Arsenic-induced neurotoxicity in patients with acute promyelocytic leukaemia.

Arsenic trioxide is an essential component of therapy for acute promyelocytic leukaemia (APL) and is currently dosed on actual body weight with no upper limit. Arsenic-induced neurotoxicity is a well-recognised complication; however, there is uncertainty about its relationship to arsenic dose and obesity. We conducted a large multicentre retrospective study of 487 patients with APL treated with arsenic-based therapy across 23 sites in Australia from 2008 to 2023. The primary outcome was incidence of neurotoxicity, and secondary outcomes included relationship of neurotoxicity to obesity and cumulative arsenic dose. Any-grade neurotoxicity occurred in 113 (23%) patients, predominantly peripheral neuropathy (91%). Most events were grade 1-2 severity (85%), with grade 3 events in 12% and grade 4-5 in 3%. The incidence of neurotoxicity increased with BMI (non-obese: 16%, obesity class I: 25%, obesity class II-III: 41%; p < 0.001). On univariable analysis, obesity class I (OR 1.81, p = 0.036), obesity class II-III (OR 3.93, p < 0.001), weight >100 kg (OR 2.72, p < 0.001), daily arsenic trioxide dose >15 mg (OR 5.05, p < 0.001) and cumulative induction dose >500 mg (OR 3.95, p < 0.001) were all significantly associated with neurotoxicity. Obesity class II-III and induction dose >500 mg remained significant on multivariable analysis. Our study highlights the strong association between BMI, arsenic trioxide dose and neurotoxicity. Pre-emptive dose reductions should be considered for obese patients receiving high doses of arsenic.

Convergent Metabotropic Signaling Pathways Inhibit SK Channels to Promote Synaptic Plasticity in the Hippocampus.

Hebbian synaptic plasticity at hippocampal Schaffer collateral synapses is tightly regulated by postsynaptic small conductance (SK) channels that restrict NMDA receptor activity. SK channels are themselves modulated by G-protein-coupled signaling pathways, but it is not clear under what conditions these are activated to enable synaptic plasticity. Here, we show that muscarinic M1 receptor (M1R) and type 1 metabotropic glutamate receptor (mGluR1) signaling pathways, which are known to inhibit SK channels and thereby disinhibit NMDA receptors, converge to facilitate spine calcium transients during the induction of long-term potentiation (LTP) at hippocampal Schaffer collateral synapses onto CA1 pyramidal neurons of male rats. Furthermore, mGluR1 activation is required for LTP induced by reactivated place-cell firing patterns that occur in sharp-wave ripple events during rest or sleep. In contrast, M1R activation is required for LTP induced by place-cell firing patterns during exploration. Thus, we describe a common mechanism that enables synaptic plasticity during both encoding and consolidation of memories within hippocampal circuits.SIGNIFICANCE STATEMENT Memory ensembles in the hippocampus are formed during active exploration and consolidated during rest or sleep. These two distinct phases each require strengthening of synaptic connections by long-term potentiation (LTP). The neuronal activity patterns in each phase are very different, which makes it hard to map generalized rules for LTP induction onto both formation and consolidation phases. In this study, we show that inhibition of postsynaptic SK channels is a common necessary feature of LTP induction and that SK channel inhibition is achieved by separate but convergent metabotropic signaling pathways. Thus, we reveal a common mechanism for enabling LTP under distinct behavioral conditions.

Comprehensive geriatric assessment is useful in an elderly Australian population with diffuse large B-cell lymphoma receiving rituximab-chemotherapy combinations.

