Echocardiographic study of early left ventricular remodeling in highly trained preadolescent footballers

Almost all the studies of athlete's heart have been carried out on adult and older adolescent players; hence the limited data on the cardiac response to exercise in the beginning of the active sports career in the youngest athletes. The study was designed to examine the physiological limits of left ventricle (LV) cavity size and wall thickness in elite footballers at the preadolescent age, it the beginning of the active sports career. Ninety-four highly trained male footballers (mean aged 12.85 ± 0.84) competing in the Serbian Football League and 47 age-matched healthy male controls, aged 12–14, were enrolled in the study. All the echocardiographic findings were adjusted to BSA^?0.5, while left ventricle mass (LVM) was additionally adjusted to BSA^?1.5. Reference ranges were defined as values of 5–95th centile according to the mean values in both groups. The proportions of the footballers with LV dimensions outside expected ranges were additionally noted. The data indicate significant increases in absolute values of LV dimensions, aortic root size and left atrium (p < 0.001) in preadolescent professional footballers compared with the values expected for age-matched controls, whereas there are no differences in absolute values of ventricular septal and posterior wall thickness, LV wall thickness and LVM (p > 0.05). Upon body-size adjustments, significant increases were observed in all echocardiographic parameters (p < 0.001). Our data indicate an early cardiac remodeling, already apparent in preadolescence, even after a short period of training.     

Ceruloplasmin and antioxidative enzymes in pre-eclampsia

Objective: To evaluate diagnostic value of ceruloplasmin together with other enzymatic and nonenzymatic antioxidants (superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and uric acid) and to evaluate the level of oxidative stress in patients with pre-eclampsia (PE) and compare it with normal pregnancy.

Methods: In this prospective study, antioxidative markers were investigated in two groups of pregnant women: patients with pre-eclampsia (n?=?32) and the healthy pregnant women (n?=?60). The following antioxidative markers and enzymes were evaluated: serum ceruloplasmin levels, uric acid, superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px).

Results: Serum levels of ceruloplasmin, uric acid and SOD were significantly higher in the PE group compared to the control group. Serum levels of GSH-Px were not significantly higher in the PE group compared to the control group. Serum ceruloplasmin and serum uric acid have the best diagnostic accuracy for oxidative stress in PE and are more accurate compared to antioxidative enzymes -SOD and specially more accurate than GSH-Px.

Conclusions: Serum ceruloplasmin level may have significant role as the markers of oxidative stress in pre-eclampsia especially when used in combination with uric acid levels.     

Billateral Polycystic Kidneys in a Girl with WAGR Syndrome

The WAGR contiguous gene deletion syndrome is a combination of Wilms tumor, aniridia, genito-urinary abnormalities, and mental retardation. An 8.5-year-old girl was initially investigated at the age of 18 months for congenital bilateral aniridia, cataracts, glaucoma and epicantus. The ultrasound (US) scan showed polycystic kidney disease. FISH study revealed deletion of the WT1 and PAX6 gene in the 11p13 WAGR region. Forty days after the first kidney US, the second US revealed a 3 cm tumor in the right kidney: a Wilms tumour, treated successfully with the Wilm’s tumor protocol. The authors conclude that the identification of the deletions in the WAGR region in patients with aniridia should definitely be done. In addition, Wilms tumor can have a very rapid growth, which, per se requires frequent and careful ultrasound kidney controls. Polycystic kidneys can be part of the WAGR presentation.     

Nephrotic syndrome occurring during tiopronin treatment for cystinuria

Cystinuria is an autosomal recessive disorder characterized with abnormal tubular reabsorption of cystine and dibasic amino acids leading to cystine urolithiasis. The classical form is caused by mutations in the SLC3A1 gene (OMIM 220100). The cornerstone of the treatment is high hydration and alkalization of the urine to achieve urine pH between 7.0 and 7.5, at which point, cystine solubility in the urine is optimal. These measures very often fail, and thus addition of sulfhydryl agents like penicillamine and tiopronin (mercaptopropionyl glycine) is recommended. Herein, we report a 3-year-old boy with cystinuria resulting in recurrent nephrolithiasis requiring surgery and extracorporeal shock wave lithotripsy. Nine months after introduction of tiopronin, the boy manifested generalized edema, oliguria, and biochemical indices of nephrotic syndrome. Tiopronin was withdrawn, and the boy was given only supportive treatment. Within 10 days, he entered into clinical and biochemical remission. Pediatricians should be aware of this adverse effect of tiopronin, and therefore, testing of the urine with strips or sulfosalicylic acid at least once weekly at home may be very helpful for early detection of proteinuria.     

