N-terminal modification of an LAH4-derived peptide increases mRNA delivery in the presence of serum.

The recently developed mRNA-based coronavirus SARS-CoV-2 vaccines highlighted the great therapeutic potential of the mRNA technology. Although the lipid nanoparticles used for the delivery of the mRNA are very efficient, they showed, in some cases, the induction of side effects as well as the production of antibodies directed against particle components. Thus, the development of alternative delivery systems is of great interest in the pursuit of more effective mRNA treatments. In the present work, we evaluated the mRNA transfection capacities of a series of cationic histidine-rich amphipathic peptides derived from LAH4. We found that while the LAH4-A1 peptide was an efficient carrier for mRNA, its activity was highly serum sensitive. Interestingly, modification of this cell penetrating peptide at the N-terminus with two tyrosines or with salicylic acid allowed to confer serum resistance to the carrier.

Contrast media-induced nephropathy in Tunisia: prospective case-control study with cardio-nephrological monitoring.

Introduction: vascular opacification using iodinated contrast media (ICM) is often the primary diagnostic and therapeutic approach. However, the risk of post-injection nephrotoxicity of ICM is significantly higher in patients with underlying nephropathy. This study aimed to determine the incidence of Contrast Media Induced Nephropathy (CMIN) and identify predictive factors for its occurrence in patients from a cardiology department. Methods: our prospective study involved 158 patients who underwent coronary angiography or angioplasty at the cardiology department between December 2017 and May 2018. Two types of ICM were used in our study: Iopromide and Iohexol. All patients received either physiological serum (9‰) or bicarbonate serum (14‰) intravenously for hydration. We defined impaired renal function as an increase in creatinine ranging from 10 to 26 µmol/L, while CMIN was defined as an increase in serum creatinine exceeding 26.5 µmol/L. We investigated the factors associated with CMIN using logistic regression analysis. Results: the mean age of our patients was 60 ± 11 years (range: 29-82), with a predominance of men 63.9% (n=101). The most common cardiovascular risk factors were tobacco (36.1%, n = 57), diabetes (48.1%, n =76), hypertension (55%, n = 87). Pre-procedural creatinine averaged 81.1 ± 47.3 µmol / L with extremes ranging from 39 to 600 µmol / L. The median Mehran risk score was 3.2 (range: 0- 15). The interventional cardiology act consisted of coronary angiography in 86.2% (n=136) of cases, coronary angioplasty in 2.5% (n=4) of cases. We used iohexol and iopromide in 57.6% (n=91) and 42.4% (n=67) of cases, respectively. The overall incidence of CMIN was 9.5% (n=9). The multivariable regression analysis identified 4 risk factors independently linked to the occurrence of CMIN which were Pre-existing renal failure (OR: 6.05, 95%CI [1.23-29.62], p = 0.026), anemia (OR: 0.043, CI [1.03-8.96], p = 0.043), the toxic dose of PC (OR: 4.7, CI [1.28-17.7], p=0.02), and at a Mehran score = 11 (OR: 3.7, CI [0.88-15.6], p=0.036). Conclusion: the most effective approach for CMIN is prevention, which focuses on addressing modifiable risk factors to minimize the risk especially in patients with pre-existing renal failure.

A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Safety and Efficacy of ThymoQuinone Formula (TQF) for Treating Outpatient SARS-CoV-2.

