Supraglottic Myxedema Presenting as a Complication of Hypothyroidism: A Case Report.

Myxedema is a medical emergency with high mortality rates if not treated aggressively. Here, we present a middle-aged female with complaints of generalized body swelling for one year, shortness of breath, hoarseness of voice, neck swelling, and cough for 20 days. The patient was diagnosed to be having severe hypothyroidism with polyserositis. Contrast-enhanced computed tomography (CECT) of the neck and thorax revealed extensive soft tissue edema causing airway narrowing, bilateral pleural effusion, moderate pericardial effusion, and features of atypical pneumonia. The patient was started on levothyroxine and antibiotics as per cultures to which she had initially improved; however, she developed ventilator-associated pneumonia leading to sepsis, acute respiratory distress syndrome followed by refractory type 1 respiratory failure and succumbed.

Community-acquired multidrug-resistant pneumonia, bacteraemia, and infective endocarditis: A case report.

BACKGROUND: The prevalence of multidrug-resistant (MDR) bacteria has increased globally, with extensive drug-resistant (XDR) bacteria posing a threat to patients. CASE SUMMARY: This case report describes a young man admitted for suspected tropical fever infections who experienced rapid deterioration in health. Despite negative results for tropical fever infections, he had neutrophilic leucocytosis, acute kidney injury, and chest imaging findings suggestive of bilateral consolidations. On day two, he was diagnosed with infective endocarditis with possible rheumatic heart disease and MDR methicillin-resistant Staphylococcus aureus bacteraemia, and community-acquired pneumonia. Despite treatment with broad-spectrum antibiotics, he did not respond and succumbed to death on day five. CONCLUSION: This case highlights that clinicians/public should be aware of MDR community-acquired pneumonia, bacteraemia, and endocarditis which ultimately culminate in high rates of morbidity and mortality. Early identification of pathogenic strain and prompt antibiotic treatment are a mainstay for the management and prevention of early fatalities. Simultaneously, route cause analysis of community-acquired MDR/XDR pathogens is a global need.

Synthesis of green zinc-oxide nanoparticles and its dose-dependent beneficial effect on spermatozoa during preservation: sperm functional integrity, fertility and antimicrobial activity.

Introduction: The development of an effective extender is important for semen preservation and the artificial insemination (AI) industry. This study demonstrates the beneficial effect of zinc oxide nanoparticles (ZnO-NPs) as an additive to semen extenders to improve semen quality, fertility, and antibacterial activity during liquid preservation in a boar model. Methods: Initially, to find out the safe concentration of ZnO-NPs in sperm cells, a wide range of ZnO-NP concentrations (0, 5, 10, 50, 100, 500, and 1,000 µM) were co-incubated with sperm at 37°C for a cytotoxic study. These NP concentrations were compared to their salt control zinc acetate (ZA) at the same concentrations and to a control group. The effect of the different concentrations of ZnO-NPs on sperm motility, membrane integrity, mitochondrial membrane potential (MMP), and apoptosis was assessed. Accordingly, the non-toxic dose was selected and supplemented in MODENA extender to determine its beneficial effect on the boar semen parameters mentioned and the lipid peroxidation (LPO) levels during liquid preservation at 16°C for 6 days. The non-cytotoxic dosage was subsequently chosen for AI, fertility investigations, and the evaluation of the antibacterial efficacy of ZnO-NPs during preservation hours. An antibacterial study of ZnO-NPs and its salt control at doses of 10 µM and 50 µM was carried out by the colony forming unit (CFU) method. Results and discussion: The cytotoxic study revealed that 5, 10, and 50 µM of ZnO-NPs are safe. Consequently, semen preserved in the MODENA extender, incorporating the non-toxic dose, exhibited 10 and 50 µM ZnO-NPs as the optimal concentrations for beneficial outcomes during liquid preservation at 16°C. ZnO-NPs of 10 µM concentration resulted in a significantly (p < 0.05) improved conception rate of 86.95% compared to the control of 73.13%. ZnO-NPs of 10 and 50 µM concentrations exhibit potent antimicrobial action by reducing the number of colonies formed with days of preservation in comparison to the negative control. The investigation concluded that the incorporation of 10 µM ZnO-NPs led to enhancements in sperm motility, membrane integrity, and MMP, attributed to a reduction in the malondialdehyde (MDA) levels. This improvement was accompanied by a concurrent increase in fertility rates, including farrowing rate and litter size, during the liquid preservation process. Furthermore, ZnO-NPs exhibited an antimicrobial effect, resulting in decreased bacterial growth while preserving boar semen at 16°C for 6 days. These findings suggest that ZnO-NPs could serve as a viable alternative to antibiotics, potentially mitigating antibiotic resistance concerns within the food chain.

