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The direct anterior approach (DAA) for total hip arthroplasty has been popularized in the last decade as a minimally invasive approach used by many surgeons, including the authors, to preserve the integrity of muscle groups and their insertions and the dynamic hip stability resulting in less surgical trauma and faster recovery process with decreased postoperative pain. This surgical approach is not without a variety of complications and pitfalls. This review aims to identify any potential drawbacks and challenges associated with the DAA in THA and guide surgeons on minimizing and avoiding them. [ABSTRACT FROM AUTHOR]

Objective. – Until recently, prostacyclin (PGI2) biological activities were thought to be exclusively mediated by cell surface receptors named IP. Recent studies have instead identified a novel pathway of PGI2 signaling, occurring through activation of peroxisome proliferator-activated receptors (PPARs) located in the nucleus. The availability of stable PGI2 analogs with different affinity for IP receptors and PPARs provides the possibility to test the importance and function of this dual pathway in vitro and in vivo. In this study, the in vivo angiogenic properties of different PGI2 analogs and the potential relationship between PPAR-mediated pathways, vascular endothelial growth factor (VEGF), and angiogenesis were investigated.Methods and results. – By using the murine corneal model of angiogenesis, we found that PGI2 analogs able to act on nuclear PPARs, such as iloprost and carbaprostacyclin (cPGI), induce angiogenesis in vivo. In contrast, cicaprost, a PGI2 analog that only acts on IP receptors, has no in vivo angiogenic activity. Interestingly, angiogenesis induced by iloprost and cPGI does not differ in extent and morphology from that induced by VEGF and is associated with local increment of VEGF mRNA expression and protein levels. Finally, iloprost-induced angiogenesis is significantly decreased by systemic inhibition of VEGF activity, obtained by gene transfer of a soluble form of the VEGF receptor Flt-1.Conclusions. – These data demonstrate that stable PGI2 analogs may have angiogenic properties in vivo, depending on their ability to act on PPARs. The resulting angiogenic process appears to be mediated by VEGF. These findings indicate that important physiological activities in the cardiovascular system, such as angiogenesis and VEGF induction, may be modulated by PGI2 through specific activation of the PPAR signaling pathway in vivo, with potentially important fundamental and clinical implications. [Copyright &y& Elsevier]

Several studies have proposed a relationship between blood pressure and inflammation. Interleukin-6 (IL-6) is a multifunctional cytokine involved in inflammation and tissue injury and potentially influencing blood pressure. Recently, a common polymorphism of the IL-6 gene, associated with differences in the transcription rate of the protein, has been described. The aim of this study was to investigate a possible association between genetic variations of the -174GC polymorphism of the IL-6 gene promoter and hypertension in humans. IL-6 gene promoter polymorphism was evaluated by polymerase chain reaction followed by restriction enzyme analysis in 210 elderly italian patients affected by essential hypertension (EH) and 177 age- and sex-matched controis. The distribution of IL-6 genotypes was 85 GG, 88 GC, 37 CC in the hypertensive patients and 65 GG, 73 GC, 39 CC in the control subjects, in this elderly cohort, no statistically significant association was found between the two groups (P = 0.45 for GG homozygous, P = 0.89 for GC heterozygous and P = 0.27 for CC homozygous). In conclusion the -174 GC polymorphism of the IL-6 gene promoter is not a marker for EH in this sample of elderly Italians. [ABSTRACT FROM AUTHOR]

This article, published in the journal Endoscopy, presents the findings of a retrospective cohort study that aimed to evaluate the diagnostic yield of small bowel capsule endoscopy in patients on antithrombotic therapy for suspected small bowel bleeding. The study analyzed data from 369 patients, including 95 patients on antithrombotic therapy. The results showed that patients on antithrombotic therapy were typically older and had more comorbidities compared to the control group. Additionally, angioectasia was found to be the most frequent positive finding in patients on both antiplatelet and anticoagulant therapy. [Extracted from the article]

