Whistleblower Issue and Its Relevance in Autism Research

http://austinpublishinggroup.com/neuropsychiatry-cognitive-science/fulltext/ajncn-v1-id1001.php

On August 27, 2014, CDC scientist Dr. William Thompson admitted that he and other authors had omitted vital data from a 2004 study of possible connections between MMR vaccines and autism. Dr. Thompson also acknowledged a biologically plausible relationship between Thimerosal (a mercury-based preservative) in vaccines and autistic-like symptoms. He additionally reported that the CDC has withheld information about a relationship between Thimerosal and tic disorders. Whether or not a person thinks that the admissions made by this CDC scientist reflect the truth, admitting fraud in the CDC's neurodevelopmental disorders research is certainly newsworthy. Why then has the mainstream media been mostly silent on the issue? The coverage of this story has been mostly limited to the blogosphere. Some of the mainstream media's top stories have instead included: "Artists draws his dog in whimsical scenes" (ABC News, 9/17/14); "Is the tide changing for the NFL" (MSNBC, 9/17/2014); and "Vikings: Peterson must stay away", and "Final hours before Scotland's big vote" (CNN, 9/17/14).

Admittedly, this CDC whistleblower story is controversial. This is due, in part, to enormous and far-reaching liability ramifications, to the disturbing number of potentially affected children, and because those that could be held accountable hold powerful and authoritative governmental positions. We can only speculate if the mainstream media is simply not interested in this topic, or if their silence reflects a form of disagreement, or if possibly their lack of coverage is due to external pressure to extinguish the story. The limited mainstream media coverage of such a weighty scientific matter reveals the importance of scientists themselves having a public voice on critical public policy issues. Throughout history scientists speaking loudly about dangerous toxins have saved many lives and prevented untold pain and deformities. Clear examples are Pink disease (caused by mercury in teething powders), lead poisoning diseases (from lead-based paints and other products), and thalidomide causing birth defects. And also, of course, the discovery that mercury causes neurological damage. The mainstream media's silence here emphasizes the value of peer-reviewed science journals as an avenue for scientists to be a part of necessary public dialogues. This story also raises the issue of the importance of transparency in research and the availability of public databases to independent researchers. 

The current datasets used by the CDC in their own research on vaccines and autism are not easily accessible to independent researchers. For example, one of the databases used by the CDC that reportedly showed no relationship between thimerosal and autism is no longer available to anyone outside of the CDC to examine. Neuropsychiatric disorder research data transparency is especially important considering today's staggering numbers of neurodevelopmental disorders, which in the United States has increased to about 1 in every 6 children. This has predominately been an increase in autism and attention deficit/ hyperactivity disorders, but there has also been an increase in tic disorders. World-wide neuro developmental disorders today are causing heavy consequences on the affected individuals and their families. How this unfolds remains to be seen. However, assuming continued mainstream media silence, it is likely that this whistleblower story along with its potential implications will remain missing from the forefront of public discussion.

Dendritic Spine Modifications in Synaptic Plasticity

              http://austinpublishinggroup.com/neurology-neurosciences/fulltext/ann-v2-id1015.php

Synapticplasticity is regarded as the cellular mechanism underlying the refinement of neural connections during development and learning/memory functions in adults. Alterations in dendritic spine morphology (elongation or shrinkage) and/or spine density occur with synaptic plasticity. This structural modification has been proposed to enable persistent, long-term change in synapses. Here we review spine modifications associated with synaptic plasticity and discuss their contributions to synaptic plasticity and brain diseases.

Dendritic spines are small postsynaptic structures protruding from dendrites and the primary site of excitatory input. About 90% of excitatory synapses occur on spines on the excitatory neurons in the adult cortex. Spines are usually divided into three types based on the size, spine head shape, and spine neck length. Mushroom spines have large heads and constricted narrow necks, thin spines have small heads and slender necks, while stubby spines have no distinct heads and necks. This categorization is to provide an easy classification while the actual distribution of spine shapes is of a continuum.

The recent development of two-photon imaging allows spine morphology and dynamics to be studied in great detail using timelapse and repetitive imaging, and has enabled the study of spine alterations in response to physiological or pathological events. For example, dendritic spines are dynamic in genesis and elimination, especially during brain development. In adolescence, spines show much higher elimination than formation which results in net spine loss or pruning. However in the adult, the rate of spine genesis and elimination is much reduced and roughly equivalent, which maintains the stability of spine density.

Spines are considered a unique calcium compartment. Spine plasticity is demonstrated by their capacity to undergo both rapid (seconds) and persistent (months to years) alterations in response to either physiological or pathological events. Large spines may be the storage site of stable long-term memory, while filopodia are considered as the immature form of spine which can be transformed into mature spines or eliminated. Spine plasticity is exhibited in two forms: changes in spine morphology/size and changes in spine density. Both changes reflect altered synaptic connections and strength. In neurodegenerative and psychiatric diseases, spine density and morphology are altered, and these changes may partially account for alterations in brain functions associated with these diseases. Thus a better understanding of spine pathology may provide better therapeutic intervention.

A Rare Case of Unilateral Lower Limb Spasticity: Two Rare Mutations

                          http://austinpublishinggroup.com/neurological-disorders-epilepsy/

The SPG11gene was first analyzed, revealing homozygous or compound heterozygous mutations in 30/97 (30.9%) of pro bands, the largest SPG11 series reported to date, and by far the most common cause of complex spastic paraplegia Hereditary spastic paraplegia (HSP) is a group of clinically and genetically heterogeneous neurological disorders characterized by path physiologic hallmark of length-dependent distal axonal degeneration of the corticospinal tracts. HSP can be transmitted as an Autosomal Dominant (AD), Autosomal Recessive (AR), X-linked (XL), or mitochondrial manner. Here we describe a 15-yr-oldboy with abnormal posturing of right lower limb (dystonia and spasticity) during walking, who MRI is showed thinned out corpus callosum. Patients younger brother also had weakness in the lower limbs and Similar MRI findings. Mutation analysis revealed two rare variations in the SPG 11 gene not reported in medical literature till date.

