, current activation and deactivation were also slowed down (up to two- and threefold, respectively, in 25 mM BAPTA), suggesting a role of [Ca]i in the kinetics of channel opening and closing

Calcium channels in hair cells of frog semicircular canals

-