Unraveling the molecular landscape of lead-induced cochlear synaptopathy: a quantitative proteomics analysis.

Introduction: Exposure to heavy metal lead can cause serious health effects such as developmental neurotoxicity in infants, cognitive impairment in children, and cardiovascular and nephrotoxic effects in adults. Hearing loss is one of the toxic effects induced by exposure to lead. Previous studies demonstrated that exposure to lead causes oxidative stress in the cochlea and disrupts ribbon synapses in the inner hair cells. Methods: This study investigated the underlying mechanism by evaluating the changes in the abundance of cochlear synaptosomal proteins that accompany lead-induced cochlear synaptopathy and hearing loss in mice. Young-adult CBA/J mice were given lead acetate in drinking water for 28 days. Results: Lead exposure significantly increased the hearing thresholds, particularly at the higher frequencies in both male and female mice, but it did not affect the activity of outer hair cells or induce hair cell loss. However, lead exposure decreased wave-I amplitude, suggesting lead-induced cochlear synaptopathy. In agreement, colocalization of pre- and post-synaptic markers indicated that lead exposure decreased the number of paired synapses in the basal turn of the cochlea. Proteomics analysis indicated that lead exposure increased the abundance of 352 synaptic proteins and decreased the abundance of 394 synaptic proteins in the cochlea. Bioinformatics analysis indicated that proteins that change in abundance are highly enriched in the synaptic vesicle cycle pathway. Discussion: Together, these results suggest that outer hair cells are not the primary target in lead-induced ototoxicity, that lead-induced cochlear synaptopathy is more pronounced in the basal turn of the cochlea, and that synaptic vesicle cycle signaling potentially plays a critical role in lead-induced cochlear synaptopathy.

Extractive Spectrophotometric Detection of Sn(II) Using 6-bromo-3-hydroxy-2-(5-methylfuran-2-yl)-4H-chromen-4-one.

For the determination of tin(II) traces, an extractive spectrophotometric approach is devised. The applied method serves a powerful tool for determination of tin(II), involves the formation of yellow colored complex after the binding of 6-bromo-3-hydroxy-2-(5-methylfuran-2-yl)-4H-chromen-4-one (BHMF) and tin(II) in 1:2 stiochiometry in a slightly acidic medium (HCl). The complex shows absorbance at 434 nm with respect of the blank reagent. The outcomes of spectral investigation for complexation showed a Beer's range of 0-1.3 µg Sn mL-1, molar absorptivity, specific absorptivity and Sandell's complex sensitivity are 9.291 × 104 L mol-1 cm-1, 0.490 mL g-1 cm-1 and 0.002040 µg cm-2 at 434 nm that was stable for two days. The interferences study results showed that this method is free from interferences, when tested with metal ions including Ag, Be, Bi, Ca, Cd, Ce, Co, Hg, Mo, Re, Pt, Se,Ti, U, V, W and other common cations, anions, and complexing agents. The applied method is quite simple, highly selective, and sensitive with good re-producibility. This method has been satisfactorily by utilizing the proposed procedure, and its applicability has been tested by analyzing synthetic samples and an alloy sample of gunmetal. The procedure assumes this because of the scarcity of better methods for determining tin(II). The results are in good agreement with the certified value.

Exploring the ameliorative potential of Bacopa monnieri in acetic acid induced ulcerative colitis in mice.

The aim of the present study was to evaluate the role of Bacopa monnieri in acetic-acid-induced ulcerative colitis in mice. Acetic acid (3%v/v, in 0.9% saline) was infused intrarectally to induce ulceration in mice. Administration of acetic acid resulted in severe inflammation of the colon along with an increase in the myeloperoxidase (MPO) activity assessed on 7th day. Treatment with Bacopa monnieri extract (20 mg/kg and 40 mg/kg, p.o) and saponin-rich fraction (5 mg/kg and 10 mg/kg; p.o) for 7 days i.e. 2 days before and 5 days after acetic acid infusion, significantly attenuated the colonic inflammation in a dose-dependent manner. Furthermore, it also reduced the MPO levels and the disease activity score as compared to the control group. It may be concluded that Bacopa monnieri has the potential for ameliorating acetic-acid-induced colitis and its saponin-rich fraction may be responsible for this effect.

Tadalafil ameliorates memory deficits, oxidative stress, endothelial dysfunction and neuropathological changes in rat model of hyperhomocysteinemia induced vascular dementia.

