A proteomic study to unveil lead toxicity-induced memory impairments invoked by synaptic dysregulation.

Lead (Pb2+), a ubiquitously present heavy metal toxin, has various detrimental effects on memory and cognition. However, the molecular processes affected by Pb2+ causing structural and functional anomalies are still unclear. To explore this, we employed behavioral and proteomic approaches using rat pups exposed to lead acetate through maternal lactation from postnatal day 0 (P0) until weaning. Behavioral results from three-month-old rats clearly emphasized the early life Pb2+ exposure induced impairments in spatial cognition. Further, proteomic analysis of synaptosomal fractions revealed differential alteration of 289 proteins, which shows functional significance in elucidating Pb2+ induced physiological changes. Focusing on the association of Small Ubiquitin-like MOdifier (SUMO), a post-translational modification, with Pb2+ induced cognitive abnormalities, we identified 45 key SUMO target proteins. The significant downregulation of SUMO target proteins such as metabotropic glutamate receptor 3 (GRM3), glutamate receptor isoforms 2 and 3 (GRIA 2 and GRIA3) and flotilin-1 (FLOT1) indicates SUMOylation at the synapses could contribute to and drive Pb2+ induced physiological imbalance. These findings identify SUMOylation as a vital protein modifier with potential roles in hippocampal memory consolidation and regulation of cognition. Data availbility: The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD034212".

Cerebrospinal Fluid from Patients with Sporadic Amyotrophic Lateral Sclerosis Induces Degeneration of Motor Neurons Derived from Human Embryonic Stem Cells.

Disease modeling has become challenging in the context of amyotrophic lateral sclerosis (ALS), as obtaining viable spinal motor neurons from postmortem patient tissue is an unlikely possibility. Limitations in the animal models due to their phylogenetic distance from human species hamper the success of translating possible findings into therapeutic options. Accordingly, there is a need for developing humanized models as a lead towards identifying successful therapeutic possibilities. In this study, human embryonic stem cells-BJNHem20-were differentiated into motor neurons expressing HB9, Islet1, and choline acetyl transferase using retinoic acid and purmorphamine. These motor neurons discharged spontaneous action potentials with two different frequencies (< 5 and > 5 Hz), and majority of them were principal neurons firing with < 5 Hz. Exposure to cerebrospinal fluid from ALS patients for 48 h induced several degenerative changes in the motor neurons as follows: cytoplasmic changes such as beading of neurites and vacuolation; morphological alterations, viz., dilation and vacuolation of mitochondria, curled and closed Golgi architecture, dilated endoplasmic reticulum, and chromatin condensation in the nucleus; lowered activity of different mitochondrial complex enzymes; reduced expression of brain-derived neurotrophic factor; up-regulated neurofilament phosphorylation and hyperexcitability represented by increased number of spikes. All these changes along with the enhanced expression of pro-apoptotic proteins-Bax and caspase 9-culminated in the death of motor neurons.

Systemic mastocytosis: predominantly involving the bone, a case report.

Systemic mastocytosis (SM) is a rare clonal disorder of mast cells that can range from chronic smouldering type to aggressive mast cell leukaemia. It presents with non-specific symptoms like urticaria pigmentosa, unexplained flushing, hypotension and abdominal cramps, which may lead to a misdiagnosis, if there is no high index of clinical suspicion. This is a case report of a 52-year-old lady, with systemic mastocytosis, who presented with severe chronic back ache and no other clinical features. X - ray revealed lytic lesions in the lumbar vertebrae and bone marrow aspiration and a trephine biopsy examination showed infiltration by mast cells, with a positivity for Toluidine blue stain and CD 117. She was also noted to have peripheral eosinophilia, which is frequently encountered with this condition. She was diagnosed to have chronic indolent systemic mastocytosis which involved the bone predominantly.

Photobiomodulation by helium neon and diode lasers in an excisional wound model: A single blinded trial.

