Sensorineural Hearing Loss in a Child with Succinic Semialdehyde Dehydrogenase Deficiency.

Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal-recessive disorder of gamma-aminobutyric acid (GABA) metabolism, resulting in accumulation of GABA and gamma-hydroxybutyric acid (GHB) in physiological fluids. Approximately 450 patients have been diagnosed worldwide with this inherited neurotransmitter disorder. We report on a five-year-old male patient, homozygous for the pathogenic variant (NM_170740:c.1265G>A) in ALDH5A1 presenting with an unexpected association of typical SSADH deficiency manifestations with bilateral sensorineural hearing loss (SNHL). Brainstem evoked response audiometry (BERA) testing showed mid-frequency sensorineural hearing damage that suggested a hereditary component to SNHL. Whole exome sequencing (WES) failed to discern other genetic causes of deafness. Several variants of uncertain significance (VUS) detected in genes known for their role in hearing physiology could not be verified as the cause for the SNHL. It is known that central auditory processing depends on a delicate balance between excitatory and inhibitory neurotransmission, and GABA is known to play a significant role in this process. Additionally, excessive concentrations of accumulated GABA and GBH are known to cause a down-regulation of GABA receptors, which could have an adverse influence on hearing function. However, these mechanisms are very speculative in context of SNHL in a patient with inherited disorder of GABA metabolism. Injury of the globi pallidi, one of hallmarks of SSADH deficiency, could also be a contributory factor to SNHL, as was suspected in some other inborn errors in metabolism. We hope that this case will contribute to the understanding of phenotypic complexity of SSADH deficiency.

Abdominal aortic aneurysm volume and relative intraluminal thrombus volume might be auxiliary predictors of rupture-an observational cross-sectional study.

Objectives: The study aimed to identify differences and compare anatomical and biomechanical features between elective and ruptured abdominal aortic aneurysms (AAAs). Methods: Data (clinical, anatomical, and biomechanical) of 98 patients with AAA, 75 (76.53%) asymptomatic (Group aAAA) and 23 (23.46%) ruptured AAA (Group rAAA), were prospectively collected and analyzed. Anatomical, morphological, and biomechanical imaging markers like peak wall stress (PWS) and rupture risk equivalent diameter (RRED), comorbid conditions, and demographics were compared between the groups. Biomechanical features were assessed by analysis of Digital Imaging and Communication in Medicine images by A4clinics (Vascops), and anatomical features were assessed by 3Surgery (Trimensio). Binary and multiple logistic regression analysis were used and adjusted for confounders. Accuracy was assessed using receiving operative characteristic (ROC) curve analysis. Results: In a multivariable model, including gender and age as confounder variables, maximal aneurysm diameter [MAD, odds ratio (OR) = 1.063], relative intraluminal thrombus (rILT, OR = 1.039), and total aneurysm volume (TAV, OR = 1.006) continued to be significant predictors of AAA rupture with PWS (OR = 1.010) and RRED (OR = 1.031). Area under the ROC curve values and correct classification (cc) for the same parameters and the model that combines MAD, TAV, and rILT were measured: MAD (0.790, cc = 75%), PWS (0.713, cc = 73%), RRED (0.717, cc = 55%), TAV (0.756, cc = 79%), rILT (0.656, cc = 60%), and MAD + TAV + rILT (0.797, cc = 82%). Conclusion: Based on our results, in addition to MAD, other important predictors of rupture that might be used during aneurysm surveillance are TAV and rILT. Biomechanical parameters (PWS, RRED) as valuable predictors should be assessed in prospective clinical trials. Similar studies on AAA smaller than 55 mm in diameter, even difficult to organize, would be of even greater clinical value.

Expanding the Phenotypic Spectrum: Chronic Kidney Disease in a Patient with Combined Oxidative Phosphorylation Defect 21.

