8,9 Direct cell-cell contact can

also induce transdifferentiation in adult stem cells. The expression of cardiomyocyte markers has been observed via the co-culturing of mesenchymal stem cells with cardiomyocytes.10 Blood-derived human adult endothelial progenitor cells have also been converted #Selleckchem BMS 387032 randurls[1|1|,|CHEM1|]# into cardiomyocytes through co-culturing with Inhibitors,research,lifescience,medical rat cardiomyocytes.11 Transdifferentiation can also be achieved by the administration of some chemicals, as has been shown by studies that report the transdifferentiation of mesenchymal stem cells into cardiomyocytes by exposure to 5-Azacytidine.6,12 Although the reprogrammed cells are known to have expressed cardiomyocyte markers, they are not functional in vitro.13 Factors in the cell-free extract can also induce stem cells isolated from different species to differentiate into cardiomyocytes. Human mesenchymal stem cells isolated from the bone marrow12 and adipose tissue14,15 express cardiomyocyte markers Inhibitors,research,lifescience,medical when permeabilized by streptolysin

O in the presence of the rat cardiomyocyte extract. Human adipose-derived stem cells can be reprogrammed to cardiomyocytes by lipofection-mediated transfection with the cell extract from neonatal rat cardiomyocytes.16 Most of these studies were Inhibitors,research,lifescience,medical performed on mesenchymal stem cells. Profound changes in gene expression are involved in cell differentiation. Epigenetic modification changes the cell fate and provides a molecular basis for cell plasticity.17 Chromatin-modifying agents, Trichostatin A (TSA) and 5-Aza-2-Deoxycytidine (5-aza-dC) have been shown to improve

reprogramming efficiency.18-20 5-Azacytidine is an analogue of a nucleoside present in DNA and RNA and can replace cytidine in DNA. It can act as an inhibitor of DNA methyl Inhibitors,research,lifescience,medical transferase. Trichostatin A is an organic component with anti-fungal properties and can inhibit the histone deacetylase enzyme family.21 5-Azacytidine Inhibitors,research,lifescience,medical is known to cause mesenchymal stem cells to express cardiomyocyte markers.6 DNA methylation inhibitors promote the morphological transformation of myoblasts into smooth muscle Farnesyltransferase cells.22 The in vivo administration of Trichostatin A has been shown to preserve cardiac performance.23 The reprogramming of differentiated somatic cells such as fibroblasts, which is easily accessible, can be considered for therapeutic use. The objective of this study was to induce the expression of cardiomyocyte markers in fibroblasts. Chromatin-modifying agents, accompanied by the cell-free cardiomyocyte extract, were used to improve the cell reprogramming efficiency.  Materials and Methods This study was performed in the Laboratory for Stem Cell Research of the Anatomy Department in Shiraz University of Medical Sciences between 2010 and 2011. Cell Culture Mouse embryonic fibroblasts (MEF) were isolated from mouse embryos on day 13 of gestation. The embryos were removed from the uterus and their conceptus was separated.

4. Liposomes as Neuropharmacological Agents Liposomes are of a great importance as nanocarriers due to their relatively large carrying capacity. They have long been used as drug delivery system to the brain, because the particles can entrap the compounds and prevent the rapid elimination

or degradation as well as promote the penetration through the BBB which in turn decreases the effective dose [49]. In addition, they do not elicit negative biological responses that generally occur when a foreign KU-57788 manufacturer material is introduced in the system. With the pretreatment and adequate formulation in the brain or in places close to the brain, Inhibitors,research,lifescience,medical the liposomes are nontoxic, nonimmunogenic, noncarcinogenic, nonthrombogenic, and biodegradable [50]. Based on the same concept the use of liposomes was proposed for the delivery of diagnostic agents across the BBB. For example, it was patented a method using a brain-specific liposome targeting vehicle capable of transporting Inhibitors,research,lifescience,medical congo red for neurodiagnostic of Alzheimer’s disease, or transporting EGF analogues for brain tumours [51]. Recently, Oku et al. published

a new method using PET imaging with positron emitter-labelled liposomes. This method allows accumulating liposomes in brain tumours and then detects small brain tumours with PET scanning Inhibitors,research,lifescience,medical [52]. 4.1. Liposomes in Parkinson’s Disease Parkinson’s disease is a progressive neurodegenerative disorder which involves the loss of dopaminergic neurons of the substantia nigra [16, 17, 53]. The neuropathological hallmark of Parkinson’s disease is the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta of the brain in addition to astrocytic gliosis and the presence of numerous other neuronal

