Treatment of localized prostate cancer using WST-09 and WST-11 mediated vascular targeted photodynamic therapy-A review.

BACKGROUND: Photodynamic therapy (PDT) is well known for its direct cytotoxicity of the free radical-producing photochemical reaction, indirect mechanisms of action including modulation of intrinsic anti-tumour immune activity, and occlusion of pathologically altered tumour vessels leading to tumour ischaemia. The aim of this work is to critically review the evidence base for the use of vascular targeted PDT (VTP) to treat low-risk prostate cancer, and to discuss perspectives and challenges yet to be overcome. A brief general overview of focal prostate cancer therapy was provided, followed by a discussion of both basic and clinical research pertaining to prostate cancer VTP, with a focus on the palladium-based WST-09 and WST-11 photosensitisers. MATERIALS AND METHOD: Literature on VTP for prostate cancer with the fallowing medical subject headings search terms: prostate cancer, photodynamic therapy, vascular targeted photodynamic therapy, bacteriopheophorbide were reviewed. The articles were selected by their relevance to the topic. RESULTS: The clinical and basic research data available to date show much promise for WST-09, and WST-11 based VTP eventually joining the standard urologist's armamentarium against prostate cancer. With good reported tolerability and efficacy VTP can be proposed as an intermediate treatment for local low risk disease, halfway between watchful waiting and radical therapy.

Vascular-targeted photodynamic therapy in the treatment of neovascular age-related macular degeneration: Clinical perspectives.

Vascular targeted photodynamic therapy (VTP), with use of verteporfin as a photosensitizer is one of the few therapies, which has been shown to effectively slow the progression of the "wet" form of age-related macular degeneration (AMD), and even to stabilize visual acuity over many years. Although, due to considerable advance of AMD treatment, it is currently not recommended in monotherapy of AMD, however, its combination with steroids and anti-angiogenic biologic drugs may reveal high therapeutic potential in the treatment of neovascular AMD. The future of VTP as a method of AMD treatment is development of new selective and targeted photosensitizer and combination of this method with other therapeutic strategies targeting cellular structures or pathways involved in AMD progression.

Phenotypic spectrum of epidermolysis bullosa associated with α6ß4 integrin mutations.

BACKGROUND: Integrin α6ß4 is a transmembrane receptor and a key component of the hemidesmosome anchoring complex. It is involved in cell-matrix adhesion and signalling in various tissues. Mutations in the ITGA6 and ITGB4 genes coding for α6ß4 integrin compromise dermal-epidermal adhesion and are associated with skin blistering and pyloric atresia (PA), a disorder known as epidermolysis bullosa with PA (EB-PA). OBJECTIVES: To elucidate the molecular pathology of skin fragility in eight cases, disclose the underlying ITGA6 and ITGB4 mutations and study genotype-phenotype correlations. METHODS: DNA was isolated from ethylenediaminetetraacetic acid-blood samples, and the coding exons and exon-intron boundaries of ITGA6 and ITGB4 were amplified by polymerase chain reaction (PCR), and directly sequenced. Skin samples were submitted to immunofluorescence mapping with antibodies to adhesion proteins of the dermal-epidermal junction. Primary keratinocytes were isolated, and used for RNA and protein extraction, reverse transcription PCR and immunoblotting. Ultrastructural analysis of the skin was performed in one patient. RESULTS: We disclose 10 novel mutations, one in ITGA6 and nine in ITGB4. Skin cleavage was either intraepidermal or junctional. Lethal outcome and PA correlated with loss-of-function mutations in two cases. Solely mild skin involvement was associated with deletion of the C-terminus of ß4 integrin. Combinations of missense, nonsense or frameshift mutations caused severe urinary tract involvement in addition to skin fragility in five cases. CONCLUSIONS: The present study reveals novel ITGA6 and ITGB4 gene mutations and supports previous reports showing that the phenotype may lack PA and be limited to skin and nail involvement. In four out of six cases of EB-PA, life expectancy was not impaired. A high frequency of urinary tract involvement was found in this study, and represented the main cause of morbidity. Low levels of ß4 integrin expression were compatible with hemidesmosomal integrity and a mild skin phenotype.

Role of nitric oxide in physiology and pathology of the gastrointestinal tract.

