IL-8 and IFN-gamma in tear fluid of patients with cystic fibrosis.

Cystic fibrosis (CF) is inherited as an autosomal recessive disorder. It is caused by mutations in the protein-coding gene of chromosome 7, resulting in chronic pulmonary disease and pancreatic insufficiency. The disease affects all secretory epithelia, including the eye. The pathogenesis of ocular changes in CF is still unknown, but the involvement of immunologic processes in patients with CF has been studied in recent years. We measured interleukin-8 (IL-8) and interferon-gamma (IFN-gamma) levels in tears in a group of patients and a group of normal controls to determine if the levels of these cytokines are elevated in CF. The levels of these cytokines in tears and the clinical severity of CF and eye disease were compared. Tear samples were collected from 24 patients with CF at the department of pediatric diseases, Medical University of Bialystok, Poland. Cytokine levels were determined by ELISA. Ophthalmic examinations, including tests for keratoconjunctivitis sicca (dry eye), were used to study the ocular surface. The tear levels of IL-8 and IFN-gamma in the CF patients were significantly higher than those in controls. The clinical severity of CF correlated significantly with the IL-8 and IFN-gamma levels. We found positive correlation between the tear levels of IFN-gamma and dry eye findings in CF patients. Our results suggest that the inflammatory cytokines IL-8 and IFN-gamma may play key roles in the regulation of ocular surface inflammation and the immunologic reaction in patients with CF. The tear levels of IL-8 and IFN-gamma may be candidate markers for evaluation of the clinical status of CF and eye disease. These findings help to provide a new insight into the pathogenesis of dry eye in patients with CF and provide potential targets for therapy.     

Long-term results and tolerability of tandem peptide receptor radionuclide therapy with <Superscript>90</Superscript>Y/<Superscript>177</Superscript>Lu-DOTATATE in neuroendocrine tumors with respect to the primary location: a 10-year study

Introduction

The peptide receptor radionuclide therapy (PRRT) with ⁹⁰Y and ¹⁷⁷Lu is a form of molecular targeted therapy for inoperable or disseminated neuroendocrine tumors (NET).

Aim

The aim of the study was to evaluate clinical results and long-term side effects of tandem ⁹⁰Y /¹⁷⁷Lu-DOTATATE therapy in patients with NET. Additionally, we evaluated clinical results with reference to the primary site.

Materials and methods

59 patients with disseminated NET were included in the study prospectively. 3–5 cycles of combined 1:1 ⁹⁰Y/¹⁷⁷Lu-DOTATATE (total injected activity 11.1–16.65 GBq) with mixed amino acids for kidney protection were performed.

Results

During a median follow-up of 75.8 months, the PFS was 32.2 months, and the OS was 82 months; 25 patients died. Depending on primary tumor’s site, the PFS and the OS for pancreatic NET vs. small bowel, NET vs. large bowel, NET were 30.4 vs. 29.5 vs. 40.3 and 78.9 vs. 58.1 vs. 82.5, respectively. The observed 5-year overall survival was 63%, and a 2-year risk of progression was 39.4%. The following imaging response was observed: CR in 2%, PR in 22%, SD in 65%, and PD in 6% patients. The disease control rate was 89%. The objective response rate was 24%. The PRRT was well tolerated by all patients. One patient (2%) revealed MDS, and one patient (2%) grade 3 nephrotoxicity. No other grade 3 and 4 hematological or renal toxicity was observed.

Conclusions

These results indicated the tandem ⁹⁰Y/¹⁷⁷Lu-DOTATATE therapy for patients with disseminated/inoperable NET as highly effective and safe, considering long-term side effects. In the majority of patients, clinical improvement was observed.

     

Elevated level of metabotropic glutamate receptor 2/3 in the prefrontal cortex in major depression

