Evaluation and selection of candidates for renal transplantation at the Clinical Hospital Center in Rijeka

On December 31, 2001, 2486 patients with terminal renal failure received dialysis treatment in Croatia. Only one third of the patients are registered on the national waiting list for cadaveric kidney transplant. In most of the others, transplantation is impossible because of comorbidity. This is mainly due to the steadily growing age of the dialytic population and therefore a higher incidence of cardiovascular disease and diabetes. Still, evaluation of the potential recipients of cadaveric kidney transplant, registered on the waiting list, often reveals contraindications for transplantation. The aim of this study was to determine the incidence and type of contraindications in transplant candidates, found during immediate preoperative evaluation. Analysis of these data should help in determining how contraindications can be early detected and prevented. Before registering onto the national waiting list transplant candidates need to be thoroughly investigated including detailed history, physical examination, routine diagnostic procedures and additional examinations, if needed, to exclude or evaluate the possibly existing contraindications for transplantation. During the period from January 1997 until June 2002, 145 potential recipients from the national waiting list were referred to the Rijeka University Hospital Center and evaluated for kidney transplantation. Eighty-eight patients underwent transplantation. Preoperative evaluation revealed contraindications for transplantation in 52 (35.9%) candidates. Twenty-two (15.2%) patients had a positive cross-match with donor lymphocytes, 6 (4.1%) patients refused transplantation, and in 24 (16.6%) patients serious comorbidity was the reason for not being accepted for transplantation and for their withdrawal from the national waiting list. Comorbidity was mainly due to cardiovascular disease (12 patients--8.3%) and infection (8 patients--5.5%). These data show a high incidence of contraindications found during the immediate preoperative evaluation of potential kidney recipients. It was the case in more than one third of patients. During the evaluation of potential candidates for kidney transplantation special attention should be addressed to the presence of cardiovascular morbidity and infection. Peripheral vascular occlusive disease, cardiac status and/or cerebrovascular disease should be evaluated. Measures used to treat or reduce the development of complications include an optimal control of blood pressure, serum phosphate, hyperparathyroidism, dyslipidemia, and renal anemia. The sites of infection must be treated and eradicated, because immunosuppressive treatment is a threat to the transplant recipient's life. The second most common cause of refusal of potential candidates was a positive cross-match with donor lymphocytes. Sensitization to human leukocyte antigens can be prevented by the avoiding of blood transfusions and use of erythopoietin in treating renal anemia. To minimize the morbidity and mortality, the potential kidney recipients should undergo rigorous selection and thorough evaluation before including them into the waiting list for kidney transplantation. Afterwards, regular examinations are obligatory to reveal contraindications, proceed to medical interventions and treat concomitant diseases in time, which can influence the patient's survival. In case that contraindications for transplantation arise, the patient must be temporarily or definitely removed from the waiting list.     

Novel OCTN2 mutations: No genotype–phenotype correlations: Early carnitine therapy prevents cardiomyopathy

Primary systemic carnitine deficiency or carnitine uptake defect (OMIM 212140) is a potentially lethal, autosomal recessive disorder characterized by progressive infantile‐onset cardiomyopathy, weakness, and recurrent hypoglycemic hypoketotic encephalopathy, which is highly responsive to L ‐carnitine therapy. Molecular analysis of the SLC22A5 (OCTN2) gene, encoding the high‐affinity carnitine transporter, was done in 11 affected individuals by direct nucleotide sequencing of polymerase chain reaction products from all 10 exons. Carnitine uptake (at Km of 5 μM) in cultured skin fibroblasts ranged from 1% to 20% of normal controls. Eleven mutations (delF23, N32S, and one 11‐bp duplication in exon 1; R169W in exon 3; a donor splice mutation [IVS3+1 G > A] in intron 3; frameshift mutations in exons 5 and 6; Y401X in exon 7; T440M, T468R and S470F in exon 8) are described. There was no correlation between residual uptake and severity of clinical presentation, suggesting that the wide phenotypic variability is likely related to exogenous stressors exacerbating carnitine deficiency. Most importantly, strict compliance with carnitine from birth appears to prevent the phenotype. © 2002 Wiley‐Liss, Inc.     

