Relationship between sedimentation sign and morphological grade in symptomatic lumbar spinal stenosis.

PURPOSE: We aimed to study the relationship between two morphological parameters recently described on MRI images in relation to lumbar spinal stenosis (LSS): the first is the sedimentation sign (SedS) and the second is the morphological grading of lumbar stenosis. MATERIALS AND METHODS: MRIs from a total of 137 patients were studied. From those, 110 were issued from a prospective database of symptomatic LSS patients, of whom 73 were treated surgically and 37 conservatively based on symptom severity. A third group consisting of 27 subjects complaining of low back pain (LBP) served as control. Severity of stenosis was judged at disc level using the four A to D grade morphological classification. The presence of a SedS was judged at pedicle level, above or below the site of maximal stenosis. RESULTS: A positive SedS was observed in 58, 69 and 76% of patients demonstrating B, C and D morphology, respectively, but in none with grade A morphology. The SedS was positive in 67 and 35% of the surgically and conservatively treated patients, respectively, and in 8% of the LBP group. C and D morphological grades were present in 97 and 35% of patients in the surgically and conservatively treated group, respectively, and in 18% of the LBP group. Presence of a positive SedS carried an increased risk of being submitted to surgery in the symptomatic LSS group (OR 3.5). This risk was even higher in the LSS patients demonstrating grade C or D morphology (OR 65). DISCUSSION AND CONCLUSION: One-third of surgically treated LSS patients do not present a SedS. This sign appears to be a lesser predictor of treatment modality in our setting of symptomatic LSS patients compared to the severity of stenosis judged by the morphological grade.

Disc degeneration: current surgical options.

Chronic low back pain attributed to lumbar disc degeneration poses a serious challenge to physicians. Surgery may be indicated in selected cases following failure of appropriate conservative treatment. For decades, the only surgical option has been spinal fusion, but its results have been inconsistent. Some prospective trials show superiority over usual conservative measures while others fail to demonstrate its advantages. In an effort to improve results of fusion and to decrease the incidence of adjacent segment degeneration, total disc replacement techniques have been introduced and studied extensively. Short-term results have shown superiority over some fusion techniques. Mid-term results however tend to show that this approach yields results equivalent to those of spinal fusion. Nucleus replacement has gained some popularity initially, but evidence on its efficacy is scarce. Dynamic stabilisation, a technique involving less rigid implants than in spinal fusion and performed without the need for bone grafting, represents another surgical option. Evidence again is lacking on its superiority over other surgical strategies and conservative measures. Insertion of interspinous devices posteriorly, aiming at redistributing loads and relieving pain, has been used as an adjunct to disc removal surgery for disc herniation. To date however, there is no clear evidence on their efficacy. Minimally invasive intradiscal thermocoagulation techniques have also been tried, but evidence of their effectiveness is questioned. Surgery using novel biological solutions may be the future of discogenic pain treatment. Collaboration between clinicians and basic scientists in this multidisciplinary field will undoubtedly shape the future of treating symptomatic disc degeneration.

Antiapoptotic signalling by the insulin-like growth factor I receptor, phosphatidylinositol 3-kinase, and Akt.

We have found that insulin-like growth factor I (IGF-I) can protect fibroblasts from apoptosis induced by UV-B light. Antiapoptotic signalling by the IGF-I receptor depended on receptor kinase activity, as cells overexpressing kinase-defective receptor mutants could not be protected by IGF-I. Overexpression of a kinase-defective receptor which contained a mutation in the ATP binding loop functioned as a dominant negative and sensitized cells to apoptosis. The antiapoptotic capacity of the IGF-I receptor was not shared by other growth factors tested, including epidermal growth factor (EGF) and thrombin, although the cells expressed functional receptors for all the agonists. However, EGF was antiapoptotic for cells overexpressing the EGF receptor, and expression of activated pp60v-src also was protective. There was no correlation between protection from apoptosis and activation of mitogen-activated protein kinase, p38/HOG1, or p70S6 kinase. On the other hand, protection by any of the tyrosine kinases against UV-induced apoptosis was blocked by wortmannin, implying a role for phosphatidylinositol 3-kinase (PI3 kinase). To test this, we transiently expressed constitutively active or kinase-dead PI3 kinase and found that overexpression of activated phosphatidylinositol 3-kinase (PI3 kinase) was sufficient to provide protection against apoptosis. Because Akt/PKB is believed to be a downstream effector for PI3 kinase, we also examined the role of this serine/threonine protein kinase in antiapoptotic signalling. We found that membrane-targeted Akt was sufficient to protect against apoptosis but that kinase-dead Akt was not. We conclude that the endogenous IGF-I receptor has a specific antiapoptotic signalling capacity, that overexpression of other tyrosine kinases can allow them also to be antiapoptotic, and that activation of PI3 kinase and Akt is sufficient for antiapoptotic signalling.