There is an urgent need for an oral drug for the treatment of mild to moderate outpatient SARS-CoV-2. Our preclinical and clinical study's aim was to determine the safety and preliminary efficacy of oral TQ Formula (TQF), in the treatment of outpatient SARS-CoV-2. In a double-blind, placebo-controlled phase 2 trial, we randomly assigned (1:1 ratio) non-hospitalized, adult (>18 years), symptomatic SARS-CoV-2 patients to receive oral TQF or placebo. The primary endpoints were safety and the median time-to-sustained-clinical-response (SCR). SCR was 6 days in the TQF arm vs. 8 days in the placebo arm (p = 0.77), and 5 days in the TQF arm vs. 7.5 days in the placebo arm in the high-risk cohort, HR 1.55 (95% CI: 0.70, 3.43, p = 0.25). No significant difference was found in the rate of AEs (p = 0.16). TQF led to a significantly faster decline in the total symptom burden (TSB) (p < 0.001), and a significant increase in cytotoxic CD8+ (p = 0.042) and helper CD4+ (p = 0.042) central memory T lymphocytes. TQF exhibited an in vitro inhibitory effect on the entry of five SARS-CoV-2 variants. TQF was well-tolerated. While the median time-to-SCR did not reach statistical significance; it was shorter in the TQF arm and preclinical/clinical signals of TQF activity across multiple endpoints were significant. Therefore, a confirmatory study is planned.

Covid-19: Comparisons by Country and Implications for Future Pandemics

BackgroundWe set out in this paper to compare Covid-19 results by country to better understand the factors leading to the differing results found internationally. MethodsWe used publicly available large datasets to explore differences by country for Covid-19 mortality statistics. We continuously challenged our projections with reality and numbers from countries around the world, allowing us to refine our models and better understand the progression of the epidemic. All our predictions and findings were discussed and validated from a clinical viewpoint. ResultsWhile no lockdown resulted in higher mortality, the difference between strict lockdown and lax lockdown was not terribly different and favored lax lockdown. Only one of the top 44 countries had long and strict restrictions. Strict restrictions were more common in the worst performing countries in terms of Covid mortality. The United States had both the largest economic growth coupled with the largest rate of mortality. Those who did well economically, had lower mortality and less pressure on their population. Yet they had less mortality than average and less than their neighbors. ConclusionsCountries with the least restrictions fared best economically. Some of them fared well in terms of mortality, even better than neighboring countries with similar social structures and more severe restrictions. The mortality rates in the USA, however, appeared to suffer from very high obesity rates. Norway and the northern European countries have less strict restrictions from the rest of Europe and had lower mortality rates. COVID-19 mortality was associated with vitamin D status.

Correlation of Fgf23 and Balp with Bone Mineral Density in Hemodialysis Patients.

BACKGROUND: Chronic kidney disease (CKD) is associated with numerous complications such as bone mineral disorder. The aim of our study was to analyze the correlation of bone turnover markers with Bone Mineral Density (BMD) measurements in Tunisian end stage renal diseases (ESRD) patients. METHODS: This study included 100 ESRD Tunisian patients. Their estimated glomerular filtration rate (eGFR) was < 15 mL × min-1 × (1.73 m2)-1, which requires hemodialysis. Bone-specific alkaline phosphatase (BALP) serum concentration was determined with a chemiluminescence immunoassay. Fibroblast Growth Factor 23 (FGF23) serum was assessed by Enzyme-Linked Immunosorbent Assay method. The serum levels of 25-Hydroxyvitamin D (25(OH)D), intact parathyroid hormone (iPTH) and Beta cross-laps (CTX) was measured by Electrochemiluminescence Technology. DEXA (dual-energy x-ray absorptiometry) technique was used to evaluate BMD. RESULTS: We observed a statistically significant negative correlation between BALP levels and total body BMD (r = -0.268; P = 0.015) particularly in femoral neck (FN) (r = -0.219; P = 0.037). BALP concentrations were negatively associated with total BMD especially in FN for patients with BMI < 30, FGF23 concentrations were also negatively correlated with BMD in lumbar spine site (LS) (r = -0.209; P = 0.046). For osteopenic patients we found an inverse correlation between 25(OH)D concentrations and BMD in LS position (r = -0.336; P = 0.038). In men group, we have also found a negative correlation between iPTH and total BMD (r = -0.326; P = 0.015). However we found a positive correlation between calcium expression and BMD in LS site (r = 0.270; P = 0.031). CONCLUSIONS: FGF23 and BALP can predict bone loss in ESRD through their strong correlation with BMD in LS and FN sites respectively.