Environmental and genetic conditions can cause proteins to misfold or to accumulate abnormally due to impaired clearance. The chaperones which include heat shock proteins, aid survival by preventing protein mis-folding and the formation of cytotoxic protein aggregates. An increasing number of studies point to important roles for molecular chaperones in the biology of neurodegenerative diseases. Heat shock proteins can suppress neurotoxicity in animal models of Parkinson's and polyglutamine diseases, suggesting potential new therapeutic approaches in neurodegenerative disorders associated with abnormal protein folding and toxicity. Recent findings suggest that heat shock proteins can also be neuroprotective in Alzheimer's disease, but this area of research remains largely unexplored. This paper will review the literature related to the role of heat shock proteins in Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Malignant hypertension causes anatomical and functional damage in several target organs, in particular brain, retina, heart and kidneys. Although vascular lesions in the gastroenteric tract are known to occur in several instances, their clinical relevance is unknown. In this study five cases of malignant hypertension, presenting with acute abdominal symptoms, are reported. A history of essential arterial hypertension was present in three patients; while one patient had a previous diagnosis of renovascular hypertension and one patient had renoparenchymal hypertension. However, in all cases the antihypertensive treatment was discontinued and inadequate before the accelerated malignant phase. The acute abdominal symptoms at presentation were due to intestinal infarction in 3 patients and acute pancreatitis in 2 patients. One patient with intestinal infarction died of postoperative cardiogenic shock. Our data are in agreement with previous reports describing the possible intra-abdominal complications of malignant hypertension. The therapeutic approach in such conditions should always consider an effective antihypertensive treatment in conjunction with surgical options. [ABSTRACT FROM AUTHOR]

Migraine is the most frequent subtype of primary headache. It affects about 18% of females and 6% of males in the general population. Despite this high frequency the disease is substantially underdiagnosed and undertreated. Several hypotheses have been put forward to explain the pathogenesis of migraine; at present, a derangement of vascular tone is believed to be an essential component for the development of clinical attacks of the disease. Helicobacter pylori infection, the most common cause of gastritis and peptic ulcer, has been recently associated with various primary functional vascular disorders such as primary Raynaud's phenomenon and recurrent spontaneous abortion. The infection causes a persistent activation of the immune system, which results in local and systemic release of a variety of vasoactive substances. Recent evidence suggest that infection with H. pylori may also be associated with migraine. In patients with migraine who are infected with H. pylori, eradication of the bacterium resulted in the complete disappearance of migraine attacks in 20% of individuals and a significant decrease in intensity, duration and frequency of symptoms in the vast majority of the others. Further studies, however, remain necessary to better determine the pathogenetic mechanisms underlying this association. If confirmed, this could represent a novel diagnostic and therapeutical approach for at least a subgroup of migraineurs. [ABSTRACT FROM AUTHOR]

The Hedgehog (Hh) pathway is a crucial regulator of muscle development during embryogenesis. We have previously demonstrated that Sonic hedgehog (Shh) regulates postnatal myogenesis in the adult skeletal muscle both directly, by acting on muscle satellite cells, and indirectly, by promoting the production of growth factors from interstitial fibroblasts. Here, we show that in mdx mice, the murine equivalent of Duchenne muscular dystrophy in humans, progression of the dystrophic pathology corresponds to progressive inhibition of the Hh signaling pathway in the skeletal muscle. We also show that the upregulation of the Hh pathway in response to injury and during regeneration is significantly impaired in mdx muscle. Shh treatment increases the proliferative potential of satellite cells isolated from the muscles of mdx mice. This treatment also increases the production of proregenerative factors, such as insulin-like growth factor-1 and vascular endothelial growth factor, from fibroblasts isolated from the muscle of mdx mice. In vivo, overexpression of the Hh pathway using a plasmid encoding the human Shh gene promotes successful regeneration after injury in terms of increased number of proliferating myogenic cells and newly formed myofibers, as well as enhanced vascularization and decreased fibrosis. [ABSTRACT FROM AUTHOR]

