DIAPH2 alterations increase cellular motility and may contribute to the metastatic potential of laryngeal squamous cell carcinoma.

Low 5-year survival rate in laryngeal squamous cell carcinoma (LSCC) is to large extent attributable to high rate of recurrences and metastases. Despite the importance of the latter process, its complex genetic background remains not fully understood. Recently, we identified two metastasis-related candidate genes, DIAPH2 and DIAPH3 to be frequently targeted by hemizygous/homozygous deletions, respectively, in LSCC cell lines. They physiologically regulate such processes as cell movement and adhesion, hence we found it as a rationale, to study if tumor LSCC specimens harbor mutations of these genes and whether the mutations are associated with metastasizing tumors. As a proof of concept, we sequenced both genes in five LSCC cell lines derived from lymph node metastases assuming there the highest probability of finding alterations. Indeed, we identified one hemizygous deletion (c.3116_3240del125) in DIAPH2 targeting the FH2 domain. Moreover, we analyzed 95 LSCC tumors (53 N0 and 42 N+) using the Illumina platform and identified three heterozygous single nucleotide variants in DIAPH2 targeting conserved domains exclusively in N+ tumors. By combining these results with cBioPortal data we showed significant enrichment of DIAPH2 mutations (P = 0.036) in N+ tumors. To demonstrate the consequences of DIAPH2 inactivation, CRISPR/Cas9 editing was used to obtain a heterozygous DIAPH2+/- mutant HEK-293T cell line. Importantly, the edited line shows a shift from 'proliferation' to 'migration' phenotype typically observed in metastasizing cells. In conclusion, we report that DIAPH2 alterations are present primarily in metastasizing specimens of LSCC and suggest that they may contribute to the metastatic potential of the tumor.

Recurrent CDK1 overexpression in laryngeal squamous cell carcinoma.

In this study, we analyzed the expression profile of four genes (CCNA2, CCNB1, CCNB2, and CDK1) in laryngeal squamous cell carcinoma (LSCC) cell lines and tumor samples. With the application of microarray platform, we have shown the overexpression of these genes in all analyzed LSCC samples in comparison to non-cancer controls from head and neck region. We have selected CDK1 for further analysis, due to its leading role in cell cycle regulation. It is a member of the Ser/Thr protein kinase family of proven oncogenic properties. The results obtained for CDK1 were further confirmed with the application of reverse transcription quantitative polymerase chain reaction (RT-qPCR) technique, Western blot, and immunohistochemistry (IHC). The observed upregulation of CDK1 in laryngeal squamous cell carcinoma has encouraged us to analyze for genetic mechanisms that can be responsible this phenomenon. Therefore, with the application of array-CGH, sequencing analysis and two methods for epigenetic regulation analysis (DNA methylation and miRNA expression), we tried to identify such potential mechanisms. Our attempts to identify the molecular mechanisms responsible for observed changes failed as we did not observe significant alterations neither in the DNA sequence nor in the gene copy number that could underline CDK1 upregulation. Similarly, the pyrosequencing and miRNA expression analyses did not reveal any differences in methylation level and miRNA expression, respectively; thus, these mechanisms probably do not contribute to elevation of CDK1 expression in LSCC. However, our results suggest that alteration of CDK1 expression on both mRNA and protein level probably appears on the very early step of carcinogenesis.

The Butterfly Effect: Multifaceted Consequences of Sensitizer Concentration Change in Phase Transition-based Luminescent Thermometer of LiYO2:Er3+,Yb3.