Introduction: Pathogenic variants in TARS2 are associated with combined oxidative phosphorylation deficiency 21 (COXPD21), an autosomal recessive disorder usually presenting as mitochondrial encephalomyopathy. Kidney impairment has been documented in a minority of COXPD21 patients, mostly with distal renal tubular acidosis. Case report: We report on the first COXPD21 patient with generalized tubular dysfunction and early childhood progression to chronic kidney disease (CKD). Thorough diagnostic evaluation was initiated at six months of age due to failure to thrive, muscular hypotonia, motor delay and recurrent bronchiolitis. The boy was lost to follow-up until the age of two years, when he was readmitted with elevated creatinine level, reduced estimated glomerular filtrate rate, normochromic anaemia, metabolic acidosis and hyperkalaemia. Urine abnormalities pointed to generalized tubular dysfunction. Two novel heterozygous missense variants in TARS2 gene were detected by the means of whole exome sequencing: c.1298T>G (p.Phe438Cys) of maternal origin and c.1931A>T (p.Asp644Val) of paternal origin. Currently, at 4.5 years of age, the boy has failure to thrive, severe motor and verbal delay and end stage of CKD. We referred the patient to paediatric centre that provides renal replacement therapy. Conclusion: The overall clinical course in the patient we report on corresponds well to the previously reported cases of TARS2 related COXPD21, especially in regard to neurological and developmental aspects of the disease. However, we point out the generalized tubulopathy and early occurrence of CKD in our patient as atypical renal involvement in COXPD21. Additionally, this is the first report of hypothyroidism and hypoparathyroidism in a COXPD21 patient.

Long lasting immunity in trichinellosis - insight from a small study group.

Trichinellosis in humans is most often caused by the parasite Trichinella spiralis. The clinical course of the disease is diverse and the symptoms can vary from mild to severe. Symptoms usually disappear within a few months, but encysted larvae in the muscles can cause myalgia and weakness that last for years. However, the existence of chronic trichinellosis as a disease is still debatable. This study presents the results obtained at the National Reference Laboratory for Trichinellosis - INEP, Serbia. The study was conducted to assess the immunoserological, biochemical and symptomatic disease parameters of twelve patients who acquired trichinellosis 13 and 18 years ago, respectively. They were involved in two T. spiralis outbreaks in Serbia, at the village of Kumane and the city of Belgrade (nine and three patients, respectively). Results indicated the presence of specific anti-Trichinella antibodies in 83% of the total number of patients. However, while the humoral immune response to Trichinella lasted for more than a decade reaching almost two decades after the acute infection phase (7/9 and 3/3 respectively, in two outbreaks), persistence of chronic muscular pain, as the most prolonged symptom of trichinellosis, could be found in the majority of patients from the Kumane outbreak (7/9). As a consequence, these patients suffered from limitations in daily living activities for the same period of time. The results presented in this paper are our contribution to the view that trichinellosis as a chronic disease with symptoms exists and may be related to the severity of the disease in the acute phase.

A competitive enzyme-linked immunosorbent assay for rapid detection of antibodies against Trichinella spiralis and T. britovi - one test for humans and swine.

Infection with parasites from the Trichinella genus occurs in many vertebrates but disease only occurs in humans (trichinellosis). Humans are infected after the consumption of raw or undercooked meat from infected wild or domestic animals (usually swine or horses). Using the monoclonal antibody (mAb) 7C2C5, specific for an epitope unique to the muscle larvae of the genus Trichinella, we have developed a competitive enzyme-linked immunosorbent assay (c-ELISA) that enables the rapid detection of Trichinella-specific antibodies in sera originating from two different host species (human, swine) infected with either Trichinella spiralis or Trichinella britovi. This novel c-ELISA exhibited 100% specificity and sensitivity, as confirmed by a Western blot test. The assay is easy to use (one incubation step), and the time required for the procedure (45 min) is shorter than in any other ELISA format. This test could be useful for both the detection and surveillance of Trichinella infections.

Industrial use of pepper (Capsicum annum L.) derived products: Technological benefits and biological advantages.

The recovery of pepper phytochemicals present an interesting strategy in pursuit of new bioactive compounds and natural ingredients for agro-food, cosmetic and pharma industry uses, as replacements for the synthetic compounds and also in the valorisation of plant's by-products. Besides being used as a condiment, providing characteristic pungency, colour and flavour, the new pepper-derived ingredients could be used for the preservation and extension of industrial products' lifespan, as well as additives or technological ingredients with antioxidant and antimicrobial activities. Moreover, the application of the new products in pharmaceutical formulas for the treatment of inflammatory and pain-related conditions is also a possibility, since peppers contain capsaicinoids, carotenoids, phenolic compounds, vitamin C and A, and minerals, such as iron and calcium, which have a health-promoting potential. Further studies on appropriate extraction protocols, stability, safety and bioactivity are necessary to provide novel and promising pepper ingredients for food, cosmetic, and pharmaceutical applications.

Immunomodulatory potential of particular Trichinella spiralis muscle larvae excretory-secretory components.