AIM: The present study investigates the potential of Tadalafil, a phosphodiesterase-5 inhibitor, in a rat model of hyperhomocysteinemia induced vascular dementia. METHODS: Hyperhomocysteinemia induced vascular dementia in Wistar rats was produced by administering l-Methionine (1.7 g/kg/day; p.o.×8 weeks). Learning and memory was assessed by employing Morris water maze (MWM) test. Endothelial dysfunction was assessed through acetylcholine-induced endothelial-dependent vasorelaxation and serum nitrite levels. Various other biochemical and histopathological estimations were also performed. RESULTS: l-Methionine produced significant impairment in acetylcholine-induced endothelium-dependent vasorelaxation and a decrease in serum nitrite levels indicating endothelial dysfunction. Further, these animals performed poorly on Morris water maze, depicting impairment of learning and memory. There was a significant rise in brain oxidative stress level (indicated by an increase in brain thiobarbituric acid reactive species and a decrease in reduced glutathione levels). Increase in brain acetylcholinesterase activity; brain myeloperoxidase activity and brain neutrophil infiltration (a marker of inflammation) were also observed. Tadalafil (5 and 10 mg/kg, p.o.)/Donepezil (0.5 mg/kg, i.p., serving as standard) treatment ameliorated l-Methionine induced endothelial dysfunction; memory deficits; biochemical and histopathological changes in a significant manner. CONCLUSIONS: It may be concluded that tadalafil has shown efficacy in the rat model of l-Methionine induced vascular dementia and that phosphodiesterase-5 can be considered as an important therapeutic target for the treatment of vascular dementia.

Thromboxane A2 synthase inhibition ameliorates endothelial dysfunction, memory deficits, oxidative stress and neuroinflammation in rat model of streptozotocin diabetes induced dementia.

RATIONALE: Vascular dementia (VaD) is the second leading cause of dementia worldwide. It is very important to find the possible pharmacological agents which may be useful in management and therapy of VaD. OBJECTIVES: The present study investigates the effect of ozagrel, a selective thromboxane A2 (TXA2) synthase inhibitor, in a rat model of VaD. METHODS: Single intraperitoneal injection of streptozotocin [STZ, (50 mg/kg)] was administered to Wistar rats to induced diabetes-associated vascular endothelial dysfunction and memory impairment. Morris water maze (MWM) test was employed to assess learning and memory. Endothelial dysfunction was assessed in the isolated aorta by observing endothelial-dependent vasorelaxation and levels of serum nitrite. Various biochemical and histopathological estimations were also performed. RESULTS: STZ treatment produced endothelial dysfunction, impairment of learning and memory, reduction in body weight and serum nitrite/nitrate, and increase in serum glucose, brain oxidative stress (increased brain thiobarbituric acid reactive species and decreased reduced glutathione levels), brain acetylcholinesterase activity and brain myeloperoxidase activity. Further a significant rise in brain tumor necrosis factor-α & interleukin-6 levels and brain neutrophil infiltration were also observed. Treatment of ozagrel (10 & 20 mg/kg, p. o.)/donepezil (0. 5 mg/kg, i.p., serving as standard) ameliorated STZ induced endothelial dysfunction; memory deficits; biochemical and histopathological changes. CONCLUSIONS: It may be concluded that ozagrel markedly improved endothelial dysfunction; learning and memory; biochemical and histopathological alteration associated with STZ induced dementia and that TXA2 can be considered as an important therapeutic target for the management of VaD.

Ameliorative effect of ozagrel, a thromboxane A2 synthase inhibitor, in hyperhomocysteinemia-induced experimental vascular cognitive impairment and dementia.