Clinical, postmortem and preclinical research strongly implicates dysregulation of glutamatergic neurotransmission in major depressive disorder (MDD). Recently, metabotropic glutamate receptors (mGluRs) have been proposed as attractive targets for the discovery of novel therapeutic approaches against depression. The aim of this study was to examine mGluR2/3 protein levels in the prefrontal cortex (PFC) from depressed subjects. In addition, to test whether antidepressants influence mGluR2/3 expression we also studied levels of mGluR2/3 in fluoxetine-treated monkeys. Postmortem human prefrontal samples containing Brodmann's area 10 (BA10) were obtained from 11 depressed and 11 psychiatrically healthy controls. Male rhesus monkeys were treated chronically with fluoxetine (dose escalated to 3 mg/kg, p.o.; n = 7) or placebo (n = 6) for 39 weeks. The mGluR2/3 immunoreactivity was investigated using Western blot method. There was a robust (+ 67%) increase in the expression of the mGlu2/3 protein in the PFC of depressed subjects relative to healthy controls. The expression of mGlu2/3 was unchanged in the PFC of monkeys treated with fluoxetine. Our findings provide the first evidence that mGluR2/3 is elevated in the PFC in MDD. This observation is consistent with reports showing that mGluR2/3 antagonists exhibit antidepressant-like activity in animal models and demonstrates that these receptors are promising targets for the discovery of novel antidepressants.     

The mTOR signaling pathway in the prefrontal cortex is compromised in major depressive disorder

Recent studies demonstrate that rapid antidepressant response to ketamine is mediated by activation of the mammalian target of rapamycin (mTOR) signaling pathway, leading to increased synaptic proteins in the prefrontal cortex (PFC) of rats. Our postmortem studies indicate robust deficits in prominent postsynaptic proteins including N-methyl-d-aspartate (NMDA) receptor subunits (NR2A, NR2B), metabotropic glutamate receptor subtype 5 (mGluR5) and postsynaptic density protein 95 kDa (PSD-95) in the PFC in major depressive disorder (MDD). We hypothesize that deficits in the mTOR-dependent translation initiation pathway contribute to the molecular pathology seen in the PFC of MDD subjects, and that a rapid reversal of these abnormalities may underlie antidepressant activity. The majority of known translational regulation occurs at the level of initiation. mTOR regulates translation initiation via its downstream components: p70-kDa ribosomal protein S6 kinase (p70S6K), and eukaryotic initiation factors 4E and 4B (eIF4E and eIF4B). In this study, we examined the expression of mTOR and its core downstream signaling targets: p70S6K, eIF4E, and eIF4B in the PFC of 12 depressed subjects and 12 psychiatrically healthy controls using Western blot. Levels of eIF4E phosphorylated at serine 209 (p-eIF4E-Ser209) and eIF4B phosphorylated at serine 504 (p-eIF4B-Ser504) were also examined. Adjacent cortical tissue samples from both cohorts of subjects were used in our previous postmortem analyses. There was a significant reduction in mTOR, p70S6K, eIF4B and p-eIF4B protein expression in MDD subjects relative to controls. No group differences were observed in eIF4E, p-eIF4E or actin levels. Our findings show deficits in mTOR-dependent translation initiation in MDD particularly via the p70S6K/eIF4B pathway, and indicate a potential association between marked deficits in synaptic proteins and dysregulation of mTOR signaling in MDD.     

Effects of WIN 55,212-2 mesylate (a synthetic cannabinoid) on the protective action of clonazepam, ethosuximide, phenobarbital and valproate against pentylenetetrazole-induced clonic seizures in mice

The aim of this study was to determine the effect of WIN 55,212-2 mesylate (WIN — a non-selective cannabinoid CB1 and CB2 receptor agonist) on the protective action of four classical antiepileptic drugs (AEDs: clonazepam [CZP], ethosuximide [ETS], phenobarbital [PB], and valproate [VPA]) in the mouse pentylenetetrazole (PTZ)-induced clonic seizure model.WIN (15 mg/kg, i.p.) significantly enhanced the anticonvulsant action of ETS, PB and VPA, but not that of CZP against PTZ-induced clonic seizures. The ED₅₀ values of ETS, PB and VPA were reduced from 148.0, 13.9 and 137.1 mg/kg to 104.0, 8.3 and 85.6 mg/kg, respectively (P < 0.05). WIN (5 and 10 mg/kg, i.p.) had no impact on the anticonvulsant action of all studied AEDs against PTZ-induced clonic seizures. WIN (15 mg/kg, i.p.) significantly elevated total brain concentrations of ETS and VPA, but not those of CZP and PB in mice. Moreover, WIN combined with CZP, ETS, PB and VPA significantly impaired motor performance, long-term memory and muscular strength in mice subjected to the chimney, passive avoidance and grip-strength tests, respectively.Pharmacodynamic enhancement of the anticonvulsant action of PB by WIN against PTZ-induced clonic seizures is favorable from a preclinical viewpoint. Advantageous effects of WIN in combination with ETS and VPA against PTZ-induced seizures were pharmacokinetic in nature. However, WIN combined with CZP, ETS, PB and VPA impaired motor coordination and long-term memory as well as reduced skeletal muscular strength in the experimental animals.     