BACKGROUND: Application of different kinds of lasers in clinical and experimental studies causes photobiomodulation that works at localized cellular and humoral level on various biological systems. Increased numbers of fibroblasts, myofibroblast, and degranulation of mast cells have been the observed benefits post-irradiation. OBJECTIVE: Was to find out the effect of irradiation with energy densities of 3.38 J/cm(2), 8 J/cm(2), and 18 J/cm(2) on animal tissue (albino wistar rats) in an excisional wound model and to assess changes in biochemical (hydroxyproline) and histopathological levels in excisional wound model. MATERIALS AND METHODS: The animals were divided into 4 groups, which were labeled as L1, diode laser (18 J/cm(2)), L2 Helium-neon (He-Ne, 8 J/cm(2)), L3 diode laser (3.38 J/cm(2)), and sham treatment for control was depicted by C, respectively. Histological and hydroxyproline analysis was performed on 7, 14, 21 days of post-wounding. One-way analysis of variance, ANOVA and Bonferroni's multiple comparison tests were done for tissue hydroxyproline levels. RESULTS: There was no significant increase in the hydroxyproline content (P < 0.005) when observed in study group and compared to controls. Whereas significant epithelizations was seen in group treated with He-Ne laser of intensity of 8 J/cm(2). CONCLUSION: The experimental observations suggest that low intensity helium-neon laser of 8 J/cm(2) intensity facilitated photo stimulation by tissue repair, but failed to show significant tissue hydroxyproline levels in excisional wound model.

DNA methylation patterns in luminal breast cancers differ from non-luminal subtypes and can identify relapse risk independent of other clinical variables.

The diversity of breast cancers reflects variations in underlying biology and affects the clinical implications for patients. Gene expression studies have identified five major subtypes- Luminal A, Luminal B, basal-like, ErbB2+ and Normal-Like. We set out to determine the role of DNA methylation in subtypes by performing genome-wide scans of CpG methylation in breast cancer samples with known expression-based subtypes. Unsupervised hierarchical clustering using a set of most varying loci clustered the tumors into a Luminal A majority (82%) cluster, Basal-like/ErbB2+ majority (86%) cluster and a non-specific cluster with samples that were also inconclusive in their expression-based subtype correlations. Contributing methylation loci were both gene associated loci (30%) and non-gene associated (70%), suggesting subtype dependant genome-wide alterations in the methylation landscape. The methylation patterns of significant differentially methylated genes in luminal A tumors are similar to those identified in CD24 + luminal epithelial cells and the patterns in basal-like tumors similar to CD44 + breast progenitor cells. CpG islands in the HOXA cluster and other homeobox (IRX2, DLX2, NKX2-2) genes were significantly more methylated in Luminal A tumors. A significant number of genes (2853, p < 0.05) exhibited expression-methylation correlation, implying possible functional effects of methylation on gene expression. Furthermore, analysis of these tumors by using follow-up survival data identified differential methylation of islands proximal to genes involved in Cell Cycle and Proliferation (Ki-67, UBE2C, KIF2C, HDAC4), angiogenesis (VEGF, BTG1, KLF5), cell fate commitment (SPRY1, OLIG2, LHX2 and LHX5) as having prognostic value independent of subtypes and other clinical factors.

Lung growth in infants and toddlers assessed by multi-slice computed tomography.

RATIONALE AND OBJECTIVES: Postnatal lung growth and development have primarily been evaluated from a very limited number of autopsied lungs, but it remains unclear whether alveolarization of the lung is complete during infancy and whether the conducting airways grow proportionately. The purpose of this study was to evaluate lung growth and development in vivo in infants and toddlers using multislice computed tomography. MATERIALS AND METHODS: Thirty-eight subjects (14 male, 24 female) aged 17 to 142 weeks underwent low-dose volumetric high-resolution computed tomographic imaging at an inflation pressure of 20 cm H(2)O during an induced respiratory pause. Lung volume and weight were determined, as well as airway dimensions (inner and outer area and wall area) for the trachea and the next three to four generations. RESULTS: Lung volume, air volume, and tissue volume increased linearly with body length. The air and tissue components of the lung parenchyma increased at a constant rate with each other. In addition, airway caliber decreased with increasing generation from the trachea into each lobe. Airway caliber was also correlated with body length; however, there was no interaction effect between airway generation and body length on transformed airway size. CONCLUSIONS: In vivo assessment suggests that the growth of the lung parenchyma in infants and toddlers occurred with a constant relationship between air volume and lung tissue, which is consistent with lung growth occurring primarily by the addition of alveoli rather than the expansion of alveoli. In addition, the central conducting airways grow proportionately in infants and toddlers. This information may be important for evaluating subjects with arrested lung development.