Inhibitors,research,lifescience,medical systems, associated with widespread occurrence of intracytoplasmatic alpha-synuclein positive inclusions known as the Lewy bodies and the Lewy neuritis of neuronal cells [54]. The ubiquitous protein alpha-synuclein is involved in the pathogenesis of Parkinson’s disease and comprises Inhibitors,research,lifescience,medical protein filaments of ubiquitin and alpha-synuclein that are the primary constituent of Lewy’s bodies. Aggregated alpha-synuclein binds the proteasome and potently inhibits proteasomal activity and the dopaminergic neurotransmission [55, 56]. In Parkinson’s disease the neurochemical effect is a decline in dopamine concentrations in the basal during ganglia. The clinical signs include mass loss and gastrointestinal symptoms such as indigestion and constipation due to the alpha-synuclein pathology in the autonomic nerves and ganglia. Current therapy is essentially symptomatic, and L-DOPA, the direct precursor of dopamine, is still the most effective drug for treating bradykinesia and rigidity associated with the disease. However, during chronic treatment with this drug, after a good initial response, a variety of complications emerge.

34 In this way both the origin and extent of the organophosphate poisoning can be determined. Fidder and Trichostatin A in vitro co-workers developed a procedure that is based on straightforward isolation of adducted BChE from plasma by means of affinity chromatography with a procainamide column, followed by pepsin digestion

and LC/electrospray tandem MS analysis of a specific nonapeptide, containing the phosphorylated active site serine-198 residue.35 The VX hydrolysis product, O-ethyl methylphosphonic acid, has been determined by GC–MS in serum. Recently, an LC/tandem MS method was developed for quantitative determination of IMPA in blood and urine. High levels of Inhibitors,research,lifescience,medical IMPA appeared to correlate with low levels of residual BuChE activity in the plasma.36 Diagnosis of a certain nerve agent requires toxicological analyses of the environmental

and/or blood samples for the nerve agents. A biosensor Inhibitors,research,lifescience,medical which is a potentiometer enzyme electrode has been developed to determine OP nerve agents directly.37 A fiber optic enzyme biosensor for the direct measurement Inhibitors,research,lifescience,medical of OP nerve agents is also introduced. Using the kinetic response, concentrations as low as 2 μM can be measured in less than two minutes.38 Albumin is another target following nerve agent exposure.36-40 Moreover, α-glucoronidase in Inhibitors,research,lifescience,medical liver has been proposed as a biomarker of exposure to Ops.41 Diagnosis of the delayed neurotoxic effects can be made by estimation of NTE, although it is not probable to occur following the nerve agents poisoning. Acute and Chronic Clinical Manifestations Acute Effects Clinical effects after OP exposure can be divided into acute and chronic manifestations. The acute effects of OPs depend on the site of exposure, which can be following inhalation,

skin or eye contact, or ingestion. However, large doses all exposure routes cause similar effects.36 For most OP pesticides, dermal exposure and subsequent absorption through the skin Inhibitors,research,lifescience,medical is the most common way of poisoning in occupational exposure. Percutaneous absorption of OPs varies according mafosfamide to the exposed site and the ambient temperature. The VX was absorbed nearly eight times more rapid from facial skin than from the volar forearm, and the absorption increased considerably as the temperature rose from 18 to 46°C in the site. Initial local effects of liquid include muscular fasciculation’s and sweating at the site, malaise and weakness. The initiation of these effects is immediate, usually after an interval of 10 to 30 min.42 Although occupational and accidental ingestion may occur in children and work settings, the oral route of entry is important in intentional OP pesticide poisoning.

Here, we introduce the concept of “prodromal stage” for various degenerative diseases, and propose replacement of the amnestic MCI subcategory with “prodromal Alzheimer’s disease.” for which we present the neuropsycfiological characteristics. Mild cognitive

impairment (MCI) is a concept that was introduced by Flicker et al1 and the Mayo Clinic group2,3 to fill the gap between cognitive changes Inhibitors,research,lifescience,medical associated with normal aging and those associated with dementia. The concept of MCI draws attention to cognitive disturbances that occur before the clinical diagnosis of dementia. The cognitive changes, measured by neuropsychological test scores, indicate deviation from normal aging and Inhibitors,research,lifescience,medical do not involve loss of autonomy Nevertheless, these MCI criteria are not fully specified or generally agreed upon. As a consequence, studies of MCI conducted by different research groups have divergent results (eg, the number of patients with MCI who develop frank dementia of the Alzheimer’s type in follow-up studies).3-5 Heterography of the MCI population In 2001, an international group Inhibitors,research,lifescience,medical of experts suggested the subdivision of MCI into three subcategories:6 Amnestic MCI, characterized by memory complaint, preservation of activities of daily living, and objective and isolated memory impairment

