Venetoclax pharmacokinetics in participants with end-stage renal disease undergoing haemodialysis.

AIMS: Renal insufficiency is a common comorbidity in patients with haematological malignancies. This study aimed to assess how end-stage renal disease (ESRD) might affect the pharmacokinetics of venetoclax, a Bcl-2 inhibitor, in participants with ESRD undergoing haemodialysis. METHODS: Venetoclax was administered as a single 100-mg dose to 6 female participants with ESRD (estimated glomerular filtration rate <15 mL/min) both prior to haemodialysis and between haemodialysis days and 7 healthy female participants with normal renal function (estimated glomerular filtration rate >90 mL/min). Intensive pharmacokinetic and protein binding samples were collected from all participants. Arterial and venous samples were collected from ESRD participants during haemodialysis to assess the effect of haemodialysis on venetoclax pharmacokinetics. Pharmacokinetic parameters were estimated using noncompartmental methods. RESULTS: There was no difference in plasma venetoclax concentrations between arterial and venous samples, suggesting that haemodialysis did not affect the pharmacokinetics of venetoclax. The fraction unbound (fu ) of venetoclax was ~2-fold higher for participants with ESRD compared to participants with normal renal function. The unbound maximum plasma concentration and area under the plasma concentration-time curve from time 0 to 48 h were comparable between ESRD and normal function groups. The mean half-life ranged from 10.4 to 12.2 h across groups, demonstrating that ESRD did not affect the half-life of venetoclax. No new safety signals were observed during this study. CONCLUSION: ESRD and dialysis do not alter unbound venetoclax plasma concentrations. No pharmacokinetics driven dose adjustment is needed for patients with renal insufficiency.

The multifaceted genus Acinetobacter: from infection to bioremediation.

Acinetobacter is a vast bacterial genus comprising of numerous species with variable characteristics. The enigma associated with clinical strains that have been implicated in many nosocomial outbreaks has prompted the need for continuous research on pathogens like Acinetobacter baumannii and members of the ACB complex. However, numerous species of Acinetobacter genus possess diverse metabolic capabilities and have the potential for a plethora of industrial and environment-based applications. Therefore, a comprehensive review on the entire genus, including many under-represented topics, would contribute extensive information to the scientific community indulged in Acinetobacter research. The current review is a unique compilation that attempts to provide the latest update on the genus covering its clinical as well as ecological aspects. Moreover, it is the first study of its kind that focuses on the entire genus and elaborates on the phylogenetic relationships, pathogenesis, and virulence mechanisms, followed by emerging biotechnological applications with future directions.

Codon usage behavior distinguishes pathogenic Clostridium species from the non-pathogenic species.

Genus Clostridium is of the largest genus in class Clostridia. It is comprised of spore-forming, anaerobic, gram-positive organisms. The members of this genus include human pathogens to free-living nitrogen fixing bacteria. In the present study, we have performed a comparison of the choice of preferred codons, codon usage patterns, dinucleotide and amino acid usage pattern of 76 species of Genus Clostridium. We found the pathogenic clostridium species to have smaller AT-rich genomes as compared to opportunistic and non-pathogenic clostridium species. The choice of preferred and optimal codons was also influenced by genomic GC/AT content of the respective clostridium species. The pathogenic clostridium species displayed a strict bias in the codon usage, employing 35 of the 61 codons encoding for 20 amino acids. Comparison of amino acid usage revealed an increased usage of amino acids with lower biosynthetic cost by pathogenic clostridium species as compared to opportunistic and non-pathogenic clostridium species. Smaller genome, strict codon usage bias and amino acid usage lead to lower protein energetic cost for the clostridial pathogens. Overall, we found the pathogenic members of genus Clostridium to prefer small, AT-rich codons to reduce biosynthetic costs and match the cellular environment of its AT-rich human host.

Evolution of codon and amino acid usage in bacterial protein toxins.