Elderly patients may be heterogeneous in their abilities to tolerate immunochemotherapy-associated toxicities. We describe the morbidity of rituximab-chemotherapy combinations among 205 newly-diagnosed diffuse large B-cell lymphoma (DLBCL) patients aged ≥60 years from 3 tertiary hospitals between 2009 and 2016, and explore the utility of retrospectively-assigned baseline Comprehensive Geriatric Assessment (CGA) in predicting these toxicities. Seventy-three percent (146/201) experienced grade ≥3 toxicities, 81% (163/201) needed admission, 52% (107/205) had ≥2 unplanned admissions, 82/201 (41%) required dose reductions (DR) subsequent to Cycle 1, 39/166 (23%) had chemotherapy delays and 26/198 (13%) ceased therapy early. CGA was associated with pre-emptive baseline DR and perhaps because of this, did not predict grade ≥3 toxicities, ≥2 unplanned admissions or subsequent DR. Three-year overall survival (OS) of CGA-fit, CGA-unfit and CGA-frail patients was 82%, 60% and 53%, respectively. Three-year progression-free survival (PFS) of CGA-fit, CGA-unfit and CGA-frail patients was 66%, 58% and 46%, respectively. OS of CGA-fit patients was not statistically different from CGA-unfit patients, but was superior to CGA-frail patients (hazard ratio 2·892, 95% confidence interval 1·275-6·559, P = 0·011). PFS differences were not statistically significant. Baseline DR and early therapy cessation were associated with inferior OS and PFS independent of CGA. Prospective studies are needed to confirm if CGA-adapted treatment strategies minimize morbidity and improves survival.

Tryptophan oxidation in proteins exposed to thiocyanate-derived oxidants.

Human defensive peroxidases, including lactoperoxidase (LPO) and myeloperoxidase (MPO), are capable of catalyzing the oxidation of halides (X(-)) by H2O2 to give hypohalous acids (HOX) for the purpose of cellular defense. Substrate selectivity depends upon the relative abundance of the halides, but the pseudo-halide thiocyanate (SCN(-)) is a major substrate, and sometimes the exclusive substrate, of all defensive peroxidases in most physiologic fluids. The resulting hypothiocyanous acid (HOSCN) has been implicated in cellular damage via thiol oxidation. While thiols are believed to be the primary target of HOSCN in vivo, Trp residues have also been implicated as targets for HOSCN. However, the mechanism involved in HOSCN-mediated Trp oxidation was not established. Trp residues in proteins appeared to be susceptible to oxidation by HOSCN, whereas free Trp and Trp residues in small peptides were found to be unreactive. We show that HOSCN-induced Trp oxidation is dependent on pH, with oxidation of free Trp, and Trp-containing peptides observed when the pH is below 2. These conditions mimic those employed previously to precipitate proteins after treatment with HOSCN, which accounts for the discrepancy in the results reported for proteins versus free Trp and small peptides. The reactant in these cases may be thiocyanogen ((SCN)2), which is produced by comproportionation of HOSCN and SCN(-) at low pH. Reaction of thiocyanate-derived oxidants with protein Trp residues at low pH results in the formation of a number of oxidation products, including mono- and di-oxygenated derivatives, which are also formed with other hypohalous acids. Our data suggest that significant modification of Trp by HOSCN in vivo is likely to have limited biological relevance.

Goals of care: a clinical framework for limitation of medical treatment.

A novel clinical framework called "goals of care" (GOC) has been designed as a replacement for not-for-resuscitation orders. The aim is to improve decision making and documentation relating to limitations of medical treatment. Clinicians assign a patient's situation to one of three phases of care - curative or restorative, palliative, or terminal -according to an assessment of likely treatment outcomes. This applies to all admitted patients, and the default position is the curative or restorative phase. GOC helps identify patients who wish to decline treatments that might otherwise be given, such as treatment with blood products. This includes patients for whom specific limitations apply because of their beliefs. GOC has been introduced at Royal Hobart Hospital, Tasmania, and at Northern Health, Melbourne. So far, audit data and staff feedback have been favourable. There have been no reported major incidents or complaints in which GOC has been causally implicated in an adverse outcome.

Conservative versus interventional management for primary spontaneous pneumothorax in adults.