Fiberoptic hemodynamic spectroscopy reveals abnormal cerebrovascular reactivity in a freely moving mouse model of Alzheimer's disease.

Many Alzheimer's disease (AD) patients suffer from altered cerebral blood flow and damaged cerebral vasculature. Cerebrovascular dysfunction could play an important role in this disease. However, the mechanism underlying a vascular contribution in AD is still unclear. Cerebrovascular reactivity (CVR) is a critical mechanism that maintains cerebral blood flow and brain homeostasis. Most current methods to analyze CVR require anesthesia which is known to hamper the investigation of molecular mechanisms underlying CVR. We therefore combined spectroscopy, spectral analysis software, and an implantable device to measure cerebral blood volume fraction (CBVF) and oxygen saturation (SO2) in unanesthetized, freely-moving mice. Then, we analyzed basal CBVF and SO2, and CVR of 5-month-old C57BL/6 mice during hypercapnia as well as during basic behavior such as grooming, walking and running. Moreover, we analyzed the CVR of freely-moving AD mice and their wildtype (WT) littermates during hypercapnia and could find impaired CVR in AD mice compared to WT littermates. Our results suggest that this optomechanical approach to reproducibly getting light into the brain enabled us to successfully measure CVR in unanesthetized freely-moving mice and to find impaired CVR in a mouse model of AD.

Striatal fibrinogen extravasation and vascular degeneration correlate with motor dysfunction in an aging mouse model of Alzheimer's disease.

Introduction: Alzheimer's Disease (AD) patients exhibit signs of motor dysfunction, including gait, locomotion, and balance deficits. Changes in motor function often precede other symptoms of AD as well as correlate with increased severity and mortality. Despite the frequent occurrence of motor dysfunction in AD patients, little is known about the mechanisms by which this behavior is altered. Methods and Results: In the present study, we investigated the relationship between cerebrovascular impairment and motor dysfunction in a mouse model of AD (Tg6799). We found an age-dependent increase of extravasated fibrinogen deposits in the cortex and striatum of AD mice. Interestingly, there was significantly decreased cerebrovascular density in the striatum of the 15-month-old as compared to 7-month-old AD mice. We also found significant demyelination and axonal damage in the striatum of aged AD mice. We analyzed striatum-related motor function and anxiety levels of AD mice at both ages and found that aged AD mice exhibited significant impairment of motor function but not in the younger AD mice. Discussion: Our finding suggests an enticing correlation between extravasated fibrinogen, cerebrovascular damage of the striatum, and motor dysfunction in an AD mouse model, suggesting a possible mechanism underlying motor dysfunction in AD.

Insight study on synthesis and antibacterial mechanism of silver nanoparticles prepared from indigenous plant source of Jharkhand.

