Described for the first time in 1971, Schimke immuno-osseous dysplasia (SIOD) is an autosomal-recessive multisystem disorder that is caused by bi-allelic mutations of SMARCAL1, which encodes a DNA ...annealing helicase. To define better the dental anomalies of SIOD, we reviewed the records from SIOD patients with identified bi-allelic SMARCAL1 mutations, and we found that 66.0% had microdontia, hypodontia, or malformed deciduous and permanent molars. Immunohistochemical analyses showed expression of SMARCAL1 in all developing teeth, raising the possibility that the malformations are cell-autonomous consequences of SMARCAL1 deficiency. We also found that stimulation of cultured skin fibroblasts from SIOD patients with the tooth morphogens WNT3A, BMP4, and TGFβ1 identified altered transcriptional responses, raising the hypothesis that the dental malformations arise in part from altered responses to developmental morphogens. To the best of our knowledge, this is the first systematic study of the dental anomalies associated with SIOD.
Abstract The endocannabinoid system serves as a retrograde negative feedback mechanism. It is thought to control neuronal activity in an epileptic neuronal network. The purpose of this study was to ...evaluate the impact of the endocannabinoid and endovanilloid systems on both epileptogenesis and ictogenesis. Therefore, we modulated the endocannabinoid and endovanilloid systems genetically and pharmacologically, and analyzed the subsequent impact on seizure progression in the kindling model of temporal lobe epilepsy in mice. In addition, the impact of seizures on associated cellular alterations was evaluated. Our principal results revealed that the endocannabinoid system affects seizure and afterdischarge duration dependent on the neuronal subpopulation being modulated. Genetic deletion of CB1-receptors (CB1Rs) from principal neurons of the forebrain and pharmacological antagonism with rimonabant (5 mg/kg) caused longer seizure duration. Deletion of CB1R from GABAergic forebrain neurons resulted in the opposite effect. Along with these findings, the CB1R density was elevated in animals with repetitively induced seizures. However, neither genetic nor pharmacological interventions had any impact on the development of generalized seizures. Other than CB1, genetic deletion or pharmacological blockade with SB366791 (1 mg/kg) of transient receptor potential vanilloid receptor 1 (TRPV1) had no effect on the duration of behavioral or electrographic seizure activity in the kindling model. In conclusion, we demonstrate that endocannabinoid, but not endovanilloid, signaling affects termination of seizure activity, without influencing seizure severity over time. These effects are dependent on the neuronal subpopulation. Thus, the data argue that the endocannabinoid system plays an active role in seizure termination but does not regulate epileptogenesis.
Abstract Endocannabinoids, including 2-arachidonoylglycerol (2-AG), activate presynaptic cannabinoid type 1 receptors (CB1R) on inhibitory and excitatory neurons, resulting in a decreased release of ...neurotransmitters. The event-specific activation of the endocannabinoid system by inhibition of the endocannabinoid degrading enzymes may offer a promising strategy to selectively activate CB1Rs at the site of excessive neuronal activation with the overall goal to prevent the development epilepsy. The aim of this study was to investigate the impact of monoacylglycerol lipase (MAGL) inhibition on the development and progression of epileptic seizures in the kindling model of temporal lobe epilepsy. Therefore, we selectively blocked MAGL by JZL184 (8 mg/kg, i.p.) in mice to analyze the effects of increased 2-AG levels on kindling acquisition and to exclude an anticonvulsive potential. Our results showed that JZL184 treatment significantly delayed the development of generalized seizures ( p = 0.0066) and decreased seizure ( p < 0.0001) and afterdischarge duration ( p < 0.001) in the kindling model of temporal lobe epilepsy, but caused only modest effects in fully kindled mice. Moreover, we proved that JZL184 treatment had no effects in conditional CB1R knockout mice lacking expression of the receptor in principle neurons of the forebrain. In conclusion, the data demonstrate that indirect CB1R agonism delays the development of generalized epileptic seizures but has no relevant acute anticonvulsive effects. Furthermore, we confirmed that the effects of JZL184 on kindling progression are CB1R mediated. Thus, the data indicate that the endocannabinoid 2-AG might be a promising target for an anti-epileptogenic approach.
