AIM: To investigate hepatitis virus, genetic and environmental factors, and their interactions in predisposing patients to liver diseases in Northeast India.
METHODS: A total of 104 jaundice patients and 124 community controls were included. Serological analysis was performed by routine enzyme-linked immunosorbent assay, and nucleic acid testing for hepatitis viruses was done by polymerase chain reaction (PCR), followed by PCR direct sequencing for viral genotyping. Cytochrome P450 2E1 (CYP2E1) polymorphism was studied by PCR-restriction fragment length polymorphism. Nitrite and volatile nitrosamines in indigenous foods consumed routinely by the Northeast Indian ethnic population were estimated by Griess’s reagent and GC-MS, respectively.
RESULTS: Hepatitis A virus (HAV) infection was predominantly prevalent (36.5%) in our cohort, followed by hepatitis B virus (HBV), hepatitis E virus (HEV) and hepatitis C virus. HBV genotype D and HEV genotype 1 were the most dominant. CYP2E1 c1/c2 genotype frequency was comparatively higher in alcoholic (P < 0.0001, OR = 30.5) and cryptogenic (P = 0.014, OR = 8.714) patients, and was associated with significantly higher hepatitis risk (P = 0.0.007, OR = 6.489). Mutant C allele of Cyp2E1 DraI frequency was comparatively higher in HAV (P = 0.006), alcoholic (P = 0.003) and cryptogenic (P = 0.014) cases, and was associated with overall hepatitis risk (P = 0.026, OR = 5.083). Indigenous foods, Gundruk, Kharoli, betel leaf and nuts were found to have the highest nitrite content.
CONCLUSION: Apart from viral factors, CYP2E1 polymorphism might be associated with increased risk of liver diseases in Northeast India. Indigenous foods that contain nitrite and nitrosamine might be an associated risk factor.
Viral hepatitis; Cytochrome P450 2E1; Gene polymorphism; Nitrites; Nitrosamines
Yersinia enterocolitica is a food-borne pathogen that preferentially infects the Peyer's patches and mesenteric lymph nodes, causing an acute inflammatory reaction. Even though Y. enterocolitica induces a robust inflammatory response during infection, the bacterium has evolved a number of virulence factors to limit the extent of this response. We previously demonstrated that interleukin-1α (IL-1α) was critical for the induction of gut inflammation characteristic of Y. enterocolitica infection. More recently, the known actions of IL-1α are becoming more complex because IL-1α can function both as a proinflammatory cytokine and as a nuclear factor. In this study, we tested the ability of Y. enterocolitica to modulate intracellular IL-1α-dependent IL-8 production in epithelial cells. Nuclear translocation of pre-IL-1α protein and IL-1α-dependent secretion of IL-8 into the culture supernatant were increased during infection with a strain lacking the 70-kDa virulence plasmid compared to the case during infection with the wild type, suggesting that Yersinia outer proteins (Yops) might be involved in modulating intracellular IL-1α signaling. Infection of HeLa cells with a strain lacking the yopP gene resulted in increased nuclear translocation of pre-IL-1α and IL-1α-dependent secretion of IL-8 similar to what is observed with bacteria lacking the virulence plasmid. YopP is a protein acetylase that inhibits mitogen-activated protein kinase (MAP kinase)- and NF-κB-dependent signal transduction pathways. Nuclear translocation of pre-IL-1α and IL-1α-dependent secretion of IL-8 in response to Yersinia enterocolitica infection were dependent on extracellular signal-regulated kinase (ERK) and p38 MAP kinase signaling but independent of NF-κB. These data suggest that Y. enterocolitica inhibits intracellular pre-IL-1α signaling and subsequent proinflammatory responses through inhibition of MAP kinase pathways.
The antimicrobial activity of alcoholic, butanolic and chloroform extracts of leaves and roots of the plant Acanthus ilicifolius ware studied. Ampicillin and clotrimazole were used as standard antibacterial and antifungal agents respectively. The result of the study revealed that the alcoholic extract and chloroform extract of leaves exhibited strong inhibitory action against Bacillus subtilis, Staphylococcus aureus, Candida albicans, Aspergillus fumigatus and Aspergillus niger and moderate inhibitory action against Pseudomonas aeruginosa and Proteus vulgaris. The rest of the extracts showed moderate activity.