The present study investigates the effect of ozagrel, a selective thromboxane A2 (TXA2) inhibitor, in rat model of hyperhomocysteinemia (HHcy)-induced vascular cognitive impairment and dementia (VCID). Wistar rats were administered L-methionine (1.7 g/kg/day; p.o. × 8 weeks) to induce VCID. Morris water maze (MWM) test was employed to assess learning and memory. Endothelial dysfunction was assessed in the isolated aorta by observing endothelial-dependent vasorelaxation and levels of serum nitrite. Various biochemical and histopathological estimations were also performed. L-methionine produced significant impairment in endothelium-dependent vasorelaxation and decreases serum nitrite levels indicating endothelial dysfunction. Further, these animals performed poorly on MWM, depicting impairment of learning and memory. Further, a significant rise in brain oxidative stress level (indicated by increase in brain thiobarbituric acid-reactive species and decrease in reduced glutathione levels), brain acetylcholinesterase activity, brain myeloperoxidase activity, brain TNF-α and IL-6 levels, and brain leukocyte (neutrophil) infiltration was also observed. Treatment of ozagrel (10 and 20 mg/kg, p. o.)/donepezil (0.5 mg/kg, i.p., serving as standard) ameliorated L-methionine-induced endothelial dysfunction, memory deficits, and biochemical and histopathological changes. It may be concluded that ozagrel markedly improved endothelial dysfunction, learning and memory, and biochemical and histopathological alteration associated with L-methionine-induced VCID and that TXA2 can be considered as an important therapeutic target for the management of VCID.

Ozagrel a thromboxane A2 synthase inhibitor extenuates endothelial dysfunction, oxidative stress and neuroinflammation in rat model of bilateral common carotid artery occlusion induced vascular dementia.

The present study investigates the potential of ozagrel, a thromboxane A2 (TXA2) synthase inhibitor, in bilateral common carotid artery occlusion (BCCAo) induced vascular dementia (VaD). Wistar rats were subjected to BCCAo procedure under anesthesia to induce VaD. Morris water maze (MWM) test was employed on 7th day post-surgery to determine learning and memory. Endothelial dysfunction was assessed in isolated aorta by observing endothelial dependent vasorelaxation and levels of serum nitrite. A battery of biochemical and histopathological estimations was performed. Expression analysis of inflammatory cytokines TNF-α and IL-6 was carried out by RT-PCR. BCCAo produced significant impairment in endothelium dependent vasorelaxation and decrease in serum nitrite levels indicating endothelial dysfunction along with poor performance on MWM represents impairment of learning and memory. There was a significant rise in brain oxidative stress level (indicated by increase in brain thiobarbituric acid reactive species and decrease in reduced glutathione levels); increase in brain acetylcholinesterase activity; brain myeloperoxidase activity; brain TNF-α & IL-6 levels, brain TNF-α & IL-6 mRNA expression and brain neutrophil infiltration (as marker of inflammation) were also observed. Treatment of ozagrel (10 & 20 mg/kg, p. o.)/donepezil (0. 5 mg/kg, i.p., serving as standard) ameliorated BCCAo induced endothelial dysfunction; memory deficits; biochemical and histopathological changes in a significant manner. It may be concluded that ozagrel markedly improved endothelial dysfunction; learning and memory; biochemical and histopathological alteration associated with BCCAo induced VaD and that TXA2 can be considered as an important therapeutic target for the treatment of VaD.

Ameliorative Effect of Phosphodiesterase-5 Inhibitor in Rat Model of Vascular Dementia.

INTRODUCTION: Cerebral hypoperfusion has been considered as major risk factor for Vascular Dementia (VaD). The present study shows the potential of Tadalafil, a phosphodiesterase-5 inhibitor, in bilateral common carotid artery occlusion (BCCAo) induced VaD in rats. MATERIALS AND METHODS: BCCAo procedure was performed under anesthesia in wistar rats to induce VaD. Morris Water-Maze (MWM) parameter was employed on 7th day post-surgery to determine learning and memory. Escape latency time, time spent in target quadrant, Path length and average swim speed taken as important parameters in MWM. Endothelial dysfunction was assessed in isolated aorta by observing endothelial dependent vasorelaxations and levels of serum nitrite. Various biochemical and histopathological estimations were also performed. RESULTS: BCCAo produced significant impairment in endothelium dependent vasorelaxation and a decrease in serum nitrite levels indicating endothelial dysfunction. Further poor performance on MWM represents impairment of learning and memory. There was a significant rise in brain oxidative stress level (indicated by increase in brain thiobarbituric acid reactive species and decrease in reduced glutathione levels). Increase in brain acetylcholinesterase activity; brain myloperoxidase activity and brain neutrophil infiltration (as marker of inflammation) were also observed. Treatment of Tadalafil (5 & 10 mg/kg, p. o.)/Donepezil (0. 5 mg/kg, i.p., serving as standard) ameliorated BCCAo induced endothelial dysfunction; memory deficits; biochemical and histopathological changes in a significant manner. CONCLUSION: It may be concluded that Tadalafil has shown efficacy in rat model of BCCAo induced VaD and that phosphodiesterase-5 can be considered as an important therapeutic target for the treatment of VaD.

