The Enigma of Mammaglobin: Redefining the Biomarker Paradigm in Breast Carcinoma.

The continuous evolution of cancer biology has led to the discovery of mammaglobin, a potential novel biomarker for breast carcinoma. This review aims to unravel the enigmatic aspects of mammaglobin and elucidate its potential role in redefining the paradigm of breast carcinoma biomarkers. We will thoroughly examine its expression in tumoral and peritumoral tissues and its circulating levels in the blood, thereby providing insights into its possible function in cancer progression and metastasis. Furthermore, the potential application of mammaglobin as a non-invasive diagnostic tool and a target for personalized treatment strategies will be discussed. Given the increasing incidence of breast carcinoma worldwide, the exploration of novel biomarkers such as mammaglobin is crucial in advancing our diagnostic capabilities and treatment modalities, ultimately contributing to improved patient outcomes.

The long-term effects of maternal deprivation on the number and size of inhibitory interneurons in the rat amygdala and nucleus accumbens.

Introduction: There is an increasing evidence supporting the hypothesis that traumatic experiences during early developmental periods might be associated with psychopathology later in life. Maternal deprivation (MD) in rodents has been proposed as an animal model for certain aspects of neuropsychiatric disorders. Methods: To determine whether early-life stress leads to changes in GABAergic, inhibitory interneurons in the limbic system structures, specifically the amygdala and nucleus accumbens, 9-day-old Wistar rats were exposed to a 24 h MD. On postnatal day 60 (P60), the rats were sacrificed for morphometric analysis and their brains were compared to the control group. Results: Results show that MD affect GABAergic interneurons, leading to the decrease in density and size of the calcium-binding proteins parvalbumin-, calbindin-, and calretinin-expressing interneurons in the amygdala and nucleus accumbens. Discussion: This study indicates that early stress in life leads to changes in the number and morphology of the GABAergic, inhibitory interneurons in the amygdala and nucleus accumbens, most probably due to the loss of neurons during postnatal development and it further contributes to understanding the effects of maternal deprivation on brain development.

Mice lacking perforin have improved regeneration of the injured femoral nerve.

The role that the immune system plays after injury of the peripheral nervous system is still not completely understood. Perforin, a natural killer cell- and T-lymphocyte-derived enzyme that mediates cytotoxicity, plays important roles in autoimmune diseases, infections and central nervous system trauma, such as spinal cord injury. To dissect the roles of this single component of the immune response to injury, we tested regeneration after femoral nerve injury in perforin-deficient (Pfp-/-) and wild-type control mice. Single frame motion analysis showed better motor recovery in Pfp-/- mice compared with control mice at 4 and 8 weeks after injury. Retrograde tracing of the motoneuron axons regrown into the motor nerve branch demonstrated more correctly projecting motoneurons in the spinal cord of Pfp-/- mice compared with wild-types. Myelination of regrown axons measured by g-ratio was more extensive in Pfp-/- than in wild-type mice in the motor branch of the femoral nerve. Pfp-/- mice displayed more cholinergic synaptic terminals around cell bodies of spinal motoneurons after injury than the injured wild-types. We histologically analyzed lymphocyte infiltration 10 days after surgery and found that in Pfp-/- mice the number of lymphocytes in the regenerating nerves was lower than in wild-types, suggesting a closed blood-nerve barrier in Pfp-/- mice. We conclude that perforin restricts motor recovery after femoral nerve injury owing to decreased survival of motoneurons and reduced myelination.

Ace/actn3 genetic polymorphisms and athletic performance of female soccer players` / Polimorfismos genéticos em ace/actn3 e desempenho atlético de atletas de futebol feminino / Polimorfismos genéticos en ace/actn3 y desempeño atlético de atletas de fútbol femenino

ABSTRACT Objective: Previous studies have shown controversial relationships between ACE and ACTN3 gene polymorphisms and sports performance. Thus, the aim of our study was to assess anaerobic and aerobic performance indicators of young female soccer players with different ACE/ACTN3 gene profiles. Methods: Twenty-seven female soccer players aged 16-18 underwent acceleration, speed, strength, anaerobic power and aerobic endurance tests and had their ACE and ACTN3 polymorphisms determined. Results: Based on genetic analysis, they were divided into the following groups: ACE II (n=2), ACE ID (n=11), ACE DD (n=14), ACTN3 XX (n=5), ACTN3 RR (n=7) and ACTN3 RX (n=15). ACE DD and ACE ID groups differed significantly in terms of results achieved on the 5 m sprint test (1.15±0.05 s vs 1.10±0.05 s, P=0.42). ACTN3 RR and RX achieved better results than the ACTN3 XX group in seven continuous vertical jumps (26.57±1.59 cm vs 25.77±2.51 cm vs 22.86±1.16 cm, respectively; P=0.007 for RR vs XX and P=0.021 for RX vs XX). Conclusion: High prevalence of ACE DD and ACTN3 RX genotypes in our subjects may suggest that faster and more powerful young females tend to perform better in soccer. Nevertheless, the absence of differences in most of the physical test results indicates that different genotypes are compatible with high-level soccer performance, meaning that it is the phenotype-genotype interaction that makes a successful female soccer player. Level of Evidence I, Prognostic studies — Investigating the effect of a patient characteristic on disease outcome.