The thalassaemias are blood disorders with hereditary transmission. Their distribution is global, with particular incidence in areas affected by malaria. Their diagnosis is mainly based on haematologic and genetic analyses. The aim of this study was to differentiate between persons with the thalassaemia trait and normal subjects by inspecting characteristics of haemochromocytometric data. The paper proposes an original method that is useful in screening activity for thalassaemia classification. A complete working system with a friendly graphical user interface is presented A unique feature of the presented work is the adoption of a two-layered classification system based on Radial basis function, which improves the performance of the system. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Peroxisome proliferator-activated receptors (PPARs) are therapeutic targets for fibrates and thiazolidinediones, which are commonly used to ameliorate hyperlipidemia and hyperglycemia in type 2 diabetes. In this study, we evaluated whether activation of PPAR alpha and PPAR gamma stimulates neoangiogenesis. RESEARCH DESIGN AND METHODS: We used selective synthetic PPAR alpha and PPAR gamma agonists and investigated their angiogenic potentials in vitro and in vivo. RESULTS: Activation of PPAR alpha and PPAR gamma leads to endothelial tube formation in an endothelial/interstitial cell co-culture assay. This effect is associated with increased production of the angiogenic cytokine vascular endothelial growth factor (VEGF). Neovascularization also occurs in vivo, when PPAR alpha and PPAR gamma agonists are used in the murine corneal angiogenic model. No vascular growth is detectable when PPAR alpha and PPAR gamma agonists are respectively used in PPAR alpha knockout mice and mice treated with a specific PPAR gamma inhibitor, demonstrating that this angiogenic response is PPAR mediated. PPAR alpha- and PPAR gamma-induced angiogenesis is associated with local VEGF production and does not differ in extent and morphology from that induced by VEGF. In addition, PPAR alpha- and PPAR gamma-induced in vitro and in vivo angiogenesis may be significantly decreased by inhibiting VEGF activity. Finally, in corneas treated with PPAR alpha and PPAR gamma agonists, there is increased phosphorylation of endothelial nitric oxide synthase and Akt. CONCLUSIONS: These findings demonstrate that PPAR alpha and PPAR gamma activation stimulates neoangiogenesis through a VEGF-dependent mechanism. Neoangiogenesis is a crucial pathological event in type 2 diabetes. The ability of PPAR alpha and PPAR gamma agonists to induce neoangiogenesis might have important implications for the clinical and therapeutic management of type 2 diabetes. [ABSTRACT FROM AUTHOR]

Abstract: A systematic study was designed to elucidate differences in cytostatic activity in vitro between HPMA-based doxorubicin conjugates synthesized using different polymerization techniques and differing in peptidyl side chain. A polymer–drug conjugate containing doxorubicin (DOX) bound to HPMA copolymer backbone through the enzymaticaly non-cleavable sequence GlyGly shows low but significant cytotoxicity in vitro in seven cancer cell lines of mouse (EL4, 38C13, 3T3, BCL1) and human (SW620, Raji, Jurkat) origin. The low cytotoxicity can be considerably increased by the presence of additional drug-free GlyPheLeuGly side chains. P1 conjugate, i.e. non-targeted HPMA copolymer bearing doxorubicin bound via a biodegradable GlyPheLeuGly sequence, synthesized by direct copolymerization of HPMA with monomeric doxorubicin and thus without additional drug-free GlyPheLeuGly sequences is less effective compared to PK1 synthesized by polymer analogous reaction and thus containing extra drug-free GlyPheLeuGly sequences. Significant activity-enhancing effect was not seen with other amino acid/oligopeptide sequences (e.g., Gly or GlyGly). The activity-enhancing effect of GlyPheLeuGly sequences is more obvious in the conjugate containing doxorubicin bound to HPMA through GlyGly sequence. Derivatization of the terminal carboxyl group of the extra GlyPheLeuGly side chains (amide, N-substituted amide, free carboxyl) does not significantly influence the cytotoxicity of the conjugates. The presence of the GlyPheLeuGly sequence in the conjugate structure increases its rate of intracellular accumulation. Normal cells (Balb/c splenocytes) accumulate less polymer–doxorubicin conjugate compared to cancer cells (T cell lymphoma EL4, B cell lymphoma Raji and T cell leukemia JURKAT). [Copyright &y& Elsevier]