BACKGROUND: Primary spontaneous pneumothorax is widely managed according to size with interventional techniques based on practice guidelines. Interventional management is not without complications and observational data suggest conservative management works. The current guidelines are based on expert consensus rather than evidence, and a systematic review may help in identifying evidence for this practice. OBJECTIVES: The objective of the review is to compare conservative and interventional treatments of adult primary spontaneous pneumothorax for outcomes of clinical efficacy, tolerability and safety. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), (The Cochrane Library, Issue 6, 2014); MEDLINE via Ovid SP (1920 to 26th June 2014); EMBASE via Ovid SP (1947 to 26th June 2014); CINAHL via EBSCO host (1980 to 26th June 2014); and ISI Web of Science (1945 to 26th June 2014). We searched ongoing trials via the relevant databases and contacted authors. We also searched the 'grey literature'. SELECTION CRITERIA: We included randomized controlled trials (RCTs) and we accepted quasi-RCTs if a systematic method of allocation was used. Participants were limited to adults aged 18 to 50 years, with their first symptomatic primary spontaneous pneumothorax with radiological evidence and no underlying lung disease. DATA COLLECTION AND ANALYSIS: Two of five authors independently reviewed all studies in the search criteria and made inclusions and exclusions according to the selection criteria. No statistical methods were necessary as there were no included trials. MAIN RESULTS: We identified 358 studies with duplicates removed. There were three potentially relevant studies that we excluded as they were not randomized controlled trials. There was one ongoing trial that was relevant and we contacted the authors and confirmed the study is ongoing at June 2014. We will update this review when this ongoing study is completed. AUTHORS' CONCLUSIONS: There are no completed randomized controlled trials comparing conservative and interventional management for primary spontaneous pneumothorax in adults. There is a lack of high-quality evidence for current guidelines in management and a need for randomized controlled trials comparing conservative and interventional management for this condition.

Who knows, who cares? Dementia knowledge among nurses, care workers, and family members of people living with dementia.

The number of people with dementia is increasing rapidly worldwide. Commensurate with population ageing, the use of nursing homes in Australia (known as residential aged care facilities) for individuals with dementia is growing. As a terminal condition, dementia is best managed by instituting a palliative approach to care. A good knowledge of dementia, including its progression and management, among staff and families of people living with dementia is essential for clear decision making and the provision of appropriate care. Yet there is limited information regarding relative levels of dementia knowledge. This paper reports the results of a study that assessed dementia knowledge among these two cohorts using the Dementia Knowledge Assessment Tool; the study surveyed 279 staff members and 164 family members of residents with dementia. Dementia knowledge deficits were evident in both cohorts across a range of areas. It is critical that dementia knowledge deficits are identified and addressed in order to support evidence-based dementia care.

A tool to aid talking about dementia and dying--development and evaluation.

BACKGROUND: Health professionals often avoid talking about death and dying with patients and relatives, and this avoidance is compounded in cases of dementia by lack of knowledge of trajectory and prognosis. Unfortunately, this impacts on care, with many terminally ill dementia clients receiving inadequate palliation and excessive intervention at end-of-life. This study developed and evaluated a tool to facilitate conversations about death and dying in aged care facilities. METHODS: This study utilised available best-practice evidence, feedback from aged care facility nursing and care staff and specialist input to develop the 'discussion tool', which was subsequently trialled and qualitatively evaluated, via thematic analysis of data from family interviews and staff diaries. The study was part of a larger mixed method study, not yet reported. The tool provided knowledge and also skills-based 'how to' information and specific examples of 'what to say'. RESULTS: The tool facilitated a more open dialogue between dementia palliation resource nurses (a role specifically developed during this project) and family members. Both resource nurses and family members gained confidence in discussing the death of their relative with dementia, and in relevant cases discussed specific decisions around future care. Family members and nurses reported satisfaction with these discussions. CONCLUSION: Providing specific skills-based support, such as the 'discussion tool' can help staff to gain confidence and change practice in situations where unfamiliar and uncomfortable practices might normally be avoided. As our populations age, health professionals will increasingly need to be able to openly discuss care options towards end-of-life.

Synaptic alterations associated with disrupted sensory encoding in a mouse model of tauopathy.

Synapse loss is currently the best biological correlate of cognitive decline in Alzheimer's disease and other tauopathies. Synapses seem to be highly vulnerable to tau-mediated disruption in neurodegenerative tauopathies. However, it is unclear how and when this leads to alterations in function related to the progression of tauopathy and neurodegeneration. We used the well-characterized rTg4510 mouse model of tauopathy at 5-6 months and 7-8 months of age, respectively, to study the functional impact of cortical synapse loss. The earlier age was used as a model of prodromal tauopathy, with the later age corresponding to more advanced tau pathology and presumed progression of neurodegeneration. Analysis of synaptic protein expression in the somatosensory cortex showed significant reductions in synaptic proteins and NMDA and AMPA receptor subunit expression in rTg4510 mice. Surprisingly, in vitro whole-cell patch clamp electrophysiology from putative pyramidal neurons in layer 2/3 of the somatosensory cortex suggested no functional alterations in layer 4 to layer 2/3 synaptic transmission at 5-6 months. From these same neurons, however, there were alterations in dendritic structure, with increased branching proximal to the soma in rTg4510 neurons. Therefore, in vivo whole-cell patch clamp recordings were utilized to investigate synaptic function and integration in putative pyramidal neurons in layer 2/3 of the somatosensory cortex. These recordings revealed a significant increase in the peak response to synaptically driven sensory stimulation-evoked activity and a loss of temporal fidelity of the evoked signal to the input stimulus in rTg4510 neurons. Together, these data suggest that loss of synapses, changes in receptor expression and dendritic restructuring may lead to alterations in synaptic integration at a network level. Understanding these compensatory processes could identify targets to help delay symptomatic onset of dementia.