BACKGROUND: The Ag-NPs by green synthesis has a notable interest because of their eco-friendliness, economic views, feasibility, and applications in a wide range. Herein, native plants of Jharkhand (Polygonum plebeium, Litsea glutinosa, and Vangueria spinosus) were selected for the current work of Ag-NP synthesis and further antibacterial activity. Green synthesis was performed for Ag-NPs using Silver nitrate solution as precursor and the dried leaf extract performs as a reductant and stabilizer here. RESULT: Visually Ag-NP formation was observed along with a colour change and confirmed by UV-visible spectrophotometry on which an absorbance peak occurs at around 400-450nm. Further characterization was done on DLS, FTIR, FESEM, and XRD. Size around 45-86 nm of synthesized Ag-NPs was predicted through DLS. The synthesized Ag-NPs exhibited significant antibacterial activity against Bacillus subtilis (Gram-positive bacteria) and Salmonella typhi (Gram-negative bacteria). The finest antibacterial activity was disclosed by the Ag-NPs synthesized by Polygonum plebeium extract. The diameter of the zone of inhibition in the bacterial plate measured was 0-1.8 mm in Bacillus and 0-2.2 mm in Salmonella typhi. Protein-Protein interaction study was performed to study the effect of Ag-NPs towards different antioxidant enzyme system of bacterial cell. CONCLUSION: Present work suggest the Ag-NPs synthesized from P. plebeium were more stable for long term and might have prolonged antibacterial activity. In the future, these Ag-NPs can be applied in various fields like antimicrobial research, wound healing, drug delivery, bio-sensing, tumour/cancer cell treatment, and detector (detect solar energy). Schematic representation of Ag-NPs green synthesis, characterization, antibacterial activity and at the end, in silico study to analyse the mechanism of antibacterial activity.

Bullous Hemorrhagic Dermatosis: A Rare Benign Cutaneous Complication of Low-Molecular-Weight Heparin.

Enoxaparin-mediated bullous hemorrhagic dermatosis (BHD) is one of the rare side effects during prophylaxis of enoxaparin for various thromboembolic events. We report a case of a 74-year-old female with multiple comorbidities who developed BHD at a distant site from subcutaneous delivery of enoxaparin. Histopathological analysis confirmed the diagnosis of BHD. Discontinuation of enoxaparin resulted in the gradual resolution of the bullae formation, and the patient was started on novel oral anticoagulation with apixaban. The usual cutaneous adverse effects of enoxaparin include maculopapular rash, pruritus, skin necrosis, eczematous dermatitis, and rarely bullous hemorrhagic dermatosis. This hemorrhagic bullae dermatosis at a distant site from the administration is a relatively rare and benign side effect of enoxaparin which is an under-recognized complication of low-molecular-weight heparin.

Acute Chest Syndrome Masquerading As Sepsis: A Rare Presentation of Sickle Cell Anemia Complication.

Sickle cell disease in adults leads to various complications by hemolytic anemia and vaso-occlusion. Acute chest syndrome (ACS) is a severe life-threatening complication that can lead to multiple organ dysfunction and rapidly progressing respiratory failure. Early recognition and timely management are vital and lifesaving. We present a case of a 38-year-old female with a past history of multiple blood transfusions, who presented with features suggestive of sepsis with multiple organ dysfunction and obstructive jaundice. The patient showed minimal response to empirical antibiotics. However, no source of infection or features of biliary obstruction was found. The possibility of a hematological disorder was suspected in the background of multiple blood transfusions, and she was eventually diagnosed to have acute chest syndrome. She improved with transfusion, drug therapy, and adequate pain control.

Condensed-phase isomerization through tunnelling gateways.

Quantum mechanical tunnelling describes transmission of matter waves through a barrier with height larger than the energy of the wave1. Tunnelling becomes important when the de Broglie wavelength of the particle exceeds the barrier thickness; because wavelength increases with decreasing mass, lighter particles tunnel more efficiently than heavier ones. However, there exist examples in condensed-phase chemistry where increasing mass leads to increased tunnelling rates2. In contrast to the textbook approach, which considers transitions between continuum states, condensed-phase reactions involve transitions between bound states of reactants and products. Here this conceptual distinction is highlighted by experimental measurements of isotopologue-specific tunnelling rates for CO rotational isomerization at an NaCl surface3,4, showing nonmonotonic mass dependence. A quantum rate theory of isomerization is developed wherein transitions between sub-barrier reactant and product states occur through interaction with the environment. Tunnelling is fastest for specific pairs of states (gateways), the quantum mechanical details of which lead to enhanced cross-barrier coupling; the energies of these gateways arise nonsystematically, giving an erratic mass dependence. Gateways also accelerate ground-state isomerization, acting as leaky holes through the reaction barrier. This simple model provides a way to account for tunnelling in condensed-phase chemistry, and indicates that heavy-atom tunnelling may be more important than typically assumed.