In this paper the physiological role of NO and isoforms of NOS in the gastrointestinal tract and the involvement of NO in pathological processes of digestive tract as well as the perspective of therapeutic use of NO-donating drugs and selective inhibitors of phosphodiesterase in the treatment of gastric diseases were presented.

Impact of low frequency pulsed magnetic fields on pain intensity, quality of life and sleep disturbances in patients with painful diabetic polyneuropathy.

AIM: The aim of this randomized, placebo-controlled, double-blind study was to assess whether a low frequency magnetic field can influence pain intensity, quality of life and sleep, and glycaemic control in patients with painful diabetic polyneuropathy. METHODS: Sixty-one patients were randomized into two groups: the study group comprised 32 patients exposed to a low frequency magnetic field, average pain duration 23 months; the control group included 29 patients who received sham exposure, average pain duration 28 months. Patients were exposed for three weeks, 20 min a day, five days a week. The magnetic field generator was a Viofor JPS device (Med & Life, Komorow, Poland). All subjects filled out the following questionnaires five times (at the beginning and after one, two, three and five weeks): SFMPQ-VAS (pain evaluation), EuroQol EQ-5D and MOS Sleep Scale. HbA(1c) was evaluated at baseline and after five weeks. RESULTS: Significant reductions in pain intensity were seen in both the study group (visual analogue scale [VAS] value of 73 mm at baseline versus 33 mm after three weeks) and controls (VAS 69 mm at baseline versus 41 mm after three weeks). The extent of pain reduction did not differ significantly between the groups at any time. Also, both groups had similar improvements in EuroQol, MOS and HbA(1c) values. CONCLUSION: Genuine magnetic field exposure has no advantage over sham exposure in reducing pain intensity, improving quality of life, and decreasing sleep disturbances and HbA(1c).

Optical biopsy using spectral camera in BCC and oral leukoplakia.

Basal cell carcinoma is one of the most common neoplasmatic diseases of the skin. Oral leukoplakia is precancerous stage. Early diagnosis of both diseases gives very good treatment results. Fluorescence spectroscopy is a new modality of diagnostics using excitation of absorbed PPIX in tumor. Spectroscopy is an objective method showing concentration and emission spectrum of protoporphyrin IX. In fluorescence spectroscopy with PPIX we used diode light 405 nm to induce fluorescence and observed significant emission peak at 630 nm. Fluorescence spectroscopy is based on searching of emission peaks of photosensitizer in areas of BCC and oral leukoplakia. In our study we used spectral camera measuring spectrum from pictures taken in different wavelengths between 570 nm and 650 nm. The pictures taken with this camera were compared with the pictures captured with Xillix Onco Life system. 20 patients with histopathologically confirmed BCC and 10 with oral leukoplakia were examinated with spectral camera and with Xillix Onco Life system 8h after local instillation of delta aminolevulinic acid. Our spectral camera made pictures with different filters for wavelength between 570 nm and 650 nm showing highest fluorescence intensity in 630 nm. Captured spectral lines were compared with NCV (numerical color value) from Xillix Onco Life. All of spectral lines taken from neoplasmatic tissues were compared with spectral lines taken from healthy tissues in symmetrical areas of body. Results were statistically processed. All of spectral lines taken from neoplasmatic tissues showed significant peak at 630 nm in the area of BCC and oral leukoplakia in all of the examinated patients. Spectral lines taken from healthy tissues were significantly different. There was no peak in 630 nm and fluorescence intensity was decreasing from 570 nm to 630 nm. Intensity of fluorescence in 630 nm was in high correlation with NCV from Xillix Onco Life.

Photodynamic diagnosis (PDD) and photodynamic therapy (PDT) in dermatology: "How we do it".

In dermatology PDT has been proven to be effective in the treatment of actinic keratoses, basal cell carcinomas (BCC), Bowen's disease, superficial squamous cell carcinomas (SCC).

Volume osmotic flows of non-homogeneous electrolyte solutions through horizontally mounted membrane.