The epidemiological information from well-defined populations regarding childhood chronic kidney disease (CKD), particularly those concerning non-terminal stages, are scanty. The epidemiology of CKD ...in children is often based on renal replacement therapy (RRT) data, which means that a considerable number of children in earlier stages of CKD are missed as they will reach end-stage renal disease (ESRD) in adulthood. Here, we report the basic epidemiological data on childhood CKD in Serbia, gathered over the 10-year period of activity of the Serbian Pediatric Registry of Chronic Kidney Disease.
Since 2000-09, data on incidence, prevalence, aetiology, treatment modalities and outcome of children aged 0-18 years, with CKD Stages 2-4 and CKD Stage 5, were collected by reporting index cases from paediatric centres.
Three hundred and thirty-six children were registered (211 boys, 125 girls, male/female ratio 1.7). The median age at registration was 9.0 years interquartile range (IQR) 3-13. Median follow-up was 4.0 years (IQR, 1-9). The median glomerular filtration rate (GFR) at the time of the registration was 39.6 mL/min/1.73m(2) (IQR, 13.8-65.4). Median annual incidence of CKD 2-5 stages was 14.3 per million age-related population (p.m.a.r.p.), while those of CKD 2-4 or CKD 5 were 9.1 and 5.7 p.m.a.r.p., respectively. The median prevalence of CKD 2-5 was 96.1 p.m.a.r.p., 52.8 p.m.a.r.p. in CKD 2-4 and 62.2 p.m.a.r.p. in CKD 5. The main causes of CKD were congenital anomalies of kidney and urinary tract and hereditary nephropathies. Kidney survival was the worst in children with glomerular diseases and in those with advanced CKD. Haemodialysis was the most common first modality of RRT. Mortality rate was 4.5%, mainly due to cardiovascular and infectious complications.
Epidemiology of paediatric CKD in Serbia is similar to that reported from developed European countries. The knowledge of the epidemiology of earlier stages of CKD is essential for both institution of renoprotective therapy and planning of RRT, a fact of paramount importance in countries with limited resources.
Several reports have documented various forms of glomerular diseases in adults with myelodysplastic syndromes (MDS), but similar reports in children are lacking. We describe two children with ...MDS-associated steroid-responsive nephrotic syndrome (NS). Patient 1, who had MDS with myelofibrosis, presented with hepatosplenomegaly, pancytopenia, chronic hepatitis, moderate proteinuria, hypocomplementemia and elevated ANA titer. During initial prednisone treatment proteinuria markedly diminished and partial but transient hematological improvement occurred. Relapse subsequently occurred that manifested by overt NS and pancytopenia. High doses of prednisolone led to remission of the renal disease, but hematological remission did not occur. Persisting pancytopenia and repeated infections terminated in sepsis, 2 years after the onset of the MDS. Patient 2, who had refractory anemia with clonal monosomy 19, presented with bowel disease, hepatosplenomegaly, anemia and non-organ-specific autoantibodies. Prednisone led to both clinical and hematological remission. The hematologic disease relapsed 12 months later, when nephrotic-range proteinuria, hematuria and mild azotemia were also found. Corticosteroid treatment led to long-lasting renal and hematologic remission, maintained by a small dosage of prednisone. In both patients, renal biopsy findings were consistent with those seen in idiopathic NS. A Medline search disclosed 16 cases of glomerulopathy in the course of MDS in adult patients. Clinical features included NS, usually accompanied by renal insufficiency with acute, chronic, or rapidly progressive glomerulonephritis. On biopsy, membranous nephropathy, crescentic or mesangial proliferative glomerulonephritis, and AL amyloidosis were found. We conclude: (1) that glomerular disease may be present and should be searched for in patients with MDS and (2) that MDS can be added to the list of rare conditions associated with corticosteroid-responsive NS in children.
