Cholecystokinin B receptor agonists alleviates anterograde amnesia in cholecystokinin-deficient and aged Alzheimer's disease mice.

BACKGROUND: As one major symptom of Alzheimer's disease (AD), anterograde amnesia describes patients with an inability in new memory formation. The crucial role of the entorhinal cortex in forming new memories has been well established, and the neuropeptide cholecystokinin (CCK) is reported to be released from the entorhinal cortex to enable neocortical associated memory and long-term potentiation. Though several studies reveal that the entorhinal cortex and CCK are related to AD, it is less well studied. It is unclear whether CCK is a good biomarker or further a great drug candidate for AD. METHODS: mRNA expressions of CCK and CCK-B receptor (CCKBR) were examined in two mouse models, 3xTg AD and CCK knock-out (CCK-/-) mice. Animals' cognition was investigated with Morris water maze, novel object recognition test and neuroplasticity with in-vitro electrophysiological recording. Drugs were given intraperitoneally to animals to investigate the rescue effects on cognitive deficits, or applied to brain slices directly to explore the influence in inducement of long-term potentiation. RESULTS: Aged 3xTg AD mice exhibited reduced CCK mRNA expression in the entorhinal cortex but reduced CCKBR expression in the neocortex and hippocampus, and impaired cognition and neuroplasticity comparable with CCK-/- mice. Importantly, the animals displayed improved performance and enhanced long-term potentiation after the treatment of CCKBR agonists. CONCLUSIONS: Here we provide more evidence to support the role of CCK in learning and memory and its potential to treat AD. We elaborated on the rescue effect of a promising novel drug, HT-267, on aged 3xTg AD mice. Although the physiological etiology of CCK in AD still needs to be further investigated, this study sheds light on a potential pharmaceutical candidate for AD and dementia.

Seizures and memory impairment induced by patient-derived anti-N-methyl-D-aspartate receptor antibodies in mice are attenuated by anakinra, an interleukin-1 receptor antagonist.

OBJECTIVE: Neuroinflammation associated with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis may facilitate seizures. We previously showed that intraventricular administration of cerebrospinal fluid from patients with anti-NMDAR encephalitis to mice precipitates seizures, thereby confirming that antibodies are directly pathogenic. To determine whether interleukin (IL)-1-mediated inflammation exacerbates autoimmune seizures, we asked whether blocking the effects of IL-1 by anakinra, a selective IL-1 receptor antagonist, blunts antibody-induced seizures. METHODS: We infused C57BL/6 mice intraventricularly with purified serum IgG from patients with anti-NMDAR encephalitis or monoclonal anti-NMDAR IgG; subdural electroencephalogram was continuously recorded. After a 6-day interval, mice received anakinra (25 mg/kg sc, twice daily) or vehicle for 5 days. Following a 4-day washout period, we performed behavioral tests to assess motor function, anxiety, and memory, followed by hippocampus tissue analysis to assess astrocytic (glial fibrillary acidic protein [GFAP]) and microglial (ionized calcium-binding adapter molecule [Iba]-1) activation. RESULTS: Of 31 mice infused with purified patient NMDAR-IgG (n = 17) or monoclonal NMDAR-IgG (n = 14), 81% developed seizures. Median baseline daily seizure count during exposure to antibodies was 3.9; most seizures were electrographic. Median duration of seizures during the baseline was 82.5 s. Anakinra administration attenuated daily seizure frequency by 60% (p = .02). Anakinra reduced seizure duration; however, the effect was delayed and became apparent only after the cessation of treatment (p = .04). Anakinra improved novel object recognition in mice with antibody-induced seizures (p = .03) but did not alter other behaviors. Anakinra reduced the expression of GFAP and Iba-1 in the hippocampus of mice with seizures, indicating decreased astrocytic and microglial activation. SIGNIFICANCE: Our evidence supports a role for IL-1 in the pathogenesis of seizures in anti-NMDAR encephalitis. These data are consistent with therapeutic effects of anakinra in other severe autoimmune and inflammatory seizure syndromes. Targeting inflammation via blocking IL-1 receptor-mediated signaling may be promising for developing novel treatments for refractory autoimmune seizures.

The effect of remimazolam on postoperative memory retention and delayed regeneration in breast surgery patients: Rationale and design of an exploratory, randomized, open, propofol-controlled, single-center clinical trial: A study protocol.