Giant granular cell tumor of the vulva.

A 55-year-old lady presented with a large skin colored growth on her vulva since the age of 15 years, which gradually increased to the present state, with the development of a new lesion on her left thigh. There were no systemic symptoms. Biopsy followed by immunohistochemistry showed features consistent with a granular cell tumor.

Altered neuronal activities in the motor cortex with impaired motor performance in adult rats observed after infusion of cerebrospinal fluid from amyotrophic lateral sclerosis patients.

Although definite evidences are available to state that, neuronal activity is a prime determinant of animal behavior, the specific relationship between local field potentials of the motor cortex after intervention with CSF from human patients and animal behavior have remained opaque. The present study has investigated whether cerebrospinal fluid from sporadic amyotrophic lateral sclerosis (sALS) patients could disrupt neuronal activity of the motor cortex, which could be associated with disturbances in the motor performance of adult rats. CSF from ALS patients (ALS-CSF) was infused into the lateral ventricle of Wistar rats. After 24h, the impact of ALS-CSF on the local field potentials (LFPs) of the motor cortex and on the motor behavior of animals were examined. The results indicate that ALS-CSF produced a bivariate distribution on the relative power values of the LFPs of the motor cortex 24h following infusion. However, the behavioral results did not show bimodality, instead showed consistent decrease in motor performance: on rotarod and grip strength meter. The neuronal activity of the motor cortex negatively correlated with the duration of ALS symptoms at the time of lumbar puncture. Although the effect of ALS-CSF was more pronounced at 24h following infusion, the changes observed in LFPs and motor performance appeared to revert to baseline values at later time points of testing. In the current study, we have shown that, ALS-CSF has the potential to perturb neuronal activity of the rat motor cortex which was associated with poor performance on motor function tests.

Duplicated rectum as interlabial mass.

Duplications of the rectum constitute one of the rare congenital anomalies. Presentation as a sequestrated interlabial mass without any associated anomaly has not been reported before. We cannot readily offer any embryological explanation for this congenital distortion. Total extirpation of the lesion was easily achieved ensuring complete cure.

Adult onset eccrine angiomatous hamartoma.

Eccrine angiomatous hamartoma (EAH) is a benign hamartoma containing eccrine glands and blood vessels. It may be present at birth or may develop during childhood. We report a patient with onset in adulthood.

Expression of E-cadherin in primary oral squamous cell carcinoma and metastatic lymph nodes: an immunohistochemical study.

BACKGROUND: E-cadherin plays an important role in cell-to-cell adhesion and cell motility and its loss is associated with oral squamous cell carcinoma (OSCC) progression. The aim of this study was to determine the expression of E-cadherin in various grades of OSCC and to correlate changes in the expression between these various grades and metastatic lymph nodes. MATERIALS AND METHODS: Immunohistochemistry (IHC) was used to detect E-cadherin expression in normal oral mucosa, primary OSCC (n = 37), and metastatic lymph nodes (n = 10). E-cadherin immunoreactivity was correlated with grades of differentiation and with clinicopathological features. RESULTS: E-cadherin immunoreactivity was found to inversely correlate with the loss of cell differentiation. The expression of E-cadherin decreased significantly in advanced cases of OSCC. However, increase in E-cadherin immunoreactivity was seen in early lesions, that is, in well differentiated (n = 9) and moderately differentiated OSCC (n = 13). Furthermore, E-cadherin was negative in majority of metastatic lymph nodes (7/10). CONCLUSIONS: Loss of the cell adhesion and E-cadherin plays an important role in progression of OSCC, that is, down regulation of its expression is associated with de-differentiation and metastasis.