Management of urolithiasis in living kidney donors.

BACKGROUND: Kidney donors with asymptomatic stones were  previously excluded from the kidney donation list because of a potential increased morbidity risk for both the recipient and the donor. Currently, recent studies tend to consider these risks as overestimated. AIM: The aim of this study was to analyze our experience in the management of urolithiasis in potential donors. METHODS: We conducted a retrospective analysis during the period (2008-2015). We included donors with urilithiasis or a family history of urolithiasis whom had urinary biochemical analysis of urolithiasis. We identified the exact location, size, and anatomy of the kidney bearing the stone were identified. RESULTS: Among 252 potentially proposed living kidney donors (LKD) in two renal transplantation centers, we noted urinary lithiasis in 8 patients (3.17%). The mean age was 40,12±20 years old with a sex-ratio M/F at 0,3. We noted urinary lithiasis on radiographs in one case, on echographs in one case and on computerized tomography kidney angiography in 5 cases. All are not obese and without any medical history. In one case, there was no lithiasis detected but chemical urinary analysis was performed because of family renal stone history. We performed a 24-hours urine test, and examined PH, calcium and oxalate. The urine analysis, showed acidic pH and hypercalciuria in all cases associated to weddelite in 3 cases, hyperoxaluria in all cases. In one case, we noted vitamin D deficiency related hyperparathyroidism. Renal transplantation has been achieved in two cases. After a mean follow up of 11,25 months [range :27-84], no urological complications were noted. CONCLUSION: Urinary lithiasis may occur in proposed living kidney donors and may not contraindicate this donation.

Primary aldosteronism diagnosed in a patient with severe renal disease.

Although initially considered a rarity, primary aldosteronism now is one of the more common causes of secondary hypertension. Based on older data, it was originally estimated that primary aldosteronism accounted for less than 1% of all patients with hypertension. Subsequent data, however, indicated that it may actually occur in as many as 5-15% of patients with hypertension. Here we present a 66-year-old patient with a history of hypertension who was diagnosed with primary hyperaldosteronism at the time he had developed a severe renal failure secondary to a vascular nephropathy. This case report illustrates the difficulties in diagnosis of primary hyperaldosteronism, and highlights the effects of the delay of diagnosis on renal survival and on patient quality of life.

Nephrotoxicity of Ciprofloxacin: Five Cases and a Review of the Literature.

Fluoroquinolones are usually well tolerated with a minimum of serious adverse effects; renal toxicity is uncommon. Apart from the renal side effects of ciprofloxacin, we aimed to highlight the renal impact of a ciprofloxacin overdose, and thus conducted a prospective study in the Department of Nephrology at La Rabta Hospital between 2010 and 2015. The cohort database was continually updated until the inclusion of five patients who were subjected to an overdose and who were initially admitted to the medical intensive care unit and then transferred to our department for acute renal failure (ARF) due to ciprofloxacin ingestion requiring urgent hemodialysis. All patients developed ARF after 12-36 h of ingestion. Renal ultrasound was normal in all cases. Twenty-four-hour proteinuria was present but not significant in one case, while microscopic hematuria was present in one case. Treatment consisted of supportive therapy and extrarenal purification by conventional intermittent hemodialysis. Four patients recovered normal renal function within 3 weeks and the remaining patient eventually had chronic kidney failure.

FGF 23, PTH and vitamin D status in end stage renal disease patients affected by VDR FokI and BsmI variants.