Toxin proteins are secreted by most pathogens as an integral part of pathogenic mechanism(s). The toxins act by either damaging the host cell membrane (for example, pore-forming toxins and RTX toxins) or by modulation of important cellular pathways (for example, inhibition of protein translation by ribosome-inactivating proteins). The mechanism of action of these toxins provides the pathogen with strategies for adaptation in the unfavorable host environment. Though, secreted by different pathogenic species, the protein toxins seem to share common features that allow the protein to bind to specific molecules and enter the host cell. Earlier studies have suggested role of several events like horizontal gene transfer and insertion-deletion mutations in evolution of protein toxins. The present study involving 125 bacterial protein toxins secreted by 49 pathogenic bacteria focuses on the role and constraints of the bacterial genome on evolution of codon and amino acid usage in respective bacterial protein toxins. We compare the nucleotide composition, codon and dinucleotide usage trends between different classes of bacterial protein toxins and between individual toxins and the parent bacterial genome expressing the toxin(s).

Expanding role of ribosome-inactivating proteins: From toxins to therapeutics.

Ribosome-inactivating proteins (RIPs) are toxic proteins with N-glycosidase activity. RIPs exert their action by removing a specific purine from 28S rRNA, thereby, irreversibly inhibiting the process of protein synthesis. RIPs can target both prokaryotic and eukaryotic cells. In bacteria, the production of RIPs aid in the process of pathogenesis whereas, in plants, the production of these toxins has been attributed to bolster defense against insects, viral, bacterial and fungal pathogens. In recent years, RIPs have been engineered to target a particular cell type, this has fueled various experiments testing the potential role of RIPs in many biomedical applications like anti-viral and anti-tumor therapies in animals as well as anti-pest agents in engineered plants. In this review, we present a comprehensive study of various RIPs, their mode of action, their significance in various fields involving plants and animals. Their potential as treatment options for plant infections and animal diseases is also discussed.

The effect of norepinephrine on clinical and hemodynamic parameters in neonates with shock: a retrospective cohort study.

There is limited data on the cardiovascular effects of norepinephrine (NE) in neonates. Our objective was to describe the clinical responses in neonates treated with NE infusion. This retrospective cohort study included neonates with evidence of shock and those who received NE infusion. PRIMARY OUTCOME: changes in mean blood pressure (MBP) at 6, 12, and 24 h post-initiation of NE. SECONDARY OUTCOMES: Changes in (i) diastolic BP, systolic BP, and vasoactive inotrope score (VIS) at 6, 12, and 24 h, (ii) urine output after initiation of NE ii) pH, lactate, fraction of inspired oxygen (FiO2) after initiation of NE, and (iv) adverse outcomes. Fifty infants received NE with mean (SD) gestational age of 34.3 (4.3) weeks and a mean birth weight of 2215 (911) g. Treatment began at a median age of 36 (IQR: 15.2, 67.2) hours of life and lasted 30.5 (IQR: 12.7, 58) hours. MBP improved from 34.4 mm Hg (SD: 6.6) at baseline to 39.4 mm Hg (SD: 10.5, p < 0.001) at 6 h, to 39.6 mm Hg (SD: 12.1, p = 0.002) at 12 h and to 40.4 mm Hg (SD: 15.5, p = 0.004) at 24 h after NE initiation. Vasoactive inotrope score declined from 30 (20, 32) to 10 (4, 30; p < 0.001) at 24 h. Urine output improved within 24 h [1.5 ml/kg/h (0.5, 2.3) at baseline to 3 (1.9, 4.3) at 24 h; p = 0.04]. Oxygen requirement decreased after NE initiation. CONCLUSION: The use of NE appears to be effective and safe for treating systemic hypotension in neonates. TRIAL REGISTRATION: Being a retrospective study, trial registration was not considered. WHAT IS KNOWN: • Dopamine has traditionally been used as the initial agent for treatment of neonatal hypotension. • Norepinephrine has recently been recommended as the first-choice vasopressor agent to correct hypotension in adults and pediatric patients, with insufficient data on the cardiovascular effects of NE in neonates What is new: • Mean blood pressure improved significantly at 6, 12, and 24 h with reduction in vasoactive infusion score at 12 and 24 h after norepinephrine infusion. • No significant change in heart rate or abnormal abdominal adverse effects noted in this study.