Akt-dependent and -independent survival signaling pathways utilized by insulin-like growth factor I.

Protein kinase B (PKB)/Akt is implicated in survival signaling in a wide variety of cells including fibroblasts and epithelial and neuronal cells. We and others have described a linear survival signaling cascade used by insulinlike growth factor I (IGF-I) that consists of the IGF-I receptor, phosphoinositide 3-kinase (PI3 kinase), Akt, and Bad. Activation of this pathway can be sufficient to protect cells from apoptosis. However, previous work had not determined whether this pathway is invariably necessary for protection from apoptosis or whether there are alternative survival signaling pathways. In this communication, we report the existence of two survival signaling pathways, one dependent on PI3 kinase and Akt and the other independent of these enzymes. We found that survival signaling initiated by IGF-I treatment of Rat-1 cells could be blocked by overexpression of a dominant negative kinase-deficient Akt (K179A) as well as by wortmannin. This demonstrates a survival signaling pathway dependent on PI3 kinase and Akt. However, when IGF-I receptors were overexpressed in a Rat-1 background (RIG cells), an alternative pathway became apparent, in which survival mediated by IGF-I was no longer sensitive to wortmannin or to overexpression of dominant negative Akt, even though Akt activation and Bad phosphorylation were still wortmannin sensitive. Experiments with inhibitors of RNA synthesis showed that transcriptional activation is dispensable for this alternative PI3 kinase/Akt-independent survival signaling. These findings demonstrate the existence of a new survival signaling pathway independent of PI3 kinase, Akt, and new transcription and which is evident in fibroblasts overexpressing the IGF-I receptor.

Alkylphosphonate modified aluminum oxide surfaces.

The surface properties of aluminum, such as chemical composition, roughness, friction, adhesion, and wear, can play an important role in the performance of micro-/nano-electromechanical systems, e.g., digital micromirror devices. Aluminum substrates chemically reacted with octadecylphosphonic acid (ODP/Al), decylphosphonic acid (DP/Al), and octylphosphonic acid (OP/Al) have been investigated and characterized by X-ray photoelectron spectroscopy (XPS), contact angle measurements, and atomic force microscopy (AFM). XPS analysis confirmed the presence of alkylphosphonate molecules on ODP/Al, DP/Al, and OP/Al. No phosphonates were found on bare Al as a control. The sessile drop static contact angle of pure water on ODP/Al and DP/Al was typically more than 115 degrees and on OP/Al typically less than 105 degrees indicating that all phosphonic acid reacted Al samples were highly hydrophobic. The root-mean-square surface roughness for ODP/Al, DP/Al, OP/Al, and bare Al was less than 15 nm as determined by AFM. The surface energy for ODP/Al and DP/Al was determined to be approximately 21 and 22 mJ/m2, respectively, by the Zisman plot method, compared to 25 mJ/m2 for OP/Al. ODP/Al and OP/Al were studied by friction force microscopy, a derivative of AFM, to better understand their micro-/nano-tribological properties. ODP/Al gave the lowest coefficient of friction values while bare Al gave the highest. The adhesion forces for ODP/Al and OP/Al were comparable.

Antiapoptotic signaling in LNCaP prostate cancer cells: a survival signaling pathway independent of phosphatidylinositol 3'-kinase and Akt/protein kinase B.

Constitutive activation of the phosphatidylinositol 3'-kinase (PI3 kinase)-Akt/protein kinase B (PKB) "survival signaling" pathway is a likely mechanism by which many cancers become refractory to cytotoxic therapy. In LNCaP prostate cancer cells, the PTEN phosphoinositide phosphatase is inactivated, leading to constitutive activation of Akt/PKB and resistance to apoptosis. However, apoptosis and inactivation of Akt/PKB can be induced in these cells by treatment with PI3 kinase inhibitors. Surprisingly, androgen, epidermal growth factor, or serum can protect these cells from apoptosis, even in the presence of PI3 kinase inhibitors and without activation of Akt/PKB, indicating the activity of a novel, Akt/PKB-independent survival pathway. This pathway blocks apoptosis at a level prior to caspase 3 activation and release of cytochrome c from mitochondria.