Targeting Molecular Measurable Residual Disease and Low-Blast Relapse in AML With Venetoclax and Low-Dose Cytarabine: A Prospective Phase II Study (VALDAC).

PURPOSE: A prospective phase II study examined the safety and efficacy of venetoclax combined with low-dose cytarabine (LDAC) in AML at first measurable residual disease (MRD) or oligoblastic relapse. METHODS: Patients with either MRD (≥1 log10 rise) or oligoblastic relapse (blasts 5%-15%) received venetoclax 600 mg once daily D1-28 plus LDAC once daily D1-10 in 28-day cycles. The primary objective was MRD response in the MRD relapse cohort or complete remission (CR/CRh/CRi) in the oligoblastic relapse cohort. RESULTS: Forty-eight adults with either MRD (n = 26) or oligoblastic (n = 22) relapse were enrolled. Median age was 67 years (range, 18-80) and 94% had received previous intensive chemotherapy. Patients received a median of four cycles of therapy; 17% completed ≥12 cycles. Patients with oligoblastic relapse had more grade ≥3 anemia (32% v 4%; P = .02) and infections (36% v 8%; P = .03), whereas grade 4 neutropenia (32 v 23%) or thrombocytopenia (27 v 15%) were comparable with the MRD relapse cohort. Markers of molecular MRD relapse included mutant NPM1 (77%), CBFB::MYH11 (4%), RUNX1::RUNX1T1 (4%), or KMT2A::MLLT3 (4%). Three patients with a log10 rise in IDH1/2 (12%) were included. By cycle 2 in the MRD relapse cohort, a log10 reduction in MRD was observed in 69%; 46% achieved MRD negative remission. In the oligoblastic relapse cohort, 73% achieved CR/CRh/CRi. Overall, 21 (44%) underwent hematopoietic cell transplantation. Median overall survival (OS) was not reached in either cohort. Estimated 2-year OS rate was 67% (95% CI, 50 to 89) in the MRD and 53% (95% CI, 34 to 84) in the oligoblastic relapse cohorts. CONCLUSION: For AML in first remission and either MRD or oligoblastic relapse, venetoclax plus LDAC is well tolerated and highly effective.

APP fragment controls both ionotropic and non-ionotropic signaling of NMDA receptors.

NMDA receptors (NMDARs) are ionotropic receptors crucial for brain information processing. Yet, evidence also supports an ion-flux-independent signaling mode mediating synaptic long-term depression (LTD) and spine shrinkage. Here, we identify AETA (Aη), an amyloid-ß precursor protein (APP) cleavage product, as an NMDAR modulator with the unique dual regulatory capacity to impact both signaling modes. AETA inhibits ionotropic NMDAR activity by competing with the co-agonist and induces an intracellular conformational modification of GluN1 subunits. This favors non-ionotropic NMDAR signaling leading to enhanced LTD and favors spine shrinkage. Endogenously, AETA production is increased by in vivo chemogenetically induced neuronal activity. Genetic deletion of AETA production alters NMDAR transmission and prevents LTD, phenotypes rescued by acute exogenous AETA application. This genetic deletion also impairs contextual fear memory. Our findings demonstrate AETA-dependent NMDAR activation (ADNA), characterizing AETA as a unique type of endogenous NMDAR modulator that exerts bidirectional control over NMDAR signaling and associated information processing.

Psychosocial factors in adults with chronic kidney disease: characteristics of pilot participants in the Tasmanian Chronic Kidney Disease study.