OBJECTIVES: The aim of this study was to evaluate the association between two VDR SNPs FokI and BsmI and mineral status in ESRD patients. DESIGN AND METHODS: Our case-control study included 100 patients with chronic renal failure in ESRD and 149 healthy subjects. We measured the serum Vitamin D levels and the serum intact PTH level by Electrochemiluminescence Technology (cobas E411 analyzer). We evaluated the serum FGF23 levels by indirect ELISA method. The genotyping of two VDR gene variants FokI and BsmI was carried out by PCR-RFLP technique. RESULTS: In our study, the FokI TT genotype was associated with lower risk of ESRD development (OR = 0.176, Padj = 0.039). The difference in PTH and FGF23 levels between cases and controls was statistically significant. The expression of FokI CT genotype in subjects with diabetic nephropathy was associated with a negative correlation between VD and PTH levels (r = -0.620, P = 0.032) and a positive correlation between VD and FGF23 levels (r = 0.967, P = 0.012). A significant differences in VD levels between patients and controls was observed in the presence of FokI TT (P = 0.044) and CT (P = 0.036) genotypes. The expression of FGF23 serum level was significantly elevated in patients than in controls in the presence of the FokI CC and BsmI AG genotypes. CONCLUSIONS: In conclusion, our study shows the existence of an association between VDR FokI, BsmI polymorphisms and mineral status in ESRD patients. The presence of VDR variants affect the protein expression of VD, phosphorus, FGF23 and PTH.

Acute renal cortical necrosis in pregnancy: Clinical course and changing prognosis.

Obstetric cortical renal necrosis is a serious complication that can lead to chronic renal failure and the need for chronic dialysis. The aim of renal cortical necrosis therapy is to restore hemodynamic stability, institute early dialytic therapy, and treat the underlying cause of the disease. Most cases of renal cortical necrosis do not recover a normal renal function despite intensive care. We describe the course of a patient who was diagnosed with acute renal cortical necrosis in pregnancy treated with hemodialysis for three years but then she recovered her renal function.

Clinicopathological findings and outcome of lupus nephritis in Tunisian children: a review of 43 patients.

We report clinical and renal histological data, treatment modalities and outcome of 43 Tunisian children with biopsy-proven lupus nephritis seen over a 23-year period. There were 39 girls and 4 boys with a mean age of 12.5 years at diagnosis of lupus nephritis and followed for a mean period of 77 months. Renal symptoms included urinary abnormalities in all patients, hypertension in 40% of cases, nephrotic syndrome in 60% of cases and renal failure in 25% of cases. Class IV and class III nephritis were observed in 48.8 % and 30.2 % respectively. Corticosteroids were used in all cases, associated to immunosuppressive therapy in 23%. Overall survival was 86% at 5 years and 74% at 10 and 15 years. Renal survival was 83% at 5 and 10 years and 63% at 15 years. Initial renal failure and tubulointerstitial fibrosis were significantly increased risk for the development of end-stage renal disease in our study group. Renal histological findings provide the basis for treatment recommendations. Timely performed renal biopsy is greatly needed to accurately determine the prognosis and to guide treatment in children lupus nephritis.

[Acquired amegacaryocytic thrombocytopenic purpura hiding acute myeloid leukemia]. / Un purpura thrombopénique amégacaryocytaire acquis qui cache une leucémie aigue myéloblastique.

Acquired amegakaryocytic thrombocytopenic purpura is a very rare condition characterized by severe thrombocytopenia linked to the reduction or disappearance of megakaryocytes in the bone marrow. It may be primary idiopathic or secondary to many pathological conditions including hematologic disorders. We report the case of a 24-year-old patient admitted for haemorrhagic syndrome caused by immunological thrombocytopenic purpura. The diagnosis was acquired amegakaryocytosis after the failure of corticotherapy and the performance of myelography. The patient was treated with ciclosporin with rapid progression to acute myeloblastic leukemia. The progression of acquired amegakaryocytosis to acute leukemia is reported but it is generally not so rapid and above all it is preceded by myelodysplastic syndrome or medullary aplasia. This study highlights the importance of a close follow-up of these pathologies with a benign-like appearance.

[Treatment of systemic AL amyloidosis: about 25 cases]. / Traitement des amyloses AL systémiques: à propos de 25 cas.