Knowledge and attitudes towards epilepsy among inhabitants of Silesia. A questionnaire study

Background and purposeEpilepsy is one of the most frequent neurological diseases. Social acceptance is very important for people with epilepsy and their relatives. The aim of the study was to assess public knowledge and attitudes towards epilepsy in Silesia.Material and methodsWe examined 419 people, inhabitants of Silesia, at the mean age of 34 ± 15 years. The study was performed using a questionnaire containing 15 questions evaluating knowledge about epilepsy and attitudes towards people with epilepsy.Results43.2% of the respondents knew an epileptic person themselves. 44.7% had witnessed an epileptic seizure; 68.8% would help a person during an epileptic seizure, but most of them (73.4%) would do it incorrectly (by putting an object into the mouth to prevent biting the tongue). 94.5% of respondents had nothing against friendship with an epileptic person, but 12.1% suggested that children with epilepsy should attend special schools. 85.9% of all those examined said that people with epilepsy should inform others about their disease, 81.9% would mention the existence of an epileptic person in their family. 40.5% of respondents believe that people with epilepsy can do the same jobs as healthy people, 75.3% would employ an epileptic person themselves.ConclusionsThe knowledge about epilepsy and first aid during epileptic seizure is still insufficient among inhabitants of Silesia. Most of the responders, especially better educated ones, declare acceptance and tolerance of people with epilepsy. More effort should be made to improve public knowledge of epilepsy by preparing wide-spread educational programmes.     

Pretreatment serum levels of bFGF and VEGF and its clinical significance in endometrial carcinoma

ObjectiveIn this study, we examined the frequency of serum elevation as well as the prognostic significance of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in endometrial cancer (EC) type I and a biologically aggressive variant of EC type II.Materials and methodsPretreatment serum levels of bFGF and VEGF were evaluated by commercially available enzyme-linked immunosorbent assay (ELISA) for cancer patient samples with type I EC (n = 70) and type II EC (n = 64) and compared to a cohort of normal individuals (n = 64). Values were correlated with clinicopathological characteristics and outcome.ResultsMedian pretreatment VEGF values were 470.4 pg/ml (range, 164.3–598.4 pg/ml) for type I EC, 608.8 pg/ml (range, 354.2–783.6 pg/ml) for type II of EC patients and 215.6 pg/ml (range, 128.3–332.9 pg/ml) for normal healthy subjects (p < 0.001). Elevated serum VEGF concentration correlated significantly with advanced FIGO stage in type II EC (p = 0.011). Median values of bFGF were 10.7 pg/ml (range, 0.5–22.5 pg/ml) for type I EC, 21.2 (range, 0.5–62.4 pg/ml) for type II EC and 1.1 (range, 0–7.2 pg/ml) in controls (p < 0.0001). The pretreatment bFGF levels correlated with advancing tumor stages in types I and II EC (p  < 0.05). Multivariate analysis with Cox proportional hazard regression models revealed that high bFGF serum level correlated with shorter overall survival (OS) in type I EC (HR, 0.39, p < 0.001) and in type II EC (HR, 0.47, p = 0.01) and disease-free survival (DFS) (HR, 0.53, p = 0.03 and HR, 0.51, p = 0.02, respectively).ConclusionHigh preoperative bFGF levels predict a poor prognosis in patients with EC, and the prognostic value is independent of established prognostic parameters. These data suggest that bFGF might potentially serve as a marker in prognosis and offer a possibility to individualize treatment regimen.     