In response to the ongoing quest for new, highly sensitive upconverting luminescent thermometers, this article introduces, for the first time, upconverting luminescent thermometers based on thermally induced structured phase transitions. As demonstrated, the transition from the low-temperature monoclinic to the high-temperature tetragonal structures of LiYO2:Yb3+,Er3+ induces multifaceted modification in the spectroscopic properties of the examined material, influencing the spectral positions of luminescence bands, energy gap values between thermally coupled energy levels, and the red-to-green emission intensities ratio. Moreover, as illustrated, both the color of the emitted light and the phase transition temperature (from 265 K, for LiYO2:Er3+, 1%Yb3+, to 180 K, for 10%Yb3+), and consequently, the thermometric parameters of the luminescent thermometer can be modulated by the concentration of Yb3+ sensitizer ions. Establishing a correlation between the phase transition temperature and the mismatch of ion radii between the host material and dopant ions allows for smooth adjustment of the thermometric performance of such a thermometer following specific application requirements. Three different thermometric approaches were investigated using thermally coupled levels (SR = 1.8%/K at 180 K for 1%Yb3+), green to red emission intensities ratio (SR = 1.5%/K at 305 K for 2%Yb3+), and single band ratiometric approach (SR = 2.5%/K at 240 K for 10%Yb3+). The thermally induced structural phase transition in LiYO2:Er3+,Yb3+ has enabled the development of multiple upconverting luminescent thermometers. This innovative approach opens avenues for advancing the field of luminescence thermometry, offering enhanced relative thermal sensitivity and adaptability for various applications.

Liver transplantation in children with hepatocellular carcinoma. Do Milan criteria apply to pediatric patients?

HCC constitutes 25-30% of primary malignant liver tumors in children. Conventional surgical excision is not possible in more than 50% of patients. LTx has recently become an important therapeutic option for adults and children with primary liver tumors. The aim of this study was a retrospective analysis of the clinical and pathological data of children with HCC treated with LTx in relation to Milan criteria assessed at diagnosis and then immediately before transplantation, in comparison with a group of patients treated conventionally. Between 1990 and 2007 we have treated 21 children diagnosed with HCC. Patients were divided into two groups: group I, 10 children treated conventionally and group II, 11 children treated with LTx regardless of previous therapy. The outcome of our patients treated conventionally with resection and chemotherapy is very poor--the disease-free survival rate is 30%. In contrast, despite that only 3 children having fulfilled adult Milan criteria, early clinical results of LTx are much superior. Total hepatectomy followed by LTx is the main treatment option for the majority of children with HCC. Decisions on the type of surgical treatment is made individually, but very early in the course of treatment.

Effects of prophylactic use of taurolidine-citrate lock on the number of catheter-related infections in children under 2 years of age undergoing surgery.

Central venous access poses a risk for the development of catheter-related infections (CRIs). The aim of this study was to evaluate prophylactic use of taurolidine-citrate (T-C) solution on the number of CRIs. Ninety-seven catheters, used in 86 children, were divided at random into two groups: Group T(-) (N=49) underwent standard aseptic procedures, and Group T(+) (N=48) received additional filling of the lines with T-C solution during intervals in cycles of parenteral nutrition or drug supply. Sixteen CRIs occurred in Group T(-) and one CRI occurred in Group T(+); this difference was significant (P<0.05). Use of T-C appears to be a safe and effective method for the prevention of CRIs.

Combined Liver-Kidney Transplantation in Children: Single-Center Experiences and Long-Term Results.

Combined liver-kidney transplantation (CLKT) is a rare procedure in pediatric patients in which liver and kidney from 1 donor are transplanted to a recipient during a single operation. The aim of our study was to analyze indications and results of CLKT in children. MATERIALS AND METHODS: Between 1990 and 2017 we performed 722 liver transplantations in children; we performed 920 kidney transplantations in children since 1984. Among them, 25 received CLKT. Primary diagnosis was fibro-polycystic liver and kidney disease in 17 patients, primary hyperoxaluria type 1 in 6 patients, and atypical hemolytic uremic syndrome-related renal failure in 2 children. Age of patients at CLKT was 3 to 23 years (median 16 years) and body mass was 11 to 55 kg (median 35.5kg). All patients received whole liver graft. Kidney graft was transplanted after liver reperfusion before biliary anastomosis. Cold ischemia time was 5.5 to 13.3 hours (median 9.4 hours) for liver transplants and 7.3 to 15 hours (median 10.4 hours) for kidney transplants. In 8 patients X-match was positive. We analyzed posttransplant (Tx) course and late results in our group of pediatric recipients of combined grafts. RESULTS: Tx follow-up ranged from 1.5 to 17 years (median 4.5 years). Two patients died: 1 patient with oxalosis lost renal graft and died 2.6 years after Tx due to complications of long-term dialysis, and 1 died due to massive bleeding in early postoperative period. Twelve patients were transferred under the care of adult transplantation centers. Six patients were dialyzed after CLKT due to acute tubular necrosis, and time of kidney function recovery was 10 to 27 days in these patients. In 1 patient with aHUS, renal function did not recover. In children with oxalosis, hemodialysis was performed for 1 month after Tx as a standard, with the aim to remove accumulated oxalate. Primary immunosuppression consisted of daclizumab or basiliximab, tacrolimus, mycophenolate mofetil, and steroids. Acute rejection occurred in 4 liver and 3 kidney grafts. One patient required liver retransplantation due to hepatitis C virus recurrence and 2 patients required kidney retransplantation. Two patients required dialysis. CONCLUSIONS: CLKT in children results in low rate of rejection and high rate of patient and graft survival.