Results of an experimental study of volume osmotic flows in a single-membrane osmotic-diffusive cell, which contains a horizontal, microporous, symmetrical polymer membrane separating water and binary or ternary electrolyte solutions are presented. In the experimental set-up, water was placed on one side of the membrane. The opposite side of the membrane was exposed to binary or ternary solutions. As binary solutions, aqueous potassium chloride or ammonia solutions were used, whereas potassium chloride in 0.25 mol x l(-1) aqueous ammonia solution or ammonia in 0.1 mol x l(-1) aqueous potassium chloride solution were used as ternary solutions. Two (A and B) configurations of a single-membrane osmotic-diffusive cell in a gravitational field were studied. In configuration A, water was placed in a compartment above the membrane and the solution below the membrane. In configuration B the position of water and solution was reversed. Furthermore, the effect of amplification of volume osmotic flows of electrolyte solutions in the single-membrane osmotic-diffusive electrochemical cell was demonstrated. The thermodynamic models of the flux graviosmotic and amplification effects were developed, and the volume flux graviosmotic effect for configurations A and B of a single-membrane osmotic-diffusive cell was calculated. The results were interpreted within the conventional instability category, increasing the diffusion permeability coefficient value for the system: concentration boundary layer/membrane/concentration boundary layer.

Photodynamic therapy of premalignant lesions and local recurrence of laryngeal and hypopharyngeal cancers.

The main advantage of photodynamic therapy (PDT) in laryngology seems to be its non-invasiveness and the possibility of using it despite previous application of conventional methods. In the study, we gave PDT to two separate groups of patients, i.e. five patients with advanced tumour (four of them with local recurrence (squamous cell carcinoma) after surgery and radiotherapy and one with a primary hypopharyngeal tumour) and five patients with leucoplakia. In the first group delta-aminolaevulinic acid (ALA) was administered orally (dose 3 g), while in the second, an ointment containing 10% ALA was applied locally. In both groups prior to irradiation, the tissue level of protoporphyrin IX was verified using an adapted Xillix Life instrument. All treated lesions were irradiated with an argon-pumped dye laser (dose range 100-250 J/cm2, wavelength 635 nm). In the first group, partial response was obtained. In these advanced cases, diminution of cancerous ulcerations was observed. In the leucoplakia group, complete response was achieved in four out of five treated patients. On the basis of our preliminary results, PDT may be useful in eradicating premalignant lesions of the oral cavity and in the palliation of advanced lesions of the oropharynx and larynx.

Collagen II containing a Cys substitution for Arg-alpha1-519: abnormal interactions of the mutated molecules with collagen IX.

Single amino acid substitutions in collagen II cause heterogeneous cartilage disorders including some chondrodysplasias and certain forms of heritable osteoarthritis. In this study, we examined molecular interactions between normal collagen II and collagen IX, and the effect of a Cys substitution for Arg-alpha1-519 in collagen II on these interactions. Binding assays showed that the association equilibrium constant of collagen IX-collagen II interaction is 15 x 10(6) M(-1). Specificity of the interaction was analyzed by the binding of collagen IX to recombinant collagen II variants lacking fragments of 234 amino acids corresponding to particular D-periods. The results indicated that the C-terminal half of collagen II, which includes the D3 and D4 periods, has a high affinity for collagen IX, and that the nontriple helical telopeptides of collagen II are not essential for the specific binding of collagen IX. Computer analysis of the surface of the mutated collagen II and binding assays showed that a Cys substitution for Arg-alpha1-519 changes electrostatic properties around the mutation site, increases the affinity of mutant collagen II for collagen IX, and possibly alters the specificity of the interaction. Thus, the results indicate that interactions between collagen II and collagen IX are site specific and that single amino acid substitutions in collagen II may change the molecular interactions with collagen IX that could destabilize the cartilaginous matrix.

Influence of alternating low frequency magnetic fields on reactivity of central dopamine receptors in neonatal 6-hydroxydopamine treated rats.

The aim of this study was to evaluate the influence of extremely low frequency magnetic field (ELF MF) on the reactivity of the central dopamine D(1) receptor in rats with dopamine neurons chemically damaged by 6-hydroxydopamine (6-OHDA), an animal model of human's Parkinson's disease. The experiment was carried out on male Wistar rats. On day 3 of postnatal life, a lasting and selective chemical damage of the central dopamine system was induced in the rats by infusion of 6-OHDA HBr (133.4 microg intracerebroventricular, base form) given bilaterally into lateral ventricles of the brain. Control animals received similar treatments injecting only vehicle. At 2 months of age, both 6-OHDA treated and control rats were randomly divided into two groups. Rats from the first group were exposed to 10 Hz sinusoidal, 1.8-3.8 mT magnetic field one hour daily for 14 days. Rats of the second group were sham exposed, with the applicator solenoid turned off. On the day after the final exposure the evaluations were made of the rat's spontaneous irritability, oral activity, and catalepsy. The MF exposed rat with chemically induced dopamine neurons damage exhibited a reduction of irritability and oral activity when stimulated with SKF 38393 (the agonist of central dopamine D(1) receptor) and some increase of catalepsy after administration of SCH 23390(the antagonist of central dopamine D(1) receptor). These results indicate that ELF MF reduce the reactivity of central dopamine D(1) receptors in rats.