BACKGROUND: Remimazolam, a benzodiazepine ultra-short-acting sedative, has been used in general anesthesia since August 2020. It is used in awake surgeries that require awakening the patient in the middle of the surgery because of its rapid awakening effect as well as antagonistic interactions. If remimazolam has associated anterograde amnesia similar to benzodiazepines, it will have a positive effect on preventing psychological trauma. However, to our knowledge, the effect of remimazolam on anterograde amnesia has not been previously examined. METHODS/DESIGN: The aim of this exploratory, open, propofol-controlled, single-center, randomized clinical trial is to examine the effect of remimazolam on postoperative memory retention and delayed regeneration. Seventy patients undergoing breast surgery will be included in the study. The patients will be randomly assigned to receive propofol or remimazolam as sedatives during surgery. The primary endpoint is the number of posters patients remember 24 hours after surgery (among 4 posters shown after awakening from anesthesia) as an assessment of anterograde amnesia. Secondary endpoints are retrograde amnesia, dose of analgesic given from the time the patient returns to the ward until 24 hours after surgery, immediate postoperative pain numerical rating scale scores, and pain numerical rating scale scores 24 hours after leaving the operating room. Recruitment will take place between October 2021 and March 2022 to achieve the target sample size. DISCUSSION: To our knowledge, this is the first trial designed to examine the effects of remimazolam on postoperative memory retention and delayed regeneration in patients undergoing breast surgery. TRIAL REGISTRATION: This clinical trial was registered at the University Hospital Medical Information Network (UMIN) Center on September 28, 2021 (UMIN-CTR: UMIN000045593).

Human herpes virus-6 encephalitis causing severe anterograde amnesia associated with rituximab, azathioprine and prednisolone combination therapy for dermatomyositis.

Human herpes virus-6 (HHV-6) reactivation is a well-recognised complication following haematological stem cell transplantation, but it is novel in the context of combination immunomodulatory therapy for autoimmune disease. We report a case of severe anterograde amnesia caused by HHV-6 encephalitis in a young female patient on rituximab, azathioprine and prednisolone for dermatomyositis (DM). The use of targeted biologic treatments for systemic autoimmune connective tissue diseases (CTDs) is increasing, particularly when refractory to conventional management. The anti-CD20 B cell depleting monoclonal antibody, rituximab is now increasingly used, often in combination with conventional immunomodulatory treatments, in certain autoimmune neurological conditions and systemic CTDs including DM. Physicians should be aware of the possibility of HHV-6 in those who develop encephalitis while CD20 B cell deplete, especially in the presence of additional immunomodulatory therapies. Prompt diagnosis and treatment of HHV-6 encephalitis with evidence-based anti-viral therapy may help reduce the extent of irreversible morbidity such as amnesia.

High-Dose Benzodiazepine Users' Perceptions and Experiences of Anterograde Amnesia.

Associations between criminal activity and the use of psychotropic substances are well established. Flunitrazepam, specifically, has been suspected of triggering, per se, violent criminal behavior and severe memory disturbances in the form of anterograde amnesia. However, data from investigations of this relationship are scarce and have been primarily derived from forensic institutions, where there may be a reporting bias. This study was a qualitative exploration of high-dose benzodiazepine users' experiences of anterograde amnesia symptoms and their beliefs about their behavior during the phases of memory impairment in a nonforensic setting. Users subjectively reported experiencing symptoms of anterograde amnesia, especially after combining short-acting benzodiazepines with alcohol, but only rarely when using slow-onset, long-acting compounds. They perceived their experiences as unpleasurable, unpredictable, and embarrassing. Their awareness developed with time, triggered by descriptions of disinhibited and erratic behavior by others. Users described being victimized during phases of anterograde amnesia in addition to engaging in violent and criminal activities themselves. Although unable to recall, many participants believed that they had been able to make rational decisions while intoxicated with flunitrazepam, disregarding notions of diminished insight. In light of the varying terminology used for the phases of memory disturbance and these findings, we suggest that forensic experts additionally explore evaluees' beliefs about amnestic periods and their self-perceptions about their behaviors during these episodes, when evaluating high-dose benzodiazepine-dependent patients.

Further improving the cognitive effect profile of electroconvulsive therapy (ECT): the case for studying carbamylated erythropoietin.