Contact allergy to metals in adolescents. Nickel release from metal accessories 7 years after the implementation of the EU Nickel Directive in Poland

Background. Contact allergy among adolescents is an important issue. Objectives. To assess the prevalence of contact allergy to metals in adolescents aged 15 years and nickel release from metal accessories that are in direct contact with the skin. Methods. Three hundred and nine females and 219 males, all 15 years old, from randomly selected secondary schools were examined and patch tested with nickel sulfate, cobalt chloride, palladium chloride, and potassium dichromate. Three hundred and ninety-nine metal accessories were tested with the dimethylglyoxime (DMG) test. Results.'Metal dermatitis' was reported by 19.4% of females and 0.5% of males. Positive patch test reactions were found in 8.5% of the adolescents (12.9% in females; 2.3% in males), namely to: nickel (12.3% of females; 1.4% of males); palladium (5.2% of females; 0.5% of males); cobalt (3.2% of females; 1.4% of males); and chromium (1.3% of females; 0.9% of males). Allergic contact dermatitis caused by metals was diagnosed in 9.7% of females and in 0.5% of males. Of the metal items, 26.1% gave positive DMG test results: 10.0% of earrings, 11.4% of snaps, and 56.2% of belt buckles. Conclusions. Despite the implementation of the Nickel Directive in Poland, nickel still remains an important causal factor for allergic contact dermatitis. Numerous metal accessories do not comply with the Directive.     

Prognostic potential of topoisomerase IIα and HER2 in a retrospective analysis of early advanced breast cancer patients treated with adjuvant anthracycline chemotherapy

Background

After surgery and anthracycline adjuvant treatment, about 60% of early advanced breast cancer patients develop recurrence. These differences in treatment outcome indicate the need to identify markers for risk of recurrence. The aim of this study was the retrospective analysis of relationship between tumour features (topoisomerase II?? (TOPOII??), human epidermal growth factor receptor 2 (HER2), hormone receptors, cytokeratin (CK)5/6 expression and proliferation rate) and disease-free survival (DFS) of breast cancer patients treated with anthracyclines in adjuvant setting.

Material and methods

The study was performed in the group of 172 patients (mean age: 52.8 years, T1-T2, N1-N2, M0). HER2, TOPOII??, estrogen receptor (ER) and progesterone receptor (PgR) expression and proliferation rate were studied immunohistochemically. HER2 overexpression was confirmed by fluorescence in situ hybridisation (FISH). These data were correlated with 5-year DFS.

Results

In univariate analysis, lower TOPOII?? expression (median value ≤ 11.9%) and tumour grade G1 + G2 were favourable prognostic factors. All tumours were classified into four subtypes: (1) lower TOPOII?? expression and G1 + G2, (2) lower TOPOII?? expression and G3, (3) higher TOPOII?? expression and G3, and (4) higher TOPOII?? expression and G1 + G2. In Cox multivariate regression analysis, tumour subtype distinguished by TOPOII?? expression and grade was independent prognostic factor for DFS. All patients (n = 52) with TOPOII?? lower expression and G1 + G2 tumours, survived 5 years without any evidence of disease.

Conclusion

The results suggest that lower TOPOII?? expression and lower tumour grade are favourable prognostic factors for early advanced breast cancer patients after adjuvant anthracycline chemotherapy.     

Effect of 6-hydroxydopamine treatment on kynurenine aminotransferase-I (KAT-I) immunoreactivity of neurons and glial cells in the rat substantia nigra

Parkinson’s disease (PD), a progressive neurodegenerative disorder, is characterized by a preferential loss of dopaminergic neurons in the substantia nigra pars compacta (SNPC). Neurons in the SNPC are known to express tyrosine hydroxylase (TH); therefore, in a commonly used PD model, 6-hydroxydopamine (6-OHDA), a selective catecholamine neurotoxin, induces neuronal death in SNPC. We have shown with immunohistochemical techniques that kynurenine aminotransferase-I (KAT-I), the enzyme taking part in the formation of kynurenic acid (KYNA)—the only known endogenous selective NMDA receptor antagonist and a potent neuroprotective agent—is also expressed in the rat SNPC. We found that KAT-I and TH co-exist in the very same neurons of SNPC and that 6-OHDA injected into the lateral ventricle produced loss of the majority of nigral neurons. Densitometric analysis proved that, in consequence of 6-OHDA treatment, not only TH but also KAT-I immunoreactivity diminished considerably in the remaining SNPC neurons. Astrocytes in the substantia nigra were found to express KAT-I under normal conditions; the amount of this enzyme increased after administration of 6-OHDA, whereas microglial cells became KAT-I immunoreactive only after 6-OHDA treatment. Since intrinsic KYNA in SNPC neurons is perceptibly insufficient to protect them from the deleterious effect of 6-OHDA, it is hypothesized that biochemical approaches which increase KYNA content of the central nervous system might prevent the deleterious effect of 6-OHDA and, supposedly, also the neuronal degradation characterizing PD.