Gaucher disease: diagnosis and treatment

Gaucher's disease is the most common lysosomal storage disorder. It was identified in 1882 by Phillipe Gaucher, a French dermatologist. However, it was not until 1965 that Gaucher disease was found to be due to a deficiency in the enzyme glucocerebrosidase (EC 3.2.1.45) which breaks down glucocerebroside, a cell membrane component. The deficiency in this enzyme leads to an accumulation of glucocerebroside within the lysosomes of macrophages throughout the body. Gaucher's disease is classified into three types: type 1 (non-neuronopathic), type 2 (acute neuronopathic), and type 3 (subacute neuronopathic). Of the three, type 1 is the most common, affecting one in 40,000-200,000 people and having a high prevalence among Ashkenazi Jews, affecting one in 450-1500. The signs and symptoms of type 1 disease demonstrate marked heterogeneity, from asymptomatic or mildly symptomatic, to severe disability with disfigurement and even death. Hepatosplenomegaly and thrombocytopenia are well documented. Less well-recognized are often insidious skeletal complications which affect the majority of type 1 patients and which are its most debilitating feature. In addition to clinical suspicion, some morphologic, hematologic and biochemical indicators can help establish the diagnosis. However, definitive diagnosis is only made by determining the catalytic activity of the lysosomal enzyme glucocerebrosidase. Confirmation of heterozygosity requires the use of molecular biotechnology methods. About 150 mutations of the glucocerebrosidase gene have been identified in patients with Gaucher's disease, some of which are predictive of phenotype. The history of treatment of Gaucher disease started with splenectomy and continued with bone marrow transplantation, before the recent introduction of safe and effective enzyme replacement therapy. In Croatia, nine patients with type 1 Gaucher's disease have been identified so far. Seven patients are on enzyme replacement therapy, and past results demonstrated significant improvement in all clinical symptoms, without development of any side effects. However, new treatments, such as substrate balance therapy and gene therapy, may become available within the next few years. The place, if any, that such therapies will have in the treatment of patients with Gaucher's disease will be dependent on the results of clinical studies currently in progress.     

The slow and infraslow oscillations of cortical neural network

ObjectiveIn this study we investigated the properties of infraslow oscillations (ISOs) ?0.05 Hz and delta frequency band in the patients during the epileptic discharges and in healthy persons who performed a variety of mental and physical tasks.MethodsThe EEG signals were recorded on the subjects who were divided into three groups. In the first group were patients with global epileptic seizures, while in the second group were patients with focal epileptic seizures. In the third group were healthy volunteers who performed different mental and physical tasks.ResultsBy analyzing EEG data of epileptic patients, we showed that frequency peak exists at 1.5 Hz which is typical for general and focal epileptic seizures. In the type of general epileptic discharges the role of the slow rhythms at 0.05 Hz, was particularly pronounced and their origin was in fluctuations of cortical neural network. The properties of parameter spectral coherency of ISOs in healthy persons point to their important role in brain functioning.ConclusionsOur results suggested that the role of ISOs could be extended, because they were detected in healthy human subjects during carrying out different tasks. Investigating the properties of parameter spectral coherency, we showed that in this case correlation between different regions of the brain was significantly modulated with ISOs.     

Theta oscillatory dynamics of inhibitory control,error processing,and post-error adjustments: Neural underpinnings and alcohol-induced dysregulation in social drinkers

Background

Alcohol intoxication impairs inhibitory control, resulting in disinhibited, impulsive behavior. The anterior cingulate cortex (ACC) plays an essential role in a range of executive functions and is sensitive to the effects of alcohol, which contributes to the top-down cognitive dysregulation. This study used a multimodal approach to examine the acute effects of alcohol on the neural underpinnings of inhibitory control, inhibition failures, and neurobehavioral optimization as reflected in trial-to-trial dynamics of post-error adjustments.