Objectives: To examine the association of the -173 single-nucleotide G/C polymorphism of the macrophage migration inhibitory factor gene (MIF) and serum macrophage migration inhibitory factor (MIF) concentrations in a group of Italian patients with hereditary periodic fevers (HPF), tested during a symptom-free phase of their disease. Methods: Genomic DNA for MIF and serum MIF were evaluated in 22 patients with HPF and compared with healthy controls of the same ethnic group. The MIF-173G/C polymorphism was genotyped using polymerase chain reaction (PCR) and visualized by ethidium bromide staining. Serum MIF levels were measured by enzyme-linked immunosorbent assay (ELISA). Results: MIF-173*C allele frequency and MIF serum concentrations were significantly higher in patients with HPF than in controls, with no statistically significant difference between familial Mediterranean fever (FMF) and hyperimmunoglobulinaemia D/periodic fever syndrome (HIDS) and no correlation with specific MIF genotypes. Conclusions: The MIF-173*C allele was found more frequently in patients with HPF than in controls and MIF serum concentrations were considerably elevated in attack-free phases, suggesting a persistent state of subclinical cytokine activation with MIF involvement in the autoinflammatory cascade. [ABSTRACT FROM AUTHOR]

Objectives. Single nucleotide polymorphisms in genes encoding inflammatory molecules may determine genetic profiles associated with increased risk of development and progression of cardiovascular diseases. In this study, we evaluated distribution and reciprocal interaction of a set of functionally important polymorphisms of genes encoding prototypical inflammatory molecules in subjects with peripheral arterial occlusive disease (PAOD) and critical limb ischemia (CLI). We also investigated whether synergistic interactions between these pro-inflammatory gene polymorphisms influence the risk of PAOD and CLI. Design, subjects and methods. In a genetic association study that included 157 PAOD patients and 206 controls, the following gene polymorphisms were analysed: C-reactive protein ( CRP) 1059 G/C, interleukin-6 ( IL-6)-174 G/C, macrophage migration inhibitory factor ( MIF)-173 G/C, monocyte chemoattractant protein ( MCP-1) – 2518 A/G, E-selectin ( E-Sel) Ser128Arg, intercellular adhesion molecule-1 ( ICAM-1) 469 E/K, matrix metalloproteinase ( MMP)−1 -1607 1G/2G, MMP-3-1171 5A/6A and MMP-9-1563 C/T. Results: We found that IL-6, E-sel, ICAM-1, MCP-1, MMP-1 and MMP-3 gene polymorphisms were significantly and independently associated with PAOD. We also found that these pro-inflammatory polymorphisms determine genetic profiles that are associated with different levels of risk for PAOD and CLI, depending on the number of high-risk genotypes concomitantly carried by a given individual. Conclusions: Pro-inflammatory genetic profiles are significantly more common in subjects with PAOD. Synergistic effects between pro-inflammatory genotypes might be potential markers for the presence and severity of atherosclerotic disorders. [ABSTRACT FROM AUTHOR]