Acanthus ilicifolius; agar cup-plate method; antimicrobial activity; mangrove
The steroidogenic acute regulatory protein (StAR) is required for adrenal and gonadal steroidogenesis and for male sexual differentiation. StAR acts on the outer mitochondrial membrane (OMM) to facilitate movement of cholesterol from the OMM to the inner mitochondrial membrane to be converted to pregnenolone, the precursor of all steroid hormones. The mechanisms of the action of StAR remain unclear; the peripheral benzodiazepine receptor, an OMM protein, appears to be involved, but the identity of OMM proteins that interact with StAR remain unknown. Here we demonstrate that phosphorylated StAR interacts with voltage-dependent anion channel 1 (VDAC1) on the OMM, which then facilitates processing of the 37-kDa phospho-StAR to the 32-kDa intermediate. In the absence of VDAC1, phospho-StAR is degraded by cysteine proteases prior to mitochondrial import. Phosphorylation of StAR by protein kinase A requires phosphate carrier protein on the OMM, which appears to interact with StAR before it interacts with VDAC1. VDAC1 and phosphate carrier protein are the first OMM proteins shown to contact StAR.
To determine the comparability between cause of death by a single physician coder and a two-physician panel, using verbal autopsy.
The study was conducted between May 2007 and June 2008. Within a week of a perinatal death in 38 rural remote communities in Guatemala, the Democratic Republic of Congo, Zambia and Pakistan, VA questionnaires were completed. Two independent physicians, unaware of the others decisions, assigned an underlying cause of death, in accordance with the causes listed in the chapter headings of the International classification diseases and related health problems, 10th revision (ICD-10). Cohen's kappa statistic was used to assess level of agreement between physician coders.
There were 9461 births during the study period; 252 deaths met study enrollment criteria and underwent verbal autopsy. Physicians assigned the same COD for 75% of stillbirths (K=0.69; 95% confidence interval: 0.61–0.78) and 82% early neonatal deaths (K=0.75; 95% confidence interval: 0.65–0.84). The patterns and proportion of stillbirths and early neonatal deaths determined by the physician coders were very similar compared to causes individually assigned by each physician. Similarly, rank order of the top 5 causes of stillbirth and early neonatal death were identical for each physician.
This study raises important questions about the utility of a system of multiple coders that is currently widely accepted, and speculates that a single physician coder may be an effective and economical alternative to VA programs that use traditional two-physician panels to assign COD.
verbal autopsy; perinatal death; comparing coders
Ascarosides are small-molecule signals that play a central role in C. elegans biology, including dauer formation, aging, and social behaviors, but many aspects of their biosynthesis remain unknown. Using automated 2D NMR-based comparative metabolomics, we identified ascaroside ethanolamides as shunt metabolites in C. elegans mutants of daf-22, a gene with homology to mammalian 3-ketoacyl-CoA thiolases predicted to function in conserved peroxisomal lipid β-oxidation. Two groups of ethanolamides feature β-keto functionalization confirming the predicted role of daf-22 in ascaroside biosynthesis, whereas α-methyl substitution points to unexpected inclusion of methylmalonte at a late stage in the biosynthesis of long-chain fatty acids in C. elegans. We show that ascaroside ethanolamide formation in response to defects in daf-22 and other peroxisomal genes is associated with severe depletion of endocannabinoid pools. These results indicate unexpected interaction between peroxisomal lipid β-oxidation and the biosynthesis of endocannabinoids, which are major regulators of lifespan in C. elegans. Our study demonstrates the utility of unbiased comparative metabolomics for investigating biochemical networks in metazoans.