RESUMO Objetivo: Estudos anteriores mostraram relações controvertidas entre os polimorfismos dos genes ACE e ACTN3 e desempenho esportivo. Assim sendo, o objetivo deste estudo foi avaliar os indicadores de desempenho anaeróbico e aeróbico de jovens futebolistas do sexo feminino com diferentes perfis dos genes ACE/ACTN3. Métodos: Vinte e sete jogadoras com idade entre 16 e 18 anos realizaram testes de aceleração, velocidade, força, potência anaeróbica e resistência aeróbica e os polimorfismos de seus genes ACE e ACTN3 foram determinados. Resultados: Com base na análise genética, elas foram divididas nos seguintes grupos: ACE II (n = 2), ACE ID (n = 11), ACE DD (n = 14), ACTN3 XX (n = 5), ACTN3 RR (n = 7) e ACTN3 RX (n = 15). Os grupos ACE DD e ACE ID diferiram significativamente quanto aos resultados obtidos no sprint test de 5 metros (1,15 ± 0,05 s vs. 1,10 ± 0,05 s, P = 0,42). Os grupos ACTN3 RR e RX atingiram resultados melhores do que o grupo ACTN3 XX em sete saltos verticais contínuos (26,57 ± 1,59 cm vs. 25,77 ± 2,51 cm vs. 22,86 ± 1,16 cm, respectivamente; P = 0,007 para RR vs. XX e P = 0,021 para RX vs. XX). Conclusão: A alta prevalência de genótipos RX em ACE DD e ACTN3 em nossa amostra pode sugerir que as jovens atletas mais rápidas e com maior potência tendem a ter melhor desempenho no futebol. No entanto, a ausência de diferença na maioria dos resultados dos testes físicos indica que genótipos distintos são compatíveis com o desempenho futebolístico de alto nível, o que significa que é a interação fenótipo-genótipo que faz uma jogadora de futebol ser bem-sucedida. Nível de Evidência I, Estudos prognósticos - Investigação do efeito de característica de um paciente sobre o desfecho da doença.

RESUMEN Objetivo: Estudios anteriores mostraron relaciones controvertidas entre los polimorfismos de los genes ACE y ACTN3 y desempeño deportivo. Siendo así, el objetivo de este estudio fue evaluar los indicadores de desempeño anaeróbico y aeróbico de jóvenes futbolistas del sexo femenino con diferentes perfiles de los genes ACE/ACTN3. Métodos: Veintisiete jugadoras con edad entre 16 y 18 años realizaron tests de aceleración, velocidad, fuerza, potencia anaeróbica y resistencia aeróbica y fueron determinados los polimorfismos de sus genes ACE e ACTN3. Resultados: Con base en el análisis genético, ellas fueron divididas en los siguientes grupos: ACE II (n = 2), ACE ID (n = 11), ACE DD (n = 14), ACTN3 XX (n = 5), ACTN3 RR (n = 7) y ACTN3 RX (n = 15). Los grupos ACE DD y ACE ID difirieron significativamente cuanto a los resultados obtenidos en el sprint test de 5 metros (1,15 ± 0,05 s vs. 1,10 ± 0,05 s, P = 0,42). Los grupos ACTN3 RR y RX alcanzaron resultados mejores que el grupo ACTN3 XX en siete saltos verticales continuos (26,57 ± 1,59 cm vs. 25,77 ± 2,51 cm vs. 22,86 ± 1,16 cm, respectivamente; P = 0,007 para RR vs. XX y P = 0,021 para RX vs. XX). Conclusión: La alta prevalencia de genotipos RX en ACE DD y ACTN3 en nuestra muestra puede sugerir que las jóvenes atletas más rápidas y con mayor potencia tienden a tener mejor desempeño en el fútbol. Sin embargo, la ausencia de diferencia en la mayoría de los resultados de los tests físicos indica que genotipos distintos son compatibles con el desempeño futbolístico de alto nivel, lo que significa que es la interacción fenotipo-genotipo que hace que una jugadora de fútbol sea exitosa. Nivel de Evidencia I, Estudios pronósticos - Investigación del efecto de característica de un paciente sobre el desenlace de la enfermedad.

