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Safety and Effectiveness of Intravenous vs Oral Iron for Treatment of Anemia in the Prenatal and Postpartum Periods
EVIDENCE-BASED ANSWER In the prenatal setting, treatment of iron deficiency anemia with IV iron rather than oral iron may slightly increase the hemoglobin level 3 to 6 weeks after treatment and around the time of birth1; however, there is no significant effect on postpartum hemorrhage, need for blood transfusion, or rates of breast-feeding.1 (Strength of Recommendation [SOR]: C, consensus, disease-oriented evidence, usual practice, expert opinion, or case series for studies of diagnosis, treatment, prevention, or screening.) In the postpartum setting among patients with iron deficiency anemia, IV iron therapy is associated with increased treatment adherence, a slight reduction in fatigue in the first month, and lower risk of constipation compared with oral iron treatment.2 (SOR: The analysis suggested that IV iron increased hemoglobin levels slightly more than oral iron (mean difference = 0.49; 95% CI, 0.28–0.69) when measured 3 to 6 weeks after treatment and likely reduced anemia status around birth (relative risk [RR] = 0.85; 95% CI, 0.77–0.93; four RCTs; n = 1,240; moderate-certainty evidence).1 Receiving IV iron rather than oral iron during pregnancy decreased the likelihood that patients would have a hemoglobin level of less than 11 g/dL at the time of delivery (RR = 0.85; 95% CI, 0.77–0.93; number needed to treat [NNT] with IV rather than oral iron = 11; moderate-certainty evidence). The reviewers noted that IV iron did not seem to increase the risk of adverse effects compared with oral iron for the specific adverse effects chosen for comparison (ie, risk of severe infection, prolonged hospital stay, admission to the intensive care unit); however, there was significant heterogeneity in the reporting of adverse effects across the trials, which limits confidence in this conclusion.
Journal Article
Cariprazine alleviates core behavioral deficits in the prenatal valproic acid exposure model of autism spectrum disorder
RationaleAutism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social communication and interaction and restricted, repetitive behaviors. The unmet medical need in ASD is considerable since there is no approved pharmacotherapy for the treatment of these deficits in social communication, interaction, and behavior. Cariprazine, a dopamine D3-preferring D3/D2 receptor partial agonist, is already approved for the treatment of schizophrenia and bipolar I disorder in adults; investigation in patients with ASD is warranted.ObjectivesThe aim of this study was to investigate the effects of cariprazine, compared with risperidone and aripiprazole, in the rat prenatal valporic acid (VPA) exposure model on behavioral endpoints representing the core and associated symptoms of ASD.MethodsTo induce the ASD model, time-mated Wistar rat dams were treated with VPA during pregnancy. Male offspring were assigned to groups and studied in a behavioral test battery at different ages, employing social play, open field, social approach-avoidance, and social recognition memory tests. Animals were dosed orally, once a day for 8 days, with test compounds (cariprazine, risperidone, aripiprazole) or vehicle before behavioral assessment.ResultsCariprazine showed dose-dependent efficacy on all behavioral endpoints. In the social play paradigm, only cariprazine was effective. On the remaining behavioral endpoints, including the reversal of hyperactivity, risperidone and aripiprazole displayed similar efficacy to cariprazine.ConclusionsIn the present study, cariprazine effectively reversed core behavioral deficits and hyperactivity present in juvenile and young adult autistic-like rats. These findings indicate that cariprazine may be useful in the treatment of ASD symptoms.