The human TERT (hTERT) gene encodes the telomerase catalytic subunit which plays a role in telomerase regulation. Telomerase is activated in more than 90% of all human malignancies and understanding how telomerase is regulated is necessary for implementation of successful anti-cancer therapies. microRNAs (miRNAs) are important regulators of gene expression in eukaryotic cells but evidence of their role in telomerase regulation has not been documented. To determine whether hTERT activity is regulated by multiple miRNAs, eight miRNAs which have putative binding sites in the hTERT 3′UTR together with miR-138-5p were evaluated in luciferase assays with a reporter containing the hTERT 3′UTR. Six miRNAs (let-7g*, miR-133a, miR-138-5p, miR-342-5p, miR-491-5p, and miR-541-3p) specifically inhibited the expression of the reporter luciferase-driven constructs and let-7g*, miR-133a, miR-138-5p, and miR-491-5p also downregulated endogenous telomerase activity in cells. Moreover, all six miRNAs significantly inhibited cell proliferation. miRNAs (miR-133a, miR-138-5p, 342-5p, 491-5p, 541-3p) also have predicted binding sites within the 3′UTR of three genes involved in Wnt signaling (TCF7, MSI1, and PAX5). These miRNAs inhibited the expression of the luciferase reporter constructs containing 3′UTRs of these genes and downregulated protein expression of the TCF7 transcription factor, which mediates the canonical Wnt pathway. Together, these results suggest the existence of a miRNA regulatory network involving the hTERT and Wnt pathway.
Six million stillbirths (SB) and early neonatal deaths (END) occur annually worldwide, mostly in rural settings distant from health facilities. We used verbal autopsy (VA), to understand causes of non-hospital, community-based SB and END from four low-income countries.
This prospective observational study utilized the train-the-trainer method. VA interviewers conducted standardized interviews; in each country data were reviewed by two local physicians who assigned an underlying causes of deaths (COD).
There were 252 perinatal deaths (118 END; 134 SB) studied from pooled data. Almost half (45%) the END occurred on postnatal day 1, 19%on the second day and 16% the third day. Major early neonatal COD were infections (49%), birth asphyxia (26%), prematurity (17%) and congenital malformations (3%). Major causes of SB were infection (37%), prolonged labor (11%), antepartum hemorrhage (10%), preterm delivery (7%), cord complications (6%) and accidents (5%).
Many of these SB and END were from easily preventable causes. Over 80% of END occurred during the first 3 days of postnatal life, and >90% were due to infection, birth asphyxia and prematurity. The causes of SB were more varied, and maternal infections were the most common cause. Increased attention should be targeting at interventions that reduce maternal and neonatal infections and prevent END, particularly during the first 3 days of life.
The goal was to determine the effect of training in newborn care and resuscitation on 7-day (early) neonatal mortality rates for very low birth weight (VLBW) infants. The study was designed to test the hypothesis that these training programs would reduce neonatal mortality rates for VLBW infants.
Local instructors trained birth attendants from 96 rural communities in 6 developing countries in protocol and data collection, the World Health Organization Essential Newborn Care (ENC) course, and a modified version of the American Academy of Pediatrics Neonatal Resuscitation Program (NRP), by using a train-the-trainer model. To test the impact of ENC training, data on infants of 500 to 1499 g were collected by using a before/after, active baseline, controlled study design. A cluster-randomized, controlled trial design was used to test the impact of the NRP.
A total of 1096 VLBW (500–1499 g) infants were enrolled, and 98.5% of live-born infants were monitored to 7 days. All-cause, 7-day neonatal mortality, stillbirth, and perinatal mortality rates were not affected by ENC or NRP training.
Neither ENC nor NRP training of birth attendants decreased 7-day neonatal, stillbirth, or perinatal mortality rates for VLBW infants born at home or at first-level facilities. Encouragement of delivery in a facility where a higher level of care is available may be preferable when delivery of a VLBW infant is expected.
neonatal mortality; perinatal mortality; stillbirth; developing countries; health care systems; very low birth weight; prematurity
Early growth faltering is common but is difficult to reverse after the first 2 years of life.
To describe feeding practices and growth in infants and young children in diverse low-income settings prior to undertaking a complementary feeding trial.