Concomitant Interstitial Lung Disease With Psoriasis.

Interstitial lung disease is occasionally reported in patients with psoriasis as drug-induced pneumonitis secondary to concomitant use of immunosuppressants in most cases. Although few cases have been reported describing the simultaneous existence of psoriasis and interstitial pneumonia, there are no reports that clearly show their direct association. A 55-year-old male known case of psoriasis and hypertension presented to the emergency department with complaints of pain and weakness of bilateral upper limbs following an episode of seizure and shortness of breath on exertion for one year. Following workup, the patient was diagnosed to have interstitial lung disease. There was no history of any immunosuppressant or use of biologics. So, immune dysfunction triggered by psoriasis might have caused the lung fibrotic changes. Careful monitoring of lung and skin lesions is vital for diagnosing psoriasis-associated pneumonia.

Linear stability of a falling film over a heated slippery plane.

A detailed parametric study on the linear stability analysis of a three-dimensional thin liquid film flowing down a uniformly heated slippery inclined plane is carried out for disturbances of arbitrary wavenumbers, where the liquid film satisfies Newton's law of cooling at the film surface. A coupled system of boundary value problems is formulated in terms of the amplitudes of perturbation normal velocity and perturbation temperature, respectively. Analytical solution of the boundary value problems demonstrates the existence of three dominant modes, the so-called H mode, S mode, and P mode, where the S mode and P mode emerge due to the thermocapillary effect. It is found that the onset of instabilities for the H mode, S mode, and P mode reduces in the presence of wall slip and leads to a destabilizing influence. Numerical solution based on the Chebyshev spectral collocation method unveils that the finite wavenumber H-mode instability can be stabilized, but the S-mode instability and the finite wavenumber P-mode instability can be destabilized by increasing the value of the Marangoni number. On the other hand, the Biot number shows a dual role in the H-mode and S-mode instabilities. But the P-mode instability can be made stable with the increasing value of the Biot number and the decreasing values of the Marangoni number and the Prandtl number. Furthermore, the H-mode and S-mode instabilities become weaker, but the P-mode instability becomes stronger, with the increasing value of the spanwise wavenumber. In addition, the shear mode emerges in the numerical simulation when the Reynolds number is large, which can be destabilized slightly with the increasing value of the Marangoni number; however, it can be stabilized with the increasing value of the slip length and introducing the spanwise wavenumber to the infinitesimal perturbation.

Atrial Fibrillation in Scrub Typhus: A Series of Four Cases.

Scrub typhus, also known as bush typhus, is an acute febrile zoonosis caused by Orientia tsutsugamushi, transmitted by the bite of chigger mite. Patients with scrub typhus can have many different presentations such as acute hearing loss, interstitial pneumonitis, acute respiratory distress syndrome, myocarditis, pericarditis, meningoencephalitis, acute renal failure, acute hepatic failure, and septic shock. The occurrence of multi-organ dysfunction is responsible for high mortality seen in scrub typhus patients. Cardiovascular involvement can also occur in the form of arrhythmia, which leads to an increase in mortality in these patients, and if associated with ischemic heart disease and acute heart failure, it leads to higher mortality. The early use of antibiotics and telemetry monitoring along with aggressive management of patients can decrease the complications and mortality seen in these patients. This study describes a series of four scrub typhus patients with new-onset atrial fibrillation who were managed with either direct current (DC) cardioversion, amiodarone, or diltiazem.

Spin-Forbidden Carbon-Carbon Bond Formation in Vibrationally Excited α-CO.