[The role of free radicals in inflammatory states, ulceration, and ulcers of the stomach and duodenum]. / Rola wolnych rodników w stanach zapalnych, owrzodzeniu i w chorobie wrzodowej zoladka i dwunastnicy.

The free radicals derived from oxygen have been implicated in damage caused to the gastroduodenal mucosa. The association between the mucosal production of reactive oxygen radicals in the gastric antrum and duodenum, Helicobacter pylori density and duodenal ulcer has been previously described. The role of interleukin IL-8 in the inflammatory process and its relationship with reactive oxygen radicals has also been investigated. These results indicate that oxygen radicals play an important role in the mechanism of ulcer aggravation induced by a variety of different factors.

[Fluorescence diagnostics of premalignant and malignant changes in patients with Barrett's esophagus: doubts and hopes]. / Diagnostyka fluorescencyjna zmian przednowotworowych i nowotworowych u chorych z przelykiem Barretta--watpliwosci i nadzieje.

Increasing incidence of esophageal adenocarcinoma that mostly arises from Barrett's esophagus (BE) has been observed. Therefore sensitive methods for early detection of dysplasias and adenocarcinomas in BE are more and more necessary. Fluorescence endoscopy is an alternative or complementary to standard four-quadrant biopsies technique. The basics of diagnostics application of tissue autofluorescence and exogenous dyes fluorescence such as protoporphyrin IX, induced by 5-aminolevulinic acid are summarized. There are two methods of fluorescence diagnostics of dysplasia in BE: point fluorescence spectroscopy and real-time fluorescence imaging. Fluorescence spectroscopy is sensitive and specific but can be targeted only toward lesions visible in white-light endoscopy. Fluorescence imaging allows to examine large areas for occult foci of dysplasia but selectivity is somewhat limited by the background fluorescence of Barrett's mucosa. Laser induced fluorescent endoscopy (LIFE) images of esophageal dysplasia are presented. Up-to date results of fluorescence spectroscopy and fluorescence imaging of BE are reviewed. These results indicate fluorescence diagnostics promising and clinically useful for detection of early adenocarcinoma and dysplasia in BE.

[The influence of smoking, hypertension and diabetes mellitus on the rehabilitation duration among the patients having non-Q infarction]. / Wplyw palenia tytoniu, nadcisnienia tetniczego i cukrzycy na czas trwania wczesnej rehabilitacji kardiologicznej u chorych z zawalem serca bez zalamka Q.

In Poland ischaemic heart disease (IHD) is one of the main reasons of death among young people. The most serious manifestation of IHD is heart infarction. To plan medical care organization it is important to know, how long will patients spend in hospital in the case of acute myocardial infarction (AMI). This data depends on early rehabilitation duration time. Influence of smoking, hypertension and diabetes mellitus on duration time of rehabilitation was analyzed in the study. No influence of analyzed risk factors on rehabilitation was noticed in male, in the opposite to female. Female having hypertension and diabetes were rehabilitated longer then patients without these risk factors.

[Photodynamics in gynaecology]. / Zastosowanie metody fotodynamicznej w ginekologii.

Photodynamic procedures were intended for early detection and therapy of neoplastic diseases. Fluorescence diagnosis is based on the detection of the fluorescence of exo- and endogenous photosensitizers selectively accumulated in pathological tissues. Photodynamic therapy is based on the selective destruction of neoplastic tissue resulting from interaction between photosensitizer, light and oxygen. The main fields of the clinical use of photodynamics are pulmonology, gastroneterology, urology and dermatology. The article presents the theoretical principles of fluorescence diagnosis and photodynamic therapy followed by the review of up-to-date literature concerning the use of photodynamics in diseases of the genital tract in women.