Journal Article
IRE1 signaling exacerbates Alzheimer’s disease pathogenesis
Altered proteostasis is a salient feature of Alzheimer’s disease (AD), highlighting the occurrence of endoplasmic reticulum (ER) stress and abnormal protein aggregation. ER stress triggers the activation of the unfolded protein response (UPR), a signaling pathway that enforces adaptive programs to sustain proteostasis or eliminate terminally damaged cells. IRE1 is an ER-located kinase and endoribonuclease that operates as a major stress transducer, mediating both adaptive and proapoptotic programs under ER stress. IRE1 signaling controls the expression of the transcription factor XBP1, in addition to degrade several RNAs. Importantly, a polymorphism in the XBP1 promoter was suggested as a risk factor to develop AD. Here, we demonstrate a positive correlation between the progression of AD histopathology and the activation of IRE1 in human brain tissue. To define the significance of the UPR to AD, we targeted IRE1 expression in a transgenic mouse model of AD. Despite initial expectations that IRE1 signaling may protect against AD, genetic ablation of the RNase domain of IRE1 in the nervous system significantly reduced amyloid deposition, the content of amyloid β oligomers, and astrocyte activation. IRE1 deficiency fully restored the learning and memory capacity of AD mice, associated with improved synaptic function and improved long-term potentiation (LTP). At the molecular level, IRE1 deletion reduced the expression of amyloid precursor protein (APP) in cortical and hippocampal areas of AD mice. In vitro experiments demonstrated that inhibition of IRE1 downstream signaling reduces APP steady-state levels, associated with its retention at the ER followed by proteasome-mediated degradation. Our findings uncovered an unanticipated role of IRE1 in the pathogenesis of AD, offering a novel target for disease intervention.
Journal Article
Effect of Perioperative Lidocaine, Propofol and Steroids on Pulmonary Metastasis in a Murine Model of Breast Cancer Surgery
Addressing the hypothesis that anaesthetic-analgesic technique during cancer surgery might influence recurrence or metastatic spread is a research priority. Propofol, which has anti-inflammatory properties in vitro, is clinically associated with reduced risk of cancer recurrence compared with sevoflurane anaesthesia in retrospective studies. Amide local anaesthetics, such as lidocaine, have cancer inhibiting effects in vitro. Steroids have anti-inflammatory and immunosuppressive effects and are associated with improved recovery after major non-cancer surgery. We compared the effects of propofol, lidocaine and methylprednisolone on postoperative metastasis in a murine model of breast cancer surgery under sevoflurane anaesthesia. 4T1 tumour cells were introduced into the mammary fat-pad of female BALB/c mice and the resulting tumour resected seven days later under general anaesthesia with sevoflurane. Mice (n = 72) were randomized to four treatment groups: Sevoflurane alone (control); Propofol group received 5 mg.kg−1; Lidocaine group received 1.5 mg.kg−1 followed by 2 mg.kg−1.h−1 infusion; Methylprednisolone group received 30 mg.kg−1 methylprednisolone. The primary outcome measure was pulmonary metastasis colony count, as assessed by in-vitro proliferation, two weeks post-operatively. This was achieved by treating the post-mortem lung tissue with collagenase IV, straining and culturing for 14 days prior to colony count. Compared with control, lidocaine and propofol each individually reduced pulmonary metastasis colonies; mean (SD) 846 (±581) vs. 88 (±52) vs. 34 (±44) respectively, (p = 0.0001 and p = 0.0001). Methylprednisolone increased lung metastasis, 2555 (±609) vs. 846 (±581), p = 0.0001. Post-operative hepatic metastatic disease and serum interleukin-6 and vascular endothelial growth factor levels were similar in all groups. In conclusion, in a murine model of breast cancer surgery during sevoflurane anaesthesia, propofol and lidocaine each decreased pulmonary metastasis, while methylprednisolone increased it.