Excretory-secretory antigens of Trichinella spiralis muscle larvae can induce the semi-matured status of rat dendritic cells. This may at least partly be the consequence of transient activation of extracellular signal-regulated kinases 1/2 (ERK1/2). Here we investigated the potential of several components of excretory-secretory antigens (native fraction containing 45, 49 and 53kDa proteins and recombinant Tsp53, representing one of the constituents of this fraction) to demonstrate previously observed effects of excretory-secretory antigens on dendritic cells in vitro, characterised by establishment of a particular phenotype (very low MHC II expression, moderate CD86 expression and significant ICAM-1 expression) and functional properties (low production of pro-inflammatory cytokine IL-12p70, and high production of IL-10 and TGF-ß). Dendritic cells activated by these components were able to provoke proliferation of naïve T cells and their polarisation towards Th2 and anti-inflammatory responses. The investigated antigens had almost the same capacity to induce IL-4 and IL-10 production from T cells as excretory-secretory antigens, but failed to induce significant TGF-ß synthesis. It could be concluded that the investigated excretory-secretory antigens components can largely reproduce the immunomodulatory effects of the complete excretory-secretory antigens and therefore may be considered as molecules important for creation of the anti-inflammatory milieu achieved by the parasite.

Morphologic predictors of in hospital mortality in acute type III aortic dissection. / Morfologicheskie prediktory gospital'noi smertnosti u bol'nykh s ostrym rassloeniem aorty III tipa.

INTRODUCTION: In-hospital mortality of acute aortic type III dissection ranged about 12%. Complicated dissections represent about 18% of all cases, and require open surgery or TEVAR. More morphological predictors of in hospital mortality are needed to differentiate patients who should be selected for immediate, surgical or endovascular intervention. METHODS: From January 2009 to December 2014, 74 patients with acute aortic type III dissection were enrolled at Clinic of Vascular and Endovascular Surgery in Belgrade Serbia and retrospectively analyzed. Every MSCT was observed in regard to morphologic characteristics of dissection. RESULTS: By analyzing morphologic parameters in patients between survival and non-survival group only localization of intimal tear showed statistical significance (p=0,020). The size of the intimal tear didn't reach statistical significance with the tendency of doing so in a larger sample of patients (p=0,063) with the cut-off value of 9.55mm. The shape of the true lumen was on the border of statistical significance (p=0,053). CONCLUSION: Inner curvature intimal tear localization, huge intimal tear as well as elliptic shape of the true lumen together should raise awareness to a subgroup at risk for in hospital mortality. More liberal endovascular treatment in this subgroup of patients is advocated.

Differences between immediate and late onset of spinal cord ischemia after open and endovascular aortic interventions.

Spinal cord ischemia remains the most impressive and colliding complication following open surgical and endovascular aortic procedures. Paraparesis and paraplegia are devastating, having a major invalidating impact on the patient's life. Also for the surgeon and the entire team this dramatic adverse event causes a significant concussion. Surgeons faced this problem in practice in the 1950s when this surgery started being applied. Even A. Carrel in 1910 said, "The main danger of the aortic operation does not come from the heart or from the aorta itself, but from the central nervous system". As the number of these surgeries grew, some were followed by the spinal cord ischemia. Now, in 21st century, problem of spinal cord ischemia still exists. By understanding the reasons of its development we shall be able to find more useful methods for prevention as well as for the treatment. The aim of this article was to search what is behind this dreadful complication, explaining different mechanisms which take part in its development during endovascular and open surgical treatment.

Spinal cord ischemia after aortic surgery.

This article discusses the etiology of spinal cord ischemia (SCI) mechanisms that may lead to paraplegia during open and endovascular repair from an anatomical and physiological perspective as well as the role of various protective measures used in prevention of this dreadful complication of aortic surgery. There are many adjuncts that must be considered to reduce the risk of spinal cord injury, such as revascularisation of intercostal arteries, maintenance of high mean blood pressure, spinal cord drainage and a few new promising models like NIRS and MISACE which usefulness is yet to be determined. These measures and techniques as well as possible etiology mechanisms of SCI are discussed, highlighting the evidence available for each method, the practical ways in which they may be used, giving some new theories and explanations.

Posterior approach for sciatic aneurysm repair - technical note.

Aneurysm of the persistent sciatic artery is a rare cause of limb ischemia, which is a challenge for both diagnosis and treatment. After successful diagnosis adequate treatment may require skills in open and endovascular surgery. We present a patient with the aneurysm of the persistent sciatic artery treated by bypass procedure with PTFE graft using posterior approach. We named this procedure "dorsal bypass". Detailed explanation of clinical presentation, diagnosis and the surgical procedure is given in this paper.

