Functional characterisation of twelve terpene synthases from actinobacteria.

Fifteen type I terpene synthase homologs from diverse actinobacteria that were selected based on a phylogenetic analysis of more than 4000 amino acid sequences were investigated for their products. For four enzymes with functions not previously reported from bacterial terpene synthases the products were isolated and their structures were elucidated by NMR spectroscopy, resulting in the discovery of the first terpene synthases for (+)-δ-cadinol and (+)-α-cadinene, besides the first two bacterial (-)-amorpha-4,11-diene synthases. For other terpene synthases with functions reported from bacteria before the products were identified by GC-MS. The characterised enzymes include a new epi-isozizaene synthase with monoterpene synthase side activity, a 7-epi-α-eudesmol synthase that also produces hedycaryol and germacrene A, and four more sesquiterpene synthases that produce mixtures of hedycaryol and germacrene A. Three phylogenetically related enzymes were in one case not expressed and in two cases inactive, suggesting pseudogenisation in the respective branch of the phylogenetic tree. Furthermore, a diterpene synthase for allokutznerene and a sesterterpene synthase for sesterviolene were identified.

Clinical and anatomic correlates of objectively measured zonular dehiscence in 427 postmortem pseudophakic eyes.

OBJECTIVE: This study aims to objectively measure the degree of zonular dehiscence in postmortem eyes and to assess for clinical and anatomic correlates. DESIGN: Cross-sectional study. MATERIALS: Four hundred and twenty-seven postmortem pseudophakic human eyes. METHODS: Eyes were obtained from the Lions Gift of Sight Eye Bank. Microscope photographs were taken of the eyes in Miyake-Apple view, and region-of-interest analysis was performed using ImageJ to measure the area, circumference, and diameter of the capsular bag, the ciliary ring, and the capsulorhexis. Clinical and anatomic parameters were assessed using simple linear regression analysis and one-way analysis of variance with post hoc Bonferroni testing. Zonular dehiscence was measured via 2 surrogates: capsule area over ciliary ring area ratio (CCR) and capsule-ciliary ring decentration (CCD). Low CCR and high CCD indicate more zonular dehiscence. RESULTS: CCR was significantly inversely correlated with smaller capsulorhexi (p = 0.012), lower intraocular lens power (p < 0.00001), younger age at death (p = 0.00002), and a longer cataract-to-death time (p = 0.00786). CCR also was significantly lower in glaucomatous cases (p = 0.0291). CCD was significantly correlated with longer cataract-to-death time (p = 0.000864), larger ciliary ring area (p = 0.001), more posterior capsule opacification (p = 0.0234), and higher Soemmering's ring opacity (p = 0.0003). There was also significantly more decentration in male eyes than in female eyes (p = 0.00852). CONCLUSIONS: CCR and CCD are novel measures of zonular dehiscence in postmortem eyes, with many interesting correlates. An enlarged ciliary ring area is possibly associated with zonular dehiscence in pseudophakic eyes and may be a quantifiable surrogate in vivo.

Clinical correlations of extraocular motility limitation pattern in orbital fracture cases: a retrospective cohort study in a level 1 trauma centre.

PURPOSE: Ocular pathology (OP) following orbital fracture can vary vastly in complexity and severity. Extra-ocular motility (EOM) limitations are frequently present in orbital trauma cases, with patterns of duction limitations being symmetrical or asymmetrical. The aim of this study was to identify if there was any association between increased OP following orbital fracture cases based on the pattern of EOM deficits. METHODS: This is a retrospective cohort study of patients with fractured orbits presenting with or without EOM limitations to a level 1 trauma center between August 2015 to January 2018. All pertinent elements of the ophthalmic examination were recorded. Outcome measures: Chi-square analyses assessed for association between symmetrical or asymmetrical EOM limitation and OP. Odds ratios were calculated with 95% confidence interval. RESULTS: 278 orbits with wall fractures were included in this study. A significant correlation between EOM limitation and increased OP following orbital trauma was found (p = 0.000081). Cases with symmetrical and asymmetrical EOM limitation were 7.9 (95%CI: 2.3-27.2) and 5.22 (95%CI: 1.9-13.9) times more likely to have OP than cases with no EOM limitation, respectively. With extraocular muscle entrapment excluded, cases with symmetrical limitations had a significantly higher incidence of OP than cases with asymmetrical limitations (p = 0.0161). CONCLUSIONS: OP is frequently observed in cases of orbital fracture. While any EOM limitations should prompt the clinicians to anticipate OP, intra-ocular injury may be more likely in cases of symmetrical EOM limitation. Future prospective studies are needed to further elucidate the relationship between EOM symmetricity and OP following orbital trauma.