This cross-sectional study was conducted through the Global Network for Women’s and Children’s Health Research in Guatemala, Democratic Republic of Congo, Zambia, and Pakistan. Feeding questionnaires were administered to convenience samples of mothers of 5- to 9-month old infants and 12- to 24-month-old toddlers. After standardized training, anthropometric measurements were obtained from the toddlers. Following the 2006 World Health Organization Growth Standards, stunting was defined as length-for-age < −2SD, and wasting as weight-for-length < −2SD. Logistic regression was applied to evaluate relationships between stunting and wasting and consumption of meat (including chicken and liver and not including fish).
Data were obtained from 1,500 infants with a mean (± SD) age of 6.9 ± 1.4 months and 1,658 toddlers with a mean age of 17.2 ± 3.5 months. The majority of the subjects in both age groups were breastfed. Less than 25% of the infants received meat regularly, whereas 62% of toddlers consumed these foods regularly, although the rates varied widely among sites. Stunting rate ranged from 44% to 66% among sites; wasting prevalence was less than 10% at all sites. After controlling for covariates, consumption of meat was associated with a reduced likelihood of stunting (OR = 0.64; 95% CI, 0.46 to 0.90).
The strikingly high stunting rates in these toddlers and the protective effect of meat consumption against stunting emphasize the need for interventions to improve complementary feeding practices, beginning in infancy.
Complementary feeding; infant growth; infant nutrition; stunting
Contusion spinal cord injury (SCI) animal models are used to study loss of muscle function and mass. However, parallels to the human condition typically have been confounded by spontaneous recovery observed within the first few post-injury weeks, partly because of free cage activity. We implemented a new rat model combining SCI with cast immobilization (IMM) to more closely reproduce the unloading conditions experienced by SCI patients. Magnetic resonance imaging was used to monitor hindlimb muscles' cross-sectional area (CSA) after SCI, IMM alone, SCI combined with IMM (SCI+IMM), and in controls (CTR) over a period of 21 days. Soleus muscle tetanic force was measured in situ on day 21, and hindlimb muscles were harvested for histology. IMM alone produced a decrease in triceps surae CSA to 63.9±4.9% of baseline values within 14 days. In SCI, CSA decreased to 75.0±10.5% after 7 days, and recovered to 77.9±10.7% by day 21. SCI+IMM showed the greatest amount of atrophy (56.9±9.9% on day 21). In all groups, muscle mass and soleus tetanic force decreased in parallel, such that specific force was maintained. Extensor digitorum longus (EDL) and soleus fiber size decreased in all groups, particularly in SCI+IMM. We observed a significant degree of asymmetry in muscle CSA in SCI but not IMM. This effect increased between day 7 and 21 in SCI, but also in SCI+IMM, suggesting a minor dependence on muscle activity. SCI+IMM offers a clinically relevant model of SCI to investigate the mechanistic basis for skeletal muscle adaptations after SCI and develop therapeutic approaches.
atrophy; immobilization; magnetic resonance imaging; SCI; skeletal muscle
Data from eight breast cancer genome sequencing projects identified 25 patients with HER2 somatic mutations in cancers lacking HER2 gene amplification. To determine the phenotype of these mutations, we functionally characterized thirteen HER2 mutations using in vitro kinase assays, protein structure analysis, cell culture and xenograft experiments. Seven of these mutations are activating mutations, including G309A, D769H, D769Y, V777L, P780ins, V842I, and R896C. HER2 in-frame deletion 755-759, which is homologous to EGFR exon 19 in-frame deletions, had a neomorphic phenotype with increased phosphorylation of EGFR or HER3. L755S produced lapatinib resistance, but was not an activating mutation in our experimental systems. All of these mutations were sensitive to the irreversible kinase inhibitor, neratinib. These findings demonstrate that HER2 somatic mutation is an alternative mechanism to activate HER2 in breast cancer and they validate HER2 somatic mutations as drug targets for breast cancer treatment.