Papilin in development; a pericellular protein with a homology to the ADAMTS metalloproteinases.

Papilin is an extracellular matrix glycoprotein that we have found to be involved in, (1) thin matrix layers during gastrulation, (2) matrix associated with wandering, phagocytic hemocytes, (3) basement membranes and (4) space-filling matrix during Drosophila development. Determination of its cDNA sequence led to the identification of Caenorhabditis and mammalian papilins. A distinctly conserved 'papilin cassette' of domains at the amino-end of papilins is also the carboxyl-end of the ADAMTS subgroup of secreted, matrix-associated metalloproteinases; this cassette contains one thrombospondin type 1 (TSR) domain, a specific cysteine-rich domain and several partial TSR domains. In vitro, papilin non-competitively inhibits procollagen N-proteinase, an ADAMTS metalloproteinase. Inhibiting papilin synthesis in Drosophila or Caenorhabditis causes defective cell arrangements and embryonic death. Ectopic expression of papilin in Drosophila causes lethal abnormalities in muscle, Malpighian tubule and trachea formation. We suggest that papilin influences cell rearrangements and may modulate metalloproteinases during organogenesis.

Gravitational effects in the passive osmotic flows across polymeric membrane of electrolytic solutions.

Results of experimental study of volume flux in one-membrane system were presented. This system contains horizontal, microporous and symmetrical flat polymeric membrane (Nephrophan), which separate water and electrolyte solution. As binary solutions, aqueous ammonia solutions, which density is lower than water density, were used. As ternary solutions the ammonia with KC1 (0.1 or 0.2 mole.l-1) in aqueous solution were used. The density of ternary solutions was lower, higher or the same as water density. Two configurations of membrane system (A and B) in gravitational field were studied. In configuration A, water was in compartment over the membrane and the solution was under the membrane. In configuration B the succession was reverse. The thermodynamic model of flux graviosmotic effect was elaborated, and the calculations of this effect were performed for A and B configurations of one membrane system. The experimental results are interpreted in terms of gravitational instability that reduces concentration boundary layer dimensions and increases the diffusion permeability coefficient value of the complex: boundary layer/membrane/boundary layer.

Structure and function of procollagen C-proteinase (mTolloid) domains determined by protease digestion, circular dichroism, binding to procollagen type I, and computer modeling.

Procollagen C-proteinase-2 (pCP-2, mTld) is derived from the longest splicing variant of the gene encoding bone morphogenetic protein 1 (BMP-1). The variants have identical amino terminal signal peptides, prodomains and astacin-like protease domains. However, they differ in the length of their carboxy terminal part, which in pCP-2 has the composition CUB1, CUB2, EGF-like1, CUB3, EGF-like2, CUB4, CUB5, and C-tail. In the shorter form, pCP-1 (i.e., BMP-1), the sequence ends after the CUB3-domain. Using a combination of mutagenesis and structural approaches, we have investigated the structure and function of subfragments of pCP-2. The full-length latent recombinant enzyme and its N-terminally truncated form lacking the prodomain were tested for their enzymic activity. The intact protein showed only partial processing of procollagen type I, whereas the truncated form expressed enzymic activity indistinguishable from its native counterpart purified from chick embryo tendons. These results clearly demonstrated that the prodomain is required for the latency of the enzyme but not for its correct folding. Limited proteolysis of the recombinant protein with alpha-chymotrypsin produced four discrete fragments revealing the location of cleavage sites between the repetitive CUB/EGF domains. The results provide evidence that the CUB sequences form independently folded modules that are stabilized by two pairs of internal disulfide bridges. The modules are linked to each other by more flexible, hinge-like peptides. Solid-phase binding assays with isolated CUB domains and immobilized procollagen type I demonstrated that the first three but not the last two CUB domains specifically bound to the substrate. To define putative sites for CUB-CUB or CUB-substrate interactions, we generated molecular models for pCP-2 CUB domains. The models were obtained using as a template the structure of CUB domain in zona pellucida adhesion protein PSP-I/PSP-II from porcine sperm. The predicted conformations for homology models were, subsequently, confirmed by circular dichroism spectroscopy of polypeptide domains isolated following limited proteolysis with alpha-chymotrypsin.