[Acute pyelonephritis]. / Vignette diagnostique de l'étudiantLa pyélonéphrite aiguë.

The present review details the recommendations for the management of acute pyelonephritis in adults. Acute pyelonephritis corresponds to the infection of the upper urinary tract and is particularly common in women between the age of 15 and 65 years. Symptoms usually include fever, chills, flank pain, nausea and vomiting. There are different types of pyelonephritis, and their management may differ upon the patient's comorbidities and the pathogenic agent. The first step in the management of a patient with suspected acute pyelonephritis focuses on the need for hospitalization. Bacteriological samples should always be collected before the initiation of antibiotics. The antibiotic therapy will then be adapted according to the profile of the infecting pathogen.

Cette vignette reprend les recommandations de prise en charge de la pyélonéphrite aiguë (PNA) de l'adulte. La PNA est une infection urinaire haute, particulièrement fréquente chez la femme entre 15 et 65 ans. La symptomatologie typique associe fièvre, frissons, douleur au niveau de la loge rénale, nausées et vomissements. Il existe différents types de PNA dont la prise en charge peut varier selon les comorbidités du patient ou le type de bactéries. Devant toute PNA, la première étape est d'évaluer la nécessité d'une hospitalisation. Les prélèvements à visée bactériologique doivent toujours précéder l'initiation de l'antibiothérapie, dont le spectre sera adapté en fonction de la sensibilité antibiotique du germe mis en évidence.

Effect of Phase Change Material Cooling Vests on Body Thermoregulation and Thermal Comfort of Patients With Paraplegia: A Human Subject Experimental Study.

STUDY DESIGN: Randomized experimental study. OBJECTIVE: Compared to able-bodied people, patients with paraplegia due to thoracic spinal cord injury (SCI) are at an increased risk of heat illnesses during exercise due to impaired thermoregulatory responses. To overcome this limitation, we investigated the performance of three phase change material (PCM) cooling vests of different melting temperatures (Eijsvogels, #49) and coverage area of the trunk. METHODS: Sixteen participants were divided into three groups according to their injury level. All were tested for V20 full vest (20°C Tm, 75% coverage). Mid-thoracic and high-thoracic groups were tested for V14 vest (14°C Tm, 75% coverage). The mid-thoracic group was tested for V20 half vest (20°C Tm, 50% coverage). The participants performed a 30-min arm-crank exercise followed by a recovery period inside a controlled hot climatic chamber. The heart rate, segmental skin (Tskin), and core temperature (Tcore) values were recorded, and subjective questionnaires were taken. RESULTS: Compared to no vest (NV) test, all the vests showed an effective decrease in Tskin values of the trunk. However, the decrease in Tskin was not enough to induce a significant decrease in Tcore in all three groups. Mid-thoracic and low-thoracic groups showed a reduction in the increasing Tcore by the end of the exercise and recovery period. Finally, the level of thermal comfort was enhanced for the three groups. CONCLUSION: The effectiveness of cooling vests for persons with paraplegia is dependent on injury level and thus the ratio of sensate to insensate skin. Future studies necessitate the investigation of the cooling effects of PCM vests at a lower Tm with a larger sample size.

Meningioma genomics: a therapeutic challenge for clinicians.