BACKGROUND: Psychosocial factors including depression, anxiety and lower social support are common in patients with chronic kidney disease (CKD). However the influence of these potentially modifiable risk factors on morbidity and mortality in this renal population is unknown. The Tasmanian Chronic Kidney Disease study is a prospective cohort study which aims to examine the influence of both biomedical and psychosocial factors on disease progression, decision making and length and quality of life in adults with severe CKD, prior to kidney replacement therapy (KRT). This paper describes the recruitment, baseline characteristics and initial follow-up of pilot participants. METHODS: Adults aged > 18 years with stage 4 CKD (eGFR 15-29 mls/min/1.73 m2) and not receiving dialysis were recruited via treating physicians. Measures included depression (9-item Patient Health Questionnaire), anxiety (Beck Anxiety Inventory) and social support (Multidimensional Scale of Perceived Social Support). Primary outcomes were kidney disease progression, use of KRT and health-related quality of life (Kidney Disease and Quality of Life Short Form and the EQ-5D). RESULTS: Of those invited (n = 105), 49 provided consent and completed baseline assessment. There were no significant differences between responders and non-responders in age, gender and socio-economic status (all p > 0.05). Participants were predominantly male (63.3%) with a mean age of 72.6 ± 10.2 years. Mean serum creatinine was 241 ± 62 µmol/L with mean eGFR 22 ± 5 mls/min/1.73 m2. Prevalence of major depression and moderate to severe anxiety was 10% and 9% respectively. Less severe depression and fewer anxiety symptoms were associated with higher health-related quality of life. Follow-up at 10-months showed CKD progression in 34% of participants (use of KRT in 16%, stage 5 CKD without KRT in 18%), one death, with the remainder stable at CKD stage 3 or 4. CONCLUSIONS: Results indicate that a larger prospective study is feasible and has the capacity to examine the influence of biomedical and psychosocial factors on kidney disease progression, use of dialysis and transplantation, and salient personal and economic outcomes. Findings have the potential to provide an evidence base for revising healthcare provision in order to optimize the care of patients with CKD.

The goals of care framework and the perioperative period: A practical approach.

The goals of care (GOC) framework (2014) is an illness phase categorisation system that enables limitations of medical treatment (LOMT) to be documented and communicated within a healthcare system. It incorporates a clinical assessment of illness phase and GOC discussion on aims and LOMT for an episode of care. Together, this results in documentation of a GOC category that guides treatment escalation decisions during episodes of patient deterioration. Confusion exists about incorporating this framework into the perioperative period, particularly management of treatment escalation required for patient survival during surgery that is at variance with agreed goals and limitations. A historical tendency for automatic and unilateral suspension of limitations during surgery may be susceptible to ethical or medicolegal challenge. This article highlights the difference between the GOC framework and 'not for resuscitation' framework, considers the unique considerations of the perioperative period and addresses misconceptions of the GOC framework in patients undergoing surgery. Finally, it provides an approach to the GOC framework for patients considered for surgery by emphasising illness phase assessment and the need for the GOC category to accurately reflect the clinical situation throughout the perioperative period, guiding treatment escalation intraoperatively and postoperatively.

Catabolite control protein A controls hydrogen peroxide production and cell death in Streptococcus sanguinis.

Streptococcus sanguinis is a commensal oral bacterium producing hydrogen peroxide (H2O2) that is dependent on pyruvate oxidase (Spx) activity. In addition to its well-known role in bacterial antagonism during interspecies competition, H2O2 causes cell death in about 10% of the S. sanguinis population. As a consequence of H2O2-induced cell death, largely intact chromosomal DNA is released into the environment. This extracellular DNA (eDNA) contributes to the self-aggregation phenotype under aerobic conditions. To further investigate the regulation of spx gene expression, we assessed the role of catabolite control protein A (CcpA) in spx expression control. We report here that CcpA represses spx expression. An isogenic ΔccpA mutant showed elevated spx expression, increased Spx abundance, and H2O2 production, whereas the wild type did not respond with altered spx expression in the presence of glucose and other carbohydrates. Since H2O2 is directly involved in the release of eDNA and bacterial cell death, the presented data suggest that CcpA is a central control element in this important developmental process in S. sanguinis.

The role of the GluR2 subunit in AMPA receptor function and synaptic plasticity.