Localized and persistent erythema nodosum leprosum - a rare variant?

Erythema nodosum leprosum (ENL) or Type-2 Lepra reaction is a manifestation of type III hypersensitivity response and usually occurs in certain cases of lepromatous and borderline lepromatous leprosy. It is usually generalized and evanescent, and responds well to oral corticosteroid therapy. Here we report an unusual case of persistent and localized ENL in a 19-year-old girl, which could be diagnosed with the aid of skin biopsy and histopathological examination.

Effect of low intensity helium-neon (He-Ne) laser irradiation on diabetic wound healing dynamics.

OBJECTIVE: The aim of this study was to determine the effect of low-energy He-Ne laser treatment on wound healing dynamics (histological and biochemical) in diabetic rats. BACKGROUND DATA: Low-energy laser photostimulation at certain wavelengths can enhance tissue repair by releasing growth factors from fibroblasts and can facilitate the healing process of diabetic wounds. MATERIALS AND METHODS: A circular 4 cm2 excisional wound was created on the dorsum of the experimentally (Alloxan)-induced diabetic rats. In the study group (N = 24) the wound was treated with He-Ne laser (632.8 nm wavelength) at a dose of 4.8 J/cm2 for 5 days a week until the wound healed completely. The control group (N = 24) was sham-irradiated. The results were statistically analyzed by an independent t test for biochemical analysis and the nonparametric Mann-Whitney U test for histopathological parameters. RESULTS: The analysis of the biochemical parameters and histopathological parameters of the wounds showed that the laser-treated group healed faster and better as compared to the control group (p < 0.0001). The laser-treated group healed on average by the 18th day whereas, the control group healed on average by the 59th day. CONCLUSION: Laser photostimulation promotes the tissue repair process of diabetic wounds.

Specificity in stress response: epidermal keratinocytes exhibit specialized UV-responsive signal transduction pathways.

UV light, a paradigmatic initiator of cell stress, invokes responses that include signal transduction, activation of transcription factors, and changes in gene expression. Consequently, in epidermal keratinocytes, its principal and frequent natural target, UV regulates transcription of a distinctive set of genes. Hypothesizing that UV activates distinctive epidermal signal transduction pathways, we compared the UV-responsive activation of the JNK and NFkappaB pathways in keratinocytes, with the activation of the same pathways by other agents and in other cell types. Using of inhibitors and antisense oligonucleotides, we found that in keratinocytes only UVB/UVC activate JNK, while in other cell types UVA, heat shock, and oxidative stress do as well. Keratinocytes express JNK-1 and JNK-3, which is unexpected because JNK-3 expression is considered brain-specific. In keratinocytes, ERK1, ERK2, and p38 are activated by growth factors, but not by UV. UVB/UVC in keratinocytes activates Elk1 and AP1 exclusively through the JNK pathway. JNKK1 is essential for UVB/UVC activation of JNK in keratinocytes in vitro and in human skin in vivo. In contrast, in HeLa cells, used as a control, crosstalk among signal transduction pathways allows considerable laxity. In parallel, UVB/UVC and TNFalpha activate the NFkappaB pathway via distinct mechanisms, as shown using antisense oligonucleotides targeted against IKKbeta, the active subunit of IKK. This implies a specific UVB/UVC responsive signal transduction pathway independent from other pathways. Our results suggest that in epidermal keratinocytes specific signal transduction pathways respond to UV light. Based on these findings, we propose that the UV light is not a genetic stress response inducer in these cells, but a specific agent to which epidermis developed highly specialized responses.

Psammomatous extra-calvarial meningioma of the neck.

A case of Primary extraraniul meningioma of the parapharyngcal space arising simulitueouly as two distinct tumour masses from two sepurae cranial nerves is reported. The paucity of reported eases is the evidence for its rarily.