Emerging Therapeutic Potential of Mesenchymal Stem/Stromal Cells in Preeclampsia.

PURPOSE OF REVIEW: Preeclampsia is a dangerous pregnancy condition affecting both the mother and offspring. It is a multifactorial disease with poorly understood pathogenesis, lacking effective treatments. Maternal immune response, inflammation and oxidative stress leading to endothelial dysfunction are the most prominent pathogenic processes implicated in preeclampsia development. Here, we give a detailed overview of the therapeutic applications and mechanisms of mesenchymal stem/stromal cells (MSCs) as a potential new treatment for preeclampsia. RECENT FINDINGS: MSCs have gained growing attention due to low immunogenicity, easy cultivation and expansion in vitro. Accumulating evidence now suggests that MSCs act primarily through their secretomes facilitating paracrine signalling that leads to potent immunomodulatory, pro-angiogenic and regenerative therapeutic effects. MSCs have been studied in different animal models of preeclampsia demonstrating promising result, which support further investigations into the therapeutic effects and mechanisms of MSC-based therapies in preeclampsia, steering these therapies into clinical trials.

ADIPONECTIN AS A POTENTIAL BIOMARKER OF LOW BONE MINERAL DENSITY IN POSTMENOPAUSAL WOMEN WITH METABOLIC SYNDROME.

CONTEXT: Adiponectin is an abundant adipokine, which has antiinflammatory, anti-atherosclerotic and vasoprotective actions, and potential antiresorptive effects on bone metabolism. It seems to be directly involved in the improvement and control of energy homeostasis, protecting bone health and predicting osteoporotic fracture risk. OBJECTIVE: To examine the relationship between adiponectin level and bone mineral density (BMD) in post-menopausal women with metabolic syndrome (MetS) and low BMD, and to estimate the prognostic significance of adiponectin in osteoporosis. DESIGN: Clinical-laboratory cross-sectional study including 120 middle-aged and elder women (average 69.18±7.56 years). SUBJECTS AND METHODS: The anthropometric parameters were measured for all examinees. Lumbar spine and hip BMD, as well as body fat percentage, were measured using a Hologic DEXA scanner. In all subjects serum adiponectin concentration was measured by ELISA method. RESULTS: The level of adiponectin was significantly positively correlated with BMD-total, BMD of the lumbar spine and BMD of the femoral neck (r=0.618, r=0.521, r=0.567; p<0.01). Levels of adiponectin and BMD are significantly lower in post-menopausal women with MetS and osteoporosis compared to patients with osteopenia (856.87±453.43 vs. 1287.32±405.21 pg/mL, p<0.01; BMD, p<0.05), and the highest values in healthy examinees. A cut-off value of adiponectin level for osteoporosis/osteopenia was 1076.22/1392.74 pg/mL. CONCLUSIONS: Post-menopausal women with MetS have significantly lower adiponectin level and low BMD compared to healthy examinees. Adiponectin may be an early, significant and independent predictor of developing osteoporosis in women with MetS, especially in post-menopausal period.

Musculoskeletal Pain and Vitamin D Deficiency in Children: A Pilot Follow-up Study of Vitamin D Therapy in Musculoskeletal/Orthopedic Conditions.

PURPOSE OF THE STUDY: The prevalence of vitamin D deficiency in pediatric populations is high. In the present study we analyzed associations between vitamin D therapy and pain, mobility, fatigue, and daily functioning in children with musculoskeletal/orthopedic conditions suffering from chronic and recurrent pain, but also diagnosed with vitamin D deficiency. MATERIAL AND METHODS: Children with different musculoskeletal/orthopedic conditions and vitamin D deficiency were prescribed to receive vitamin D over 6 months. Thirty-five children (18 males; age 10.48 ± 3.87 years) completed a 6-month follow-up. Self- and parent/proxy rating scales were used to evaluate pain, movement, fatigue, and daily functioning. RESULTS: At a six-month follow-up assessment involving child- and parent-reported scores, worst pain intensity significantly decreased (p ≤ 0.03) after vitamin D therapy, as well as functioning problems related to pain (p ≤ 0.01). The children reported better movement and balance with less fatigue. The parents reported better functioning in everyday activities of their children. CONCLUSION: This pilot study showed that vitamin D therapy possibly reduces pain intensity and improves mobility and daily functioning in children with musculoskeletal/orthopedic disorders, chronic recurrent pain, and vitamin D deficiency. Further follow-up and randomized studies are required in order to assess the validity of clinical recommendations.

The glassy behaviour of poorly crystalline Fe2O3 nanorods obtained by thermal decomposition of ferrous oxalate.