Prophylactic potential of memantine against soman poisoning in rats.

BACKGROUND: Carbamates physostigmine and pyridostigmine have been used as a pretreatment against poisoning with nerve agents in order to reversibly inhibit and thus protect from irreversible inhibition a portion of acetylcholinesterase (AChE) in brain and respiratory muscles that is crucial for survival. Memantine, an adamantine derivative, has emerged as a promising alternative to carbamates, since it prevented the fasciculations and skeletal muscle necrosis induced by carbamates and organophosphates, including nerve agents. AIM: This experimental study was undertaken in order to investigate and compare the protective and behavioural effects of memantine and standard carbamates physostigmine and pyridostigmine in rats poisoned with soman and treated with atropine, oxime HI-6 and diazepam. Another goal was to elucidate the mechanisms of the antidotal effect of memantine and its potential synergism with standard antidotes against nerve agents. MATERIALS AND METHODS: Male Wistar rats were used throughout the experiments. In dose-finding experiments memantine was administered at dose interval 0-72 mg/kg sc 60 min before sc injection of soman. In time-finding experiments memantine was injected 18 mg/kg sc 0-1440 min before soman. Standard treatment antidotes - atropine 10 mg/kg, HI-6 50 mg/kg and diazepam 2.5 mg/kg - were administered im within 15 s post-exposure. Soman 0.75 LD50 was used to study its inhibitions of neuromuscular transmission on the phrenic nerve-diaphragm preparation in situ and of tissue AChE activity. Behavioural effects of the prophylactic antidotes were investigated by means of the rotarod test. Based on these data therapeutic index and therapeutic width was calculated for all three prophylactic agents. RESULTS: Memantine pretreatment (18 mg/kg sc) produced in rats poisoned with soman significantly better protective ratios (PRs) than the two carbamates - 1.25 when administered alone and 2.3 when combined with atropine pretreatment and 6.33 and 7.23 with atropine/HI-6 and atropine/HI-6/diazepam post-exposure therapy, respectively. The highest PR of 10.11 obtained in Atr/HI-6-treated rats was achieved after pretreatment with memantine 36 mg/kg. This additional protection lasted for 8 h. All three prophylactic regimens antagonised the soman-induced neuromuscular blockade, but the effect of memantine was fastest. Pretreatment with memantine assured higher AChE activity in brain and diaphragm than in unpretreated rats (46% vs 28% and 68% vs. 38%, respectively). All three prophylactic regimens affected the rotarod performance in rats, but the effect of memantine was relatively strongest. Memantine and pyridostigmine had lowest and highest therapeutic index and therapeutic width, respectively. CONCLUSIONS: Although memantine assures better and longer-lasting protection against soman poisoning in rats than the two carbamates, its small therapeutic index and narrow therapeutic width seriously limit its potential as a pretreatment agent. Despite its behavioural effects, memantine seems to be beneficial antidote when administered after soman, along with atropine/HI-6/diazepam therapy. Mechanism of the antidotal effect of memantine against soman poisoning appears to be a combination of AChE-protecting and NMDA receptor-blocking action.

Efficacy of antidotes and their combinations in the treatment of acute carbamate poisoning in rats.