Electroconvulsive therapy (ECT) remains the most effective acute treatment for severe depression and several other psychiatric illnesses. However, its use has been limited by concerns about cognitive adverse effects. ECT may cause temporary cognitive impairment in some patients, typically anterograde amnesia for 1-2 weeks after a course of treatment, and circumscribed retrograde amnesia. These cognitive effects largely disappear within days to weeks after treatment. Efforts to find a pharmacological agent to reduce the cognitive effects of ECT have largely been unsuccessful, with the possible exception of thyroid hormone. We review the literature on pharmacological attempts to attenuate ECT's cognitive effects, and propose a novel neuroprotective and neurotrophic agent, carbamylated erythropoietin (CEPO), for this indication.

Clinical, neuropsychological, and metabolic characteristics of transient epileptic amnesia syndrome.

OBJECTIVE: Transient epileptic amnesia (TEA) is a recently individualized syndrome occurring in adult patients that includes epileptic seizures with amnestic features and interictal memory disturbances. METHODS: We investigated the clinical, neuropsychological, and 18F-FDG positron emission tomography (18F-FDG-PET) features of 30 consecutive cases of TEA in our center. RESULTS: The mean age of onset of amnestic seizures was 59 years. Pure acute amnesia was the only epileptic manifestation in 17% of cases. Interictal electroencephalography (EEG) abnormalities were present in 57% on awake recording and in most patients in whom sleep EEG was performed (96%). Nine of 30 patients showed anterograde memory deficit and six of 30 exhibited mild executive functioning impairment. On the autobiographical memory interview (AMI), patients showed a significant deficit for the recent period of the episodic subscale. Outcome under treatment was favorable in the majority of cases. A significant improvement was noted on recollection of autobiographical memory. 18F-FDG-PET (22 cases) showed positive correlations between left mesial temporal metabolism levels and anterograde and retrograde memory scores. SIGNIFICANCE: TEA is an emerging epileptic syndrome that likely remains misidentified and misdiagnosed. Neurometabolic data support a dysfunction of a hippocampal-neocortical network sustaining episodic memory.

[Transient Epileptic Amnesia: a case report and a reappraisal]. / Amnésie transitoire épileptique ou ictus amnésique épileptique : discussion nosographique à partir d'un cas clinique.

Transient Epileptic Amnesia is a late-onset form of temporal lobe epilepsy characterized by recurrent attacks of transient retrograde and anterograde amnesia usually lasting less than one hour and beginning in late-middle to old age. Attacks commonly occur on waking, a potentially helpful diagnostic clue. The amnesic attacks may be associated with persistent memory complaints. The diagnosis is made on the basis of the clinical history, wake or sleep - deprived EEG (often repeated) and/or a clear - cut response to anticonvulsivant therapy. The pathophysiology remains poorly understood. It is uncertain whether recurrent episodes of amnesia represent ictal or post-ictal phenomena.

Salvianolic acid A exerts antiamnesic effect on diazepam-induced anterograde amnesia in mice.

Benzodiazepine was known to produce amnesia. Salvianolic acid A extracted from Salvia miltiorrhiza was an effective antioxidant. The objective of the study was to evaluate the effect of salvianolic acid A on diazepam-induced amnesia in mice. C57BL/6 mice were treated with salvianolic acid A at doses of 10, 20 and 40 mg/kg following administration with diazepam at a dose of 3 mg/kg. Morris water maze was performed to evaluate the effect of salvianolic acid A on amnesia. The antioxidative parameters in hippocampus were measured. The results showed that salvianolic acid A decreased the mean escape latency and increased the percentage of time spent in target quadrant. Salvianolic acid A reduced the content of malondialdehyde and increased the activities of superoxide dismutase, catalase and glutathione peroxidase in hippocampus. The findings demonstrated that salvianolic acid A had antiamnesic effects on diazepam-induced anterograde amnesia in mice, by augmenting the antioxidative capacity of hippocampus.

Limbic encephalitis presenting with seizures, anterograde amnesia, and psychosis in a patient seven weeks status post immature ovarian teratoma removal.