(compared with age and education norms). Multiple cognitive domain MCI, characterized by multiple areas of cognitive impairment (without associated memory deficit) not sufficiently severe to constitute dementia. Single cognitive domain (other than memory) MCI, characterized by a deficit of a specific domain as aphasia or executive dysfunction reflecting prodromal primary Inhibitors,research,lifescience,medical Epacadostat in vivo progressive aphasia or frontotemporal dementia. In order to limit the heterogeneity of the population concerned by MCI, it will soon be possible to identify the underlying pathological

disorders before the affected patients meet the Inhibitors,research,lifescience,medical criteria of dementia (Table I), using specific neuropsychological assessments and, in some cases, neuroimaging. This is the case, for example, for the following: Frontotemporal degeneration can be identified well before the stage of clinical dementia in the presence of apathy and/or behavioral disinhibition coupled with a progressive disturbance in executive functions. Primary progressive aphasia Adenosine can be identified early on the basis of anomia with speech apraxia and phonetic disintegration associated with limited atrophy of left perisylvian region. Diffuse Lewy body disease is characterized by earlyonset hallucinations, cognitive fluctuations, and extrapyramidal signs, often appearing before the development of clinical dementia. The cerebrovascular origin of cognitive disorders can be easily recognized at the early stages with appropriate combination of clinical history, neurological examination, and neuroimaging. Alzheimer’s disease (AD) can also be identified at a prodromal stage. Table I.

S3). We quantify this effect by calculating the half-maximum decay time of the BOLD response for speech and Z-VAD-FMK chemical structure Reversed speech, in each of the ROIs. Note that we

did not include the SCN responses in this analysis because they did not show a clear peak in these regions, and so an analysis of half-maximum decay time would simply pick up noise fluctuations. Figure 5 LIFG responses to reversed speech decay faster than the response to speech. (A) Group-averaged time course of BOLD activation for speech (red) and reversed speech (green) in three functionally defined ROIs. ROIs were defined by Speech versus Inhibitors,research,lifescience,medical SCN (P < ... The analysis of half-maximum decay times (Fig. 5B) reveals that in left IFG, but not in temporal ROIs, Inhibitors,research,lifescience,medical the response to reversed speech decays significantly faster than the response to speech (t (2,20) = 2.53, P < 0.05, Bonferroni corrected for multiple comparisons

across the five ROIs, Fig. 5B). Time course results for bilateral aSTS were qualitatively similar to those found in bilateral pSTS (Fig. S1). We repeated the analysis using an orthogonal contrast (Speech + Reversed vs. Rest) and replicated the decay time effect in left IFG (t (2,20) = 2.77, P < 0.05, not shown), verifying that the effect remains significant regardless of ROI definition. Inhibitors,research,lifescience,medical This effect was seen in the majority of our participants (eight out of eleven, Fig. 5C), suggesting that LIFG initially attempts to analyze reversed speech as linguistic input, but gives up once this input is recognized as nonspeech. Discussion We compared two Inhibitors,research,lifescience,medical auditory baselines commonly used in functional localizers of speech processing, reversed speech and SCN. While both baselines adequately remove activation in primary auditory cortex, reversed speech removed much of the activation in language regions as well. This effect is detrimental particularly Inhibitors,research,lifescience,medical in the left IFG, where only 3 out of 12 participants showed activated

clusters for Speech versus Reversed, compared with 11 participants in the Speech versus SCN contrast. This outcome is not threshold specific (see Fig. S2) but can be directly attributed to robust overlap between speech and reversed speech responses across the entire speech processing network, predominantly in the left IFG. A closer look at the time course and decay parameters of individual participants (Figs. S3 and ​and5C)5C) almost provides a possible explanation to this effect: activation in LIFG rises similarly in the speech and reversed conditions, but then decays faster in the reversed condition. This suggests that LIFG attempts to parse reversed speech but then attenuates its response once the input has been recognized as nonlinguistic. Our results have clear practical implications for both clinical and research applications of functional localizers of speech. In the clinical domain (e.g.