Meningiomas are amongst the most commonly encountered intracranial tumors. The majority of these tumors arise intracranially, and the remaining incidents occur along the spinal cord. Meningiomas tend to grow gradually, with many tumors arising in inaccessible locations. Such sporadic behavior poses a therapeutic challenge to clinicians, causing incomplete tumor resections that often lead to recurrence. Therefore, ongoing research seeks to find alternative systematic treatments for meningiomas, with gene-based therapeutics of high interest. Subsequently, genetic studies characterized frequent somatic mutations in NF2, TRAF7, KLF4, AKT1, SMO, and PIK3CA. These genes are communally exhibited in 80% of sporadic meningiomas. In addition, other genes such as the DUSP family, the NR4 family, CMKOR, and FOSL2, have been identified as key players in spinal meningiomas. In this perspective, we aim to investigate current genetic-based studies, with the ongoing research mainly focused on the above NF2, TRAF7, KLF4, AKT1, SMO, and PIK3CA genes and their involved pathways. In addition, this perspective can serve as a potential cornerstone for future genetic analyses of meningioma cases.

Leishmaniasis in Cameroon: what is known and is done so far? A protocol for systematic review.

INTRODUCTION: The first visceral and cutaneous leishmaniasis cases were reported in Cameroon since more than six decades. However, interest in the disease has decreased over time and data on its epidemiology across the country are scanty. This systematic review aims to update data on what is known and done so far on leishmaniasis in Cameroon. METHODS AND ANALYSIS: PubMed/MEDLINE, EMBASE and Web of Science will be searched from inception onwards. Grey literature will be identified through Google Scholar searches, dissertation databases and other relevant documents such as report of the National Control Program. Searches will be conducted between January and February 2021. All studies reporting endemicity, distribution, infecting species, vectors and reservoirs will be eligible. The main outcomes will be epidemiological data (infection rate, distribution, infecting species, vectors and animal reservoir), while the secondary outcomes will be the cases management (diagnostic, treatment, reporting, intervention…). Two reviewers will independently screen eligible papers, and potential conflicts will be resolved by involving a third reviewer as an adjudicator. Methodological quality including bias will be appraised using a methodological quality critical appraisal checklist proposed in the Joanna Briggs Institute systematic review methods manual. A narrative synthesis will describe quality and content of the epidemiological evidence. Data on prevalence and vectors will be used to draw thematic maps of the distribution of leishmaniasis in Cameroon. ETHICS AND DISSEMINATION: This study will not require ethical approval as it will be based on already published or unpublished data. The final report of this review will be published in a peer-reviewed journal, and the outcomes will be used (1) as baseline information to design further studies that will help to better refine the epidemiological situation of leishmaniasis in Cameroon, and (2) to inform both programme managers and policy-makers of the situation of leishmaniasis in the country. SYSTEMATIC REVIEW REGISTRATION: This protocol was registered with the International Prospective Register of Systematic reviews (PROSPERO; registration number: CRD42020211864) database.

Hydroxychloroquine lung pharmacokinetics in critically ill patients with COVID-19.

Different dosage regimens of hydroxychloroquine (HCQ) have been used to manage COVID-19 (coronavirus disease 2019) patients, with no information on lung exposure in this population. The aim of our study was to evaluate HCQ concentrations in the lung epithelial lining fluid (ELF) in patients infected with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the virus that causes COVID-19. This was a retrospective, observational, multicentre, pharmacokinetic study of HCQ in critically ill COVID-19 patients. No additional interventions or additional samples compared with standard care of these patients were conducted in our teaching hospital. We included all intubated COVID-19 patients treated with crushed HCQ tablets, regardless of the dosage administered by nasogastric tube. Blood and bronchoalveolar lavage samples (n = 28) were collected from 22 COVID-19 patients and total HCQ concentrations in ELF were estimated. Median (interquartile range) HCQ plasma concentrations were 0.09 (0.06-0.14) mg/L and 0.07 (0.05-0.08) mg/L for 400 mg × 1/day and 200 mg × 3/day, respectively. Median HCQ ELF concentrations were 3.74 (1.10-7.26) mg/L and 1.81 (1.20-7.25) for 400 mg × 1/day and 200 mg × 3/day, respectively. The median ratio of ELF/plasma concentrations was 40.0 (7.3-162.7) and 21.2 (18.4-109.5) for 400 mg × 1/day and 200 mg × 3/day, respectively. ELF exposure is likely to be underestimated from HCQ concentrations in plasma. In clinical practice, low plasma concentrations should not induce an increase in drug dosage because lung exposure may already be high.

Role of connexins in spinal cord injury: An update.