Nanorod ferrous oxalate dihydrate (FeC2O4 × 2H2O) which had been synthesized by the microemulsion method, was used as a precursor in the thermal decomposition process performed in air atmosphere. The formation of nanocrystalline hematite as the final product was preceded by the appearence of an intermediate product. Comprehensive study comprising several complementary techniques (x-ray diffraction, transmission electron microscopy, selected area electron diffraction, thermogravimetric/differential thermal analyses and SQUID magnetometry) confirmed that the intermediate product corresponds to the poorly crystalline Fe2O3. Due to the specific nanorod shape and poorly crystalline structure, the investigated Fe2O3 showed high coercive field value of ~0.5 T at 5 K. Special attention in this study was devoted to the peculiar magnetic properties of poorly crystalline Fe2O3, which were thoroughly investigated by employing sophisticated experimental procedures such as relaxation of thermoremanent magnetization for different cooling fields, zero field and field cooled memory effects as well as aging experiments for different waiting times. At low temperatures and weak applied magnetic fields, the investigated system behaves similarly to spin glasses, manifesting slow, collective relaxation dynamics of magnetic moments through memory, rejuvenation and aging effects.

Genetic detection of Dobrava-Belgrade hantavirus in the edible dormouse (Glis glis) in central Serbia.

Hantaviruses are endemic in the Balkans, particularly in Serbia, where sporadic cases and/or outbreaks of hantaviral human disease have been reported repeatedly, and evidenced serologically. Here, we present genetic detection of Dobrava-Belgrade virus (DOBV) hantaviral sequences in wild rodents trapped in central Serbia. All the animals were pre-screened serologically by indirect immunofluorescence (IF) test and only those with a positive finding of hantaviral antigens were further tested by polymerase chain reaction. Of the total of 104 trapped animals, 20 were found to be IF positive and of those three were positive for hantaviral RNA: one Microtus arvalis for Tula virus, and one each of Apodemus agrarius and Glis glis for DOBV. Phylogenetic analysis of the obtained sequences implies putative DOBV spillover infection of A. agrarius and G. glis from Apodemus flavicollis. However, future investigations should help to identify the most common natural host and geographical distribution of DOBV in its reservoir hosts in Serbia.

Is there a correlation between molecular markers and response to neoadjuvant chemoradiotherapy in locally advanced squamous cell esophageal cancer?

PURPOSE: To evaluate the expression of epidermal growth factor receptor (EGFR), p53, p21 and thymidylate synthase (TS) in a pretherapy biopsy specimen of locally advanced squamous cell esophageal cancer and correlate these markers with response to neoadjuvant chemoradiotherapy. METHODS: Sixty-two patients with histopathologically proven locally advanced (T3 or greater) squamous cell esophageal cancer were enrolled. The expression of EGRF, p53, p21 and TS markers was assessed with immunohistochemistry. Semiquantitative assessment of expression of these markers was performed based on the percent of the stained cells. Radiotherapy (45-50.4 Gy) was delivered concomitantly with 5-fluorouracil (5-FU)/leucovorin (LV)/cisplatin (CIS) chemotherapy. Five to 6 weeks after chemoradiation, response to treatment was assessed. Medically fit and operable patients were operated. The resected material underwent histopathological evaluation of tumor expansion, histological classification after initial multimodality treatment (yp TNM), residual status and tumor regression grade (TRG). RESULTS: Out of 62 patients enrolled, 41 (66%) were evaluated for molecular markers. Clinical response rate was 43.9%. Out of 41 patients, 12 (29%) underwent surgery. TRG 1 was noted in 58% of the patients. In a pretherapy tumor specimen, positive expression was noted in 80, 90, 80 and 71% for EGFR, p53, p21 and TS, respectively. We noted no statistically significant difference neither between tumor marker expression and clinical response to chemoradiation, nor between tumor marker expression and TRG. CONCLUSION: We registered no difference in response to treatment between EGFR, TS, p21 and p53 positive and negative staining.

Functional characterization of the muscarinic receptors involved in endothelium-dependent relaxation in isolated canine uterine artery.