In its pure form, Hereditary spastic paraplegias (HSP) is usually transmitted as an autosomal trait; Symptoms usually begin in the third in the third or fourth decade, presenting as progressive spastic weakness beginning in the distal lower extremities. However, there are variants with relatively early onset mimicking cerebral palsy. HSP has a typically long survival as respiratory function is spared1. Late in the illness, there may be urinary urgency, incontinence and fecal incontinence. In pure forms of HSP, spastic leg weakness is often accompanied by posterior column abnormalities and bladder bowel dysfunction. By contrast, when recessively inherited HSP may have complex forms in which altered corticospinal and dorsal column function is accompanied by significant involvement of other regions of nervous system, including amyotrophy, mental retardation, optic atrophy and sensory neuropathy.

Here we present a 15 yr old boy with complex hereditary spastic paraparesis, which is asymmetric in involvement i.e. right side affected more than left, along with mild mental retardation and thin corpus callosum, showing two heterozygous variations in the SPG 11 gene at a time. These two variations are extremely rare and not reported in medical literature till date, giving a unique presentation in the index case with right lower limb dystonia with spasticity. 15-yr-old-male, residing at Bangladesh was admitted in this hospital with chief complaints of insidious onset and gradually progressive weakness of both lower limbs for last 1 year. The weakness was distal to start with and gradually progressed to involve the proximal limb. There was abnormal posturing of the right foot especially during walking (Video 1) for the same duration which subsided during sleep.

Primary Squamous Papillary-Type Craniopharyngioma in the Cerebellopontine Angle: Report of Two Cases

                  http://austinpublishinggroup.com/neurosurgery/fulltext/ajns-v4-id1054.php

Craniopharyngioma is a benign epithelial tumor that originates from the Rathke pouch and usually develops around the parasellarregion. By pathology the tumor is divided into two main types, the adamantinomatous type and squamous papillary type. In contrast to the usual parasellar location, primary craniopharyngioma developing in the Cerebellopontine (CP) angle is extremely rare, with only eleven cases reported to date. Ten of these cases were of the adamantinomatous type and one was of the squamous papillary type. Here, we report the neuroradiological findings from two additional cases of squamous papillary-type craniopharyngioma that developed in the CP angle and were isolated from the parasellar region.

The patient was therefore operated on via a lateral sub occipital approach. A cystic tumor was identified, with a rust-colored component being visible through the wall of the capsule. Following the opening of the cyst a motor oil-like fluid and semisolid component were drained. The 3^rd nerve and pituitary stalk were identified beyond the arachnoid membrane with neither showing any sign of contact with the tumor (Figure 1e).

Postoperative MRI revealed near-total resection of the tumor (Figure 1f). Neuropathology showed that the wall of the cyst was composed of squamous epithelium with a papillary structure (Figure 1g). In contrast, the tumor contained keratinous material, cholesterin crystal and a fibrous inflammatory granuloma (Figure 1h), and was diagnosed as a squamous papillary-type craniopharyngioma. Postoperatively, the patient’s hearing acuity, facial numbness and gait disturbance improved. No sign of recurrence has been observed on follow-up examination for six years.

Is there Correlation between Subclinical Hypothyroidism and Diabetic Nephropathy?

                         http://austinpublishinggroup.com/nephrology/currentissue.php

Diabetes mellitus (DM) is the most common chronic metabolic disease which its incidence is increasing rapidly. The prevalence of DM in urban Iranian population aged ≥20 years was 8.1% in 2008. Diabetic nephropathy (DN) is one of the main chronic complications in type 1 and 2 diabetes and is currently the most common cause for end stage renal disease (ESRD). It is reported that diabetes contributes to approximately 40 percent of newly developed ESRD patients each year. Diabetic nephropathy is likely multi-factorial. Although genetic and environmental factors can involved in diabetic nephropathy, resulted hemodynamic and metabolic changes can not clearly justify the diabetic nephropathy progression.

The prevalence of thyroid disorders is higher in diabetic patients and subclinical hypothyroidism (SCH) being the most disorder. SCH has been associated with endothelial dysfunction and probably atherosclerotic risk factors. Hypothyroidism causes remarkable changes in glomerular filtration rate (GFR), tubular function, water and electrolyte balances but association of SCH and diabetic nephropathy (DN) has not been evaluated so far. The aim of this study was to correlate SCH with DN in Iranian patients with type 2 diabetes.

In a cross- sectional study, we recruited 150 patients with type 2 diabetes. Patients with: past history of thyroid disease, taking drugs with effects on thyroid tests and albuminuria and any sever intercurrent illness were excluded. Furthermore, patients with type 1 diabetes, pregnancy, lactation, malignancy and liver failure were also excluded. Patients were informed completely about the study’s aims and if they fulfilled the written informed consent, they were entered in the study. We recorded the demographic characteristics including: age, height, weight, blood pressure and body mass index (BMI). BMI was calculated according to this formula: Weight (kg)/height (m2). Blood pressure of the right arm was taken in a sitting position after resting for ten minutes. After 8 hours overnight fasting, blood samples were obtained from the brachial vein. Fasting plasma glucose was measured by the glucose oxidase method (Human, Germany). Total cholesterol, triglyceride (TG), and high density lipoprotein (HDL) were measured by enzymatic method (Parsazmon Karaj, Iran). Low density lipoprotein (LDL) was calculated according to Friedwall formula {LDL= total cholesterol-(HDL+TG/5)}. Glycated hemoglobin A1C (HbA1C) was assessed by Column chromatography (Biosource kit, Barcelona, Spain).Urinary albumin was measured as the albumin to creatinine ratio (ACR) in a morning sample. Urine albumin in spot urine was measured by Immunoturbidometry assay (Parsazmon, Karaj, Iran). Urine creatinine was measured by enzymatic colorimetric assay. Urinary microalbumin ≥30 and < 300 mg per gram of creatinine in urine was considered as microalbuminuria and level ≥300 was considered as macroalbumiuria. Estimated GFR (e GFR) (ml/min/1.73 m2) was calculated according to equation of the Modification of Diet in Renal Disease. DN was defined as an increased ACR of ≥ 30 mg/gr in the absence of other renal abnormalities or e GFR less than 60 ml/min/1.73 m2according to KDOQI recommendation. Serum thyroid stimulating hormone (TSH) was measured by immunoradiometric assay, and free T4 was determined using radioimmunoassay.