Cloning and sequencing of the genes that encode the neuromuscular junction receptors revealed that embryonic muscle receptors result from the assembly of five subunits in the stoichiometry α2, α, γ, and δ, while adult receptors are made from α2, β, ε, and δ.15 Sequence homologies and low-stringency hybridization soon

led researchers to clone a series of genes encoding for proteins that resemble those of the neuromuscular junction receptors, but displaying significant differences. To date, 12 genes encoding for α2 to α10 and β2 to β4 have been isolated in vertebrates and their chromosomic localization identified. Inhibitors,research,lifescience,medical Following an international agreement, the nomenclature between α and β subunits was made according to specific sequences of these proteins, with a subunits showing the highest degree of homology with their muscle counterpart and the Inhibitors,research,lifescience,medical presence of

two adjacent cysteines in the N-terminal AZD8055 nmr extracellular domain.16 It is widely accepted that nAChRs result, as the muscle receptors, from the assembly of five subunits, each of which spans the membrane four times (Figure 1B).15,17,18 This basic structural feature is common to a series of ligand-gated channels, Inhibitors,research,lifescience,medical which include the serotonin receptor 5-HT3, zinc-activated protein (ZAC), the glycine receptors, and the γ-aminobutyric acid (GABA) receptors GABAA and GABAC. The large extracellular domain comprises the ligand-binding

site and the ionic pore lies in the center of the assembly. Each of the five subunits lines the pore by its second transmembrane domain. Despite the lack of a full crystal structure of the nAChRs, Inhibitors,research,lifescience,medical it is believed that the natural ligand ACh or nicotine binds at the interface between two adjacent subunits in the extracellular domain. Thus, the contribution of two adjacent subunits to Inhibitors,research,lifescience,medical the formation of the ligand-binding domain implies that both subunits will define the physiological and pharmacological properties of the resulting receptor. Although some subunits such as α7 can assemble in a homomeric manner, most receptors result from the heteromeric assembly of at least two subunits, for instance α4β2. In the case of heteromeric receptors, a further complexity can arise Sodium butyrate for triplet combinations, such as α4α6β2, etc. This gives rise to a wider diversity of the receptor function, which correlates with the pattern of expression of the different subunits. Binding of an agonist stabilizes the receptor in the active open state and causes cations to rapidly diffuse across the minute ionic pore. Significant differences in physiological properties, in terms of sensitivity to the agonist and time course of response, can be observed between different subtypes of nAChRs.

6 The TP53 gene contains 11 exons. It has two transcriptional start sites in exon 1, and alternative splicing occurs

in intron 2 and between exons 9 and 10. The gene also contains an internal promoter and transcription initiation site in intron 4.7 Sequence comparison of the P53 protein from different species shows five highly conserved regions. Two common polymorphic variants of P53 exist, arising from a single base-pair substitution at codon 72, encoding either a proline or an arginine residue.8,9 Although both polymorphic forms share similar growth-suppressive Inhibitors,research,lifescience,medical activities, recent studies suggesting subtle differences in their regulation and potency may be reflected in increased Lonafarnib manufacturer cancer susceptibility

in some Inhibitors,research,lifescience,medical individuals.10,11 Presence of single nucleotide polymorphism (SNP) in the MDM2 promoter has been associated with earlier tumor genesis in patients with Li–Fraumeni syndrome, as well as decreased survival in patients with chronic lymphocytic leukemia (CLL). In addition, cells homozygous [G/G] for SNP 309 were found to have 10-fold increased resistance to topoisomerase II inhibiting drugs.12 The p73 gene has been mapped to chromosome 1p36.3, a locus that is deleted in neuroblastoma and some other human cancers. The P73 gene encodes Inhibitors,research,lifescience,medical at least four distinct isoforms; the full-length version, which gives rise to the protein called P73α, and three splice variants, which encode proteins referred to as P73β, γ and δ. P73 has been shown to mediate at least some functions