Acetylcholine interacts with endothelial muscarinic receptors releasing nitric oxide and causing vasodilatation. To identify the receptor subtype responsible for acetylcholine-induced relaxation in canine uterine artery, the usual organ bath method for in vitro investigation on isolated blood vessels was applied. Using a range of muscarinic receptor antagonists such as atropine (nonselective), pirenzepine (M(1)-selective), methoctramine (M(2)-selective) and p-fluoro-hexahydro-sila-difenidol (p-FHHSiD) (M(1)/M(3)) and determining pA2 value of those antagonists through Shild analysis, we aimed at establishing a precise receptor mechanism underlying acetylcholine-induced relaxation in isolated canine uterine artery. The relaxation of uterine arterial rings in response to acetylcholine in the presence or absence of selective muscarinic receptors antagonists was calculated using concentration response curves. Acetylcholine induced concentration-dependent and endothelium-dependent relaxation of arterial rings precontracted with phenylephrine (pEC(50) = 6.90 +/- 0.02). Muscarinic receptors antagonists atropine, pirenzepine, methoctramine and p-FHHSiD competitively antagonized the response to acetylcholine and obtained pA(2) values were 9.91 +/- 0.06, 6.60 +/- 0.04, 6.21 +/- 0.08 and 8.05 +/- 0.1, respectively. This study showed that acetylcholine induced endothelium-dependent relaxation of canine uterine artery by stimulation of muscarinic receptors localized on the endothelial cells. On the basis of differential antagonist affinity, we suggest that the muscarinic receptors involved in the acetylcholine-induced relaxation of canine uterine artery are predominantly of M(3) subtype.

Gitelman's syndrome as a cause of poorly controlled hypokalemia.

Gitelman's syndrome is a rare autosomal recessive tubulopathy caused by a defect of the thiazide-sensitive sodium chloride co-transporter at the distal tubule, leading to hypokalemia, metabolic alkalosis, hypomagnesemia, hypocalciuria and low-to-normal blood pressure. Clinical features include transient periods of muscle weakness and tetany, dizziness, abdominal pains and constipation. Patients can also present with convulsions due to severe metabolic alkalosis or hypomagnesemia. Therefore, early recognition and treatment are important. Diagnosis of Gitelman's syndrome is usually made incidentally during adolescence or early adulthood based on clinical and biochemical findings. In this paper we present the case of a 23-year-old female patient referred to our nephrology department for severe hypokalemia. Complementary evaluation revealed hypokalemia, hypomagnesemia, metabolic alkalosis, increased chloride and sodium urinary excretion and reduced urinary calcium excretion with normal renal function. A diagnosis of Gitelman syndrome was established. Treatment included magnesium and potassium salts and potassium saving diuretics. In general, the long-term prognosis of Gitelman's syndrome is good if the patient adhere with the treatment.

Genetic analysis of Dobrava-Belgrade virus from western Serbia--a newly detected focus in the Balkan Peninsula.

Dobrava-Belgrade virus (DOBV) is a hantavirus species that causes the most severe form of haemorrhagic fever with renal syndrome (HFRS) in Europe. DOBV has been detected in three Apodemus rodents: A. flavicollis, A. agrarius and A. ponticus. These emerging viruses appear throughout the Balkan Peninsula including Serbia as its central part. In this study, we examined the seroprevalence, molecular epidemiology and phylogenetics of DOBV from A. flavicollis captured at six Serbian localities. Furthermore, we applied microsatellite typing of host animal genome to analyse the role of host kinship in DOBV animal transmission. The overall IgG seropositivity rate over 3 years (2008-2010) was 11.9% (22/185). All seropositive samples were subjected to RT-PCR and DNA sequencing for S and L genome segments (pos. 291-1079 nt and 2999-3316 nt, respectively). DOBV was genetically detected in three samples from mountain Tara in western Serbia, a newly detected DOBV focus in the Balkans. No sequence data from human cases from Serbia are available for the studied period. However, collected DOBV isolates in this work phylogenetically clustered together with isolates from Serbian human cases dating from 2002, with 1.9% nucleotide divergence. We determined the level of kinship between seropositive and seronegative animal groups and found no significant difference, suggesting that horizontal virus transmission in the studied population was the same within and among the hatches. Our findings are the first genetic detection of DOBV in rodents in Serbia. We confirm wide and continuous hantavirus presence in the examined parts of the Balkans, underlying the necessity of continual monitoring of hantavirus circulation in A. flavicollis.

Osteogenic effect of a gastric pentadecapeptide, BPC-157, on the healing of segmental bone defect in rabbits: a comparison with bone marrow and autologous cortical bone implantation.