Connexins (Cxs) are a family of transmembrane proteins that assemble into groups of six, forming what is known as a connexon or a hemichannel. Connexins are named based on their molecular weight, e.g. Cx43 is the connexin protein that weighs 43 kDa. Two hemichannels, each from a different cell, can link up end-to-end forming a gap junction. In the nervous system, gap junctions facilitate metabolite exchange between neighboring cells, in addition to electrical and chemical impulses. Many animal studies have been conducted to investigate the role of different types of Cxs in spinal cord injury (SCI) - most notably Cx43 - and the potential for targeting them with inhibitors. In this review, the authors discuss these studies and provide an update on recent connexin specific pharmacological agents that may potentially pave the way for the use of connexin inhibition in the management of SCI in humans, if more translational studies are done.

Gender and neglected tropical disease front-line workers: Data from 16 countries.

BACKGROUND: Delivery of preventive chemotherapy (PC) through mass drug administration (MDA) is used to control or eliminate five of the most common neglected tropical diseases (NTDs). The success of an MDA campaign relies on the ability of drug distributors and their supervisors-the NTD front-line workers-to reach populations at risk of NTDs. In the past, our understanding of the demographics of these workers has been limited, but with increased access to sex-disaggregated data, we begin to explore the implications of gender and sex for the success of NTD front-line workers. METHODOLOGY/PRINCIPAL FINDINGS: We reviewed data collected by USAID-supported NTD projects from national NTD programs from fiscal years (FY) 2012-2017 to assess availability of sex-disaggregated data on the workforce. What we found was sex-disaggregated data on 2,984,908 trainees trained with financial support from the project. We then analyzed the percentage of males and females trained by job category, country, and fiscal year. During FY12, 59% of these data were disaggregated by sex, which increased to nearly 100% by FY15 and was sustained through FY17. In FY17, 43% of trainees were female, with just four countries reporting more females than males trained as drug distributors and three countries reporting more females than males trained as trainers/supervisors. Except for two countries, there were no clear trends over time in changes to the percent of females trained. CONCLUSIONS/SIGNIFICANCE: There has been a rapid increase in availability of sex-disaggregated data, but little increase in recruitment of female workers in countries included in this study. Women continue to be under-represented in the NTD workforce, and while there are often valid reasons for this distribution, we need to test this norm and better understand gender dynamics within NTD programs to increase equity.

3-month prognostic impact of severe acute renal failure under veno-venous ECMO support: Importance of time of onset.

PURPOSE: Veno-venous ECMO is increasingly used for the management of refractory ARDS. In this context, acute kidney injury (AKI) is a major and frequent complication, often associated with poor outcome. We aimed to identify characteristics associated with severe renal failure (Kidney Disease Improving Global Outcome (KDIGO) 3) and its impact on 3-month outcome. METHODS: Between May 2009 and April 2016, 60 adult patients requiring VV-ECMO in our University Hospital were prospectively included. RESULTS: AKI occurrence was frequent (75%; n=45), 51% of patients (n=31) developed KDIGO 3 - predominantly prior to ECMO insertion - and renal replacement therapy was required in 43% (n=26) of cases. KDIGO 3 was associated with a lower mechanical ventilation weaning rate (24% vs 68% for patients with no AKI or other stages of AKI; p<0.001) and a higher 90-day mortality rate (72% vs 32%, p=0.002). Multivariate logistic regression suggested that KDIGO 3 occurrence prior to ECMO insertion, as well as PaCO2>57mmHg and mSOFA>12 were independent risks factors for 90-day mortality. CONCLUSION: KDIGO 3 AKI occurrence is correlated with the severity of patients' clinical condition prior to ECMO insertion and is negatively associated with 90-day survival.

Prevalence and Characteristics of Hepatitis Delta Virus Infection in a Tertiary Hospital Setting in Cameroon.