in common with P53, including apoptosis, transcriptional transactivation of P21WAF1/CIP1, a known target of P53, and suppression Inhibitors,research,lifescience,medical of cell growth. But unfortunately, a contribution of P63 to tumor suppression has not yet been established.13 Function Wild-type TP53 functions in Inhibitors,research,lifescience,medical checkpoint control after DNA damage, resulting in either a delay in cell cycle progression at the G/S border to allow DNA repair or apoptosis. TP53 has also been implicated directly in DNA repair and in G2 arrest.14 Under normal conditions, P53 is a short-lived protein that is present in cells at a barely detectable level. Upon exposure of cells to various forms of exogenous stress, such as DNA damage, heat shock, hypoxia, and etc., there is a stabilization of P53, which is responsible for an ensuing cascade of events, resulting in either cell cycle arrest else or in apoptosis.15 Further functions of P53 include senescence, and angiogenesis, centrosome duplication, adhesion and metastasis.16 A role for P53 in preventing malignant progression was subsequently demonstrated by the observations that transfection of P53 into cultured cells inhibited transformation by a number of oncogenes, and that mice lacking the P53 gene rapidly developed tumors with high incidence.

In this particular domain, the mood-congruency hypothesis is of key relevance. According to this hypothesis, positive mood should facilitate information processing of positive information and negative mood should facilitate information processing of negative information (Bower 1981).

Mood induction methods help us to gain insights into the question of how mood affects cognitive processes in a systematic way and therefore have become a widely used technique to investigate the interplay between mood and cognition (for a review, see Gotlib and Joormann 2010). There is ample evidence that people in a happy Inhibitors,research,lifescience,medical mood show selective attention for positive stimuli (Rowe et Inhibitors,research,lifescience,medical al. 2007). Accumulating evidence demonstrates that sad mood is associated with an attentional bias that functions in favor of processing emotionally negative information. Such attentional biases have been observed in emotional disturbances such as sad mood (Beck et al. 1987; Gilboa–Schechtman et al. 2000; Niedenthal et al. 2000), clinical depression (Gotlib et al. 2004), and anxiety (Rapee and Heimberg 1997; Koster et al. 2006). Some studies regarding

cognitive processes in sad mood point to an attentional bias for negative content Inhibitors,research,lifescience,medical (e.g., McCabe et al. 2000), but others have failed to find such an attentional bias (MacLeod et al. 1986; Mogg et al. 1993). There is little corresponding literature on facial emotion Inhibitors,research,lifescience,medical perception and sad mood in normal participants. Bouhuys et al. (1995) reported a study in which facial emotion recognition was compared in normal healthy adults after sad and happy mood inductions and no effect of sad mood was observed. Recently, Chepenik et al. (2007) showed that sad mood affected memory for both emotional words and facial emotion recognition in a healthy sample find more experimentally put into a sad mood state. It is reasonable to Inhibitors,research,lifescience,medical speculate that this divergence in the literature is attributable to variations in methodology. For instance,

it has been conjectured that unlike emotional words, the processing of valenced pictures is rooted in the semantic system and has “privileged access” to networks involved no in both processing and storing affective information (Bradley et al. 1997). Evidence for this supposition has been put forth by De Houwer and Hermans (1994), who confirmed that while valenced pictures interfered with the categorization of valenced words, valenced word distracters failed to interfere with valenced pictorial categorization. Considering the inherent information emotional faces convey about interpersonal evaluation, a topic that is of high relevance to the study of the effects of sad mood states (Davidson et al. 1989), it follows that we, along with others (e.g., Langenecker et al. 2005; Joormann and Gotlib 2007) argue that studying emotional faces is critical to understanding sad mood.

One of these studies reveals limitations of the current model (Figure 5(f)). That is, the model does not consider the erosion and volume change of drug carriers. Parameter estimates for the simulations are listed in Table 3. Table 3 Parameter estimates for simulations in Figure 5. We first analyze the effects

of drug hydrophobicity on release kinetics (Figure 5(a)). Zeng et al. [14] encapsulated anticancer drug doxorubicin into electrospun PLLA NFs. Due to its hydrophilicity, doxorubicin hydrochloride could barely be dispersed in a mixture of chloroform and acetone for the electrospinning Inhibitors,research,lifescience,medical of PLLA and drug. As a result, a large portion of doxorubicin hydrochloride appeared on the surface of the PLLA NFs. The good solubility of doxorubicin hydrochloride in the release medium