BACKGROUND: Physostigmine and its analogues neostigmine, pyridostigmine and rivastigmine are carbamates nowadays used in many indications, including antidotal effects against antimuscarinic poisonings, reversal of competitive neuromuscular block, myasthenia gravis, Alzheimer's disease and prophylaxis against nerve agent intoxications. Use of these medicinal carbamates, but also of carbamate insecticides, created need for research into the potential and mechanisms of action of several antidotes against carbamate poisonings, including anticholinergics and oximes. AIM: The goal of this experimental study was to ascertain the life-preserving potential of anticholinergics atropine, hexamethonium and d-tubocurarine, oxime HI-6 and their combinations in rats poisoned with physostigmine or pyridostigmine. MATERIALS AND METHODS: Experiments were performed in Wistar rats. Carbamates were injected subcutaneously (sc) and antidotes intramuscularly (im). Median lethal dose (LD50) in animals treated with antidotes were compared to the ones in saline-treated rats and protective ratios (PRs) were calculated. Atropine (5, 10 and 20 mg/kg), hexamethonium (5, 10 and 20 mg/kg), d-tubocurarine (0.005, 0.010 and 0.020 mg/kg) and oxime HI-6 (25, 50 and 100 mg/kg) were used as monotherapies and in dual combinations, where atropine was the obligatory antidote. Biochemical experiments consisted in measuring of the cholinesterase activities in brain, whole blood and diaphragm in rats 5, 15, 30, 60, 120 and 240 min after poisoning with 0.8 LD50 of physostigmine or pyridostigmine. RESULTS: All the tested antidotes assured some degree of protection against the two carbamates. Atropine and hexamethonium produced better protection in physostigmine-poisoned rats, while d-tubocurarine and HI-6 were more efficacious in pyridostigmine-intoxicated animals. Oxime HI-6 50 mg/kg reactivated acetylcholinesterase (AChE) in brain inhibited by physostigmine and in diaphragm inhibited by pyridostigmine. CONCLUSIONS: Mechanism of physostigmine-induced lethal effect is predominantly central and it involves inhibition of brain AChE, while pyridostigmine produces the same effect exclusively outside the central nervous system, by inhibiting AChE in the respiratory muscles. As a consequence, increasing doses of atropine and their combination with hexamethonium assure excellent protection against physostigmine toxicity, while the best protection against pyridostigmine is provided by a strictly peripherally acting antinicotinic d-tubocurarine and bispyridinium oxime HI-6. The oxime acts as antidote against physostigmine and pyridostigmine poisoning by reactivating AChE in the brain and diaphragm, respectively.

Confocal Synaptology: Synaptic Rearrangements in Neurodegenerative Disorders and upon Nervous System Injury.

The nervous system is a notable exception to the rule that the cell is the structural and functional unit of tissue systems and organs. The functional unit of the nervous system is the synapse, the contact between two nerve cells. As such, synapses are the foci of investigations of nervous system organization and function, as well as a potential readout for the progression of various disorders of the nervous system. In the past decade the development of antibodies specific to presynaptic terminals has enabled us to assess, at the optical, laser scanning microscopy level, these subcellular structures, and has provided a simple method for the quantification of various synapses. Indeed, excitatory (glutamatergic) and inhibitory synapses can be visualized using antibodies against the respective vesicular transporters, and choline-acetyl transferase (ChAT) immunoreactivity identifies cholinergic synapses throughout the central nervous system. Here we review the results of several studies in which these methods were used to estimate synaptic numbers as the structural equivalent of functional outcome measures in spinal cord and femoral nerve injuries, as well as in genetic mouse models of neurodegeneration, including Alzheimer's disease (AD). The results implicate disease- and brain region-specific changes in specific types of synapses, which correlate well with the degree of functional deficit caused by the disease process. Additionally, results are reproducible between various studies and experimental paradigms, supporting the reliability of the method. To conclude, this quantitative approach enables fast and reliable estimation of the degree of the progression of neurodegenerative changes and can be used as a parameter of recovery in experimental models.

Naloxone Antagonizes Soman-induced Central Respiratory Depression in Rats.

The influence of naloxone on respiration impaired by the highly toxic organophosphate nerve agent soman in anaesthetized rats was investigated. Soman, administered in a dose that was ineffective in blocking the electrically induced contractions of the phrenic nerve-diaphragm preparation in situ, induced a complete block of the spontaneous respiratory movements of the diaphragm, indicating the domination of central over the peripheral effects. Naloxone dose-dependently antagonized the soman-induced respiratory blockade. Atropine, at a dose that was per se ineffective in counteracting soman-induced respiratory depression, potentiated the protective effects of naloxone and completely restored respiration. Naloxone remained completely ineffective in antagonizing respiratory depression induced by the muscarinic receptor agonist the oxotremorine. It is assumed that naloxone antagonizes soman-induced respiratory inhibition by blocking endogenous opioidergic respiratory control pathways that are independent of the stimulation of muscarinic receptors.

Giant primary retroperitoneal seminoma: A case report.

INTRODUCTION: Primary extragonadal seminomas are rare tumors. There have been only a few cases of the primary retroperitoneal seminomas reported in the literature up to date. CASE REPORT: We reported a 56-year-old man with giant primary retroperitoneal seminoma presented with the enlargement of the left side of the abdomen and deep venous thrombosis of the left leg. Computed tomography of the abdomen showed a large tumor occupying the left part of the retroperitoneal space with 23 x 13 cm in diameter. Firm tumor mass having 25 x 15 cm in diameter was surgically removed from the left retroperitoneum. The tumor adhered the tunica adventitia of the aorta and it was carefully resected from the aortic wall. The diagnosis of seminoma was made during histopathological examination. The patient underwent chemotherapy. Two years after finished chemotherapy the patient accepted left orchiectomy with the aim of eliminating the possibility of the occult malignancy of the testicle. Histopathological analysis of the testicular tissue was normal and the diagnosis of primary retroperitoneal seminoma was confirmed. CONCLUSION. Despite its small incidence in general population, the diagnosis of retroperitoneal seminoma should be considered in male patients with nonspecific symptoms and with retroperitoneal tumor mass.