Fourier transform infrared spectroscopy of laser-irradiated cryogenic crystals shows that vibrational excitation of CO leads to the production of equal amounts of CO2 and C3O2. The reaction mechanism is explored using electronic structure calculations, demonstrating that the lowest-energy pathway involves a spin-forbidden reaction of (CO)2 yielding C(3P) + CO2. C(3P) then undergoes barrierless recombination with two other CO molecules forming C3O2. Calculated intersystem crossing rates support the spin-forbidden mechanism, showing subpicosecond spin-flipping time scales for a (CO)2 geometry that is energetically consistent with states accessed through vibrational energy pooling. This spin-flip occurs with an estimated ∼4% efficiency; on the singlet surface, (CO)2 reconverts back to CO monomers, releasing heat which induces CO desorption. The discovery that vibrational excitation of condensed-phase CO leads to spin-forbidden C-C bond formation may be important to the development of accurate models of interstellar chemistry.

Transporting and concentrating vibrational energy to promote isomerization.

Visible-light absorption and transport of the resultant electronic excitations to a reaction centre through Förster resonance energy transfer1-3 (FRET) are critical to the operation of biological light-harvesting systems4, and are used in various artificial systems made of synthetic dyes5, polymers6 or nanodots7,8. The fundamental equations describing FRET are similar to those describing vibration-to-vibration (V-V) energy transfer9, and suggest that transport and localization of vibrational energy should, in principle, also be possible. Although it is known that vibrational excitation can promote reactions10-16, transporting and concentrating vibrational energy has not yet been reported. We have recently demonstrated orientational isomerization enabled by vibrational energy pooling in a CO adsorbate layer on a NaCl(100) surface17. Here we build on that work to show that the isomerization reaction proceeds more efficiently with a thick 12C16O overlayer that absorbs more mid-infrared photons and transports the resultant vibrational excitations by V-V energy transfer to a 13C18O-NaCl interface. The vibrational energy density achieved at the interface is 30 times higher than that obtained with direct excitation of the interfacial CO. We anticipate that with careful system design, these concepts could be used to drive other chemical transformations, providing new approaches to condensed phase chemistry.

Observation of an isomerizing double-well quantum system in the condensed phase.

Molecular isomerization fundamentally involves quantum states bound within a potential energy function with multiple minima. For isolated gas-phase molecules, eigenstates well above the isomerization saddle points have been characterized. However, to observe the quantum nature of isomerization, systems in which transitions between the eigenstates occur-such as condensed-phase systems-must be studied. Efforts to resolve quantum states with spectroscopic tools are typically unsuccessful for such systems. An exception is CO adsorbed on NaCl(100), which is bound with the well-known OC-Na+ structure. We observe an unexpected upside-down isomer (CO-Na+) produced by infrared laser excitation and obtain well-resolved infrared fluorescence spectra from highly energetic vibrational states of both orientational isomers. This distinctive condensed-phase system is ideally suited to spectroscopic investigations of the quantum nature of isomerization.

Persistent peripheral presence of Staphylococcus aureus promotes histone H3 hypoacetylation and decreases tyrosine hydroxylase protein level in rat brain tissues.

OBJECTIVE: Growing evidences suggest systemic pathogen-induced neuroimmune interaction is a major risk factor for several neurological disorders. Our goal was to investigate whether asymptomatic peripheral carriage of Staphylococcus aureus, a widespread opportunistic pathogen, could modulate selective molecular features in brain tissues. METHODS: To address this, a peripheral infection model was developed by challenging Wistar rats repeatedly with a clinical strain of S. aureus. Animals infected with S. aureus (10 CFU for three times in 10 days) showed significant changes in acetylation profile of selective lysine (K) residues K9 (H3K9), K14 (H3K14) and K27 (H3K27) of histone H3 in the hippocampus and prefrontal cortex (PFC). RESULTS: Although S. aureus was restricted peripherally, the infection induced hypoacetylation of H3K9, H3K14 and H3K27 in the hippocampus and H3K27 in the PFC. Histone H3 hypoacetylation in the hippocampus and PFC was also detected when rats were challenged with an engineered invasive strain of E. coli K12, SK3842. This confirmed that modulation of epigenetic landscape in distal brain tissues may not be specific to S. aureus. Moreover, the tyrosine hydroxylase protein, the rate limiting enzyme in dopamine synthesis pathway whose gene-expression is regulated by H3 acetylation at the promoter, was remarkably reduced in the brain tissues of the infected hosts. CONCLUSION: The results indicate that commensals like S. aureus, in spite of being largely restricted to the peripheral tissues, could modulate the homeostasis of molecular features in brain tissues whose maintenance is critical for preserving normal neurological functions.