A paraneoplastic syndrome associated with anti-N-methyl-D-asparate (NMDA) receptors can initially present as a neurologic or psychiatric disturbance. Removal of the tumor is usually curative, and the syndrome is associated with the presence, rather than the history, of tumor. We present a case in which a 25-year-old, Hispanic woman presented with seizures, memory loss, and unusual behavioral changes. The woman had a teratoma removed 2 months earlier. Because of the time course, a paraneoplastic syndrome was initially considered unlikely. Brain imaging, electroencephalography (EEG) and neurologic work-up were negative. The patient was treated for a suspected somatoform disorder and psychosis. Based on the clinical picture, the working diagnosis was changed to delirium due to paraneoplastic limbic encephalitis. A course of intravenous immunoglobins (IVIg), and high dose steroids was administered. The patient's symptoms improved, and she was discharged home. After discharge, studies came back positive for antibodies against NR1/NR2 of the NMDA receptor.

Scopolamine induced amnesia is reversed by Bacopa monniera through participation of kinase-CREB pathway.

Scopolamine, an anticholinergic drug, is reported to produce amnesia by interference of long term potentiation and has been used for discerning the efficacy of various antiamnesic drugs. The intoxication with anticholinergics and benzodiazepines tend to produce neurodegeneration which cause memory deficits. Our earlier reports have shown the antiamnesic drug, B. monniera to be capable of alleviating diazepam induced memory deficits. We have now tested how scopolamine affects downstream signaling molecules of long term potentiation and if B. monniera can also modulate the scopolamine induced amnesia. We used Morris water maze scale to test the amnesic effect of scopolamine and its reversal by B. monniera. Rota-rod test was used to screen muscle coordination activity of mice before water maze investigations were carried out. The results showed that scopolamine downregulated protein kinase C and iNOS without affecting cAMP, protein kinase A, calmodulin, MAP kinase, nitrite, CREB and pCREB. B. monniera reversed the scopolamine induced amnesia by significantly improving calmodulin and by partially attenuating protein kinase C and pCREB. These observations suggest involvement of calmodulin in evoking antiamnesic effects of B. monniera.

Memory loss caused by beta-amyloid protein is rescued by a beta(3)-adrenoceptor agonist.

Accumulation of the neurotoxic beta-amyloid protein (Abeta) in the brain is a key step in the pathogenesis of Alzheimer's disease (AD). Although transgenic mouse models of AD have been developed, there is a clear need for a validated animal model of Abeta-induced amnesia which can be used for toxicity testing and drug development. Intracranial injections of Abeta(1-42) impaired memory in a single trial discriminative avoidance learning task in chicks. Memory inhibition was closely associated with the state of aggregation of the Abeta peptide, and a scrambled-sequence of Abeta(1-42) peptide failed to impair memory. Abeta had little effect on labile (short-term and intermediate) memory, but blocked consolidation of memory into long-term storage mimicking the type of anterograde amnesia that occurs in early AD. Since noradrenaline exerts a modulatory influence on labile memory in the chick, we examined the effects of two beta-adrenoceptor (AR) agonists on Abeta-induced amnesia. A beta(3)-AR agonist (CL316243), but not a beta(2)-AR agonist, rescued Abeta-induced memory loss, suggesting the need for further studies on the role of beta(3)-ARs in AD.

Nootropic activity of lipid-based extract of Bacopa monniera Linn. compared with traditional preparation and extracts.

OBJECTIVES: The aim was to design an alternative solvent-free extraction method using the hydrophilic lipid Gelucire (polyethylene glycol glycerides) for herbal extraction and to confirm the efficacy of extraction using biological screening. METHODS: Bacopa monniera Linn. (BM) was selected for the study. Conventional methanolic extract (MEBM), Ayurvedic ghrita (AGBM) and lipid extracts (LEBM) were prepared and standardised by high-performance thin-layer chromatography (HPTLC). Nootropic activity in rats was evaluated using the two-trial Y-maze test and the anterograde amnesia induced by scopolamine (1 mg/kg i.p.) determined by the conditioned avoidance response. The extracts were administered daily at doses of 100, 200 and 400 mg/kg orally. At the end of the conditioned avoidance response test, brain monoamine levels were estimated by HPLC. KEY FINDINGS: The LEBM, MEBM and AGBM contained 3.56%, 4.10% and 0.005% bacoside A, respectively. Significantly greater spatial recognition was observed with LEBM (P < 0.001 at 400 and 200 mg/kg) and MEBM (P < 0.001 at 400 mg/kg, P < 0.01 at 200 mg/kg) than AGBM. The conditioned avoidance response was significantly higher in the groups treated with high doses of LEBM and MEBM than AGBM. There were significant decreases in brain noradrenaline (P < 0.001) and 5-hydroxytryptamine (P < 0.01) levels and an increase in dopamine levels (P < 0.05) in the LEBM-treated groups compared with the stress control group. CONCLUSIONS: The proposed LEBM is solvent free, does not have the shortcomings associated with conventional extraction, and had comparable nootropic activity to the MEBM.