Gastrectomy often results in increased likelihood of osteoporosis, metabolic aberration, and risk of fracture, and there is a need for a gastric peptide with osteogenic activity. A novel stomach pentadecapeptide, BPC-157, improves wound and fracture healing in rats in addition to having an angiogenic effect. Therefore, in the present study, using a segmental osteoperiosteal bone defect (0.8 cm, in the middle of the left radius) that remained incompletely healed in all control rabbits for 6 weeks (assessed in 2 week intervals), pentadecapeptide BPC-157 was further studied (either percutaneously given locally [10 microg/kg body weight] into the bone defect, or applied intramuscularly [intermittently, at postoperative days 7, 9, 14, and 16 at 10 microg/kg body weight] or continuously [once per day, postoperative days 7-21 at 10 microg or 10 ng/kg body weight]). For comparison, rabbits percutaneously received locally autologous bone marrow (2 mL, postoperative day 7). As standard treatment, immediately after its formation, the bone defect was filled with an autologous cortical graft. Saline-treated (2 mL intramuscularly [i.m.] and 2 mL locally into the bone defect), injured animals were used as controls. Pentadecapeptide BPC-157 significantly improved the healing of segmental bone defects. For instance, upon radiographic assessment, the callus surface, microphotodensitometry, quantitative histomorphometry (10 microg/kg body weight i.m. for 14 days), or quantitative histomorphometry (10 ng/kg body weight i.m. for 14 days) the effect of pentadecapeptide BPC-157 was shown to correspond to improvement after local application of bone marrow or autologous cortical graft. Moreover, a comparison of the number of animals with unhealed defects (all controls) or healed defects (complete bony continuity across the defect site) showed that besides pentadecapeptide intramuscular application for 14 days (i.e., local application of bone marrow or autologous cortical graft), also following other pentadecapeptide BPC-157 regimens (local application, or intermittent intramuscular administration), the number of animals with healed defect was increased. Hopefully, in the light of the suggested stomach significance for bone homeostasis, the possible relevance of this pentadecapeptide BPC-157 effect (local or intramuscular effectiveness, lack of unwanted effects) could be a basis for methods of choice in the future management of healing impairment in humans, and requires further investigation.

The influence of serum paraproteins on Burstein's reaction for beta-lipoproteins.

Using sulfonated polysaccharides to precipitate beta-lipoprotein in serum, we obtained high values in certain cases with normal serum lipids. Therefore, we examined whether there are proteins in such sera which precipitate under conditions optimal for beta-lipoprotein insolubilization. The results show that certain IgG paraproteins are precipitable by sulfonated polysaccharides giving erroneously high values for beta-lipoprotein.

Absorption of the impact energy in the palmar soft tissues.

In 30 anatomical specimens of the forearm the dynamic fracture of radius has been performed with a special hammer. In these specimens the pure kinetic energy of the fracture of the radius and the absorption of the impact energy in the palmar soft tissues has been determined.

Basicity of nitropyrazoles and their simultaneous spectrophotometric determination.

The protonation constants of some 1-, 3(5)-, 3-, 4- and 5-nitropyrazoles have been determined, and compared with those of nitroimidazoles. The effect of the position of the nitro group in the pyrazole and imidazole ring is discussed. The ortho effects of the nitro group in pyrazole and imidazole are compared and found to have identical values. The effect of the nitro group on protonation constants is greater when the nitro group is close to the pyridine nitrogen atom. This, together with the ability of N-unsubstituted nitropyrazoles to dissociate to give nitropyrazole anions, with an accompanying shift of the spectra to longer wavelengths, permits the simultaneous spectrophotometric determination of nitropyrazoles.

Influence of pyridine and urea on the rat brain ATPase activity.

The neurotoxicity of pyridine and urea was investigated in respect to their ability to alter the activity of synaptosomal membrane Na+/K(+)-ATPase and Mg(2+)-ATPase. In vitro treatment with pyridine and urea stimulated Na+/K(+)-ATPase activity in a dose-dependent manner up to 40% and 60%, respectively. Mg(2+)-ATPase activity increased up to 40% after pyridine treatment, while urea had no effect at all. The neuroactive potencies of pyridine and urea were evaluated by estimating parameters Km and delta Vmax for enzyme stimulation, as well as Hill coefficient to estimate the levels of cooperativity for pyridine and urea binding. The results suggest that pyridine stimulates both enzymes, probably by interacting with some neuronal membrane components, and altering the lipid micro-environment of the ATPases. In contrast, urea stimulates the Na+/K(+)-ATPase only, assumingly by acting on it directly or via some other regulatory mechanism. Stimulation of Na+/K(+)-ATPase and Mg(2+)-ATPase by the substances tested and subsequent alteration of neuronal cell functioning could contribute to the CNS dysfunction upon chronic exposure to pyridine and urea.

Mechanism and kinetics of synthesis of allicin.