Melatonin pre-treatment mitigates SHSY-5Y cells against oxaliplatin induced mitochondrial stress and apoptotic cell death.

Oxaliplatin (Oxa) treatment to SH-SY5Y human neuroblastoma cells has been shown by previous studies to induce oxidative stress, which in turn modulates intracellular signaling cascades resulting in cell death. While this phenomenon of Oxa-induced neurotoxicity is known, the underlying mechanisms involved in this cell death cascade must be clarified. Moreover, there is still little known regarding the roles of neuronal mitochondria and cytosolic compartments in mediating Oxa-induced neurotoxicity. With a better grasp of the mechanisms driving neurotoxicity in Oxa-treated SH-SY5Y cells, we can then identify certain pathways to target in protecting against neurotoxic cell damage. Therefore, the purpose of this study was to determine whether one such agent, melatonin (Mel), could confer protection against Oxa-induced neurotoxicity in SH-SY5Y cells. Results from the present study found Oxa to significantly reduce SH-SY5Y cell viability in a dose-dependent manner. Alternatively, we found Mel pre-treatment to SH-SY5Y cells to attenuate Oxa-induced toxicity, resulting in a markedly increased cell viability. Mel exerted its protective effects by regulating reactive oxygen species (ROS) production and reducing superoxide radicals inside Oxa-exposed. In addition, we observed pre-treatment with Mel to rescue Oxa-treated cells by protecting mitochondria. As Oxa-treatment alone decreases mitochondrial membrane potential (Δψm), resulting in an altered Bcl-2/Bax ratio and release of sequestered cytochrome c, so Mel was shown to inhibit these pathways. Mel was also found to inhibit proteolytic activation of caspase 3, inactivation of Poly (ADP Ribose) polymerase, and DNA damage, thereby allowing SH-SY5Y cells to resist apoptotic cell death. Collectively, our results suggest a role for melatonin in reducing Oxa induced neurotoxicity. Further studies exploring melatonin's protective effects may prove successful in eliciting pathways to further alter the neurotoxic pathways of platinum compounds in cancer treatment.

Induction of intestinal stemness and tumorigenicity by aberrant internalization of commensal non-pathogenic E. coli.

Commensal Escherichia coli has been identified as a major protagonist of microbe-induced colorectal oncogenesis. Its tumour-promoting attribute is linked to the expression of DNA-damaging genotoxins. Using a constitutively invasive variant of non-pathogenic E. coli, we demonstrate that chronic presence of internalized E. coli leads to enhanced oncogenicity in colon cancer cells. Instead of genomic damage, the tumorigenic effect is mediated through an expansion of the cancer stem cell (CSC) population, likely through dedifferentiation of lineage-committed intestinal epithelial cells. Stemness-linked intestinal tumorigenicity is directly correlated to absence of microbial virulence factor expression and is specific for intestinal cells. The enriched CSC fraction remains stable in the absence of the instigating bacteria and can foster stemness traits in unexposed cells through secreted factors. Mechanistically, aberrant host invasion leads to realignment of multiple host signal transduction cascades, notably mutually re-enforcing NF-κB and ß-catenin activation, through reciprocal modulation of microbe sensing pathways Nod1/Rip2 and TLR/MyD88. The expanded tumorigenic CSC population is marked by enhanced malignancy traits, long-term self-renewal capacity and robust tumorigenic ability, both in vitro and in vivo. Our study shows that microbe-induced oncogenicity is not a strict correlate of commensal virulence and can be invoked by even non-pathogenic E. coli by engendering tumorigenic stemness in host cells.