Bacopa monniera alleviates N(omega)-nitro-L-arginine arginine-induced but not MK-801-induced amnesia: a mouse Morris watermaze study.

N-methyl-D-aspartate (NMDA) receptor and nitricoxide syntheses are the emerging target sites for development of novel drug molecules because their modulation affects the long term potentiation (LTP) process. NMDA receptor antagonists and nitric oxide synthase inhibitors induce amnesia in animals and therefore have been employed for evaluation of efficacy of several novel antiamnesic agents.Bacopa monniera Linn (syn. Brahmi) is commonly used in the ancient Indian medical system for improvement of memory deficit.We have earlier described the involvement of GABAergic and cholinergic system to account for the antiamnesic effects of B. monniera on diazepam- and scopolamine-induced amnesia.In extension to our previous study this study was designed to investigate the downstream mechanism of B. monniera by evaluation of its effect on MK-801 (an NMDA receptor antagonist) and N(w)-nitro-L-arginine (L-NNA) (a nitric oxide inhibitor)induced memory deficit. We used a Morris water maze scale and compared the degree of reversal of amnesia induced by the two agents. Male Swiss albino mice were subjected to a Rotarod muscle incoordination test followed by water maze tasks.Our data revealed that L-NNA and MK-801 produced anterograde and retrograde amnesia and B. monniera significantly attenuated the L-NNA-induced anterograde amnesia, partially reversing L-NNA-induced retrograde amnesia. On the other hand, B. monniera neither attenuated the MK-801-induced anterograde amnesia nor improved retrograde amnesia caused by it.

Bacopa monniera ameliorates amnesic effects of diazepam qualifying behavioral-molecular partitioning.

Benzodiazepines are known to produce amnesia by involvement of GABAergic system and by interference of long term potentiation (LTP). In this study, we examined effect of Bacopa monniera on downstream molecules of LTP after diazepam-induced amnesia in mice. We used a Morris water maze scale for evaluating the effect of Bacopa monniera after screening for muscle coordination by rota rod. The index of acquisition and retrieval was recorded as escape latency time (ELT). Behavioral results showed that Bacopa monniera (120 mg kg(-1) oral) significantly reversed diazepam- (1.75 mg kg(-1) i.p.) induced amnesia in Morris water maze task. The molecular studies revealed that diazepam upregulated mitogen activated protein kinase (MAP kinase), phosphorylated CREB (pCREB) and inducible nitric oxide synthase (iNOS), while it downregulated nitrite, nitrate, total nitrite, cAMP response element binding protein (CREB) expression, phosphodiesterase, cyclic adenosine monophosphate (cAMP) without affecting calmodulin levels. Bacopa monniera suppressed the diazepam induced upregulation of MAP kinase, pCREB and iNOS and attenuated the downregulation of nitrite. It did not affect the cAMP, PDE, nitrate, total nitrite, total CREB level. These behavioral findings displayed the reversal of diazepam-induced amnesia by Bacopa monniera without qualifying the molecular details although some downstream molecules of LTP may be involved.

Bacopa monniera exerts antiamnesic effect on diazepam-induced anterograde amnesia in mice.

RATIONALE: As Benzodiazepines are known to produce amnesia by involvement of the GABAergic system, we examined Bacopa monniera, an herb known for memory enhancement for reversal of memory deficits caused by diazepam. OBJECTIVES: The objective of the study was to study the effect of standardized extract of B. monniera on diazepam-induced amnesia in mice using Morris water maze. MATERIALS AND METHODS: We used the rota rod test as a screening measure for muscle incoordination followed by the Morris water maze scale to evaluate the effect of B. monniera on amnesia. The index of acquisition and retrieval was recorded with varying doses of Bacopa. RESULTS: The results revealed antiamnesic effects of B. monniera (120 mg kg(-1) oral) on diazepam (1.75 mg kg(-1) intraperitoneal)-induced amnesia. The degree of reversal by Bacopa was significant as it progressively reduced escape latency time when mice treated with diazepam were subjected to acquisition trials. CONCLUSIONS: The antiamnesic effects of Bacopa suggest likely a gamma-aminobutyric acid-benzodiazepine pathway possibly affecting long-term potentiation.