Methods

Adult social drinkers served as their own controls by participating in the Go/NoGo task during acute alcohol and placebo conditions in a multi-session, counterbalanced design. Distributed source modeling of the magnetoencephalographic signal was combined with structural magnetic resonance imaging to characterize the spatio-temporal dynamics of inhibitory control in the time-frequency domain.

Results

Successful response inhibition (NoGo) elicited right-lateralized event-related theta power (4 to 7 Hz). Errors elicited a short-latency increase in theta power in the dorsal (dACC), followed by activity in the rostral (rACC), which may underlie an affective “oh, no!” orienting response to errors. Error-related theta in the dACC was associated with subsequent activity of the motor areas on the first post-error trial, suggesting the occurrence of post-error output adjustments. Importantly, a gradual increase of the dACC theta across post-error trials closely tracked improvements in accuracy under placebo, which may reflect cognitive control engagement to optimize response accuracy. In contrast, alcohol increased NoGo commission errors, dysregulated theta during correct NoGo withholding, and abolished the post-error theta enhancement of cognitive control.

Conclusions

Confirming the sensitivity of frontal theta to inhibitory control and error monitoring, the results support functional and temporal dissociation along the dorso-rostral axis of the ACC and the deleterious effects of alcohol on the frontal circuitry subserving top-down regulation. Over time, alcohol-induced disinhibition may give rise to compulsive drinking and contribute to alcohol misuse.     

Antitumor activity of novel <Emphasis Type="Italic">N</Emphasis>-sulfonylpyrimidine derivatives on the growth of anaplastic mammary carcinoma in vivo

Purpose: The purpose of this study was to investigate in vivo antitumor activity of newly synthesized N-sulfonylpyrimidine derivatives 1-(p-toluenesulfonyl)cytosine (4H), 1-(p-toluenesulfonyl)cytosine hydrochloride (4H×HCl) and zinc(II) complex of 1-(p-toluenesulfonyl)cytosine (4K). Materials and methods: In order to do that we have used mouse anaplastic mammary carcinoma (AMCa). Tumor cells (10⁶) in a volume of 0.02 ml were transplanted into the thigh of the right hind leg of CBA mice. All compounds were dissolved in distilled water immediately before injecting to animals. Results: Antitumor effect of these compounds depends on drug doses and time interval between tumor transplantation and drug application. Further the efficacy of these compounds depends on number of drug injections, i. e. whether drug was given in single or in multiple doses. Multiple doses of 400 mg/kg of 1-(p-toluenesulfonyl)cytosine (4H) showed good antitumor effect when applied on day 1, 3, 5, 7 and 9 after tumor transplantation. Still good but slightly lower antitumor effect was also achieved when that compound was given in a single dose (1,200 mg/kg) on day 1 after tumor transplantation. The longest period of tumor growth time was obtained after application of 1-(p-toluenesulfonyl)cytosine hydrochloride (4H×HCl) given as a single dose (300 mg/kg) on day 1 or on day 6 after tumor implantation. However, antitumor effect of zinc(II) complex of 1-(p-toluenesulfonyl)cytosine (4K) was very strong when 300 mg/kg was given on day 1 or day 6, while this effect was slightly lower when drug (200 mg/kg/inj) was given on day 1, 3, 5, 7 and 9 or on day 6, 8, 10, 12 and 14. Conclusion: In this work it has been found that N-1-sulfonylcytosine derivatives have strong antitumor activity against mouse mammary carcinoma which is a good reason for further research of these compounds both in experimental and preclinical studies.     

The effect of hydroxychloroquine on platelet activation in model experiments

Journal of Thrombosis and Thrombolysis - Hydroxychloroquine (HCQ) is an antimalarial agent with pleiotropic effects and now represents a cornerstone in the management of patients with autoimmune...     

Detection of DNA mutations based on analysis of multiple wavelength excitation/emission fluorescence kinetics curves in real-time PCR

The key method for therapies of various cancer types could be the molecular-targeted therapy, based on individual gene profile for each patient. One of the main procedures used for genetic testing is the real-time polymerase chain reaction (real-time PCR).