Oral acetate supplementation attenuates N-methyl D-aspartate receptor hypofunction-induced behavioral phenotypes accompanied by restoration of acetyl-histone homeostasis.

RATIONALE: Aberrations in cellular acetate-utilization processes leading to global histone hypoacetylation have been implicated in the etiology of neuropsychiatric disorders like schizophrenia. OBJECTIVES: Here, we investigated the role of acetate supplementation in the form of glyceryl triacetate (GTA) for the ability to restore the N-methyl D-aspartate (NMDA) receptor-induced histone hypoacetylation and to ameliorate associated behavioral phenotypes in mice. RESULTS: Taking cues from the studies in SH-SY5Y cells, we monitored acetylation status of specific lysine residues of histones H3 and H4 (H3K9 and H4K8) to determine the impact of oral GTA supplementation in vivo. Mice treated chronically with MK-801 (10 days; 0.15 mg/kg daily) induced hypoacetylation of H3K9 and H4K8 in the hippocampus. Daily oral supplementation of GTA (2.9 g/kg) was able to prevent this MK801-induced hypoacetylation significantly. Though MK-801-stimulated decreases in acetyl-H3K9 and acetyl-H4K8 were found to be associated with ERK1/2 activation, GTA seemed to act independent of this pathway. Simultaneously, GTA administration was able to attenuate the chronic MK-801-induced cognitive behavior phenotypes in elevated plus maze and novel object recognition tests. Not only MK-801, GTA also demonstrated protective effects against behavioral phenotypes generated by another NMDA receptor antagonist, ketamine. Acute (single injection) ketamine-mediated hyperactivity phenotype and chronic (10 days treatment) ketamine-induced phenotype of exaggerated immobility in forced swim test were ameliorated by GTA. CONCLUSION: The signature behavioral phenotypes induced by acute and chronic regimen of NMDA receptor antagonists seemed to be attenuated by GTA. This study thus provides a therapeutic paradigm of using dietary acetate supplement in psychiatric disorders.

Administration of N-acetylserotonin and melatonin alleviate chronic ketamine-induced behavioural phenotype accompanying BDNF-independent and dependent converging cytoprotective mechanisms in the hippocampus.

Though growing evidence implicates both melatonin (MLT) and its immediate precursor N-acetylserotonin (NAS) in the regulation of hippocampal neurogenesis, their comparative mechanistic relationship with core behavioural correlates of psychiatric disorders is largely unknown. To address this issue, we investigated the ability of these indoleamines to mitigate the behavioral phenotypes associated with NMDA-receptor (NMDAR) hypofunction in mice. We demonstrated that exogenous MLT and NAS treatments attenuated the NMDAR antagonist (ketamine) induced immobility in the forced swim test (FST) but not the classical striatum-related hyperlocomotor activity phenotype. The MLT/NAS-mediated protection of the phenotype in FST could be correlated to the ability of these indoleamines to counteract the deleterious effects of chronic ketamine on pro-survival molecular events by restoring the activities in MEK-ERK and PI3K-AKT pathways in the hippocampus. MLT seems to modulate these pathways by promoting accumulation of the mature form of BDNF above the control (vehicle-treated) levels, perhaps via MLT receptor-dependent mechanisms and in the process overcoming the ketamine-induced down-regulation of BDNF. In contrast, NAS appears to partly restore the ketamine-induced decrease of BDNF to the control levels. In spite of this fundamental difference in modulating BDNF levels in the upstream events, both MLT and NAS seem to overlap in the TrkB-induced downstream pro-survival mechanisms in the hippocampus, providing protection against NMDAR-hypofunction related cellular events. Perhaps, this also signifies the physiological importance of robust MLT synthesizing machinery that converts serotonin to MLT, in ensuring positive impact on hippocampus-related symptoms in psychiatric disorders.