Genomics; Breast Cancer; Receptor Tyrosine Kinase; Oncogene
Background and Aim
Increasing evidence has indicated a close association of host-gut flora metabolic interaction with obesity. Flos Lonicera, a traditional herbal medicine, is used widely in eastern Asia for the treatment of various disorders. The aim of this study was to evaluate whether unfermented or fermented formulations of Flos Lonicera could exert a beneficial impact to combat obesity and related metabolic endotoxemia.
Obesity and metabolic endotoxemia were induced separately or together in rats through feeding a eight-week high fat diet either alone (HFD control group) or in combination with a single LPS stimulation (intraperitoneal injection, 0.75 mg/kg) (LPS control group). While, the mechanism of action of the Lonicera formulations was explored in vitro using RAW 264.7 and HCT 116 cell lines as models.
In cell-based studies, treatment with both unfermented Flos Lonicera (UFL) and fermented Flos Lonicera (FFL) formulations resulted in suppression of LPS-induced NO production and gene expression of vital proinflammatory cytokines (TNF-α, COX-2, and IL-6) in RAW 264.7 cells, reduced the gene expression of zonula occludens (ZO)-1 and claudin-1, and normalized trans epithelial electric resistance (TEER) and horseradish peroxidase (HRP) flux in LPS-treated HCT-116 cells. In an animal study, treatment of HFD as well as HFD+LPS groups with UFL or FFL resulted in a notable decrease in body and adipose tissue weights, ameliorated total cholesterol, HDL, triglyceride, aspartate transaminase and endotoxin levels in serum, reduced the urinary lactulose/mannitol ratio, and markedly alleviated lipid accumulation in liver. In addition, exposure of HFD as well as HFD+LPS groups with UFL or FFL resulted in significant alteration of the distribution of intestinal flora, especially affecting the population of Akkermansia spp. and ratio of Bacteroidetes and Firmicutes.
This evidence collectively demonstrates that Flos Lonicera ameliorates obesity and related metabolic endotoxemia via regulating distribution of gut flora and gut permeability.
To characterize patient-derived xenografts (PDXs) for functional studies,
we made whole-genome comparisons with originating breast cancers representative
of the major intrinsic subtypes. Structural and copy number aberrations were
found to be retained with high fidelity. However, at the single-nucleotide
level, variable numbers of PDX-specific somatic events were documented, although
they were only rarely functionally significant. Variant allele frequencies were
often preserved in the PDXs, demonstrating that clonal representation can be
transplantable. Estrogen-receptor-positive PDXs were associated with
ESR1 ligand-binding-domain mutations, gene amplification,
or an ESR1/YAP1 translocation. These events produced different
endocrine-therapy-response phenotypes in human, cell line, and PDX
endocrine-response studies. Hence, deeply sequenced PDX models are an important
resource for the search for genome-forward treatment options and capture
endocrine-drug-resistance etiologies that are not observed in standard cell
lines. The originating tumor genome provides a benchmark for assessing genetic
drift and clonal representation after transplantation.
Pathogen-associated molecular patterns (PAMPs) trigger host immune response by activating pattern recognition receptors like toll-like receptors (TLRs). However, the mechanism whereby several pathogens, including viruses, activate TLRs via a non-PAMP mechanism is unclear. Endogenous “inflammatory mediators” called damage-associated molecular patterns (DAMPs) have been implicated in regulating immune response and inflammation. However, the role of DAMPs in inflammation/immunity during virus infection has not been studied. We have identified a DAMP molecule, S100A9 (also known as Calgranulin B or MRP-14), as an endogenous non-PAMP activator of TLR signaling during influenza A virus (IAV) infection. S100A9 was released from undamaged IAV-infected cells and extracellular S100A9 acted as a critical host-derived molecular pattern to regulate inflammatory response outcome and disease during infection by exaggerating pro-inflammatory response, cell-death and virus pathogenesis. Genetic studies showed that the DDX21-TRIF signaling pathway is required for S100A9 gene expression/production during infection. Furthermore, the inflammatory activity of extracellular S100A9 was mediated by activation of the TLR4-MyD88 pathway. Our studies have thus, underscored the role of a DAMP molecule (i.e. extracellular S100A9) in regulating virus-associated inflammation and uncovered a previously unknown function of the DDX21-TRIF-S100A9-TLR4-MyD88 signaling network in regulating inflammation during infection.