Nanotechnology- A Promising Approach for Suicide Gene Therapy

            http://austinpublishinggroup.com/nanomedicine-nanotechnology/fulltext/ajnn-v4-id1042.php

Cancer is one of the world’s most dreadful diseases and the battle against cancer continues till date. Suicide gene therapy for cancer is one of the best approaches for annihilation of cancer. In brief, suicide gene codes for an enzyme which converts a nontoxic prodrug into toxic metabolites and subsequently mediates death of host cells itself on account of which it is named “suicide” gene therapy. These suicide gene when constitutively expressed by the cells not only mediates death of host cells but also inflicts strong bystander effects on neighboring cells by predisposing them to toxic downstream metabolites. Due to such advantages, they manifest minimal systemic toxicity and are also effective against many drug resistance cancer cells. Among all existing suicide genes, Cytosine Deaminase (CD) and Herpes Simplex Virus-thymidine kinase (HSVtk) have shown promising results initially and has been investigated extensively since long. The HSVtk enzyme initially phosphorylates the prodrug Ganciclovir (GCV) to its monophosphate form, which is subsequently phosphorylated again by endogenous cellular kinase to generate nucleotide analogs (di- and triphosphate forms of GVC). Triphosphate form of GCV is then readily incorporated into DNA during the course of DNA synthesis and acts as a chain terminator to prevent further DNA synthesis, which ultimately induces cell death.

The therapeutic efficacy of HSVtk suicide gene therapy is often limited by cell-to-cell contact which is a prerequisite for transport of downstream metabolic byproducts of ganciclovir to neighboring cells so as to attain bystander-killing effect. As an outcome of such drawbacks, HSVtk suicide gene does not seem to be effective against different cell types. In contrary to this, Cytosine Deaminase (CD) efficiently converts prodrug 5-Fluorocytosine (5- FC) into therapeutically active anticancer agent 5-Fluorouracil (5- FU), which subsequently permeates across the cell membrane to mediate bystander killing effects on adjacent neighboring cells. Thus, 5-FC/CD system attains suicide gene therapy much more efficiently as compared to other counterparts. Although 5-FC/CD system attains better therapeutic outcomes, it is ineffective against 5-FC resistant cancer cells and thus its anticancer potential could not be generalized for all cancer types. In order to overcome such drawback, Gopinath et al. have designed Cytosine Deaminase-Uracil Phosphoribosyltransferase (CD-UPRT) bifunctional suicide gene construct in which Uracil Phosphoribosyltransferase (UPRT) acts upon product of CD i.e. 5-FU and converts it further into other toxic metabolites.

The therapeutic effect of suicide genes can be enhanced by combinatorial approaches. In combination therapy, two or more drugs with similar or different mode of action are employed to realize synergistic anticancer therapeutic potentials. Such synergistic anticancer potential of combination of radiation therapy and 5-FC/ CD plus UPRT gene therapy was demonstrated by Kambara et al. against malignant gliomas [8]. Apart from this, the combination therapy also provides scope for exploiting radio sensitizing properties of 5-FU and by stander effects during the course of treatment. Many research groups have reported the use of suicide gene in combination with chemotherapy and radiation to enhance the therapeutic effect and to overcome the drug resistance. Gopinath et al. were the first to report the applications of silver nanoparticles for synergizing the therapeutic effect of suicide gene. They have also reported the synergistic therapeutic effect of suicide gene with anticancer drug curcumin. One of the major challenging tasks in suicide gene therapy is lack of suitable vectors for targeted delivery of suicide gene to cancer cells. The application of such DNAbased therapeutics is largely limited due to poor cellular uptake, degradation by serum nucleases and rapid renal clearance following systemic administration. In addition to these, organ specific targeted DNA therapy has been a major challenge to overcome off-target gene therapy. In order to circumvent these limitations, numerous organ specific targeted nanocarriers have been developed recently for systemic administration.

Bedside Ocular Ultrasound for Diagnosis of Visual Disturbances in Hypertensive Disorders of Pregnancy

              http://austinpublishinggroup.com/medical-sciences/fulltext/ams-v1-id1011.php

A 41year-old woman in her first pregnancy attended our emergency department due to high blood pressure, headaches and visual disturbances. She was taken to the operating room for an emergency caesarean section. In postoperative she developed HELLP syndrome. Due to the persistence of the headaches and visual disturbances, an ocular ultrasound was performed which showed, in both eyes, a laminar hyperechogenic image in the vitreous cavity compatible with bilateral serous retinal detachment (Figure 1). Measurement of the diameter of the optic nerve sheath was similar in both eyes, 5, 4mm in the right eye and 5, 5mm in the left eye, which was indicative of increased intracranial pressure [1-4]. A Cranial CT scan was performed and was normal. In the following days, blood pressure was controlled and the headaches and visual disturbances were no longer present. An ocular ultrasound no longer showed images of retinal detachment nor increased intracranial pressure (Figure 2). We believe that bedside ocular ultrasound is a useful tool in hypertensive disorders that are associated with visual disturbances.

Comparison of Local versus General Anaesthesia for Carpal Tunnel Release

             http://austinpublishinggroup.com/musculoskeletal-disorders/fulltext/ajmd-v4-id1043.php

Carpal tunnel syndrome (CTS) is a common neuropathy, affecting the median nerve as it passes under the transverse carpal ligament. CTS is described as a nerve compression at the wrist plane, CTS causes numbness and tingling in the hand and fingers. Sir James Paget defined CTS first in1853, and since then, in the 1950s a scientist named George Phalen popularized the diagnosis and treatment of CTS. The aetiology of CTS is considered idiopathic in most cases but it is still controversial. Conservative treatment consists of splinting or corticosteroid injections and surgical release of the carpal tunnel are the treatment method options. There has been continued debate over the optimal management of this disease. Decision of the surgeon has consistently varied.