Graves' disease patients with iron deficiency anemia: serologic evidence of co-existent autoimmune gastritis.

BACKGROUND: Graves' disease (GD) has been associated with iron deficiency anemia (IDA). Atrophic gastritis leads to IDA and has been associated with autoimmune thyroid disease. This study prospectively determined the prevalence of atrophic gastritis markers and the relationship between these markers and markers of IDA in GD subjects. METHODS: Newly diagnosed GD patients (90) and controls (41) were studied. Of the newly diagnosed GD patients, 65 were consecutively enrolled and identified with GD irrespective of anemia, 25 had GD and IDA. Thyroid function, hematologic indices, and atrophic gastritis markers [parietal-cell antibodies (PCab), Helicobacter pylori antibodies (H. pylori ab), mean serum gastrin levels] were examined. RESULTS: GD patients presenting with IDA were twice as likely (64% vs. 32%, P=0.049) to harbor PCabs when compared to all other GD subjects. Unselected GD subjects (n=65) had significantly higher PCab (37% vs. 7%, P<0.001) compared to controls. Gastrin levels were significantly elevated in all GD subjects compared to controls (105 vs. 39 pg/ml, P<0.0001). This difference was magnified in PCab+ subjects (202 vs. 64 pg/ml, P=0.003). In all GD subjects, PCabs were associated with increased gastrin levels (202 vs. 75 pg/ml, P=0.0004) and lower ferritin levels (52 vs. 95, P=0.05). In GD anemic subjects, PCabs were associated with lower mean corpuscular volume (75 vs. 81, P=0.001). Gastrin levels correlated inversely with ferritin levels in all GD subjects and positively with TIBC in GD anemic subjects. CONCLUSIONS: A significant subset of patients presenting with GD may suffer from IDA due to concurrent autoimmune atrophic gastritis.

Base Composition and Host Adaptation of the SARS-CoV-2: Insight From the Codon Usage Perspective.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been spreading rapidly all over the world and has raised grave concern globally. The present research aims to conduct a robust base compositional analysis of SARS-CoV-2 to reveal adaptive intricacies to the human host. Multivariate statistical analysis revealed a complex interplay of various factors including compositional constraint, natural selection, length of viral coding sequences, hydropathicity, and aromaticity of the viral gene products that are operational to codon usage patterns, with compositional bias being the most crucial determinant. UpG and CpA dinucleotides were found to be highly preferred whereas, CpG dinucleotide was mostly avoided in SARS-CoV-2, a pattern consistent with the human host. Strict avoidance of the CpG dinucleotide might be attributed to a strategy for evading a human immune response. A lower degree of adaptation of SARS-CoV-2 to the human host, compared to Middle East respiratory syndrome (MERS) coronavirus and SARS-CoV, might be indicative of its milder clinical severity and progression contrasted to SARS and MERS. Similar patterns of enhanced adaptation between viral isolates from intermediate and human hosts, contrasted with those isolated from the natural bat reservoir, signifies an indispensable role of the intermediate host in transmission dynamics and spillover events of the virus to human populations. The information regarding avoided codon pairs in SARS-CoV-2, as conferred by the present analysis, promises to be useful for the design of vaccines employing codon pair deoptimization based synthetic attenuated virus engineering.

Surfactant dysfunction disorder masquerading as meconium aspiration syndrome and persistent pulmonary hypertension of the newborn.

About 10% of term neonates present with respiratory distress at birth. The most common aetiologies include transient tachypnoea of the newborn, pneumonia and meconium aspiration syndrome (MAS). Hyaline membrane disease (HMD) in a term infant occurs either as primary HMD, secondary surfactant deficiency or congenital surfactant dysfunction. A detailed history supported with appropriate radiological and laboratory investigations can help a clinician reach a diagnosis. We report a case of surfactant dysfunction disorder which presented as severe MAS and persistent pulmonary hypertension of the newborn. In the infant described, the significant history of a sibling death with severe neonatal respiratory disease led us to think of diffuse developmental lung diseases especially surfactant dysfunction syndromes. Exome sequencing detected a heterozygous missense variation in exon 21 of the ATP binding cassette protein member 3 (ABCA3) gene. Based on the clinical picture supported with the exome sequencing, a diagnosis of surfactant dysfunction disorder (ABCA3 deficiency) was confirmed.