Vascular complications after pediatric liver transplantation from the living donors.

Early arterial or portal vein thrombosis is a complications that can lead to graft loss and patient death or need of immediate retransplantation. The aim of the study was to assess the incidence, causes, treatment, and outcome of vascular thrombosis after living related donor liver transplantation (LRdLTx). Between 1999 and 2004 71 LRdLTx were performed in children aged from 6 months to 10 years. Vascular thrombosis was found in 12 recipients. Hepatic artery thrombosis (HAT) occurred in 4 (5.6%), portal vein thrombosis (PVT) in 8 (11.2%) cases. HAT occurred 5 to 8 days, PVT 1 to 22 days after LTx. Diagnosis of vascular thrombosis was confirmed by routine Doppler ultrasound examination. Thrombectomy was successful in one patient with HAT and in three patients with PVT. Venous conduit was performed in one patient with PVT after second thrombosis. Two children developed biliary strictures as a late complication of HAT and required additional surgical interventions. Two children with PVT developed portal hypertension with esophageal bleeding, which required surgical intervention; one another underwent endoscopic variceal ligation for grade III varices. Follow-up ranged from 7 to 60 months. One patient died as a result of HAT after retransplantation due to multiple intrahepatic abscesses 2 months after first transplant. Any risk factors of vascular thrombosis that can be controlled should be avoided after transplantation. Routine posttransplant Doppler examination should be performed at least twice a day within 7 to 14 posttransplant days. Immediate thrombectomy should be always carried out to avoid late complications and even mortality.

Effect of Immunosuppressive Treatment on Carotid Atherosclerosis in Renal Transplant Recipients.

BACKGROUND: The aim of this study was to compare the effect of immunosuppressive regimens using either mammalian target of rapamycin inhibitors (mTORi) or calcineurin inhibitors (CNI) on the risk of atherosclerosis in renal transplant patients. MATERIALS AND METHODS: The study involved a group of 24 recipients treated with mTORi (mTORi group) and a group of 20 recipients treated with immunosuppressive regimen based on CNI (CNI group). Laboratory and clinical markers of cardiovascular risk in both groups were investigated. Carotid atherosclerosis was evaluated by measurement of the intima media thickness (IMT) of the common and internal carotid artery walls and detection of carotid plaques by a high-resolution ultrasonography. The study was performed 3-24 years after transplantation. RESULTS: The mTORi group showed higher level of total cholesterol (242 vs 201 mg/dL; P < .004), low-density lipoprotein cholesterol (140 vs 116 mg/dL; P < .05), and triglycerides (226 vs 168 mg/dL; P < .01). Posttransplant diabetes developed in 34% of mTORi group compared with 25% in the CNI group. The mean of IMT (left and right) of common and internal carotid arteries was similar in both groups. Carotid plaques were detected in 46% of patients from the mTORi group and 25% from CNI group (P < .02). The presence of carotid plaques combined with an IMT of >0.9 mm were associated with male gender, mTORi treatment (P = .03), and cardiovascular events. The incidence of coronary heart disease was higher in mTORi group than in CNI group (53% vs 20%; P = .03). CONCLUSIONS: There was not beneficial effect of immunosuppressive treatment with mTORi on carotid atherosclerosis in renal transplant patients.