Journal Article
Effects of Lidocaine and Src Inhibition on Metastasis in a Murine Model of Breast Cancer Surgery
Breast cancer recurs in 20% of patients following intended curative resection. In vitro data indicates that amide local anaesthetics, including lidocaine, inhibit cancer cell metastasis by inhibiting the tyrosine kinase enzyme Src. In a murine breast cancer surgery model, systemic lidocaine reduces postoperative pulmonary metastases. We investigated whether the additional administration of bosutinib (a known Src inhibitor) influences lidocaine’s observed beneficial effect in this in vivo model. Female BALB/c mice (n = 95) were inoculated with 25,000 4T1 cells into the mammary fad pad and after 7 days the resulting tumours were excised under sevoflurane anaesthesia. Experimental animals were randomized to one of four treatments administered intravenously prior to excision: lidocaine, bosutinib, both lidocaine and bosutinib in combination, or saline. Animals were euthanized 14 days post-surgery and lung and liver metastatic colonies were evaluated. Post-mortem serum was analysed for MMP-2 and MMP-9, pro-metastatic enzymes whose expression is influenced by the Src pathway. Lidocaine reduced lung, but not liver metastatic colonies versus sevoflurane alone (p = 0.041), but bosutinib alone had no metastasis-inhibiting effect. When combined with lidocaine, bosutinib reversed the anti-metastatic effect observed with lidocaine on sevoflurane anaesthesia. Only lidocaine alone reduced MMP-2 versus sevoflurane (p = 0.044). Both bosutinib (p = 0.001) and bosutinib/lidocaine combined (p = 0.001) reduced MMP-9 versus sevoflurane, whereas lidocaine alone did not. In a murine surgical breast cancer model, the anti-metastatic effects of lidocaine under sevoflurane anaesthesia are abolished by the Src inhibitor bosutinib, and lidocaine reduces serum MMP-2. These results suggest that lidocaine may act, at least partly, via an inhibitory effect on MMP-2 expression to reduce pulmonary metastasis, but whether this is due to an effect on Src or via another pathway remains unclear.
Journal Article
Effect of Perioperative Lidocaine and Cisplatin on Metastasis in a Murine Model of Breast Cancer Surgery
Mortality from breast cancer is usually attributable to metastasis. In vitro data suggest that amide local anaesthetics, e.g. lidocaine, inhibit metastasis by multiple mechanisms and recent in vivo data support this. Experimental data also suggest that opioids may inhibit cisplatin chemotherapy. Whether lidocaine would influence cisplatin chemotherapy has not been evaluated.
4T1 cells were injected into the mammary gland of immunocompetent female BALB/c mice, with resection of the tumour under sevoflurane anaesthesia one week later. Mice (n=45) were randomized into one of three groups: The cisplatin group received 3 mg.kg
cisplatin; cisplatin and lidocaine group received 3 mg.kg
cisplatin and lidocaine bolus of 1.5 mg.kg
followed by an infusion of 2 mg.kg-1.h
The control group received sevoflurane only. All agents were given perioperatively. After 14 postoperative days, post-mortem lung, serum and liver samples were collected. Primary outcome measure was lung metastasis colony count.
During sevoflurane anaesthesia, the addition of lidocaine to cisplatin significantly decreased metastatic lung colony count [(mean±SD) (157±87)] compared to control [846±581, (p=0.001)], and cisplatin alone [580±383, (p=0.018)]. However, liver metastasis colony count was not reduced with the combination of cisplatin and lidocaine (9.3±13.9) when compared to control (74.7±257.3), p=0.78 or to cisplatin alone (110±388.8), p=0.569. Serum VEGF and interleukin-6 concentrations were not significantly different.
In a 4T1 murine model of breast cancer surgery, under sevoflurane anaesthesia, lidocaine enhanced the metastasis-inhibiting action of cisplatin. Clinical evaluation of the hypothesis that co-administration of systemic lidocaine during cisplatin chemotherapy seems warranted.