Selectivity for La3+ ion by synthesized 4-((5-methylfuran-2-yl)methylene)hydrazono)methyl)phenol receptor and its spectral analysis.

The functionalized molecules with specific molecular sites appear to be a promising approach for detection of cation in UV-visible and fluorescence spectroscopy. The synthesized receptor 4-((5-methylfuran-2-yl)methylene)hydrazono)methyl)phenol MFMHMP was found selective for La3+ among Ag+, K+, Na+, Be2+, Mg2+, Ca2+, Eu3+, Al3+, La3+, Zr4+, Th4+, UO22+, Fe3+, Fe2+, Co2+, Ni2+, Cu2+, Zn2+, Cd2+ and Hg2+ metal ions used as their nitrates by UV-visible spectroscopy and fluorescence spectroscopy. The binding nature of MFMHMP with La3+ ion was analyzed by UV-visible, fluorescence, IR, mass spectroscopy and cyclic voltammetric studies. The stoichiometry was established to be 1:1 by Benesi-Hildebrand, mole-ratio method and method of continuous variation (Job's method) with good association affinity K = 6.245 × 104 M-1. Computational studies and Density functional theory (DFT) calculation gives the proof of electron transfer during excitation and emission. Binding energy of complex through Density Function Theory -62.387 kcal/mol has also indication of strong binding. The electron transfer energy of Higher occupied molecular orbital (HOMO) to Lower unoccupied molecular orbital (LUMO) is about 4.662 eV for MFMHMP+La3+ Complex. Among that all transitions HOMO → LUMO + 8 and HOMO → LUMO + 9 play a key role for the blue shift transition during complexation.

Potential of carnosine, a histamine precursor in rat model of bilateral common carotid artery occlusion-induced vascular dementia.

The present study investigates the potential of Carnosine, a histamine precursor in rat model of bilateral common carotid artery occlusion (BCCAo)-induced vascular dementia (VaD). Wistar rats were subjected to BCCAo procedure under anaesthesia to induce VaD. The rats were subjected to Morris water maze (MWM) test (6th day onwards post-surgery). MWM test was employed to assess learning and memory of the animals whereby escape latency time, time spent in target quadrant and Path length (distance travelled) taken as important parameters. Serum nitrite level; Brain thiobarbituric acid reactive substances (TBARS) and reduced glutathione (GSH) levels; Brain acetylcholinesterase (AChE) activity; brain Myeloperoxidase activity (MPO) and neutrophil count were estimated as per standard procedures. BCCAo in rats produced a significant vascular endothelial dysfunction, as reflected by decrease in serum nitrite levels. Further, these animals showed poor performance on MWM, depicting impairment of learning and memory. There was a significant rise in brain oxidative stress level as indicated by increase in TBARS and decrease in GSH levels. An increase in brain AChE activity was also observed. Moreover, these rats also exhibited an increase in MPO activity and neutrophil infiltration in brain (as marker of inflammation). Treatment of Carnosine (200 and 400 mg/kg, i.p.)/Donepezil (0.3 mg/kg, i.p.) ameliorated BCCAo-induced memory deficits; endothelial dysfunction; biochemical and histopathological changes. It is concluded that Carnosine has shown efficacy in rat model of BCCAo-induced VaD and can be considered as an important therapeutic agent for the treatment of VaD.

Homocysteine excess: delineating the possible mechanism of neurotoxicity and depression.

Homocysteine (Hcy) is a nonproteogenic sulfur containing amino acid derived from dietary methionine through demethylation. Homocysteine can be re-methylated to methionine [precursor of S-adenosylmethionine (SAM)] via the re-methylation or 5-methyltetrahydrofolate pathway or undergoes transsulfuration to form cysteine by the action of metabolic enzymes and cofactors. Impaired metabolism due to genetic alteration in metabolic enzymes (methionine synthase, methyltetrahydrofolate reductase (MTHFR), cystathionine ß-synthase (CßS), and cystathionine-γ-lyase (CγL) or deficiency in cofactors (vitamin B6 , B12 , folate) may lead to acquired metabolic anomaly known as hyperhomocysteinemia. Hcy excess decreases the S-adenosylmethionine (SAM)-dependent synthesis of catecholamines, viz. dopamine, norepinephrine, epinephrine, and noncatecholamine, viz. serotonin (5-HT), due to genetic alteration in key enzyme MTHFR in the homocysteine metabolism pathway that leads to depression. Thus, hyperhomocysteinemia (HHcy)-induced SAM level is influenced by the single nucleotide polymorphism (SNP) MTHFR C677T. Furthermore, HHcy leads to production of precarious neurotoxic product homocysteic acid (HCA) and cysteine sulfinic acid (CSA) which acts as an N-methyl-D-aspartate (NMDA) receptor agonist and has neurotoxic effects on dopaminergic neurons. In the current review, an attempt has been made to discuss the neurotoxic effects of HHcy in the pathogenesis of depression.