Nucleoside phosphate analogues of biological interest, and their synthesis via aryl nucleoside H-phosphonates as intermediates.

This review presents a brief account of the chemistry and mechanistic aspects of aryl H-phosphonates, and selected applications of this class of compounds as intermediates in the synthesis of a wide range of biologically important analogues of nucleoside phosphates, and oligonucleotides, in which the phosphate moieties are replaced by other structurally related groups. The aryl nucleoside H-phosphonates, compounds of controlled reactivity, have proven to be more versatile and superior to various mixed anhydrides as synthetic intermediates, particularly for preparation of nucleotide analogues bearing P-N or P-S bonds in various configurational arrangements at the phosphate moiety.

Behavioral effects of occupational exposure to organophosphorous pesticides in female greenhouse planting workers.

51 women employed in gardening enterprises were studied. Of these, 26 performed planting jobs in greenhouses and were occupationally exposed to several organophosphates. The comparison group consisted of 25 women not exposed to neurotoxic chemicals. The groups were similar in terms of age, education, place of habitation, and intake of stimulants and drugs. Exposure determinations were performed during the period when pesticides were intensively used in the greenhouses (March-June). Exposure measurements included air pollution, contamination of skin and clothes, and work timing. The level of total exposure in the planting worker group was low. Psychological examinations were conducted twice: before and after the spraying season, and the Neurobehavioral Core Test Battery recommended by the WHO was administered to all subjects. The results of the psychological tests did not reveal effects of exposure after a single spraying season. Analysis of the results, however, indicated differences between the exposed and control groups on both occasions. The exposed female workers were characterized by longer reaction times and reduced motor steadiness compared to the unexposed workers. In addition, increased tension, greater depression and fatigue, more frequent symptoms of CNS disturbances were observed in the exposed women compared to the controls.

Liver transplantation across ABO blood groups in children.

Late results after ABOI LTx are inferior to ABO compatible organs. We report seven patients who received LTx across ABO group for emergency indications. The blood type combinations were: A to O in three, B to O in two, and B to A in two. Episodes of acute and chronic rejection, immunosuppression, and biochemical and functional tests after transplantation as well as patient and graft survival were compared between ABOI group and patients with compatible ABO group transplanted due to FLF (group I) or in an elective setting (group II). Four children are alive. Two children died of sepsis and CNS damage or MOF, and one patient died during transplantation because of cardiac failure. All recipients of ABOI grafts received immunosuppression with cyclosporine or tacrolimus and steroids. MMF was added in two subjects, and induction with antilymphocyte globulins used in five patients. An acute rejection episode was diagnosed in two recipients between 7 and 11 days after LTx. All four living patients with ABOI grafts are doing well with follow-up time between 11 months and 5 years. In one patient PTLD occurred at 1 year after ABOI LTx but was cured by discontinuation of immunosuppression and administration of rituximab. Graft survival in the ABOI group was 57.1% versus 71% in group I and 73% in group II. Respective patients survival was 57.1% 71%, and 82.0% respectively. In conclusion, in urgent cases ABOI transplantation is justified in pediatric patients when compatible grafts are not available.

Acute coagulopathy after reperfusion of the liver graft in children correction with recombinant activated factor VII.