Carpal tunnel release (CTR) is known as an effective treatment for idiopathic CTS. CTR is performed with a variety of techniques such as endoscopic (ECTR) or open (OCTR). Literature has not got consensus on the superiority of any one technique to another. Local anaesthesia (LA) and general anaesthesia (GA) are anaesthetic options on the surgical treatment of CTS. LA is safe, fast, and effective, but the injection could be painful. In one recent series, about 10% of patients indicated that they would prefer another form of anaesthesia. When applying the local anaesthetics under the skin patient could have pain and pain could make the patient uncomfortable. Also from the surgeon side discomfort of the patient could affect the surgical procedure and sometimes visualization of the surgical area could be difficult due to oedema caused by local anaesthetics. These problems in surgical procedure could affect the clinical results of the surgery. Sedation or GA could make the procedure more comfortable.

The aim of the present study was to compare the effects of the anaesthetic methods on the patient’s clinical results. To our knowledge this is the first report that compares the clinical outcomes of the open CTR with GA or LA. Computerized patient database was searched to identify all patients with CTS who underwent open CTR between January 2009 and January 2013 at Fatih Sultan Mehmet Training and Research Hospital. The year 2013 was selected to ensure a minimum one-year follow-up. At the result of the search total of 148 patients (169 CTS hands) were found. Of the 148 patients (169 CTS hands) 21 patients were operated bilaterally and excluded from study. Of the 127 patient operated monolaterally. One patient died from another reason and 14 patients was not available and excluded from the study. Fifty five patients operated with GA (group A) and 57 patients with LA (group B). The last available 50 monolateral patient operated by the same surgeon for each group included to the study.

Fronto-Temporal Dementia: A Case Report

          http://austinpublishinggroup.com/molecular-biology/fulltext/jmbmi-v3-id1023.php

Fronto-temporal dementia (FTD) is the most common form of primary degenerative dementia after Alzheimer’s disease that affects middle age with an estimated prevalence at 15 per 100,000 in the population aged between 45 – 65 years. FTD is often misdiagnosed due to its early onset, clinical and pathological heterogeneity. Neuroimaging is known to assist in early diagnosis of these disorders. We present a case of a 59 year old woman with FTD.

A 59 year old female was diagnosed with major depressive disorder and borderline personality disorder of about a year’s duration. There were continued behavioral changes, with periods of aggression and impulsiveness at times. Also, there was ongoing worsening of memory with poor concentration. She later developed irritable mood and poor appetite. Examination on her last hospital visit showed a well groomed, alert, calm and cooperative patient. She had normal speech and normal psychomotor activity. Her mood was labile; she was however coherent and relevant showing reactive affects. She was a suicidal however objectively hallucinating.

The patient’s medications included fluoxetine 20mg daily, sodium valproate 200mg twice daily, clonazepam 0.5mg when necessary. She underwent magnetic resonance imaging (MRI) of the brain in view of her worsening memory and concentration. This showed evidence of mild frontotemporal lobe involution (Figure 1). Incidentally, there was also an enlarged anterior pituitary gland (1.02 x 1.3 cm) seen.

She was also referred to the nuclear medicine department for brain perfusion imaging – this forms part of molecular imaging and was done byacquiring SPECT images of the brain using Tc-99m HMPAO (Exametazime) injected into a pre-inserted IV line in a quiet dimly lit room. The scan showed a relatively decreased perfusion in the frontotemporal region, involving the anterior cingulate and anterior temporal cortices seen in Figure 2. These findings were in agreement with the findings of MRI and together with the clinical history and signs, consistent with frontotemporal dementia with a diagnosis of Pick’s disease most likely.

The concept of frontotemporal dementia includes a group of primary degenerative dementia disorders that presents with predominant frontal lobe and /or temporal lobe symptoms. These include Pick’s disease (often referred to in broader term of frontotemporal dementia), frontotemporal lobar degeneration (FTLD) also called dementia lacking distinctive histological features (DLDH), frontotemporal lobar degeneration with motor neuron disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia with parkinsonism linked to chromosome 17 and others.

Darwinian Factors in the Clinical Expression of Multiple Sclerosis

                       http://austinpublishinggroup.com/multiple-sclerosis/fulltext/ajmsn-v2-id1020.php

Many predisposing factors for multiplesclerosis (MS), such as HLA types and geomagnetic fields have been described but the search for a single essential factor has been like searching for the rainbow’s end. The most notable feature in the epidemiology of MS in the Western world has been its rise from unknown to the most prevalent disabling neurodegenerative disease of young adults. We suggest that this may be largely or entirely attributable to societal changes that have increasingly isolated populations from micro-organisms that form part of the human microbiome and which are essential for an effective maturation of immune defence mechanisms. This Darwinian explanation suggests a rational approach to both prevention and treatment of MS, by substituting for the loss or absence of factors that millions of years of evolution have led the immune system to ‘expect’ to encounter early in life.

BCG: Bacille Calmette-Guérin; CDMS: Clinically Definite Multiple Sclerosis; CIS: Clinically Isolated Syndrome; EBV: Epstein- Barr virus; HERV: Human Endogenous Retrovirus; HLA: Human Leucocyte Antigen; IL: Interleukin; INF-α: Interferon Alpha; MAIT: Mucosal-associated Invariant T Cells; MAMP: Microbe-associated Molecular Pattern; MHC: Major Histocompatibility Complex; MRI: Magnetic Resonance Imaging; MS: Multiple Sclerosis; TCR: T Cell Antigen Receptor; TNF-α: Tumour Necrosis Factor Alpha; Treg: Regulatory T Cell; PRR: Pattern Recognition Receptor; TLR: Toll-like Receptor; RA: Retinoic Acid.

Current treatment strategies for multiple sclerosis (MS) are essentially empirical because no single clear underlying cause of the disease has been determined. Numerous genomic and environmental risk factors for MS have been described, but problems of cause and effect remain unresolved. It has indeed been stated, with considerable justification, that MS research is “low on fact, high on fiction”.