Complications of operative treatment of injuries of peripheral arteries

In 1991 and 1992, a total of 97 patients with 106 peripherial arterial injuries underwent surgery at the Institute for Cardiovascular Diseases, Clinical Centre of Serbia. Civilian injuries accounted for 53 (54.6%) patients (94.3% males, age range: 16-63 yr, mean: 35.2), and 44 patients had war injuries (93.2% males, age range: 19-61 yr, mean: 34.8). The injuries affected the superfitial femoral artery in 31 (29.24%); the popliteal artery in 28 (26.41%); the brachial artery in 17 (16.04%); the posterior tibial artery in 6 (5.66%); the axillary artery in 5 (4.72%); the anterior tibial artery in 5 (4.72%); the tibioperoneal trunk in 4 (3. 77%); the common femoral artery in 4 (3.77%); the external iliac artery in 2 (1.89%); the profound femoral artery in 2 (1.89%); the radial artery in 1 (0.94%); and ulnar artery in 1 (0.94%).A total of 98 reconstructive procedures were used to treat these patients. Graft interposition carried out in 50 (51.02%); by pass in 25 (25. 51%); end-to-end anastomosis in 9 (9.18%); suture in 8 (8.16%); ligation in 4 (4.08%); and patch-angioplasty in 2 (2.04%). Primary reconstruction of injured arteries was performed in 72.2% and secondary repair in 27.8% cases.Infection developed in 51 (52.57%) patients, and it was significantly (P<0.05) more common in the war injuries (70.45%) and in secondary repairs (88.89%). The presence of associated lesions (69.56%) was also correlated with a greater rate of infection.Amputation was necessary in 21 (21.65%) of our patients, and was significantly (P<0.05) more often performed after secondary (44.44%) than primary operations (12.86%) and in the presence of associated injuries (32.61%).     

Chloroquine-Mediated Lysosomal Dysfunction Enhances the Anticancer Effect of Nutrient Deprivation

Purpose

To investigate the ability of chloroquine, a lysosomotropic autophagy inhibitor, to enhance the anticancer effect of nutrient deprivation.

Methods

Serum-deprived U251 glioma, B16 melanoma and L929 fibrosarcoma cells were treated with chloroquine in vitro. Cell viability was measured by crystal violet and MTT assay. Oxidative stress, apoptosis/necrosis and intracellular acidification were analyzed by flow cytometry. Cell morphology was examined by light and electron microscopy. Activation of AMP-activated protein kinase (AMPK) and autophagy were monitored by immunoblotting. RNA interference was used for AMPK and LC3b knockdown. The anticancer efficiency of intraperitoneal chloroquine in calorie-restricted mice was assessed using a B16 mouse melanoma model.

Results

Chloroquine rapidly killed serum-starved cancer cells in vitro. This effect was not mimicked by autophagy inhibitors or LC3b shRNA, indicating autophagy-independent mechanism. Chloroquine-induced lysosomal accumulation and oxidative stress, leading to mitochondrial depolarization, caspase activation and mixed apoptotic/necrotic cell death, were prevented by lysosomal acidification inhibitor bafilomycin. AMPK downregulation participated in chloroquine action, as AMPK activation reduced, and AMPK shRNA mimicked chloroquine toxicity. Chloroquine inhibited melanoma growth in calorie-restricted mice, causing lysosomal accumulation, mitochondrial disintegration and selective necrosis of tumor cells.

Conclusion

Combined treatment with chloroquine and calorie restriction might be useful in cancer therapy.     

Recessive CHRM5 variant as a potential cause of neurogenic bladder

Neurogenic bladder is caused by disruption of neuronal pathways regulating bladder relaxation and contraction. In severe cases, neurogenic bladder can lead to vesicoureteral reflux, hydroureter, and chronic kidney disease. These complications overlap with manifestations of congenital anomalies of the kidney and urinary tract (CAKUT). To identify novel monogenic causes of neurogenic bladder, we applied exome sequencing (ES) to our cohort of families with CAKUT. By ES, we have identified a homozygous missense variant (p.Gln184Arg) in CHRM5 (cholinergic receptor, muscarinic, 5) in a patient with neurogenic bladder and secondary complications of CAKUT. CHRM5 codes for a seven transmembrane-spanning G-protein-coupled muscarinic acetylcholine receptor. CHRM5 is shown to be expressed in murine and human bladder walls and is reported to cause bladder overactivity in Chrm5 knockout mice. We investigated CHRM5 as a potential novel candidate gene for neurogenic bladder with secondary complications of CAKUT. CHRM5 is similar to the cholinergic bladder neuron receptor CHRNA3, which Mann et al. published as the first monogenic cause of neurogenic bladder. However, functional in vitro studies did not reveal evidence to strengthen the status as a candidate gene. Discovering additional families with CHRM5 variants could help to further assess the genes' candidate status.