BACKGROUND: Several studies have proven that massive blood loss increases postoperative morbidity and mortality in liver graft recipients. Since we have successfully corrected coagulopathy preoperatively using an intravenous (IV) bolus of recombinant activated factor VII (rFVIIa) in 2 patients with fulminant liver failure, we observed that there was rapid reversal of preexisting advanced coagulopathy in another 40 patients with high risk for intraoperative bleeding by this treatment immediately before transplantation. Recently to control hemostasis we have administered rFVIIa also to patients presenting with acute coagulopathy and nonsurgical bleeding after graft reperfusion as described herein. MATERIALS AND METHODS: We have used rFVIIa in 7 children presenting with severe coagulopathy and nonsurgical bleeding after liver graft reperfusion. The dosage of rFVIIa ranged between 37 and 148 mcg/kg. An antifibrinolytic agent (aprotinin, tranexamic acid) was administered simultaneously. RESULTS: APTT before rFVIIa was 86.10 to 183 seconds, (mean, 132.1 +/- 39.88), after the bolus of rFVIIa 49.4 to 206.1 (mean, 112.7 +/- 58.53), and at the end of surgery 71.70 to 180 (mean, 110.3 +/- 40.98). INR after reperfusion was 1.82 to 3.91 (mean, 2.56 +/- 0.67), 1.03 to 1.92 (mean, 1.54 +/- 0.35) after rFVIIa, and 1.74 to 5.58 (mean, 2.64 +/- 1.35) at the end of surgery. Before rFVIIa administration intraoperative blood transfusions after graft reperfusion were 900 to 4200 mL of red blood cells (RBC) (0.82-5.4 total blood volume) and after reperfusion 0 to 1800 mL of RBC (0-2.5 TBV). No postoperative vascular complications were observed. CONCLUSIONS: A single dose of rFVIIa effectively reverses the severe coagulopathy developing after graft reperfusion, establishing effective hemostasis in liver transplant recipients without an increased risk of thrombotic complications.

Liver retransplantation in children in Poland.

An average of 15% of patients require retransplantation due to irreversible liver graft failure due to primary graft nonfunction, chronic rejection, vascular and biliary complications, or infections. The survival of patients and grafts after retransplantation is inferior to that after primary transplantation. The purpose of the present study was to examine the incidence, indications, and outcome of retransplantation in children. In our center 169 liver transplantations had been performed in 154 patients, and 14 patients (9%) required 15 retransplantations: nine in the early postoperative period, five late after primary transplantation, and one late after the second transplantation. One-year patient survival after primary transplantation was 82%, but after early retransplantation it was 55%.

Switching cyclosporine blood concentration monitoring from C0 to C2 in children late after liver transplantation.

BACKGROUND: Measurement of cyclospoprine (CsA) blood levels at 2 hours after oral administration (C(2)) has been proposed as a better measurement of trough level (C(0)) due to reduced intrapatient variability, acute rejection rate and renal toxicity. The aim of the present study was to assess whether there was any advantage to conversion from C(0) to C(2) CsA blood level monitoring in children late after liver transplantation. We reviewed the data from 44 children more than 1 year after liver transplantation. We measured the daily dose of CsA and the C(0) level before switching versus the daily dose and C(2) level at 6 months after conversion, in addition to the alanine aminotransferase (ALT) activity, creatinine blood concentration, and episodes of acute rejection. RESULTS: Conversion from C(0) to C(2) monitoring was not associated with a significant change in mean daily dose of CsA, mean concentration of creatinine, ALT activity or occurrence of rejection episodes. CONCLUSION: Switching from C(0) to C(2) monitoring did not seem to proffer any benefits for children late after liver transplantation.

Surgical treatment of progressive familial intrahepatic cholestasis: comparison of partial external biliary diversion and ileal bypass.

AIMS: Progressive familial intrahepatic cholestasis (PFIC, Byler's disease) is an autosomal recessive disorder resulting in liver fibrosis/cirrhosis and liver insufficiency. Before the 1990s, liver transplantation was the only effective therapy for these children. During the last 12 years, two alternative methods of surgical treatment have been proposed: partial external biliary diversion (PEBD) and ileal bypass procedure (IB), which allow for effective elimination of bile acids accumulated in the body. In this study, we compare the efficacy of these surgical techniques for PFIC. METHODS: During the last 20 years, we have treated 52 children with PFIC. PEBD was done in 21 patients (since 1995), and IB in 5 patients (since 1998), transplantation was performed in 9 patients (since 1990). The efficacy of non-transplantation surgical treatment was assessed by patients' clinical outcome, liver biochemistry, and survival without transplantation during a follow-up period of 12 to 48 months. RESULTS: In 15 out of 21 patients clinical symptoms improved after PEBD and liver function tests normalised (blood bile acids), 1 patient had to be converted to IB due to too high output biliary fistula, 2 patients were transplanted and 3 are considered for transplantation. Out of the 5 children after IB, 4 improved clinically and biochemically, but, after 12 months, symptoms recurred in 3 patients, one patient was converted successfully to PEBD. No significant influence on growth was observed, irrespective of the type of treatment in this group of patients. CONCLUSIONS: PEBD is more effective than IB for the permanent improvement of symptoms of PFIC. Ileal bypass procedure, although initially effective, does not ensure good long-term results in more than 50 % of patients, probably due to intestinal re-absorption of bile acids increasing over time.