Cellular immune disturbances, and T lymphocyte function in particular, have been previously implicated in idiopathic nephrotic syndrome (INS) of childhood. There are different patterns of cytokine ...expression in various forms of glomerulonephritis, which suggests that local production of these peptides plays an important role in the pathogenesis and progression of glomerulonephritis. To investigate T-cell and monocyte/macrophage cytokine production in INS, interleukin-12 (IL-12) and interferon-gamma (IFN-gamma) production by peripheral blood mononuclear cells (PBMC) of 11 children with steroid-sensitive nephrotic syndrome (SSNS), 9 with focal segmental glomerulosclerosis (FSGS), and 17 healthy controls was determined. Children with SSNS were studied in relapse, during corticosteroid treatment, and in stable remission, off corticosteroid treatment. IL-12 was not detected in serum, urine, and in supernatants of unstimulated PBMC. IL-12 production by concanavalin A (Con A)-stimulated PBMC of children with SSNS and FSGS was not different from controls. IFN-gamma production by Con A-stimulated PBMC was decreased in children with relapsing SSNS, both in relapse and and during corticosteroid treatment. However, in stable remission it was similar to controls. Markedly decreased IFN-gamma production (P<0.001) was observed by pokeweed mitogen-stimulated PBMC of relapsing SSNS patients and moderately decreased production by PBMC of FSGS patients. This study has established a decreased production of IFN-gamma by PBMC of relapsing SSNS and FSGS patients, but does not allow differentiation between these two different conditions. IL-12 did not have a pathogenic role in either SSNS or FSGS.
Tricyclic antidepressants, such as amitriptyline (Elavil), and the nontricyclic agent, fluoxetine (Prozac), bind to growth-regulatory intracellular histamine receptors, associated with anti-estrogen ...binding sites in microsomes and nuclei. The prototype anti-estrogen binding site/intracellular histamine receptor ligand, N,N-diethyl-2-4-(phenylmethyl)phenoxyethanamine HCl, inhibits normal cell proliferation in vitro but stimulates tumor growth in vivo. Because of their structural similarity to N,N-diethyl-2-4-(phenylmethyl)phenoxyethanamine HCl, we carried out studies to determine whether amitriptyline and fluoxetine stimulate tumor growth and/or development in rodents at concentrations relevant to the treatment of human depression (equivalent human dose range, approximately 100-150 mg/day for amitriptyline and approximately 20-80 mg/day for fluoxetine). All experiments were performed blinded. In studies of growth stimulation of transplantable syngeneic tumors, groups of mice were inoculated s.c. with C-3 fibrosarcoma cells or given i.v. or s.c. injections of B16f10 melanoma cells, followed 24 h later by daily i.p. injections of saline, amitriptyline, or fluoxetine. Tumor latency (fibrosarcoma), aggregate tumor weight (s.c. injected melanoma), or time to death from pulmonary metastasis (i.v. injected melanoma) was determined; drug-induced stimulation of DNA synthesis in C-3 fibrosarcoma cells in vitro was correlated with tumor growth acceleration in vivo. In a mammary carcinogenesis model, the effects of chronic saline, amitriptyline, or fluoxetine administration on the rate and frequency of development of mammary tumors in rats fed dimethylbenzanthracene (DMBA) were compared. Eight of 20 amitriptyline- or fluoxetine-treated mice developed fibrosarcoma tumors by day 5, as compared to none of 20 saline controls (P less than 0.002). Similarly, 20 of 21 DMBA-treated rats receiving the antidepressant drugs developed 33 mammary tumors by week 15 as compared to 5 tumors in 4 of 7 DMBA-treated rats receiving saline (P less than 0.001). For both models, tumor latency decreased 30-40% and, in the DMBA model, tumor frequency increased greater than 2-fold in the antidepressant-treated rats as compared to controls. Stimulation of fibrosarcoma growth in vivo correlated with a corresponding bell-shaped drug-induced increase in DNA synthesis in vitro. While the median time to death from pulmonary metastases did not differ among groups given i.v. injections of melanoma cells, a significant (P less than 0.01) stimulation of growth of s.c. injected melanoma was observed in mice receiving the antidepressants.
Schimke immuno-osseous dysplasia (SIOD) is a rare autosomal recessive spondylo-epiphyseal dysplasia. The characteristic features of SIOD include 1) short stature with hyperpigmented macules and an ...unusual facies, 2) proteinuria with progressive renal failure, 3) lymphopenia with recurrent infections, and 4) cerebral ischaemia. Although 25 patients have been reported with this disorder, the clinical course and phenotype of SIOD are not well characterized. This report summarizes the clinical findings, course and treatment of reported patients and includes 14 additional patients with SIOD. We emphasize the high incidence of cerebral ischaemia and ocular abnormalities, define the high incidence of thyroid dysfunction and blood cytopenia, and confirm the absence of effective and durable medical therapies.
Schimke immuno-osseous dysplasia is a multi-system autosomal recessive disorder with variable expression that affects the skeletal, renal, immune, vascular, and haematopoietic systems. Medical therapy is limited especially for more severely affected individuals.
