The effect of levocarnitine supplementation on dialysis-related hypotension: A systematic review, meta-analysis, and trial sequential analysis.

BACKGROUND: Dialysis patients have been shown to have low serum carnitine due to poor nutrition, deprivation of endogenous synthesis from kidneys, and removal by hemodialysis. Carnitine deficiency leads to impaired cardiac function and dialysis-related hypotension which are associated with increased mortality. Supplementing with levocarnitine among hemodialysis patients may diminish incidence of intradialytic hypotension. Data on this topic, however, lacks consensus. METHODS: We conducted electronic searches in PubMed, Embase and Cochrane Central Register of Controlled Trials from January 1960 to 19th November 2021 to identify randomized controlled studies (RCTs), which examined the effects of oral or intravenous levocarnitine (L-carnitine) on dialysis-related hypotension among hemodialysis patients. The secondary outcome was muscle cramps. Study results were pooled and analyzed utilizing the random-effects model. Trial sequential analysis (TSA) was performed to assess the strength of current evidence. RESULTS: Eight trials with 224 participants were included in our meta-analysis. Compared to control group, L-carnitine reduced the incidence of dialysis-related hypotension among hemodialysis patients (pooled OR = 0.26, 95% CI [0.10-0.72], p = 0.01, I2 = 76.0%). TSA demonstrated that the evidence was sufficient to conclude the finding. Five studies with 147 participants showed a reduction in the incidence of muscle cramps with L-carnitine group (pooled OR = 0.22, 95% CI [0.06-0.81], p = 0.02, I2 = 74.7%). However, TSA suggested that further high-quality studies were required. Subgroup analysis on the route of supplementation revealed that only oral but not intravenous L-carnitine significantly reduced dialysis-related hypotension. Regarding dose and duration of L-carnitine supplementation, the dose > 4,200 mg/week and duration of at least 12 weeks appeared to prevent dialysis-related hypotension. CONCLUSION: Supplementing oral L-carnitine for at least three months above 4,200 mg/week helps prevent dialysis-related hypotension. L-carnitine supplementation may ameliorate muscle cramps. Further well-powered studies are required to conclude this benefit.

The association between olfactory and gustatory dysfunction and chronic kidney disease.

BACKGROUND: Olfactory and gustatory changes may contribute to poor appetite and food aversion in chronic kidney disease (CKD), though the prevalence of olfactory and gustatory dysfunction is not known in the CKD population. METHODS: We conducted a cross-sectional study among 3527 US adults aged ≥40 years old in the National Health and Nutrition Examination Survey (NHANES) between 2013 and 2014. We measured the prevalence of olfactory and gustatory dysfunction among patients with CKD defined as eGFR < 60 ml/min/1.73m2 using the "scratch and sniff" NHANES Pocket Smell Test and quinine whole-mouth test. We also examined the association between CKD and olfactory/gustatory dysfunction, and nutritional markers. RESULTS: The prevalence of olfactory dysfunction was 30% among CKD and 15% among non-CKD (p < 0.001). The prevalence of gustatory dysfunction was 13% among CKD and 17% among non-CKD (p = 0.10). After adjusting for confounders, CKD was significantly associated with olfactory dysfunction (OR = 1.47, 95% CI [1.07, 2.01]; p = 0.02) but not gustatory dysfunction (OR = 1.76, 95%CI [0.99, 3.11]; p = 0.05). Among the CKD population, the odds of olfactory dysfunction was 72% higher for every 10 kg decrease in grip strength (OR = 1.72, 95% CI [1.39, 2.13]; adjusted p = 0.005). CONCLUSION: CKD was associated with higher odds of olfactory but not gustatory dysfunction. Olfactory dysfunction was associated with lower grip strength among those with CKD. Screening and early intervening on olfactory dysfunction among CKD may preserve muscle strength and improve nutritional status in this vulnerable population.

Author Correction: Pre-eclampsia: pathogenesis, novel diagnostics and therapies.

In the version of this article originally published online, the date when Francois Mauriceau published one of the earliest descriptions of pre-eclampsia was incorrectly stated to be 1637, which is actually his year of birth. The work was published in 1668. This error has been corrected in the PDF and HTML versions of the article.

Pre-eclampsia: pathogenesis, novel diagnostics and therapies.

Pre-eclampsia is a complication of pregnancy that is associated with substantial maternal and fetal morbidity and mortality. The disease presents with new-onset hypertension and often proteinuria in the mother, which can progress to multi-organ dysfunction, including hepatic, renal and cerebral disease, if the fetus and placenta are not delivered. Maternal endothelial dysfunction due to circulating factors of fetal origin from the placenta is a hallmark of pre-eclampsia. Risk factors for the disease include maternal comorbidities, such as chronic kidney disease, hypertension and obesity; a family history of pre-eclampsia, nulliparity or multiple pregnancies; and previous pre-eclampsia or intrauterine fetal growth restriction. In the past decade, the discovery and characterization of novel antiangiogenic pathways have been particularly impactful both in increasing understanding of the disease pathophysiology and in directing predictive and therapeutic efforts. In this Review, we discuss the pathogenic role of antiangiogenic proteins released by the placenta in the development of pre-eclampsia and review novel therapeutic strategies directed at restoring the angiogenic imbalance observed during pre-eclampsia. We also highlight other notable advances in the field, including the identification of long-term maternal and fetal risks conferred by pre-eclampsia.