Codon usage signatures in the genus Cryptococcus: A complex interplay of gene expression, translational selection and compositional bias.

The fungal genus Cryptococcus comprises of several diverse species. The pathogens forming Cryptococcus neoformans/ Cryptococcus gatti species complex are of immense clinical significance owing to the high frequency of infections and deaths globally. Three closely related non-pathogenic species namely, Cryptococcus amylolentus, Cryptococcus wingfieldii and Cryptococcus depauperatus are the non-pathogenic ancestral species from which pathogenic lineages have diverged. In the current study, a comprehensive analysis of factors influencing the codon and amino acid usage bias in six pathogenic and three non-pathogenic species was performed. Our results revealed that though compositional bias played a crucial role, translational selection and gene expression were the key determinants of codon usage variations. Analysis of relative dinucleotide abundance and codon context signatures revealed strict avoidance of TpA dinucleotide across genomes. Multivariate statistical analysis based on codon usage data resulted in discrete clustering of pathogens and non-pathogens which correlated with previous reports on their phylogenetic distribution.

Diverse species in the genus Cryptococcus: Pathogens and their non-pathogenic ancestors.

The genus Cryptococcus comprises of more than 30 species. It consists of clinically significant pathogenic Cryptococcus neoformans/Cryptococcus gattii species complex comprising of a minimum of seven species. These pathogens cost more than 200,000 lives annually by causing cryptococcal meningoencephalitis. The evolution of the pathogenic species from closely related non-pathogenic species of the Cryptococcus amylolentus complex is of particular importance and several advances have been made to understand their phylogenetic and genomic relationships. The current review briefly describes the sexual reproduction process followed by an individual description of the members focusing on their key attributes and virulence mechanisms of the pathogenic species. A special section on phylogenetic studies is aimed at understanding the evolutionary divergence of pathogens from non-pathogens. Recent findings from our group pertaining to parameters affecting codon usage bias in six pathogenic and three non-pathogenic ancestral species and their corroboration with existing phylogenetic reports are also included in the current review.

Preoperative Cognitive Abnormality, Intraoperative Electroencephalogram Suppression, and Postoperative Delirium: A Mediation Analysis.

BACKGROUND: Postoperative delirium is a common complication that hinders recovery after surgery. Intraoperative electroencephalogram suppression has been linked to postoperative delirium, but it is unknown if this relationship is causal or if electroencephalogram suppression is merely a marker of underlying cognitive abnormalities. The hypothesis of this study was that intraoperative electroencephalogram suppression mediates a nonzero portion of the effect between preoperative abnormal cognition and postoperative delirium. METHODS: This is a prespecified secondary analysis of the Electroencephalography Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES) randomized trial, which enrolled patients age 60 yr or older undergoing surgery with general anesthesia at a single academic medical center between January 2015 and May 2018. Patients were randomized to electroencephalogram-guided anesthesia or usual care. Preoperative abnormal cognition was defined as a composite of previous delirium, Short Blessed Test cognitive score greater than 4 points, or Eight Item Interview to Differentiate Aging and Dementia score greater than 1 point. Duration of intraoperative electroencephalogram suppression was defined as number of minutes with suppression ratio greater than 1%. Postoperative delirium was detected via Confusion Assessment Method or chart review on postoperative days 1 to 5. RESULTS: Among 1,113 patients, 430 patients showed evidence of preoperative abnormal cognition. These patients had an increased incidence of postoperative delirium (151 of 430 [35%] vs.123 of 683 [18%], P < 0.001). Of this 17.2% total effect size (99.5% CI, 9.3 to 25.1%), an absolute 2.4% (99.5% CI, 0.6 to 4.8%) was an indirect effect mediated by electroencephalogram suppression, while an absolute 14.8% (99.5% CI, 7.2 to 22.5%) was a direct effect of preoperative abnormal cognition. Randomization to electroencephalogram-guided anesthesia did not change the mediated effect size (P = 0.078 for moderation). CONCLUSIONS: A small portion of the total effect of preoperative abnormal cognition on postoperative delirium was mediated by electroencephalogram suppression. Study precision was too low to determine if the intervention changed the mediated effect.