The lung disease severity following influenza A virus (IAV) infection is dependent on the extent of inflammation in the respiratory tract. Severe inflammation in the lung manifests in development of pneumonia. Therefore, it is very critical to identify cellular factors and dissect the molecular/cellular mechanism controlling inflammation in the respiratory tract during IAV infection. Knowledge derived from these studies will be instrumental in development of therapeutics to combat the lung disease associated with IAV infection. Towards that end, in the current study we have identified a cellular factor S100A9 which is responsible for enhanced inflammation during IAV infection. In addition, we have characterized a signal transduction pathway involving various cellular receptors and signaling adaptors that are involved in mediating S100A9-dependent inflammatory response. Thus, our studies have illuminated a cellular/molecular mechanism that can be intervened by therapeutics to reduce and control IAV-associated lung inflammatory disease like pneumonia.
Little evidence is available to document that mechanical ventilation is an antecedent of systemic inflammation in preterm humans. We obtained blood on postnatal day 14 from 726 infants born before the 28th week of gestation and measured the concentrations of 25 inflammation-related proteins. We created multivariable models to assess the relationship between duration of ventilation and protein concentrations in the top quartile. Compared to newborns ventilated for fewer than 7 days (N=247), those ventilated for 14 days (N=330) were more likely to have elevated blood concentrations of pro-inflammatory cytokines (IL-1β, TNF-α), chemokines (IL-8, MCP-1), an adhesion molecule (ICAM-1), and a matrix metalloprotease (MMP-9), and less likely to have elevated blood concentrations of two chemokines (RANTES, MIP-1β), a matrix metalloproteinase (MMP-1), and a growth factor (VEGF). Newborns ventilated for 7-13 days (N=149) had systemic inflammation that approximated the pattern of newborns ventilated for 14 days. These relationships were not confounded by chorioamnionitis or antenatal corticosteroid exposure, and were not altered appreciably among infants with and without bacteremia. These findings suggest that two weeks of ventilation are more likely than shorter durations of ventilation to be accompanied by high blood concentrations of pro-inflammatory proteins indicative of systemic inflammation, and by low concentrations of proteins that might protect from inflammation-mediated organ injury.
inflammation; ventilation; preterm infant; cytokine; chemokine
CD55 limits excessive complement activation on the host cell surface by accelerating the decay of C3 convertases. In this study, we observed that hepatitis C virus (HCV) infection of hepatocytes or HCV core protein expression in transfected hepatocytes upregulated CD55 expression at the mRNA and protein levels. Further analysis suggested that the HCV core protein or full-length (FL) genome enhanced CD55 promoter activity in a luciferase-based assay, which was further augmented in the presence of interleukin-6. Mutation of the CREB or SP-1 binding site on the CD55 promoter impaired HCV core protein-mediated upregulation of CD55. HCV-infected or core protein-transfected Huh7.5 cells displayed greater viability in the presence of CD81 and CD55 antibodies and complement. Biochemical analysis revealed that CD55 was associated with cell culture-grown HCV after purification by sucrose density gradient ultracentrifugation. Consistent with this, a polyclonal antibody to CD55 captured cell culture-grown HCV. Blocking antibodies against CD55 or virus envelope glycoproteins in the presence of normal human serum as a source of complement inhibited HCV infection. The inhibition was enhanced in the presence of both the antibodies and serum complement. Collectively, these results suggest that HCV induces and associates with a negative regulator of the complement pathway, a likely mechanism for immune evasion.
Despite the remarkable success of imatinib against Bcr-Abl, development of secondary resistance, most often due to point mutations in the Bcr-Abl tyrosine kinase (TK) domain, is quite common. Of these, the T315I “gatekeeper” mutation is resistant to all currently registered Bcr-Abl TK inhibitors (TKIs) with the notable exception of ponatinib (Iclusig™), which was very recently approved by the United States Food and Drug Administration (FDA). Besides ponatinib, numerous strategies have been developed to circumvent this problem. These include the protein synthesis inhibitor omacetaxine (Synribo®), and “switch-control” inhibitors. Dual Bcr-Abl and aurora kinase inhibitors represent another promising strategy. Finally, several promising synergistic combinations, such as TKIs with histone deacetylase inhibitors (HDACIs), warrant attention.