BACKGROUND/AIMS: Hepatitis B virus (HBV) and hepatitis D virus (HDV) coinfection is associated with more severe liver disease than HBV alone. More knowledge on the epidemiology and clinical impact of HDV-infected individuals is needed in Cameroon.We aimed at determining the frequency of anti-HDV antibody testing in hepatitis B surface antigen (HBsAg) positive patients, the proportion of anti-HDV positivity, and the characteristics of anti-HDV positive compared to anti-HDV negative patients in a tertiary hospital setting in Cameroon. METHODS: A cross-sectional study was conducted. Clinical records of chronic HBV-infected patients attending the gastroenterology unit at the Douala General Hospital from 2010 to 2014 were reviewed. RESULTS: Of 365 files of HBsAg-positive patients defined as chronic HBV infection, 80.5% (294) were tested for anti-HDV antibodies, among whom 10.5% (31/294) were positive. Median aspartate aminotransferase (P < 0.0001), alanine aminotransferase (P < 0.0001), and gamma glutaryl transpeptidase (P < 0.0001) were significantly higher while platelets count (P < 0.002) and prothrombin time (P < 0.0001) were significantly lower in anti-HDV positive compared to anti-HDV negative patients. Liver necroinflammation (P < 0.0001), fibrosis score (P < 0.0001), and decompensated cirrhosis (P < 0.0001) were also significantly associated with anti-HDV positivity. CONCLUSION: The proportion of anti-HDV antibody positivity remains high in this setting and was significantly associated with more severe liver disease compared to those who were anti-HDV negative. More studies are needed to evaluate rates of HDV testing in other centers in Cameroon and the subregion. Preventive strategies for HBV prevention, which also apply to HDV, must still be reinforced by healthcare providers and policy makers.

Neurotrophic Effects of Mu Bie Zi (Momordica cochinchinensis) Seed Elucidated by High-Throughput Screening of Natural Products for NGF Mimetic Effects in PC-12 Cells.

Post-mitotic central nervous system (CNS) neurons have limited capacity for regeneration, creating a challenge in the development of effective therapeutics for spinal cord injury or neurodegenerative diseases. Furthermore, therapeutic use of human neurotrophic agents such as nerve growth factor (NGF) are limited due to hampered transport across the blood brain barrier (BBB) and a large number of peripheral side effects (e.g. neuro-inflammatory pain/tissue degeneration etc.). Therefore, there is a continued need for discovery of small molecule NGF mimetics that can penetrate the BBB and initiate CNS neuronal outgrowth/regeneration. In the current study, we conduct an exploratory high-through-put (HTP) screening of 1144 predominantly natural/herb products (947 natural herbs/plants/spices, 29 polyphenolics and 168 synthetic drugs) for ability to induce neurite outgrowth in PC12 dopaminergic cells grown on rat tail collagen, over 7 days. The data indicate a remarkably rare event-low hit ratio with only 1/1144 tested substances (<111.25 µg/mL) being capable of inducing neurite outgrowth in a dose dependent manner, identified as; Mu Bie Zi, Momordica cochinchinensis seed extract (MCS). To quantify the neurotrophic effects of MCS, 36 images (n = 6) (average of 340 cells per image), were numerically assessed for neurite length, neurite count/cell and min/max neurite length in microns (µm) using Image J software. The data show neurite elongation from 0.07 ± 0.02 µm (controls) to 5.5 ± 0.62 µm (NGF 0.5 µg/mL) and 3.39 ± 0.45 µm (138 µg/mL) in MCS, where the average maximum length per group extended from 3.58 ± 0.42 µm (controls) to 41.93 ± 3.14 µm (NGF) and 40.20 ± 2.72 µm (MCS). Imaging analysis using immunocytochemistry (ICC) confirmed that NGF and MCS had similar influence on 3-D orientation/expression of 160/200 kD neurofilament, tubulin and F-actin. These latent changes were associated with early rise in phosphorylated extracellular signal-regulated kinase (ERK) p-Erk1 (T202/Y204)/p-Erk2 (T185/Y187) at 60 min with mild changes in pAKT peaking at 5 min, and no indication of pMEK involvement. These findings demonstrate a remarkable infrequency of natural products or polyphenolic constituents to exert neurotrophic effects at low concentrations, and elucidate a unique property of MCS extract to do so. Future research will be required to delineate in depth mechanism of action of MCS, constituents responsible and potential for therapeutic application in CNS degenerative disease or injury.

Estimation of glomerular filtration rate to adjust vancomycin dosage in critically ill patients: superiority of the Chronic Kidney Disease Epidemiology Collaboration equation?