Diagnosis and monitoring of cytomegalovirus infection after liver transplantation in children.

Cytomegalovirus infection (CMV) complicated the posttransplant course in 9 of 24 children after liver transplantation. We found specific antibodies (IgG and IgM) to be of very low value in diagnosis and monitoring of CMV infection after liver transplantation. Detection of CMV-DNA by PCR method in the blood or urine was very useful for diagnosis, but less for monitoring of the course of disease and its treatment. Measurements of early immediate CMV antigen (IEA), in peripheral blood leucocytes allowed for very early diagnosis of CMV infection and correlated well with the course of disease and response to treatment of the patient.

Rhythm patterns of basic brain bioelectric activity in workers chronically exposed to carbon disulfide.

The work aimed at defining the pattern and frequency of rhythm disturbances in basic brain bioelectric activity in EEG recordings, routinely regarded as normal, in workers exposed to chronic carbon disulfide (CS2) poisoning, without detected symptoms of organic lesions in the nervous system. The study covered 188 viscose spinners occupationally exposed to changing concentrations of CS2 vapours whose mean annual results of measurements ranged between 10 and 35 mg/m3, and the mean individual exposure fell within the range of 9.9-41.6 mg/m3 (mean--25.8 mg/m3). The frequency of alpha rhythm was analysed in EEG recordings with exclusive or nearly exclusive alpha rhythm in two groups studied. The presence or absence of subjective symptoms was taken as a criterion for the selection of subjects. Group I was composed of 116 subjects with subjective symptoms. Group II consisted of 72 workers with neither subjective nor objective symptoms. The age in group I ranged from 26 to 65 years (mean, 48.7 years), and the duration of employed from 5 to 39 years (mean, 23.3 years). The complaints reported were of neurasthenic and polyneuropathic type. The age in group II ranged from 28 to 63 years (mean, 49.4 years), the duration of occupational exposure accounted for 8-43 years (mean, 25.6 years). The control group included 194 persons with EEG routinely regarded as normal, matched by gender, age and work shift distribution. The subjects in Group I reported most frequently the following complaints: headache (72.4%), vertigo (48.3%), increased emotional irritability (42.2%), dysmnesia (36.2%), sleep disorders (27.6%), concentration difficulties (25.9%), limb pains (36.2%) and paraesthesia (27.6%). In the groups of subjects chronically exposed to CS2, both with subjective neurological symptoms, and without subjective or objective neurological symptoms, EEG recordings, routinely regarded as normal, did not reveal constant and symmetrical frequency of alpha rhythm waves. EEC recordings in the CS2 exposed workers with subjective neurological symptoms revealed almost constant frequency (12.9%) or slightly fluctuating frequency (41.4%) in 54.3% of subjects. In 45.7% of subjects considerable fluctuation of alpha rhythm frequency at the range of 3-4 Hz was found. Frequency disturbances applied to both sides, however, they were more pronounced in the leftside leads. Statistical analysis showed, neither in Group I nor in Group II, significant relationship between the pattern of alpha rhythm frequency fluctuations, the duration of CS2 exposure and the cumulative exposure index. Substantial and asymmetric fluctuations of alpha rhythm frequency found in the exposed group of subjects with subjective symptoms were considered as subclinical disturbances in the function of the central nervous system.

Neurological and neurophysiological examinations of workers occupationally exposed to organic solvent mixtures used in the paint and varnish production.