Gatekeeper mutations; T315I; Bcr-Abl; ponatinib; homoharringtonine; omacetaxine; AT9283; HDAC inhibitors
The B-cell lymphoma-2 (Bcl-2) family of proteins regulates the intrinsic, or mitochondrial pathway of apoptosis, the final common mechanism of cell death in response to a variety of physiologic and pharmacologic signals, and plays a central role in AML pathogenesis, prognosis and responsiveness to chemotherapy. Traditionally thought to be an important survival factor for multiple myeloma cells, the anti-apoptotic Bcl-2 family protein myeloid cell leukemia-1 (Mcl-1) has recently been shown in preclinical studies to be critical to the development and maintenance of AML, making it an attractive therapeutic target in this disease. Several characteristics, such as its very short half-life, distinguish Mcl-1 from other anti-apoptotic Bcl-2 family members. Additionally, Mcl-1 levels are regulated by a large number of pathways affecting its transcription, translation and degradation. A variety of approaches exploiting these features has been developed to inhibit directly or indirectly the anti-apoptotic function of Mcl-1. Many of these lend themselves well to combination therapies, leading to striking synergism, at least in preclinical models. In this brief review, we highlight some of the more promising strategies targeting Mcl-1 in AML, with a particular emphasis on rational combinations of novel agents.
AML; Mcl-1; navitoclax; obatoclax; sorafenib; CDK inhibitors
Bone replacement materials must be able to regulate both osteoblastic synthesis of new bone and osteoclastic resorption process in order to maintain the balance of bone remodeling. Osteoclasts generate from differentiation of mononuclear cells. In the present study, we have studied the osteoclast-like-cells responses (differentiation from mononuclear cells and resorption) to beta tricalcium phosphate (β-TCP) doped with zinc (Zn) and strontium (Sr). Osteoclast-like-cells differentiation and resorption was studied in vitro using osteoclast-like-cells precursor RAW 264.7 cell, supplemented with receptor activator of nuclear factor κβ ligand (RANKL). Morphological and immunohistochemical analysis confirmed successful differentiation of osteoclast-like-cells on the doped and undoped β-TCP substrates after 8 days of culture. Cells on the substrate surface expressed specific osteoclast markers such as; actin ring, multiple nucleus, tartrate-resistant acid phosphatase (TRAP) synthesis, and vitronectin receptor. However, quantitative TRAP assay indicated the inhibiting effect of Zn on osteoclast differentiation. Although, Zn doped β-TCP restricted osteoclast-like-cells differentiation, the samples were resorbed much faster. An increased resorption pit volume was noticed on Zn doped β-TCP samples after 28 days of culture compared to pure and Sr doped β-TCP. In this work, we demonstrated that β-TCP bone substitute materials can be successfully resorbed by osteoclast-like-cells, where both osteoclast-like-cells differentiation and resorption were modulated by Zn and/or Sr doping- a much needed property for successful bone remodeling.
Beta-tricalcium phosphate; Zn/Sr doping; osteoclast-like cells; TRAP assay; Resorption lacunae
Major depressive disorder (MDD) is a global health concern. This study examined the efficacy, safety and tolerability of an extended-release (ER) formulation of levomilnacipran, an antidepressant approved for the treatment of MDD in adults.
This 10-week (1-week placebo run-in period, 8-week double-blind treatment, 1-week down-taper), multicentre, double-blind, placebo-controlled, parallel-group, fixed-dose study was conducted between June 2011 and March 2012. Adult outpatients (age 18–75 yr) with MDD were randomly assigned (1:1:1) to placebo or to levomilnacipran ER 40 mg/day or 80 mg/day. For primary efficacy, we analyzed the Montgomery–Åsberg Depression Rating Scale (MADRS) change from baseline to week 8 using a mixed-effects model for repeated-measures approach on the intent-to-treat (ITT) population. For secondary efficacy, we used the Sheehan Disability Scale (SDS), and for safety, we examined adverse events and laboratory, vital sign/physical and electrocardiography findings.