The purpose of this study was to determine the best estimate of glomerular filtration rate (GFR) to adjust vancomycin (VAN) dosage in critically ill patients. Seventy-eight adult intensive care unit patients received a 15 mg/kg loading dose of VAN plus a 30 mg/kg/day continuous infusion. Steady-state concentration was measured 48 hours later and the dose was adjusted to obtain a target concentration ranging from 20 to 25 mg/l. GFR was estimated by measured creatinine clearance (CLCR), Cockcroft, Modification of Diet in Renal Disease and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations. The required dose providing the target concentration was 36±17 mg/kg/day. The first dosage had to be increased in 51% of all patients and in 84% of trauma patients (highest GFR), but had to be decreased in 17% of patients. The closest relationship between clearances of vancomycin was observed with CKD-EPI to GFR. The correlation between clearances of vancomycin and measured CLCR was significant but was rather poor with Cockcroft and Modification of Diet in Renal Disease equation. On the Bland and Altman plots, measured CLCR provided a lower bias but a larger confidence interval and a weaker precision than CKD-EPI. For VAN dose adjustments in intensive care unit patients, Cockcroft formula and Modification of Diet in Renal Disease should be used with caution. In clinical practice, the physician does not have at their disposal the patient's measured CLCR when prescribing. The CKD-EPI appears to be the best predictor of clearances of vancomycin for calculation of a therapeutic VAN regimen.

[Patient with acute renal injury presenting dabigatran overdose: Hemodialysis for surgery]. / Surdosage en dabigatran chez un patient en insuffisance rénale : intérêt et limites de l'hémodialyse.

Dabigatran is a direct thrombin inhibitor indicated for stroke and systemic embolism prevention in patients with non-valvular atrial fibrillation. No reversal agent exists, but hemodialysis has been proposed as dabigatran removal method. We report a case of an 80-year-old man presenting hemorrhage with dabigatran overdose caused by obstructive acute renal failure. Before nephrostomy, several hemodialysis sessions were necessary to remove dabigatran probably because of its large volume of distribution.

[Aspirin and its danger: Reye syndrome in young adult]. / L'aspirine et ses dangers: syndrome de Reye chez un adulte jeune.

We describe the case of a 19-year-old male diagnosed with Reye syndrome within the context of viral pericarditis and salicylate ingestion. He presented a fatal brain oedema without liver failure. Brain biopsies obtained during a decompressive craniectomy led to the diagnosis.

Study of agreement of aortic, radial and femoral blood pressures during aortic endografting.

PURPOSE: To estimate the agreement between radial or femoral, and ascending aortic invasive blood pressure values. PATIENTS AND METHODS: Prospective study on 32 patients who underwent an aortic endografting under general anesthesia. After deploying the prosthesis under controlled hypotension, a catheter was introduced in the aorta to measure the staged systolic (SAP), diastolic (DAP) and mean (MAP) arterial pressures, in particular at the level of ascending aorta and femoral artery. RESULTS: No differences were observed between SAP, DAP or MAP measured in the aorta versus femoral or radial arteries. A better agreement was observed between the aortic and femoral MAP (bias of 1mmHg, limits of agreement between: -8.8mmHg and +10.8mmHg) than between the aortic and the radial MAP (bias of 1.7mmHg, limits of agreement between: -14.1mmHg and +17.5mmHg). The comparison between radial and femoral MAP was not satisfying (bias of -4.7mmHg and limits of agreement between -19.1mmHg and +9.7mmHg). CONCLUSION: The femoral MAP is more accurate to predict value of the aortic MAP than the radial MAP in a hypotensive setting. The clinician should be aware of these discrepancies in conditions of hemodynamic impairment to optimize the treatment.

[Use of ECMO (extracorporeal membrane oxygenation) in a traumatic brain injured patient with severe hypoxemia]. / Utilisation d'un ECMO (extracorporeal membrane oxygenation) dans un cas d'hypoxémie réfractaire associée à un traumatisme crânien grave.

Traumatic brain injuries are fairly sensitive to hypoxia. For patient with associated lung and brain traumas, different means used to improve oxygen blood level are poorly described. We report the use of ECMO in a refractory hypoxemia occurred to a multitrauma young patient with neurological lesions.