Second look at congenital vascular malformations: current classification, diagnostic and treatment principles.

Congenital vascular malformations (CVMs) are not rare disorders, with the overall incidence of 1.5%. Due to their complex embryology and various clinical presentations, there was a long lasting confusion among vascular specialists regarding the etiology, classification, basic principles of evaluation and treatment of these anomalies. The introduction of the Hamburg classification and its adoption by experts around the world made further studies of CVMs and comparison of results among different specialists possible. Precise diagnosis of the type and extent of the malformation is paramount for the choice of adequate treatment. In most instances this can be achieved with a detailed history, careful physical examination and a combination of appropriate non-invasive studies. Invasive tests should be reserved for confirmation of diagnosis and serve as a road map for treatment planning. Modern treatment of CVMs is based on a multidisciplinary team approach involving specialists in vascular surgery, interventional radiology, pediatrics, nuclear medicine, orthopedic surgery, plastic and reconstructive surgery and physical therapy. Surgical and endovascular techniques are used in conjunction to minimize morbidity and improve treatment outcomes.

Application of dendritic cells stimulated with Trichinella spiralis excretory-secretory antigens alleviates experimental autoimmune encephalomyelitis.

The parasitic nematode, Trichinella spiralis (T. spiralis), exerts an immunomodulatory effect on the host immune response through excretory-secretory products (ES L1) released from encysted muscle larvae. Our model of combined T. spiralis infection and experimental autoimmune encephalomyelitis (EAE) in Dark Agouti (DA) rats demonstrated a significant reduction in EAE severity in infected animals. Recently, we have created an immune status characteristic for the live infection by in vivo application of dendritic cells (DCs) stimulated with ES L1 products of T. spiralis muscle larvae. Moreover, these cells were able to ameliorate EAE when applied 7 days before EAE induction. ES L1-stimulated DCs increased production of IL-4, IL-10 and TGF-ß, and decreased production of IFN-γ and IL-17, both at the systemic level and in target organs. A significant increase in the proportion of CD4+CD25+Foxp3+ T cells was found among spleen cells, and CNS infiltrates from DA rats treated with ES L1-stimulated DCs before EAE induction, compared to controls injected with unstimulated DCs. Regulatory T cells, together with elevated levels of IL-10 and TGF-ß, are most likely involved in restraining the production of Th1 and Th17 cytokines responsible for autoimmunity and thus are responsible for the beneficial effect of ES L1-educated DCs on the course of EAE. Our results show that ES L1 antigen-stimulated DCs are able not only to provoke, but also to sustain anti-inflammatory and regulatory responses regardless of EAE induction, with subsequent amelioration of EAE, or even protection from the disease.

Relationship between the incidence of idiopathic lower extremity deep vein thrombosis and the location of the thrombus depending on the changes in atmospheric pressure.

AIM: The study analysed the relationship between the incidence of idiopathic lower extremity deep vein thrombosis (DVT) and the location of the thrombus with changes in atmospheric pressure. MATERIAL AND METHOD: During the two year period between May 2009 and April 2011, inclusively, 124 consecutive patients were diagnosed as having idiopathic lower extremity DVT at the Vascular Surgical clinic "Clinical Center of Nis", Serbia. RESULTS: The increased average daily values of atmospheric pressure for 1 millibar on the day when the event took place and 7 days before, were associated (p < 0,05) with the increase of the total risk of the occurrence of lower extremity idiopathic DVT for 5,1% (0,7-9,8%), as well as with the occurrence of idiopathic DVT above the knees (p < 0,05) for 5,9% (0,9-11,0%). The increase in the average atmospheric pressure by 1 millibar on the day when the event took place and 7 days before this in the subgroup of patients under the age of 45 years, and on the day when the event took place and 3 days before it in the subgroup of patients of the age of 45 and above, was related with the increased risk of the occurrence of lower extremity idiopathic DVT. CONCLUSION: The increase of daily values of atmospheric pressure shows a significant relationship with the incidences of idiopathic lower extremity DVT and the location of the thrombus above the knee.

Synchronous bilateral infiltrating syringomatous adenoma of the breast.