The ITT population consisted of 185 patients in the placebo group, 185 in the levomilnacipran ER 40 mg/day group and 187 in the levomilnacipran ER 80 mg/day group. Study completion rates were similar among the groups (76%–83%). On MADRS change from baseline the least squares mean difference (LSMD) and 95% confidence interval (CI) versus placebo was significant for levomilnacipran ER 40 mg/day (–3.3 [−5.5 to −1.1], p = 0.003) and 80 mg/day (−3.1, [−5.3 to −1.0], p = 0.004). On SDS change from baseline the LSMD (and 95% CI) versus placebo was also significant for levomilnacipran ER 40 mg/day (−1.8, 95% [−3.6 to 0], p = 0.046) and 80 mg/day (−2.7 [−4.5 to −0.9], p = 0.003). More patients in the levomilnacipran ER than the placebo group prematurely exited the study owing to adverse events; common adverse events (≥ 5% and ≥ double the rate of placebo) were nausea, dry mouth, increased heart rate, constipation, dizziness, hyperhidrosis, urinary hesitation and erectile dysfunction.
Limitations to our study included short treatment duration and lack of an active control arm.
Levomilnacipran ER at doses of 40 mg/day and 80 mg/day demonstrated efficacy on symptomatic and functional measures of MDD and was generally well tolerated in this patient population.
Clinical trial registration
Background and Aims:
Central venous catheter placement is an important procedure for ICU (Intensive Care Unit) patients. We studied the usefulness of ultrasonography for placement of central venous catheter by in-experienced anesthetists.
Materials and Methods:
A prospective observational study of 32 patients requiring central venous access (CVA) in surgical ICU (SICU). Data collected were patient's demographics, indication, type of catheter, success rate, attempts, complication rate and access time were recorded and compared with other studies.
The overall success rate was 89.5% in the IJV (Internal Jugular Vein) and 92.3% for SCV (Subclavian Vein) group. The success rates for insertion at first, second, and third attempt were 52.6%, 31.6%, and 5.2% for IJV and 46.2% and 53.8% for SCV. Average number of attempts made for IJV cannulation was 1.74 +/- 1.04 and 1.54 +/- 0.51 for SCV. The total time taken for IJV access was 858.78 +/- 381.9 sec, whereas in the SCV group, it was 984 +/- 328.98 seconds. In our study, overall rate of complication was 21.05% (4/19 patients) for IJV and 23.07% (3/13 patients) for SCV insertion. Incidence of various complications like arterial puncture, misplacement of CVC, hematoma, pneumothorax, and hemothorax were also noted.
This study concludes that real time ultrasound guidance during IJV and SCV cannulation can achieve higher success rate, fewer complications, number of attempts, and failure rate among inexperienced anesthetists.
Central venous catheter; inexperienced; intensive care unit; ultrasonography
The rationale is considered for promoting the availability of local, affordable, non-fortified food sources of bioavailable iron in developing countries. Intakes of iron from the regular consumption of meat from the age of six months are evaluated with respect to physiological requirements. The paper includes a description of two major randomized controlled trials of meat as a first and regular complementary food that are currently in progress. These trials involve poor communities in Guatemala, Pakistan, Zambia, Democratic Republic of the Congo and China.
iron; meat; complementary feeding
Clinical success of endodontically treated posterior teeth is determined by the postendodontic restoration. Several options have been proposed to restore endodontically treated teeth. Endocrowns represent a conservative and esthetic restorative alternative to full coverage crowns. The preparation consists of a circular equigingival butt-joint margin and central retention cavity into the entire pulp chamber constructing both the crown and the core as a single unit. The case reports discussed here are moderately damaged endodontically treated molars restored using all ceramic endocrowns fabricated using two different systems, namely, CAD/CAM and pressed ceramic.