Allicin, allyl-thiosulfinate, a pharmacologically active compound with considerable fungicidal, bactericidal, antioxidant and anticarcinogenic effects, was obtained by oxidizing allyl disulfide with acid hydrogen peroxide. The synthesis mechanism was studied by the ESR spin trap method. The kinetics of allicin synthesis was ascertained by determination of the concentration of the limiting reactant during the synthesis using HPLC and it was found that the allicin synthesis reaction was of zero order. The allicin obtained was determined using UV, FT-IR, MS, 1H and 13C NMR analysis.

Allylthiosulfinate: beta-cyclodextrin inclusion complex: preparation, characterization and microbiological activity.

An allylthiosulfinate: beta-cyclodextrin inclusion complex was synthesized and characterized using X-ray crystallography, IR spectroscopy, thermal analysis and nuclear magnetic resonance. The microbiological activity of the complex was tested on available fungi (Candida albicans ATCC 10231, Aspergillus niger ATCC 16404) and bacteria (Staphylococcus aureus ATCC 6538, Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 9027). In small concentrations, the complex inhibited the growth of the microorganisms tested. The most susceptible microorganism was Candida albicans ATCC 10231, and the least susceptible Pseudomonas aeruginosa ATCC 9027.

[Contribution to the nomenclature of variations of the cystic artery]. / Ein Beitrag zur Nomenklatur der Variationen der Arteria cystica.

INTRODUCTION: Safe procedures for laparoscopic cholecystectomy demand good knowledge of the anatomy of the terminal part of the cystic artery and its variations, and also precise dissection in and around the hepatobiliary triangle. METHOD: Good laparoscopic visualisation enables recognition of the variation of the cystic artery. Our observations are based on 1000 cholecystectomies. RESULTS: We have described and named variations of the terminal part of the cystic artery. Group I comprises the five variations of the cystic artery within the hepatobiliary triangle: (a) "normal" position; (b) frontal cystic artery; (c) backside; (d) multiple; (e) short cystic artery that arises from an aberrant right hepatic artery. Group II consists of variations of the cystic artery that approach--the gallbladder beyond the hepatobiliary triangle: (a) "low-lying"; (b) transhepatic; (c) "recurrent" cystic artery. CONCLUSION: Our classification is simple and easy to memorize and will considerably facilitate safe laparoscopic cholecystectomy.

Myocardial bridging of the left anterior descending coronary artery in monkey hearts.

The presence of myocardial bridges over the left anterior descending coronary artery (LAD) has been studied in 55 monkey (Cercopithecus aethiops) hearts. The resemblance between the Cercopithecus LAD and the one in humans has been revealed. Cercopithecus LAD was the most frequently (70.9%) overbridged artery. The bridges were usually single. Only in 2 hearts (3.6%) LAD was overbridged by 2 MB. Their length varies from 0.5 mm to 31.6 mm (average 11.7 mm). No statistically significant sexual differences in the incidence and length of MB have been reported. Atherosclerotic lesions have been reported in overbridged parts of the vessel as well as in the subepicardial ones. Intimate correlation between the presence of myocardial bridges and atherosclerosis could not be suggested.

Ultrasound measurement in defining the regional distribution of subcutaneous fat tissue.

The aim of this research is to determine the significance of ultrasound diagnostics in measuring the thickness of subcutaneous fat tissue as well as to point out sex and age differences in regional distribution of subcutaneous fat tissue. The research included 37 men and 33 women with different body mass indexes. Ultrasound measuring of subcutaneous fat tissue was conducted on 16 measuring points. The thickness of subcutaneous fat tissue measured by ultrasound and estimated proportion of fat tissue obtained by comparative methods coincided mostly on the back side of the upper arm, lower abdominal region in interspinal line and the front side of the forearm. Analysis of the subcutaneous fat tissue distribution indicates that there is more equal accumulation of fat tissue in women than in men. BMI limit value for obesity is not the same for men and women because the point at which abdominal region becomes the main storage of subcutaneous fat in body depends on sex. That BMI value represents the physiological beginning of obesity since it marks the change in distribution pattern of subcutaneous fat tissue in different body regions.

Interferometry in the assessment of biomechanical features of the masticatory system hard segments.

Biomechanical studies have found wide application and solved many problems in dental medicine. An interdisciplinary approach has allowed an ever-faster progress in the field. The aim of this study was to point out the advantages of holographic interferometry. With the use of this method, the study object is observed as a whole rather than as a substrate, thus providing a three-dimensional holographic image visualizing the load transmission from one jaw to another, tooth pressure against the alveolus, and strain of Sharpey's fibers, and yielding precise data on deformities, dislocations and force distribution.