Ilizarov method as limb salvage in treatment of massive femoral defect after unsuccessful tumor arthroplasty.

Introduction: Surgical management of massive bone defects is very challenging in terms of estimating possibilities of saving the extremity and adequate method that can make it possible. Selection of methods is additionally limited in the presence of infection at site of defect. Case report: The female patient, diagnosed with Ewing sarcoma was treated by segmental bone resection and implantation of Kotz modular tumor endoprosthesis. After 5 years the signs of infection occured and persisted with low grade intensity. After falling, 12 years following implantation, the patient acquired periprosthetic fracture. Then endoprosthesis was removed, all along with surgical debridement of wound and application of the Ilizarov apparatus. The apparatus was applied, osteotomy of callus and the tibia performed with transport of bone segments, untill reconstruction of defect and arthrodesis of the knee was achieved. Conclusion: The Ilizarov apparatus offered us huge possibilities for management of massive bone defects with natural bone which has superior biomechanical characteristics comparing to the implant. The most frequent complication of this method is a prolonged treatment period that demands good patient selection and preparation and wide surgical experience.

Sex differences in anatomical parameters of acetabulum among asymptomatic Serbian population.

BACKGROUND/AIM: Anatomical parameters of the bony components of the hip joint are essential for better understanding of etiopathogenesis of diseases like primary osteoarthrosis of the hip joint. The aim of this reserch was to examine the normal acetabular morphometry in Serbian population and to determine whether there are sex differences in anatomical parameters of the acetabulum among asymptomatic subjects. METHODS: Pelvic radiographics of 320 adult asymptomatic patients (640 hips) were analyzed in 170 men and 150 women to determine the morphology of the acetabulum in Serbian population. For each hip the center edge angle of Wiberg (CEA), the acetabular angle of Sharp (AA), acetabular depth (AD), acetabular roof obliquity (ARO) and roof angle (RA) were measured. RESULTS: The following average measurements for acetabulum geometry were obtained (x +/- SD): CEA - 33.5 +/- 6.5 degrees (33.6 +/- 5.8 degrees in male, 33.3 +/- 6.9 degrees in female), AA - 38.0 +/- 3.8 degrees (37.5 +/- 3.6 degrees in male, 38.5 +/- 3.9 degrees in female), AD - 11.9 +/- 2.8 mm (12.5 +/- 2.7 mm in male, 11.2 +/- 2.7 mm in female), ARO - 7.6 +/- 5.7 degrees (6.2 +/- 4.9 degrees in male, 9.0 +/- 6.0 degrees in female) and RA - 18.4 +/- 10.0 degrees (19.6 +/- 8.5 degrees in male, 17.1 +/- 9.5 degrees in female). There were significant differences in the CEA, AA, AD, ARO and RA related to gender (p < 0.01, t-test). CONCLUSION: There are significant gender differences in Serbian population for all the examined anatomical parameters of acetabulum. We found sex-related differences in acetabular morphology, female acetabulum being marginally more dysplastic than male acetabulum. There is also a clear tendency of female hips to be more dysplastic than male ones.

[Morphology of neurons of human subiculum proper].

Subiculum proper is an archicortical structure of the subicular complex and presents the place of origin of great majority of axons of the whole hippocampal formation. In contrast to the hippocampus which has been intensively studied, the data about human subiculum proper are quite scarce. The aim of our study was to identify morphological characteristics of neurons of the human subiculum proper. The study was performed on 10 brains of both genders by using Golgi impregnation and Nissl staining. The subiculum has three layers: molecular, pyramidal and polymorphic layer. The dominant cell type in the pyramidal layer was the pyramidal neurons, which had pyramidal shaped soma, multiple basal dendrites and one apical dendrite. The nonpyramidal cells were scattered among the pyramidal cells of the pyramidal layer. The nonpyramidal cells were classified on: multipolar, bipolar and neurons with triangular-shaped soma. The neurons of the molecular layer of the human subiculum were divided into groups: bipolar and multipolar neurons. The most numerous cells of the polymorphic layer were bipolar and multipolar neurons.