Although there is a well-described genetically determined predisposition to MS, the association is far from complete as, for example, the risk of an identical twin sibling of an affected person developing MS is only 30%. Thus any genes involved are likely to be of low penetration and influenced by the expression of some or many other genes. Notwithstanding, a large number of genetic loci, including many coding for HLA, have been determined and fine-mapped. These studies have demonstrated a central role for the immune system in the aetiopathogenesis of MS but the highly complex nature of the data will require novel tools for their analysis before any unifying factor can be delineated.

Intersection of Apoptosis and Autophagy Cell Death Pathways

         http://austinpublishinggroup.com/molecular-cellular-biology/fulltext/ajmcb-v2-id1004.php

The balance between cell survival and death is a critical parameter in the regulation of cell and tissue homeostasis. Autophagy is an evolutionarily conserved mechanism for the gross disposal and recycling of intracellular proteins in mammalian cells. Autophagy also kills cells under certain conditions, in a process called autophagic cell death; this involves pathways and mediators different from those of apoptosis. Therefore, three different mechanisms of cell death have been identified in mammalian cells; namely, apoptosis (type I), autophagic cell death (type II), and necrosis (type III). Whether and how these different processes of cell death interconnected each other has not been fully clarified. In this review we discuss the evidence supporting a mechanistic link especially focusing between apoptosis and autophagy associated cell death—including the possibility of cross–talk between the relevant signaling pathways—that could serve to maintain cellular homeostasis in mammals.

In recent decades, insight into the molecular regulation of autophagy in mammalian cells has come from the discovery and functional analysis of Autophagy-Related Gene (ATG). Autophagy is an evolutionally conserved homeostatic process for intracellular degradation by which intracellular proteins are sequestered in a double–membrane–bound autophagosome and delivered to the lysosome during stress conditions; this process facilitates both degradation and recycling of intracellular proteins in mammalian cells. The molecular machinery of autophagy co-ordinates diverse aspects of cellular and organismal responses to other dangerous stimuli such as infection. Defective autophagy underlies a wide variety of human disease and physiology including cancer, neurodegeneration, and infectious diseases. Mammalian orthologues of ATG family proteins have been identified and various functions of ATG proteins have been elucidated, including how these proteins control the formation of autophagosomes. Although autophagy was originally characterized as a cytoprotective process in yeast under starvation conditions, it is now thought to be a form of cell death along with the two classical mechanisms of apoptosis and necrosis in mammalian cells.

Three possible mechanisms for cell death have been known to exist in mammalian cells, namely apoptosis (type I cell death), autophagic cell death (type II cell death), and necrosis (type III cell death). Apoptotic cell death (type I cell death) is characterized by rounding up of the cell and reduction of cell volume, chromatin condensation, nuclear fragmentation, no modification of cytoplasmic organelle, and plasma membrane blebbing without involvement of gene activity. Since autophagy is thought to be a pro-survival pathway, whether or not autophagy indeed 

Metallo-Beta-Lactamase Producing Gram-Negative Bacteria among Patients Visiting Shahid Gangalal National Heart Centre

                          http://austinpublishinggroup.com/microbiology/fulltext/ajm-v2-id1010.php

The rapid spread of acquired Metallo-Beta-Lactamases (MBL) among major Gram-negative pathogens is an emerging threat and a matter of concern worldwide as it results into fewer therapeutic options for the treatment. Therefore, this study was undertaken to determine the prevalence of MBL producing Gram-negative bacteria isolated from different clinical samples.

A total of 490 samples were analyzed, at the Microbiology Department of Shahid Gangalal National Heart Centre (SGNHC), Bansbari, Kathmandu from December 2013 to June 2014, for routine culture and antibiotic susceptibility testing. MBL detection was done by Imipenem-EDTA Combined Disc Test.

Out of 490 samples analyzed, 107 showed positive growth. Fortytwo percent of the Gram-negative isolates were Multi Drug Resistant (MDR). Among 107 Gram-negative isolates, 66 ceftazidime resistant isolates were screened for MBL production of which 9 (13.6%) were found to be MBL positive. All MBL positive isolates were Pseudomonasaeruginosa. None other Gramnegative bacteria were found to produce MBL. Prevalence of MBL producing P. aeruginosa was 20% and all the isolates were MDR. All the MBL producing P. aeruginosa were isolated from hospitalized patients.

This study showed MBL production in a considerable number of P. aeruginosa isolates with MDR phenotypes. There is a need to track the detection of MBL producers and judicious use of carbapenems is necessary to prevent the further spread of these organisms.

AST: Antibiotic Susceptibility Test; ATCC: American Type Culture Collection; CLSI: Clinical Laboratory Standard Institute; EDTA: Ethylene-Diamine-Tetraacetic Acid; ESBL: Extended- Spectrum-Beta-Lactamase; ICU: Intensive Care Unit; MBL: Metallo- Beta-Lactamase (Metallo-β-lactamase); MBLs: Metallo-Beta- Lactamases; MDR: Multi-Drug Resistance; SPSS: Statistical Package for Social Science; TUTH: Tribhuvan University Teaching Hospital; ZOI: Zone of Inhibition.

Evolution of the Incidence, Treatment, and Mortality of Cervical Cancer in Patients Treated at Miguel Servet University Hospital of Zaragoza

                http://austinpublishinggroup.com/medical-oncology/fulltext/ajmo-v4-id1030.php

Cervical cancer is the second most frequent gynecological tumor worldwide. The main reason for this frequency is not practicing adequate cytological screening. We performed a descriptive study of patients with invasive cervical cancer treated at our center from January 2003 through December 2015. In this period, 316 patients were diagnosed with cervical cancer. The mean age was 54.39 ± 16.20 years, with a range of 19 to 90 years and a mode of 49 years. A total of 77.8% of the patients were Spanish and 22.2% were foreign. The initial treatment was surgical in 57.9% of the patients and radio-chemotherapy in 42.1%. The most frequent tumoral stage was IIB followed by IB1. The most common histological type was squamous carcinoma (61.3%), followed by adenocarcinoma (22.6%). Most of the patients, 64.2%, did not experience a relapse and overall survival was 64.9%. Notably, 86.30% of study subjects had not had an appropriate cervical cancer screening test.