Primarye systemic AL amyloidosis is a rare hematologic disorder. The majority of the therapeutic guidelines are based on phase II studies or on retrospective comparisons and case series. Our study aimed to describe all the cases of primary AL amyloidosis reported in 2 military hospitals and to make a comparison between standard melphalan-dexamethasone protocol and new agents in first-line treatment of patients with this disease. We conducted a retrospective, descriptive and multicentric study of all patients with AL amyloidosis whose data were collected during the period July 2009-June 2016. Twenty five patients were enrolled in the study (12 patients treated with melphalan-dexamethasone and 13 with bortezomib-based protocol or lenalidomide-based protocol). There was no significant difference in the epidemiological, clinical and prognostic features between the 2 groups. After a median follow up of 40 months, median overall survival was 54 months in the melphalan-dexamethasone-treated group and 60 months in the new therapies-treated group (P = 0.98). Progression-free survival was 18 months in the standard treatment group vs 11 months in the 2nd group (p = 0.08). In our small case series we haven't found a superiority of the new therapies compared to the standard protocol. This result should be confirmed by a true prospective study, mainly because of the cost of these new molecules that are not always accessible, especially in developing countries.

A new balancing three level three dimensional space vector modulation strategy for three level neutral point clamped four leg inverter based shunt active power filter controlling by nonlinear back stepping controllers.

In this paper is proposed a new balancing three-level three dimensional space vector modulation (B3L-3DSVM) strategy which uses a redundant voltage vectors to realize precise control and high-performance for a three phase three-level four-leg neutral point clamped (NPC) inverter based Shunt Active Power Filter (SAPF) for eliminate the source currents harmonics, reduce the magnitude of neutral wire current (eliminate the zero-sequence current produced by single-phase nonlinear loads), and to compensate the reactive power in the three-phase four-wire electrical networks. This strategy is proposed in order to gate switching pulses generation, dc bus voltage capacitors balancing (conserve equal voltage of the two dc bus capacitors), and to switching frequency reduced and fixed of inverter switches in same times. A Nonlinear Back Stepping Controllers (NBSC) are used for regulated the dc bus voltage capacitors and the SAPF injected currents to robustness, stabilizing the system and to improve the response and to eliminate the overshoot and undershoot of traditional PI (Proportional-Integral). Conventional three-level three dimensional space vector modulation (C3L-3DSVM) and B3L-3DSVM are calculated and compared in terms of error between the two dc bus voltage capacitors, SAPF output voltages and THDv, THDi of source currents, magnitude of source neutral wire current, and the reactive power compensation under unbalanced single phase nonlinear loads. The success, robustness, and the effectiveness of the proposed control strategies are demonstrated through simulation using Sim Power Systems and S-Function of MATLAB/SIMULINK.

Identification and regulation of Sprouty1, a negative inhibitor of the ERK cascade, in the human heart.

We screened a compendium of gene profiles from 19 paired human heart samples harvested at the time of implant and explant of a left ventricular assist device (LVAD) for novel genes regulating the Ras/MEK/ERK cascade. From this analysis we identified Sprouty1, an evolutionally conserved gene that acts as an intrinsic inhibitor of the Ras/MEK/ERK pathway. Sprouty1 mRNA and protein were significantly upregulated in the heart in response to mechanical unloading with a LVAD. The upregulation of Sprouty1 in the heart following mechanical unloading was accompanied by a significant decrease in phosphorylated ERK1/2. Gain of function experiments demonstrated that upregulation of Sprouty1 in isolated cardiac myocytes led to a significant decrease and altered kinetics of ERK1/2 phosphorylation. Immunohistochemistry of human hearts revealed that Sprouty1 was also expressed in the microvasculature. Upregulation of Sprouty1 in endothelial cells led to a significant decrease in VEGF-induced endothelial cell proliferation. To our knowledge, these findings are the first to define Sprouty expression in the heart and suggest that Sprouty1 may serve as an intrinsic mediator governing ventricular remodeling through a coordinated coupling of both myocyte and vascular alterations in response to mechanical load.