led to its rapid release from the PLLA NFs. By adding dilute ammonia, doxorubicin hydrochloride could be Inhibitors,research,lifescience,medical converted into lipophilic doxorubicin base, resulting in its uniform distribution in and sustained release from the PLLA NFs. The model captures both the rapid release of doxorubicin Inhibitors,research,lifescience,medical hydrochloride and the sustained release of doxorubicin base from the PLLA NFs (Figure 5(a)). Interestingly, doxorubicin hydrochloride and base possess a comparable rate constant of diffusion/convection, kS (0.027 versus 0.041min−1). However, doxorubicin base displays a much lower ΔG than doxorubicin hydrochloride does (−6.65 versus 7.4 × 10−21J), suggesting that PLLA is Inhibitors,research,lifescience,medical capable of retaining and Camptothecin delaying the release of hydrophobic doxorubicin base but not hydrophilic doxorubicin hydrochloride. Next, we study the influences of ion pairing on the sustained release of protein from fibers. Liao et al. [7] produced chitosan-alginate fibers from interfacial Inhibitors,research,lifescience,medical polyelectrolyte complexation. Heparin, which can interact with many growth factors due to its high negative charge density, has been used for sustained delivery of avidin and PDGF. The model successfully describes the release kinetics of avidin and PDGF (Figures

5(b) and 5(c)). In the absence of heparin, chitosan-alginate fibers release 95% of avidin over a period of 20 days. An addition of heparin into chitosan-alginate fibers not only reduces the initial bust release Megestrol Acetate from 55% to 30%, but also extends the duration of steady release. The effects of heparin concentrations on the release kinetics of avidin and PDGF are captured by the model. Compared to the nonheparin modified fibers, simulation results of the release from the 50:50 Ag/HP fibers show reductions in ΔG (from 1.03 to about −2.64 × 10−21J) and koff (from 0.1 to 0.05day−1), explaining the reduced initial burst and the prolonged steady release. PDGF with positive charges electrostatically interacts with the carboxyl groups of alginate, leading to sustained release from chitosan-alginate fibers.

Other studies implicated cellular abnormalities triggered by glycogen storage as additional factors affecting

ERT efficacy. Cardone et al. (8) demonstrated an abnormal recycling of the cation-independent Dabrafenib mannose-6-phosphate receptor (CI-MPR) in cultured PD fibroblasts. As the integrity of the CI-MPR pathway is essential for efficient uptake and lysosomal delivery of recombinant enzymes used for ERT, the abnormal trafficking of the receptor in PD fibroblasts resulted in an impaired correction of enzyme activity by rhGAA. The abnormalities of CI-MPR trafficking were more prominent in fibroblasts from severe and intermediate PD patients, apparently correlating with disease severity. Raben et al. (9) demonstrated Inhibitors,research,lifescience,medical that Inhibitors,research,lifescience,medical abnormalities of autophagy also impact on ERT efficacy and that suppression of autophagy in combination with ERT resulted in a near-complete glycogen clearance and restoration of skeletal muscle architecture in a mouse model of PD. The limitations of ERT efficacy point to the need for improved therapeutic strategies such as immune modulation, early start of ERT, pharmacological chaperone therapy (10) and its combination with ERT (11), substrate reduction (12). Gene therapy is currently under investigation as an alternative therapeutic option for the treatment of PD patients.
Pompe disease (PD) is a Inhibitors,research,lifescience,medical rare metabolic myopathy. It is caused

by the deficiency of the lysosomal enzyme acid alpha glucosidase (GAA), with a consequent generalized Inhibitors,research,lifescience,medical storage of glycogen, particularly in the heart, skeletal muscle and liver. It has been reported an overall incidence of 1 in 40.000 live birth, with a different frequency in

different races. The infantile form has an incidence of 1 in 138.000 among Caucasians. The disease is characterized by phenotypic and biochemical heterogeneity with variable age of onset, from infantile to adult age and varying levels of residual enzyme activity, which are inversely related to the severity of clinical manifestations. Inhibitors,research,lifescience,medical The disease is also characterized by wide genetic heterogeneity, and more than 200 different mutations of different severity have been described with variable genotype-phenotype correlations. In infantile Pompe disease the most affected muscles are the heart, respiratory Farnesyltransferase and proximal skeletal muscles of the limbs. The clinical onset may occur in the first weeks/months of life. Patients with the classic infantile phenotype may present with severe cardiomegaly, hypertrophic cardiomyopathy and heart failure, which are associated with generalized muscle weakness and delay in motor development. Pulmonary involvement is characterized by recurrent respiratory infections and respiratory failure. Malnutrition, poor growth, feeding difficulties, macroglossia and hepatomegaly are also evident.