After breast cancer, cervical cancer is the type of cancer with the highest incidence and mortality worldwide [1]. As many as 83% of cases of cervical cancer are diagnosed in developing countries, whereas it is less frequent in developed countries [2]. In Europe, cervical cancer ranks fourth among the most frequent types of cancer, and it is the seventh most common cause of mortality [3]. Although Spain is one of the European countries with a lowest incidence, two women die every day from cervical cancer despite the successful screening programs in place. The primary goal of this study was to determine the incidence, therapy, relapse rate, and mortality of patients diagnosed with infiltrating cervical cancer treated in our hospital in the last 13 years to assess the evolution of these factors over time.

Secondary objectives included assessing the origin of referral, tumor stage, and more frequent histological types, and determine the efficacy of screening programs. The study was performed in the Miguel de Servet University Hospital (HUMS), which is located in Zaragoza, the fifth largest city of Spain. HUMS is a third-level hospital serving a population of 530,510 people. It is also the reference hospital for gynecologic oncology of the Autonomous Community of Aragon. Aragon has a population of 1.277.471 inhabitants, which accounts for 2.85% of the Spanish population. The total population of Zaragoza is 917,288 (71% of the population of Aragon). We conducted a retrospective review of patients diagnosed with cervical cancer and treated in our hospital from January 2003 to December 2015. During the study period, a total of 316 women were diagnosed with cervical cancer.

Localized Effects in Periodic Elastoplastic Composites

http://austinpublishinggroup.com/material-science-engineering/fulltext/amse-v2-id1017.php

A method is applied for the study of the field distributions in metal matrix fiber reinforced composites with periodic microstructure in which localized damage exists in the form of complete or partial fiber loss and crack. In addition, the behavior of ceramic/metal periodically layered composites with a single broken ceramic layer is determined. The pro-posed analysis is based on continuum damage mechanics considerations, and the method of solution combines three distinct approaches. In the first one, referred to as the representative cell method, the periodic composite domain is reduced, in conjunction with the discrete Fourier transform to a finite domain problem of a single representative cell. This method has been previously applied on linear thermoelastic, smart and electrostrictive composites, but is presently extended and applied on elastoplastic composites (presently deformation and incremental plasticity). In the second approach, the appropriate far-field boundary conditions in the transform domain are applied in conjunction with the high-fidelity generalized method of cells micromechanical model for the prediction of the macroscopic behavior of the inelastic composite. The third approach consists of the application of the inelastic higher-order theory for the computation of the elastoplastic field in the transform domain. An inverse transform provides the actual field. The effect of damage is included in the analysis in the form of eigenstresses which are a priori unknown. Hence an iterative procedure is employed to obtain a convergent solution.

The proposed method is verified by a comparison with an analytical solution, and several applications illustrate the applicability of the method for metal matrix composites with localized damage in the form of a crack or fiber loss. Localized damage; Cracked fiber reinforced materials; Representative cell method; High-Fidelity generalized method of cells; Inelastic higher-order theory; Elastoplastic composites. The micromechanical analysis of composites with periodic microstructure is usually carried out by identifying and analyzing a repeating unit cell. However, when localized effects such as one or several cracks occur in the composite, the periodicity is lost and its behavior cannot be determined directly by analyzing a repeating unit cell. If these effects are nevertheless included in the analysis of the repeating unit cell, the resulting behavior would correspond to that of a composite with periodic (i.e., not localized) effects which obviously is an unrealistic situation.

In a recent article, Aboudi and Ryvkin proposed the analysis of linearly elastic composites with localized damage by representing the effect of the latter by eigenstresses. This analysis combines continuum damage mechanics considerations with three different approaches. In the first one the idea of using the eigenstresses to represent the nonlinear effects enables application of the representative cell method, Ryvkin and Nuller, based on the discrete Fourier transform which is applicable to linear problems. As a result the initial problem formulated for a domain comprising a large number of cells is reduced to a problem for a single representative cell. Appropriate far-field boundary conditions (which are not influenced by the localized effects) in the transform domain are applied in conjunction with the highfidelity generalized method of cells (HFGMC) micromechanical model which forms the second approach. The third approach consists of the application of the higher-order inelastic theory, Aboudi et al. for the computation of the field in the transform domain. An inverse transform provides the actual field. The effect of damage is included in the analysis in the form of eigenstresses which are a priori unknown. In Ryvkin and Aboudi, this approach has been also proven to be successful and effective in the analysis of cracked layered elastic composites, where one or several combinations of a transverse and two longitudinal cracks (H-cracks) caused branching have been investigated. Furthermore, it has been successfully applied for the prediction of the field distributions in electro-magneto-thermoelastic composites with cracks, cavities and inclusions, Aboudi. A brief review of various methods for the analysis of localized effects in thermoelastic composites has been recently presented by Aboudi and Ryvkin.

LECT2 – A New Cause of Hepatic Amyloidosis

                        http://austinpublishinggroup.com/liver/fulltext/al-v1-id1001.php

Amyloidosis is caused by an abnormal deposition and accumulation of insoluble protein fibrils in multiple organs, often leading to diverse clinical presentations, and possible organ failure. On Congo-Red staining, amyloid fibrils form characteristic betapleated sheets that typically show apple, green birefringence upon polarization under light microscopy. The kidney is the most common organ affected in systemic amyloidosis. The liver is involved less frequently than the kidney. In this editorial we present a recently discovered amyloid protein - LECT2 (leukocyte chemotactic factor 2) that has been documented to affect the kidney and the liver. Of more than 30 types of amyloid protein fibrils discovered thus far, LECT2 is one of the most recently described. It was initially reported to present with slowly progressive renal failure and nephrotic syndrome.

In the United States, LECT2 protein has been found to be especially prevalent among people of Hispanic ethnicity [1]. In an autopsy series, LECT2 amyloid deposits were identified within the kidney in 3.1% of Hispanics, and could represent an important but under-recognized etiology of chronic kidney disease in this population. Two large case series focusing on renal amyloidosis identified LECT2 as the second and third most common form of renal amyloidosis respectively. LECT2 fibrils are found in the glomeruli, renal vessels, and interstitium. Other organs including the liver, spleen, adrenals, and lungs but not myocardium or brain have been reported to be involved with LECT-2 amyloid protein.