Infiltrating syringomatous breast adenoma is an uncommon mammary neoplasm composed of angulated glandular structures with a variable amount of epidermoid differentiation which proliferate in a background of dense collagenous stroma. The patient presented with bilateral hardness and oedema of the nipples. Ultrasound and mammography revealed microcalcifications in retromammilary regions of both nipples. Histological examination of the resected specimens showed angulated glands and solid cords, lined by an inner layer of epithelial cells and an outer layer of myoepithelial cells, immersed in desmoplastic stroma. Within the solid cords reminiscent of squamous cells, occasionally aggregated in keratinizing cysts were found. To the best of our knowledge this is the first described case of bilateral infiltrating syringomatous breast adenoma with synchronous presentation. Infiltrating syringomatous adenoma is a rare lesion. A finding of infiltrating syringomatous adenoma in one breast should prompt careful examination of the opposite breast with adequate follow-up.

The impact of Trichinella spiralis excretory-secretory products on dendritic cells.

Parasitic nematode Trichinella spiralis exert immunomodulatory effect on the host immune response through excretory-secretory products (ES L1) released from the encysted muscle larvae. Rat bone-marrow derived dendritic cells (DCs) stimulated with ES L1 antigens acquire semi-matured status and induce Th2 and regulatory responses in vitro and in vivo. Priming naïve T cells in vitro with ES L1 pulsed DCs caused strong Th2 polarization, accompanied by elevated production of regulatory cytokines IL-10 and TGF-ß and no increase in the proportion of CD4+CD25+Foxp3+ among the effector T cell population. In vivo T cell priming resulted in mixed Th1/Th2 cytokine response, with the dominance of the Th2 type and elevated levels of regulatory cytokines. Significant increase in the proportion of CD4+CD25+Foxp3+ cells was found among recipient's spleen cells. We have achieved to create immune status characteristic for the live infection by in vivo application of DCs educated with ES L1 antigens.

The role of duplex ultrasonography in surgical treatment of acute progressive thrombophlebitis of great saphenous vein.

AIM: The aim of this paper was to determine the role of ultrasonographic examination in acute progressive thrombophlebitis (APT) of great saphenous vein (GSV) and its impact in considering indications for urgent surgical treatment. MEHODS: In this retrospective study, out of 141 consecutive patients operated due to APT of GSV above the knee, 63 were examined by ultrasonography prior surgery. RESULTS: Out of 63 operated patients, in 38 duplex ultrasonography (DUS) revealed that proximal level of phlebitic process was more than 5 cm higher than the one found during physical examination (60.3%). In this group, the mean difference between DUS and clinical finding was 8.5±3.5 cm. In 25 patients there were no differences greater than 5 cm found between DUS and physical examination (39.7%). There was statistically highly significant difference between DUS and physical examination findings (χ2=6.5, P<0.01). CONCLUSION: This study revealed significant difference between ultrasonographic and physical findings in patients with APT of GSV. DUS presented as reliable diagnostic method in examining, course-following and making decision for operative treatment of these patients.

Homeostatic modulation of stimulation-dependent plasticity in human motor cortex.

Since recently, it is possible, using noninvasive cortical stimulation, such as the protocol of paired associative stimulation (PAS), to induce the plastic changes in the motor cortex, in humans that mimic Hebb's model of learning. Application of TMS conjugated with peripheral electrical stimulation at strictly coherent temporal manner lead to convergence of inputs in the sensory-motor cortex, with the consequent synaptic potentiation or weakening, if applied repetitively. However, when optimal interstimulus interval (ISI) for induction of LTP-like effects is applied as a single pair, Motor evoked potential (MEP) amplitude inhibition is observed, the paradigm known as short-latency afferent inhibition (SLAI). Aiming to resolve this paradox, PAS protocols were applied, with 200 repetitions of TMS pulses paired with median nerve electrical stimulation, at ISI equal to individual latencies of evoked response of somatosensory cortex (N(20)) (PAS(LTP)), and at ISI of N(20) shortened for 5 msec (PAS(LTD)) - protocols that mimic LTP-like changes in the human motor cortex. MEP amplitudes before, during and after interventions were measured as an indicator based on output signals originating from the motor system. Post-intervention MEP amplitudes following the TMS protocols of PAS(LTP) and PAS(LTD) were facilitated and depressed, respectively, contrary to MEP amplitudes during intervention. During PAS(LTP) MEP amplitudes were significantly decreased in case of PAS(LTP), while in the case of PAS(LTD) an upward trend was observed. In conclusions, a possible explanation for the seemingly paradoxical effect of PAS can be found in the mechanism of homeostatic modulation of plasticity. Those findings indicate the existence of complex relationships in the development of plasticity induced by stimulation, depending on the level of the previous motor cortex excitability.