The AMPA receptor (AMPAR) GluR2 subunit dictates the critical biophysical properties of the receptor, strongly influences receptor assembly and trafficking, and plays pivotal roles in a number of forms of long-term synaptic plasticity. Most neuronal AMPARs contain this critical subunit; however, in certain restricted neuronal populations and under certain physiological or pathological conditions, AMPARs that lack this subunit are expressed. There is a current surge of interest in such GluR2-lacking Ca2+-permeable AMPARs in how they affect the regulation of synaptic transmission. Here, we bring together recent data highlighting the novel and important roles of GluR2 in synaptic function and plasticity.

Myeloperoxidase-induced genomic DNA-centered radicals.

Myeloperoxidase (MPO) released by activated neutrophils can initiate and promote carcinogenesis. MPO produces hypochlorous acid (HOCl) that oxidizes the genomic DNA in inflammatory cells as well as in surrounding epithelial cells. DNA-centered radicals are early intermediates formed during DNA oxidation. Once formed, DNA-centered radicals decay by mechanisms that are not completely understood, producing a number of oxidation products that are studied as markers of DNA oxidation. In this study we employed the 5,5-dimethyl-1-pyrroline N-oxide-based immuno-spin trapping technique to investigate the MPO-triggered formation of DNA-centered radicals in inflammatory and epithelial cells and to test whether resveratrol blocks HOCl-induced DNA-centered radical formation in these cells. We found that HOCl added exogenously or generated intracellularly by MPO that has been taken up by the cell or by MPO newly synthesized produces DNA-centered radicals inside cells. We also found that resveratrol passed across cell membranes and scavenged HOCl before it reacted with the genomic DNA, thus blocking DNA-centered radical formation. Taken together our results indicate that the formation of DNA-centered radicals by intracellular MPO may be a useful point of therapeutic intervention in inflammation-induced carcinogenesis.

Mechanism of decomposition of the human defense factor hypothiocyanite near physiological pH.

Relatively little is known about the reaction chemistry of the human defense factor hypothiocyanite (OSCN(-)) and its conjugate acid hypothiocyanous acid (HOSCN), in part because of their instability in aqueous solutions. Herein we report that HOSCN/OSCN(-) can engage in a cascade of pH- and concentration-dependent comproportionation, disproportionation, and hydrolysis reactions that control its stability in water. On the basis of reaction kinetic, spectroscopic, and chromatographic methods, a detailed mechanism is proposed for the decomposition of HOSCN/OSCN(-) in the range of pH 4-7 to eventually give simple inorganic anions including CN(-), OCN(-), SCN(-), SO(3)(2-), and SO(4)(2-). Thiocyanogen ((SCN)(2)) is proposed to be a key intermediate in the hydrolysis; and the facile reaction of (SCN)(2) with OSCN(-) to give NCS(═O)SCN, a previously unknown reactive sulfur species, has been independently investigated. The mechanism of the aqueous decomposition of (SCN)(2) around pH 4 is also reported. The resulting mechanistic models for the decomposition of HOSCN and (SCN)(2) address previous empirical observations, including the facts that the presence of SCN(-) and/or (SCN)(2) decreases the stability of HOSCN/OSCN(-), that radioisotopic labeling provided evidence that under physiological conditions decomposing OSCN(-) is not in equilibrium with (SCN)(2) and SCN(-), and that the hydrolysis of (SCN)(2) near neutral pH does not produce OSCN(-). Accordingly, we demonstrate that, during the human peroxidase-catalyzed oxidation of SCN(-), (SCN)(2) cannot be the precursor of the OSCN(-) that is produced.

Coordinated developmental recruitment of latent fast spiking interneurons in layer IV barrel cortex.

Feedforward inhibitory GABAergic transmission is critical for mature cortical circuit function; in the neonate, however, GABA is depolarizing and believed to have a different role. Here we show that the GABAA receptor-mediated conductance is depolarizing in excitatory (stellate) cells in neonatal (postnatal day [P]3-5) layer IV barrel cortex, but GABAergic transmission at this age is not engaged by thalamocortical input in the feedforward circuit and has no detectable circuit function. However, recruitment occurs at P6-7 as a result of coordinated increases in thalamic drive to fast-spiking interneurons, fast-spiking interneuron-stellate cell connectivity and hyperpolarization of the GABAA receptor-mediated response. Thus, GABAergic circuits are not engaged by thalamocortical input in the neonate, but are poised for a remarkably coordinated development of feedforward inhibition at the end of the first postnatal week, which has profound effects on circuit function at this critical time in development.