A recent large case series identified LECT2 as the second most common form of hepatic amyloidosis. In this series LECT2 accounted for up to 25% of hepatic amyloid cases. LECT2 is synthesized mainly by the liver and is considered to be a hepatokine. The exact biological function of LECT2 is not precisely known. In the liver, it acts as is an eutrophilic chemotactic factor. It also plays a role in hepatocyte regeneration. Increased expression of LECT2 has been found in hepato cellular tumors. The LECT2 gene has been mapped to chromosome 5q31.1-q32 by fluorescence in situ hybridization. This region contains a cluster of cytokine genes that include IL-4, IL-5, and IL-9.

A New History: The 2016 Revision of the WHO Classification of Tumors of Hematopoietic and Lymphoid Tissuess

                                                  http://austinpublishinggroup.com/leukemia/

Classification is the language of medicine: diseases must be described, defined and named before they can be diagnosed, treated and studied. However, a critical feature of any classification of diseases is that it be periodically reviewed and updated to incorporate new information. For many years the diagnosis of leukemia was based solely on pathologic and cytological examination of bone marrow and peripheral blood smears; however, this classification does not always reflect the genetic and clinical diversity of the disease. In this way, the World Health Organization (WHO) proposed a classification to recognize and classify different subgroups of leukemia through clinical, morphological and genetic correlation.

The “WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues” is one of the “blue book” monographs published by the International Agency for Research on Cancer (IARC; Lyon, France), created in collaboration with the Society for Hematopathology and the European Association for Haematopathology. Eight years have elapsed since the current fourth edition of the monograph was published in 2008, and remarkable progress has been made in the field in this time period. Despite this, a truly new fifth edition cannot be published for the time being, as there are still other volumes pending in the fourth edition of the WHO tumor monograph series. Therefore, the Editors of the “WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues,” with the support of the IARC and the WHO, decided to publish an updated revision of the fourth edition that would incorporate new data from the past 8 years which have important diagnostic, prognostic, and therapeutic implications.

The major changes in the classification and their rationale are presented by Swerdlow S. et al. and Arber D. et al. for lymphoid and myeloid neoplasm respectively, however it’s important to note that although some provisional entities have been promoted to definite entities and a few provisional entities have been added to the revised WHO classification, no new definite entities were permitted according to IARC guidelines. The current revision is a much needed and significant update of the 2008 WHO classificationto incorporate clinical features, morphology, immunophenotyping, cytogenetics, and molecular genetics to provide better diagnostic categories and criteria, together with biological and clinical correlates, and facilitate state-of-theart patient care, future therapeutic advances, and basic research in this field. The WHO effort to keep up-dating the classification will continue on, and hopefully provide a model of cooperation between clinicians, pathologists, scientists and hematologists from all over the world.

In the field of leukemia, many questions remain unanswered, however, this update is the first step toward a closer integration of genetic data into a clinicopathological classification. Based in this, the journal “Austin Leukemia” aims to promote research communications and provide a forum for doctors, researchers, physicians and healthcare professionals to find most recent advances in all areas of Leukemia that could be the basis for future classifications.

Lung Cancer Activity of Caralluma Species, an Overview

               http://austinpublishinggroup.com/lung-cancer-research/fulltext/ajlcr-v1-id1006.php

Uncontrolledcell division that spreads throughout the body is cancer; it’s a group of diseases which can lead to death if not controlled. External factors (tobacco, infectious organisms, and unhealthy diet) and internal factors (inherited genetic mutations, hormones, and immune conditions) are the main causes of cancer. These i.e. external and internal may act composed or in order resulting cancer, it may pass a decade from exposure to detection of cancer. Among all types of cancers lung and breast cancers are most diagnosed and leading cause of deaths in men and women. WHO report states that the common causes of cancer deaths are cancers of lung (1.59 million deaths), liver (745 000 deaths), stomach (723 000 deaths), colorectal (694 000 deaths), breast (521 000 deaths), oesophageal cancer (400 000 deaths). Mainly cancer arises from the interaction of person’s genetic factors and three types of external factors like physical carcinogens (Ultraviolet and Ionizing radiation), chemical carcinogens (Tobacco, asbestos, smoke, aflatoxin, and arsenic) and biological carcinogens (virus, bacteria and parasites). The incidence of cancer is more in developed nations than less developed nations but mortality is more (65%) in less developed nations. Prostate cancer in men and lung cancer in women is leading death cause of cancer in more developed Nations, the burden of cancer is slowly shifting to less developed Nations due to the aging of the population and increasing pervasiveness. The genus Caralluma of Asclepiadaceae comprises of approximately 350 species all around the globe. Genus Caralluma normally prefers a dry habitat and decay when they are exposed to an excess of water. The support may be necessary, as they do not contain fibrous tissue. Some of the plants grow even up to a height of 100 cm under protection. Review of literature revealed medicinal uses of genus Caralluma. The distribution of Carallumas ranges from the Mediterranean to East Indies, mostly found in Southern Europe, Iran, Iraq, African countries like Kenya, Somalia, Sudan and Ethiopia, Arabian countries like Oman, UAE and Yemen and Asian countries like Afghanistan, Pakistan, India, Nepal, Burma and Sri Lanka.

The data in the present review is retrieved from the published papers through online bibliographic databases: Google Scholar, ISI Web of Knowledge and Science Direct Navigator. There are a number of publications on caralluma but we considered the ones with lung cancer activity.

Non-Small Cell Lung Cancer is the most common type of lung cancer, among all lung cancers 85% of cases are Non-Small Cell Lung Cancers (NSCLC). NSCLC is further subdivided into Squamous Cell Carcinoma, adenocarcinoma and large cell carcinoma. The cells differ in size and shape and chemical makeup when looked under the microscope in these subtypes.