Altered expression of telomere-associated genes in leukocytes among BRCA1 and BRCA2 carriers.

Telomere dysfunction resulting from telomere shortening and deregulation of shelterin components has been linked to the pathogenesis of age-related disorders, including cancer. Recent evidence suggests that BRCA1/2 (BRCA1 and BRCA2) tumor suppressor gene products play an important role in telomere maintenance. Although telomere shortening has been reported in BRCA1/2 carriers, the direct effects of BRCA1/2 haploinsufficiency on telomere maintenance and predisposition to cancer development are not completely understood. In this study, we assessed the telomere-associated and telomere-proximal gene expression profiles in peripheral blood leukocytes from patients with a BRCA1 or BRCA2 mutation, compared to samples from sporadic and familial breast cancer individuals. We found that 25 genes, including TINF2 gene (a negative regulator of telomere length), were significantly differentially expressed in BRCA1 carriers. Leukocyte telomere length analysis revealed that BRCA1/2 carriers had relatively shorter telomeres than healthy controls. Further, affected BRCA1/2 carriers were well differentiated from unaffected BRCA1/2 carriers by the expression of telomere-proximal genes. Our results link BRCA1/2 haploinsufficiency to changes in telomere length, telomere-associated as well as telomere-proximal gene expression. Thus, this work supports the effect of BRCA1/2 haploinsufficiency in the biology underlying telomere dysfunction in cancer development. Future studies evaluating these findings will require a large study population.

Preeclampsia: Updates in Pathogenesis, Definitions, and Guidelines.

Preeclampsia is becoming an increasingly common diagnosis in the developed world and remains a high cause of maternal and fetal morbidity and mortality in the developing world. Delay in childbearing in the developed world feeds into the risk factors associated with preeclampsia, which include older maternal age, obesity, and/or vascular diseases. Inadequate prenatal care partially explains the persistent high prevalence in the developing world. In this review, we begin by presenting the most recent concepts in the pathogenesis of preeclampsia. Upstream triggers of the well described angiogenic pathways, such as the heme oxygenase and hydrogen sulfide pathways, as well as the roles of autoantibodies, misfolded proteins, nitric oxide, and oxidative stress will be described. We also detail updated definitions, classification schema, and treatment targets of hypertensive disorders of pregnancy put forth by obstetric and hypertensive societies throughout the world. The shift has been made to view preeclampsia as a systemic disease with widespread endothelial damage and the potential to affect future cardiovascular diseases rather than a self-limited occurrence. At the very least, we now know that preeclampsia does not end with delivery of the placenta. We conclude by summarizing the latest strategies for prevention and treatment of preeclampsia. A better understanding of this entity will help in the care of at-risk women before delivery and for decades after.

A Peptide mimicking a region in proliferating cell nuclear antigen specific to key protein interactions is cytotoxic to breast cancer.

Proliferating cell nuclear antigen (PCNA) is a highly conserved protein necessary for proper component loading during the DNA replication and repair process. Proteins make a connection within the interdomain connector loop of PCNA, and much of the regulation is a result of the inherent competition for this docking site. If this target region of PCNA is modified, the DNA replication and repair process in cancer cells is potentially altered. Exploitation of this cancer-associated region has implications for targeted breast cancer therapy. In the present communication, we characterize a novel peptide (caPeptide) that has been synthesized to mimic the sequence identified as critical to the cancer-associated isoform of PCNA. This peptide is delivered into cells using a nine-arginine linking mechanism, and the resulting peptide (R9-cc-caPeptide) exhibits cytotoxicity in a triple-negative breast cancer cell line, MDA-MB-436, while having less of an effect on the normal counterparts (MCF10A and primary breast epithelial cells). The novel peptide was then evaluated for cytotoxicity using various in vivo techniques, including ATP activity assays, flow cytometry, and clonogenetic assays. This cytotoxicity has been observed in other breast cancer cell lines (MCF7 and HCC1937) and other forms of cancer (pancreatic and lymphoma). R9-cc-caPeptide has also been shown to block the association of PCNA with chromatin. Alanine scanning of the peptide sequence, combined with preliminary in silico modeling, gives insight to the disruptive ability and the molecular mechanism of action of the therapeutic peptide in vivo.

Emerging new biomarkers of preeclampsia.

Preeclampsia continues to plague some of the most vulnerable women and fetuses. It is surprisingly prevalent in developing and developed nations. According to the World Health Organization, hypertension during pregnancy is a leading cause of maternal mortality in industrialized countries at 16% and up to 25% in developing countries. As the pathogenesis of this disease is being unraveled, we are afforded new opportunities to develop novel biomarkers for early identification and prevention of disease. The angiogenic markers including soluble fms-like tyrosine kinase 1, placental growth factor, and soluble endoglin have demonstrated to be the most promising, perhaps in conjunction with traditional markers such as plasma protein-13 and uterine artery Doppler studies. There is also increasing evidence that the podocyte is shed during the course of preeclampsia, which may be useful for diagnosis. Systems biology approaches to biomarker discovery such as proteomics and metabolomics are also gaining more attention and will most certainly open new avenues of research. In this review, we present the best studied biomarkers of preeclampsia to date.