The aim of this work was to examine the nervous system of workers chronically exposed to mixtures of organic solvent at concentrations within or slightly exceeding the MAC values, used in the manufacture of paints and lacquers. The tests were performed on a group of 175 people, 107 men aged 22-59 (x = 41.25), and 68 women aged 20-55 (x = 38.62). The period of employment was x = 17.34 years and cumulative dose index 16.97 for males; for females, the corresponding values were x = 14.75 and x = 11.42, respectively. The control group included 175 people (107 men and 68 women) not exposed to chemicals matched according to sex, age, and work shift distribution. The neurological examinations included subjective and objective examinations of the nervous system, electroencephalographic (EEG) and visual evoked potential (VEP) evaluations. The assessment of organic solvent exposure was performed according to the method described in PN89/Z-04008/07, and the solvent mixtures were shown to contain xylenes, ethyltoluenes, trimethylbenzenes, propylbenzene, ethylbenzene, toluene, aliphatic hydrocarbons and the components of painter's naphtha. The most frequent complaints among the exposed males included headache, vertigo, concentration difficulties, sleep disorders, sleepiness during the day, increased emotional irritability, mood swings with a tendency to anxiety. The objective neurological examinations did not reveal organic lesions in the central or peripheral nervous systems. Generalised and paroxysmal changes were most common recordings in the abnormal EEG. VEP examinations revealed abnormalities, primarily in the latency of the response evoked. The results of this study suggest that exposures to concentrations within MAC values, or below 1.5 of the MAC values of organic solvents mixtures used in the manufacture of paints and lacquers produce subclinical health effect in the nervous system.

Interactions of some organic solvents: hydrocarbons and chloroalkene.

Metabolic and toxicodynamic interactions of some organic solvents in rats repeatedly treated with medium dose levels were examined. It was shown that both n-hexane and ethylbenzene significantly inhibited tetrachloroethylene metabolism during a 2-week period. n-Hexane and tetrachloroethylene enhanced metabolism of ethylbenzene whereas ethylbenzene suppressed n-hexane metabolism only at the end of the experiment. Biochemical changes, especially the drop in the level of non-protein sulfhydryl groups in tissues of rats treated with organic solvent mixtures, were significantly less pronounced than those observed after these chemicals were administered separately. These results demonstrate that metabolic interactions between hydrocarbons and chloroalkene may lead to a modification of the biological response to these compounds.

Cardiovascular risk in kidney transplant recipients receiving mammalian target of rapamycin inhibitors.

Cardiovascular diseases (CVD) are the leading cause of mortality in renal transplant recipients. Various traditional and unconventional cardiovascular risk factors are potentiated by the adverse effects of immunosuppressive drugs. The mammalian target of rapamycin (mTOR) inhibitors have shown cardioprotective effects in experimental studies, but their influence on CVD in renal transplantation is unclear. The study included 115 kidney transplant recipients treated with mTOR inhibitors with steroids. A group of 38 patients received additionally small doses of calcineurin inhibitor. The control group consisted of 58 kidney transplant recipients randomly chosen among the population of patients transplanted at the same time, who received a calcineurin inhibitor, mycophenolate mofetil or sodium plus steroids. No differences in age, gender, duration of pretransplantat dialysis, time after transplantation, body mass index or glycated hemoglobin existed between the groups. Blood pressure and number of antihypertensive agents, high-density lipoprotein cholesterol, and uric acid levels were similar. The prevalence of diabetic, ischemic, or hypertensive nephropathy as the reason for end-stage renal disease was similar (P=.08). The study group showed higher mean values of total cholesterol (249 vs 204.6 mg/dL; P<.0001) and low-density lipoprotein 136.5 vs 117.7 mg/dL; (P=.015), as well as median values of triglycerides (202 vs 142 mg/dL; P<.0001) and proteinuria (P=.0002). mean estimated glomerular filtration rate was lower in the study group (42.9 vs 51.9 mL/min; P=.0003). Posttransplant diabetes appeared in 38% of the study group compared to 20% of the controls (P=.08). The incidence of coronary artery disease was higher among patients treated with mTOR inhibitors (P=.04). CVD, defined as myocardial infarction, percutaneous coronary intervention, stroke, aortic aneurysm, pulmonary thromboembolism, sudden cardiac death appeared in 26 study group compared with four control patients (P=.24). The risk of any CVD was not significantly higher among patients receiving mTOR inhibitors hazard ratio 1.94; 95% confidence interval 0.83-4.52). In conclusion, no correlation was observed between the duration of mTOR therapy and CVD.