Vibrio cholerae Porin OmpU Induces Caspase-independent Programmed Cell Death upon Translocation to the Host Cell Mitochondria.

Porins, a major class of outer membrane proteins in Gram-negative bacteria, primarily act as transport channels. OmpU is one of the major porins of human pathogen, Vibrio cholerae. In the present study, we show that V. cholerae OmpU has the ability to induce target cell death. Although OmpU-mediated cell death shows some characteristics of apoptosis, such as flipping of phosphatidylserine in the membrane as well as cell size shrinkage and increased cell granularity, it does not show the caspase-3 activation and DNA laddering pattern typical of apoptotic cells. Increased release of lactate dehydrogenase in OmpU-treated cells indicates that the OmpU-mediated cell death also has characteristics of necrosis. Further, we show that the mechanism of OmpU-mediated cell death involves major mitochondrial changes in the target cells. We observe that OmpU treatment leads to the disruption of mitochondrial membrane potential, resulting in the release of cytochrome c and apoptosis-inducing factor (AIF). AIF translocates to the host cell nucleus, implying that it has a crucial role in OmpU-mediated cell death. Finally, we observe that OmpU translocates to the target cell mitochondria, where it directly initiates mitochondrial changes leading to mitochondrial membrane permeability transition and AIF release. Partial blocking of AIF release by cyclosporine A in OmpU-treated cells further suggests that OmpU may be inducing the opening of the mitochondrial permeability transition pore. All of these results lead us to the conclusion that OmpU induces cell death in target cells in a programmed manner in which mitochondria play a central role.

A novel mutation in thyrotropin (thyroid-stimulating hormone) gene in congenital hypothyroidism.

A 3-year-old girl had global developmental delay with dysmorphic facies. In addition, she was found to have congenital hypothyroidism. In view of the associated dysmorphism, a karyotype analysis was done. It revealed a novel translocation mutation, 46XX t(1;14) (p22;q32). The association of this mutation with congenital hypothyroidism has been postulated in our case report. To the best of our knowledge, this mutation has never been described before in cases of congenital hypothyroidism.

Refolding and functional assembly of the Vibrio cholerae porin OmpU recombinantly expressed in the cytoplasm of Escherichia coli.

OmpU is one of the major outer membrane porins of Vibrio cholerae. OmpU has been biochemically characterized previously for its 'porin'-property. However, previous studies have used the OmpU protein extracted from the bacterial outer membrane envelope fractions. Such method of isolation imposes limitations on the availability of the protein reagent, and also enhances the possibility of the OmpU preparation being contaminated with lipid molecules of bacterial outer membrane origin, especially lipopolysaccharides (LPS). Here we report a strategy of purifying the V. cholerae OmpU protein recombinantly overexpressed in heterologous protein expression system in Escherichia coli, without its being incorporated into the bacterial membrane fraction. In our strategy, the majority of the protein was expressed as insoluble inclusion body in the E. coli cytoplasm, the protein was dissolved by denaturation in 8M urea, refolded, and purified to homogeneity in presence of detergent. Our strategy allowed isolation of the recombinant OmpU protein with significantly enhanced yield as compared to that of the wild type protein extracted from the V. cholerae membrane fraction. The recombinant V. cholerae OmpU protein generated in our study displayed functional channel-forming property in the synthetic liposome membrane, thus confirming its 'porin'-property. To the best of our knowledge, this is the first report showing an efficient refolding and functional assembly of the V. cholerae OmpU porin recombinantly expressed as inclusion body in the cytoplasm of a heterologous host E. coli.

Toluene optic neurotoxicity: magnetic resonance imaging and pathologic features.