Abstract: Noise-induced hearing loss has been associated with alterations in cochlear blood flow. Our study analyzed the expression of Vascular Endothelial Growth Factor (VEGF) and its functional receptors, Flt-1 and Flk-1, in the cochlear structures of noise-exposed and unexposed guinea pigs. VEGF is a prototypical angiogenic agent, with multiple functions on vascular biology, ranging from vascular permeability to endothelial cell migration, proliferation, differentiation, and survival. Acoustic trauma was induced by a continuous pure tone of 6kHz, at 120dB SPL for 30min. Auditory function was evaluated by electrocochleographic recordings at 2–20kHz for 7 days. Noise-induced cochlear morphological changes were studied by immunohistochemistry and scanning electron microscopy. The expression of VEGF and its receptors was examined by immunohistochemistry and western blotting analysis. The hearing threshold shift reached a level of 60dB SPL on day 1 after trauma and underwent a partial recovery over time, reaching a value of about 20dB SPL on day 7. Outer hair cell loss was more prominent in the area located 14–16mm from the apex. Increased cochlear VEGF expression was observed in noise-exposed animals, in particular at the level of stria vascularis, spiral ligament, and spiral ganglion cells. No changes were observed in the expression of VEGF-receptors. Our data suggest a role for VEGF in the regulation of the vascular network in the inner ear after acoustic trauma and during auditory recovery, with potentially important clinical and therapeutic implications. [Copyright &y& Elsevier]

LIM mineralization protein (LMP) is a novel positive regulator of the osteoblast differentiation program. In humans, three different LMP splice variants have been identified: LMP-1, LMP-2, and LMP-3. Gene transfer of human LMP-1 (hLMP-1) induces expression of genes involved in bone formation, including certain bone morphogenetic proteins (BMPs), promotes bone nodule formation in vitro, ectopic bone formation in vivo, and is therapeutic in animal models of posterior thoracic and lumbar spine fusion. To examine the osteoinductive properties of the LMP-3 in vitro and in vivo, we have generated plasmid and adenoviral vectors expressing codon-optimized hLMP-3. Here we demonstrate that gene transfer of hLMP-3 induces expression of the bone-specific genes osteocalcin, osteopontin, and bone sialoprotein and induced bone mineralization in preosteoblastic and fibroblastic cells. We also demonstrate that hLMP-3 is able to induce bone mineralization and the expression of the bone-specific genes, BMP-2, OSX, RunX2, and alkaline phosphatase in human mesenchymal stem cells in a dose-dependent manner. Finally, we demonstrate that direct gene transfer of hLMP-3 into murine skeletal muscle results in ectopic bone formation more efficiently than BMP-2. These results demonstrate that hLMP-3 gene transfer can be used to promote bone formation in cell culture and in vivo as or more efficiently than BMP-2, thus establishing feasibility and efficacy of direct gene delivery of hLMP-3 to produce bone in vivo. These results suggest that gene transfer of hLMP-3 could be developed as a bone-inductive therapeutic agent for clinical applications.Gene Therapy (2004) 11, 683-693. doi:10.1038/sj.gt.3302207 Published online 15 January 2004 [ABSTRACT FROM AUTHOR]

Recent studies have suggested an association between Helicobacter pylori infection and migraine. However, various strains of the bacterium are present, some endowed with greater pathogenicity. In particular, H. pylori type I CagA-positive strains induce a higher release of proinflammatory substances by the gastric mucosa that could trigger systemic vasospasms. The aim of the present study was to assess the prevalence of H. pylori CagA-positive strains in subjects with migraine. One hundred and seventy-five patients affected by migraine (49 with aura, 126 without aura) were consecutively enrolled and matched for sex, age, social background and geographical origin with 152 controls. Helicobacter pylori infection was assessed through 13C-urea breath test. Specific serological IgG against CagA were detected through ELISA. The prevalence of H. pylori infection was similar in migraine patients and in controls (40% vs. 39%, respectively). Among migraine patients, prevalence of infection was not related to presence or absence of aura (45% vs. 37%, respectively). However, among infected subjects, a significantly higher prevalence of CagA-positive strains was observed in patients affected by migraine with aura when compared with those affected by migraine without aura (41% vs. 19%, P < 0.01) and with controls (41% vs. 17%, P < 0.01). CagA-positive H. pylori strains were found to be strongly associated with migraine with aura. A higher inflammatory response of the gastric mucosa to more virulent strains could release substances that may act as triggers of vasospasm in peculiar cerebral arterial districts, probably implicated in the ‘aura’ phenomenon. [ABSTRACT FROM AUTHOR]