Journal Article
When is a handaxe a planned-axe? exploring morphological variability in the Acheulean
The handaxe is an iconic stone tool form used to define and symbolise both the Acheulean and the wider Palaeolithic. There has long been debate around the extent of its morphological variability between sites, and the role that extrinsic factors (especially raw material, blank type, and the extent of resharpening) have played in driving this variability, but there has been a lack of high-resolution examinations of these factors in the same study. In this paper, we present a 2D geometric morphometric analysis of 1097 handaxes from across Africa, the Levant, and western Europe to examine the patterning of this variability and what it can tell us about hominin behaviour. We replicate the findings of previous studies, that handaxe shape varies significantly between sites and entire continental regions, but we find no evidence for raw material, blank type, or resharpening in determining this pattern. What we do find, however, is that markers of reduction trajectory vary substantially between sites, suggesting that handaxes were deployed differently according to hominin need at a given site. We argue this is reflective of a continuum of reduction strategies, from those focused on the maintenance of a sharp cutting edge (i.e. direct use in cutting activities), to those focused on maintaining tip shapes, and perhaps a corresponding production of flakes. Implications for hominin behavioural flexibility are discussed.
Journal Article
Testing Models of the APC Tumor Suppressor/β-Catenin Interaction Reshapes Our View of the Destruction Complex in Wnt Signaling
The Wnt pathway is a conserved signal transduction pathway that contributes to normal development and adult homeostasis, but is also misregulated in human diseases such as cancer. The tumor suppressor adenomatous polyposis coli (APC) is an essential negative regulator of Wnt signaling inactivated in >80% of colorectal cancers. APC participates in a multiprotein “destruction complex” that targets the proto-oncogene β-catenin for ubiquitin-mediated proteolysis; however, the mechanistic role of APC in the destruction complex remains unknown. Several models of APC function have recently been proposed, many of which have emphasized the importance of phosphorylation of high-affinity β-catenin-binding sites [20-amino-acid repeats (20Rs)] on APC. Here we test these models by generating a Drosophila APC2 mutant lacking all β-catenin-binding 20Rs and performing functional studies in human colon cancer cell lines and Drosophila embryos. Our results are inconsistent with current models, as we find that β-catenin binding to the 20Rs of APC is not required for destruction complex activity. In addition, we generate an APC2 mutant lacking all β-catenin-binding sites (including the 15Rs) and find that a direct β-catenin/APC interaction is also not essential for β-catenin destruction, although it increases destruction complex efficiency in certain developmental contexts. Overall, our findings support a model whereby β-catenin-binding sites on APC do not provide a critical mechanistic function per se, but rather dock β-catenin in the destruction complex to increase the efficiency of β-catenin destruction. Furthermore, in Drosophila embryos expressing some APC2 mutant transgenes we observe a separation of β-catenin destruction and Wg/Wnt signaling outputs and suggest that cytoplasmic retention of β-catenin likely accounts for this difference.
Journal Article
Continued disappearance of the benthic amphipod Diporeia spp. in Lake Michigan: is there evidence for food limitation?
Benthic surveys were conducted in the southern basin of Lake Michigan and throughout the lake to assess trends in benthic populations, emphasizing recent changes in densities of the benthic amphipod Diporeia spp. and dreissenid mussels. In the southern basin, Diporeia populations declined 89%, 91%, and 45% between 1993 and 2002 at sites <30, 3150, and 5190 m, respectively. Lakewide, the population declined 65% between 19941995 and 2000. Over the same time period, dreissenid densities, particularly Dreissena bugensis, increased. Intensive studies at 45 m sites in the southeastern region examined changes in lipid content, age structure, and benthic food inputs relative to the hypothesis that food limitation was a factor in Diporeia's disappearance. As Diporeia densities declined to zero, lengthweight remained unchanged, and lipid content generally increased. Recruitment still occurred, but the young did not survive to become adults. Based on organic carbon, biogenic silica, and chlorophyll collected in sediment traps and found in the upper sediments, pelagic inputs to the benthic region still occurred. Our field observations and laboratory experiments did not disprove the hypothesis that food limitation from dreissenid filtering activities was the cause of the decline, but direct relationships between the loss of Diporeia and indicators of food availability were difficult to establish.
Journal Article