Toluene, a colorless liquid found in glues, paints, and industrial products, is lipid soluble and rapidly absorbed by the lipid-rich central nervous system. Prolonged exposure through occupation or purposeful inhalation may lead to neurologic abnormalities. Two men presented with multifocal central nervous system defects and bilateral optic neuropathy of unclear etiology. After numerous diagnostic tests, including brain magnetic resonance imaging, lumbar puncture, hematologic studies, and in one patient a brain biopsy, chronic inhalation of toluene was found to be the cause. Timely diagnosis is important because patients may experience improvement in neurologic and ocular manifestations with cessation of exposure, whereas continued inhalant abuse or exposure can result in permanent loss of neurologic function.

The disc as the basis of treatment for glaucoma.

The goal of the treatment of patients with glaucoma is to prevent disability or, if disability already exists, to repair the disability or at the least to prevent further disability from developing. To achieve these goals requires knowing what will happen if there is no treatment and what will happen if there is treatment. That is, one must know the possible benefits from the therapy in comparison to the damage caused by the therapy. As we will demonstrate, the classic risk factors do not provide accurate estimates of the development of disability and do not answer these two questions. The most helpful clues are provided by what the patient says, by whether the disc is damaged and by whether the disc is deteriorating. The severity of disease is best estimated by the nature of the optic disc and how it changes. This report is primarily focused on increasing the skill of the physician in being able to estimate the nature of the optic disc and how that changes. This does not, however, lessen the tremendous importance of careful history-taking and of gonioscopy. In this report, however, we focus on the evaluation of the disc. Currently disc evaluation is often not adequate because of poor examination techniques, reliance on cup/disc ratios, and reliance on the results of image analyzers. We will present here the Disc Damage Likelihood Scale, which is a user-friendly method which correlates accurately with visual field changes.

Comparison of hemorrhagic complications of warfarin and clopidogrel bisulfate in 25-gauge vitrectomy versus a control group.

PURPOSE: To estimate the risk of hemorrhagic complications associated with 25-gauge pars plana vitrectomy (PPV) when warfarin (Coumadin; Bristol-Myers Squibb, New York, NY) or clopidogrel (Plavix; Bristol-Myers Squibb) are continued throughout the surgical period, as compared with a control group. DESIGN: A single-center, retrospective, cohort study of 289 consecutive patients receiving either warfarin therapy or clopidogrel therapy or neither of those therapies who underwent 25-gauge PPV. PARTICIPANTS: Included were 61 patients (64 eyes; 64 PPV procedures) in the warfarin group and 118 (125 eyes; 136 PPV procedures) in the clopidogrel group. Warfarin patients were subdivided into 4 groups by international normalized ratio (INR). A control group included 110 patients (110 eyes; 110 PPV procedures) who were not receiving warfarin or clopidogrel. METHODS: Retrospective chart review for which the criteria included: 25-gauge PPV, minimum age of 19 years, warfarin or clopidogrel use, and, if taking warfarin, an INR obtained within 5 days of surgery. MAIN OUTCOME MEASURES: Incidence of intraoperative and postoperative hemorrhagic complications. RESULTS: The most common indications for anticoagulation therapy included: atrial fibrillation (38%), valvular heart disease (17%), and thromboembolic disease (16%). The most common indications for antiplatelet therapy included: cardiac stent (49%), coronary artery bypass grafting (24%), and history of transient ischemic attack (16%). No patient experienced anesthesia-related hemorrhagic complications resulting from peribulbar or retrobulbar block. Transient vitreous hemorrhage occurred in 1 (1.6%) of 64 PPV procedures in the warfarin group (P = 0.6531), 5 (3.7%) of 136 PPV procedures in the clopidogrel group (P = 1.0), and 4 (3.6%) of 110 PPV procedures in the control group. No choroidal or retrobulbar hemorrhages occurred in any patient. CONCLUSIONS: The rate of 25-gauge PPV hemorrhagic complications in patients who underwent systemic anticoagulation or who were receiving platelet inhibitor therapy is extremely low. Given the risks associated with stopping these therapies, the authors recommend that patients continue their current therapeutic regimen without cessation.