Sustained inhibition of brotizolam induced anterograde amnesia by norharmane and retrograde amnesia by L-glutamic acid in mice.

Benzodiazepines such as diazepam, lorazepam, are reported to produce anterograde amnesia but these do not affect the retrieval mechanism. Triazodiazepines such as alprazolam, triazolam and brotizolam produce both anterograde and retrograde amnesia. Because benzodiazepine receptor antagonists are known to reverse anterograde amnesia, we wanted to test if inverse agonist can also improve learning and memory. The present study was designed to investigate the effect of norharmane (benzodiazepine receptor inverse agonist) and L-glutamic acid (glutamate receptor agonist) on brotizolam induced anterograde and retrograde amnesia using Morris water maze task in mice. Norharmane reversed anterograde amnesia induced by brotizolam and did not reverse retrograde amnesia induced by it. L-Glutamic acid attenuated retrograde amnesia but did not affect anterograde amnesia induced by brotizolam. These results provide an opportunity to understand the mechanisms of anterograde and retrograde amnesia which may occur with interaction of presynaptic molecules or LTP modulation.

Selective anterograde amnesia with thalamus and hippocampal lesions in neuro-Behcet's disease.

Anterograde amnesia and minimal retrograde amnesia with thalamic and hippocampal lesions in neuro-Behcet's disease is rare. A 50-year-old man presented with forgetfulness and severe memory disturbance after suffering multiple oral and genital aphthous ulcers with erythema nodosum. A neurological examination and a neuropsychological assessment revealed prominent anterograde memory impairment without focal neurological deficits. On brain MRI there were high signal intensity lesions involving right anterior thalamus, left posterior basal ganglia, and left hippocampus. This is a quite selective anterogrde memory deficit in a case of neuro-Behcet's disease caused by parenchymal lesions in the thalamus and hippocampus.

Recovery of long-term anterograde amnesia, but not retrograde amnesia, after initiation of an anti-epileptic drug in a case of transient epileptic amnesia.

Transient epileptic amnesia (TEA) is characterised by recurrent brief episodes of amnesia and atypical amnesic symptoms, known as long-term anterograde amnesia and dense retrograde amnesia. It has been proposed that an antiepileptic drug (AED) can prevent not only epileptiform activity, but also accelerated forgetting. However, there have been no reports regarding the effects of such drugs on retrograde amnesia. We found that an AED prevented accelerated forgetting, but not dense retrograde amnesia, suggesting that accelerated forgetting in TEA was treatable, but retrograde amnesia was an irreversible process.

Amnesia and the hippocampus.

PURPOSE OF REVIEW: Long-term memory impairments have great medical significance and a considerable health and economic burden. Understanding their cognitive and neuroanatomical underpinnings is of crucial importance. Severe amnesia is usually observed following bilateral hippocampal pathology. This review addresses the precise role of the hippocampus and related medial temporal lobe structures in amnesia. RECENT FINDINGS: Disagreements exist over whether, following selective hippocampal damage: retrograde amnesia for episodic memories is temporally limited or extensive and ungraded; anterograde amnesia involves both recollective and familiarity processes. It is accepted that material specific impairments follow unilateral medial temporal lobe damage, with verbal and nonverbal memory lateralized to left or right, respectively. Memory for unknown faces, however, may not depend on the hippocampus. Pharmacological studies in animals, with some extension to humans, highlight promising future therapeutic interventions targeting synaptic plasticity modulation. SUMMARY: Despite considerable progress, some issues remain unresolved. The available evidence favours the view, however, that the hippocampus, in conjunction with other cortical areas, is critical for the retrieval of remote episodic memories and for both recollection and familiarity anterograde memory processes. There are as yet no effective pharmacological treatments for medial temporal lobe amnesia, but various rehabilitative techniques may be useful.