Use of light-curing units in orthodontics.

Because of their wide field of applications, light-curing units are now indispensable for orthodontists and general dentists; thus, it is important to be familiar with the various types of light-curing units, their history, specifications, advantages, and disadvantages. For this review, a search of the PubMed database (from 1966 to March 2010) was conducted using the search term "curing lights orthodontics". Eligibility of the selected studies was determined by reading the abstracts of articles identified by the search. All the articles that met the inclusion criteria were selected, and the articles collected. The reference lists of the retrieved articles were also hand searched for any applicable studies that might have been missed in the database searches. When selecting curing lights for an office, many variables need to be considered. Armed with knowledge about each curing-light category, orthodontists can evaluate their unique practice style and select the appropriate light/lights.

Current concepts in the management of esophageal perforations: a twenty-seven year Canadian experience.

BACKGROUND: Perforation of the esophagus remains a challenging clinical problem. METHODS: A retrospective review was performed of patients diagnosed with an esophageal perforation admitted to the London Health Sciences Centre from 1981 to 2007. Univariate and multivariate logistic regression was used to determine which factors had a statistically significant effect on mortality. RESULTS: There were 119 patients; 15 with cervical, 95 with thoracic, and 9 with abdominal perforations. Fifty-one percent of all the perforations were iatrogenic and 33% were spontaneous. Multivariate logistic regression analysis revealed that patients with preoperative respiratory failure requiring mechanical ventilation had a mortality odds ratio of 32.4 (95% confidence interval [CI] 3.1 to 272.0), followed by malignant perforations with 20.2 (95% CI 5.4 to 115.6), a Charlson comorbidity index of 7.1 or greater with 19.6 (95% CI 4.8 to 84.9), the presence of a pulmonary comorbidity with 13.9 (95% CI 2.9 to 97.4), and sepsis with 3.1 (95% CI 1.0 to 10.1). A wait time of greater than 24 hours was not associated with an increased risk of mortality (p=0.52). CONCLUSIONS: Malignant perforations, sepsis, mechanical ventilation at presentation, a higher overall burden of comorbidity, and a pulmonary comorbidity have a significant impact on the overall survival. Time to treatment is not as important. Restoration of intestinal continuity, either by primary repair or by excision and reanastomosis can be attempted even in patients with a greater time from perforation to treatment with respectable morbidity and mortality rates.

The fastest route between two points is not always a straight line: An analysis of air and land transfer of nonpenetrating trauma patients.

BACKGROUND: The distance beyond which helicopter transport is faster than ground for interfacility transfer of trauma patients has not been established. Our objective was to determine whether such a threshold exists. METHODS: A retrospective cohort study was conducted involving 243 patients transported by land and 139 patients by air from 13 sites during a 3-year period. Time intervals between critical events were compared for the two modes of transport at each site. RESULTS: The time interval between the decision to transfer and the actual departure time was shorter for patients transferred by land from all sites studied (mean 41.3 versus 89.7 minutes, p < 0.001). The travel time was shorter by helicopter from all sites (mean 58.4 versus 78.9 minutes, p < 0.001). The time between the decision to transfer and the arrival at the trauma center was similar at most sites but faster by land overall (mean 120.3 versus 150.0 minutes, p = 0.014). No threshold was detected beyond which helicopter transport was superior. CONCLUSIONS: Several factors other than the distance to be traveled determine the time required for interfacility transfer of trauma patients. A fixed distance threshold beyond which helicopter transport should be used does not exist. The decision as to which mode of transport to use for emergent trauma patient transfers should be based upon multiple factors including the distance traveled and ambulance availability, and must be individualized for each site that transfers patients.