Iako zdravstvena praksa vekovima unazad prepoznaje značaj psiholoških faktora za održavanje zdravlja, kao i za prevenciju i tretman bolesti, tek sedamdesetih godina prošlog veka je formirana ...zdravstvena psihologija kao zasebna naučna oblast (APA, 1976). Kao relativno mlada naučna disciplina zdravstvena psihologija se suočava sa brojnim problemima. U ovom trenutku postoji veliki broj teorija zdravstvenog ponašanja, ali konstrukti na koje se te teorije oslanjaju nisu dovoljno dobro definisani (Conner & Norman, 2005). Osim toga, metod samoizveštavanja koji se često koristi u psihologiji, u slučaju zdravstvenog ponašanja pokazuje izvesne manjkavosti, prvenstveno zbog postojanja sistematskih pristrasnosti (Hatziandreu et al., 1989). Zbog toga, stiče se utisak da zdravstvena psihologija još čeka na svoju punu afirmaciju među zdravstvenim naučnim disciplinama. U prilog takvom zaključku govori i činjenica da velika nacionalna istraživanja zdravlja uglavnom ne uključuju psihološke činioce.Pojedini savremeni metodološki pristupi ipak nude obećavajuća rešenja. Jedno od takvih je i metod uzorkovanja iskustava (Hektner, Csikszentmihalyi, & Schmidt, 2007). Osnovna ideja metoda je da se više puta dnevno, u nasumično odabranim trenucima, od ispitanika traži da odgovore na pitanja o iskustvima koja su upravo doživeli.Ovakav pristup omogućuje statističko zaključivanje o svakodnevnom životu ispitanika, a pri tome se oslanja na podatke koji su prikupljeni neposredno nakon iskustva koje je od interesa za istraživanje.Osnovni cilj ovog istraživanja je bio da se metodom uzorkovanja iskustava ispita priroda afekta koji se javlja povodom određenih oblika zdravstvenog ponašanja, te da se ustanovi da li je na osnovu tog afekta moguće predvideti buduće zdravstveno ponašanje. Uzorak ispitanika činilo je 98 mladih osoba, regrutovanih iz populacije studenata. Oni su tokom sedam dana, tri puta dnevno u nasumično odabranim trenucima, preko svojih mobilnih telefona dobijali poruku sa molbom da popune upitnik. Upitnik se odnosio na dvosatni vremenski period koji je prethodio stizanju poruke. Od ispitanika se tražilo da izveste o svom zdravstvenom ponašanju. Praćena su zdravstveno unapređujuća (fizičko vežbanje, konzumacija vode, voća, povrća i dodataka ishrani) i zdravstveno ugrožavajuća ponašanja (konzumacija cigareta, alkohola, slatkiša, brze hrane i napitaka sa kofeinom). Za svako od tih ponašanja je pitano da li je izvedeno tokom prethodnih dva sata. Ako jeste, tražena je procena intenziteta izvođenja. Ako ponašanje nije bilo izvedeno, ispitano je postojanje iskušenja (u slučaju ugrožavajućeg), i procena toga da li je ponašanje trebalo da bude izvedeno (u slučaju unapređujućeg). Nakon toga, ispitan je stepen prijatnosti afekta u vezi sa svakim od ovih pojedinačnih ishoda. Na kraju je procenjen stepen odmornosti, i prijatnosti dešavanja tokom referentnog vremenskog perioda. Osim toga, ispitano je kako na prirodu odnosa između afekta i zdravstvenog ponašanja utiču relativno trajne odlike osobe i karakteristike situacije. Za merenje bazičnih crta ličnosti korišćen je HEXACO inventar (Ashton & Lee, 2007), za opšte samopoimanje SDQ (Marsh & O’Neill, 1984), za sklonost ka preventivnom ili ka promotivnom regulatornom ponašanju upotrebljen je GRFM (Lockwood, Jordan, & Kunda, 2002), dok je za uobičajeno zdravstveno ponašanje upotrebljen upitnik sastavljen za potrebe ovog istraživanja.Jedna od ključnih hipoteza ovog istraživanja je bila da će prijatnost afekta povodom aktuelnog izvođenja zdravstveno unapređujućeg ponašanja biti prediktor intenziteta narednog unapređujućeg ponašanja. Dobijeni rezultati nisu u skladu sa ovom hipotezom.
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