Squamous cell carcinoma: Squamous cell carcinoma is also known as epidermoid carcinoma; about 25-30% of NSCLC is squamous cell carcinoma. It starts in the flat squamous cell that is lined in the airways of the lungs, squamous cell carcinoma is often linked to smoking, and these are usually located in the large bronchi that join the trachea to the lung. A Continuous cough with blood, out of breath, fatigue, discomfort when swallowing, chest pain, fever, hoarseness, weight loss and poor appetite, are the common signs and symptoms. Individuals experience hypocalcaemia which results in muscle weakness; Obstruction of the airway may lead to pneumonia and atelectasis. Squamous Cell carcinoma can be diagnosed through chest CT scan, sputum cytology, brocho scopy, PET scan and Endobronchial Ultrasound.

From Bench to Bedside: The Growing Use of Arabinoxylan Rice Bran (MGN-3/Biobran) in Cancer Immunotherapy

                     http://austinpublishinggroup.com/austin-immunology/fulltext/ai-v1-id1006.php

MGN-3/Biobran is a denatured hemicellulose obtained by reacting rice bran hemicellulose with multiple carbohydrate hydrolyzing enzymes from Shiitake mushrooms. Over the last 24 years, our fundamental research objective has been to study the biotherapeutic activity of MGN-3 as a treatment for cancer based on its ability to activate the immune system. This objective has been pursued in vitro, and in animal and human studies. This review is focused on the immunomodulatory effects of MGN-3 and on its potential as an anticancer agent. In vitro studies showed that culturing different human and murine cancer cell lines with MGN-3 resulted in a reduction of the survival rate of cancer cells. In vivo studies have also shown that MGN-3 induces tumor regression in several models of animal bearing tumor, including gastric cancer, neuroblastoma, and Ehrlich carcinoma. In addition, the anti-cancer activity of MGN-3 has been shown in human clinical trials and in several case reports on patients with Hepatocellular Carcinoma (HCC) and progressive and partially metastasized cancer. Patients that were treated with MGN-3 in addition to Conventional Therapy (CT), as compared with CT alone, showed: 1) less recurrence of cancer, 2) higher survival rate and 3) improved Quality of Life (QOL) as characterized by improvements in physical activity, appetite, sleep, and digestion, and a decrease in pain and anxiety.

This review summarizes the preclinical and clinical research on MGN-3/ Biobran since it was first patented in 1992. Various animal studies and human clinical trials including different types of malignancies have demonstrated that MGN-3 is a potent Biological Response Modifier (BRM). MGN-3 enhances the cytotoxic reactivity of immune cells with anti-cancer activity such as NK and CD8+ T cells via increasing cell granularity, stimulates the production of interferons, IL-2 and IL-12, and functions as a natural adjuvant for Dendritic Cells (DC). Therefore, MGN-3 may be used in DC-based vaccine strategies against infections and cancer. Importantly, MGN-3 is a unique BRM because it is a safe non-toxic agent and does not exhibit hyporesponsiveness. MGN- 3 has the potential to be a novel and promising immune modulatory adjuvant that could complement the existing immunotherapeutic modalities for cancer patients.

Despite the last decade of advances in treatment options, cancer remains the second leading cause of death in the United States. Unfortunately the outcome of standard cancer treatments is often poor due to the emergence of Multidrug Resistance (MDR) during the course of treatment. MDR cells are a significant factor in the failure of chemotherapeutics as evidenced by high relapse rates for the majority of patients. Therefore, to increase cancer survival and improve symptom control, there is a strong need for new and better approaches to cancer treatment. Today, the National Cancer Institute (NCI) has acknowledged the importance of immune therapy for the treatment of cancer. NCI, other health organizations, and professionals in the field of oncology are currently working to harness the immune system to fight cancer and to expand immunotherapy in combination with other types of cancer treatment, such as targeted therapy, chemotherapy, and radiation therapy.

http://austinpublishinggroup.com/austin-internal-medicine/fulltext/aim-v1-id1011.php

The development in the field of bio sensing of biochemical molecules has been rapid during the recent years. Among many sensing technologies, Silicon Nanowire (SiNW)-based Field-Effect Transistors (FETs) have been shown to be as one of the most promising building blocks for the next generation electrical circuits in recognizing a wide range of biological and chemical targets. They have been successfully used in the detection of, for example, DNA, pH, protein, glucose, virus, and vapor. Despite the significant developments in the area, it seems, however, that the underlying detection mechanism and dynamics of the SiNW FETs are not well defined, and further studies are required. Due to the large surfaceto- volume ratio, one-dimensional nanostructures are considered as one of the best candidates for ultra-sensitive sensors. SiNW FETs have been experimentally demonstrated for direct, label-free, high sensitive, highly selective, and real-time detection of biological and chemical targets at very low concentrations. The most typical configuration of this device uses a nanowire as the essential building block bonding two ends of the nanowire to a solid substrate to create a SiNW FET.

Nanowire (NW) has attracted wide attention, and analyses that focus on various aspects of the device operation have accumulated. We have offered an experimental and analytical method to observe the poly silicon NW MOSFET threshold voltage based on a simple ballistic MOSFET modeling. This paper is intended to incorporate scattering effects into the ballistic modeling and to provide a compact model of the quasi-ballistic Si NW MOSFET. Silicon NW MOSFETs attract wide attention as a promising Nano device for future highdensity LSI application. For development of the device including the circuit application, a handy tool that affords accurate prediction of device characteristics is indispensable.

The device samples were manufactured on standard 6-in. p-type wafers. A proposed hybrid sensor/memory/CMOS poly-Si nanowire structure is illustrated in (Figure 1). The bottom-gate poly-Si nanowire formation can be inserted specifically after metallization of the back-end process (BEOL). At the beginning, buried oxide was deposited on a substrate surface as the gate dielectric of nanowire FETs. A 50-nm polysilicon layer was then deposited using the CVD process. Subsequently, the poly-Si wire was patterned by the standard I-line stepper of the CMOS semiconducting process. By using reactive plasma etching for photoresist trimming followed by silicon etching, the NW dimension was scaled to a level of approximately 100nm.