Tumor necrosis factor alpha induces BID cleavage and bypasses antiapoptotic signals in prostate cancer LNCaP cells.

Survival of cancer cells in response to therapy, immune response, or metastasis depends on interactions between pro- and antiapoptotic signals. Two major proapoptotic pathways have been described: (a) a death receptor pathway; and (b) a mitochondrial pathway. We reported previously that Akt and the epidermal growth factor (EGF) receptor send separate, redundant survival signals that act to inhibit the mitochondrial proapoptotic pathway in prostate cancer LNCaP cells. However, it was unclear at what level the pro- and antiapoptotic signals interact in these cells, and it was also unclear whether these signals would inhibit the death receptor pathway. We found that EGF can protect LNCaP cells from apoptosis induced by LY294002 but not from tumor necrosis factor a (TNF-alpha)-induced apoptosis. Furthermore, TNF-alpha induced apoptosis under conditions in which Akt was active. Treatment with TNF-alpha resulted in activation of caspase 8 and cleavage of BID, which in turn induced cytochrome c release and caspase 9-dependent activation of effector caspases. Thus, proapoptotic signals induced by both TNF-alpha and LY294002 converge on mitochondria and trigger cytochrome c release. Because EGF can inhibit cytochrome c release induced by LY294002 but not cytochrome c release induced by TNF-alpha, we suggest that the EGF survival mechanism operates on the mitochondrial pathway at a site upstream of cytochrome c release. The ability of TNF-alpha to bypass survival signals from activated EGF receptor and Akt in prostate cancer cells makes death receptor signaling a promising avenue for therapeutic intervention.

[Ultrastructural organization of carcinoma Lewis (3LL) cells during cisplatin resistance formation].

The electron-microscopic analysis of the morphological status of 3LL (Lewis) carcinoma tumour cells in the process of cisplatin resistant phenotype formation has been performed. It was shown that selection of tumour cells forming cell clones characterized by more complicated nuclear and cytoplasm organization took place. The tumour cells had the diffused nuclear chromatin; nuclear envelope had the numerous pores with expanded diaphragms. The prominent nucleoli consisted of the active centres surrounded by considerable areas of the condensed nucleolar chromatin. Cell cytoplasm contained the well-developed Goldgi complex and the numerous well-structured myelinoid formations in the form of dense-wrapped concentric membrane structures. The obtained data can morphologically confirm the hypothesis of Gately D.P. and Howel S.B., 1993, thain the process of resistant phenotype formation the tumour cells can create the cellular mechanisms to remove the drug from the cell and to correct the damages of the cellular nucleus and cytoplasm.

Different growth patterns of a cancer cell population as a function of its starting growth characteristics: analysis by mathematical modelling.

The growth kinetics of a cancer cell population as a function of the total number of cells and the proportion of proliferating and resting cells at the beginning of the growth has been analysed by a mathematical model. The model takes into account the processes of cell division, death and transition from proliferation to rest and backwards. It is shown that a single cell population growing under the same environmental conditions has an extremely broad spectrum of growth patterns. The whole multiplicity of possible growth patterns has been determined by the inherent cellular growth characteristics of the population, while the growth pattern actually realized of the variety of growth curves depends on the total number of cells and the proportion of proliferating and resting cells at the initial moment of growth. The model is shown to provide a good prediction of experimentally measured kinetics of regrowth of tumour cells subcultured after various times of the growth in unfed cultures, and the kinetics of tumour cell growth after severe hypoxia. The role of cell transitions between proliferating and resting stages in the problem of growth control is discussed.

Hydrogen loading and UV-irradiation induced etch rate changes in phosphorus-doped fibers.

We show strong changes in chemical etching of phosphorus-doped fiber cores due to hydrogen loading and subsequent UV-irradiation using an atomic force microscope. The etch rate of the fiber core in a low concentration hydrofluoric acid solution (HF) is decreasing after hydrogen loading by as much as 30%. In contrast, UV-irradiation of the hydrogenated fiber increases the core etch rate to values of 27% above the etch rate of the pristine fiber. The UV-induced change in etch rate does not depend on pulse fluence, but only on total dose. We attribute the changes in etch rate to a hydrogen- and radiation-induced modification of color center population.

The SEIRA spectroscopy data of nucleic acids and phospholipids from sensitive- and drug-resistant rat tumours.

It is known that tumour progression towards drug resistance is one of the main factors resulting in the failure of cancer treatment. As tumour progression is based on the genetic instability, the study of the structure of nucleic acid from tumour cells is of great importance both for basic knowledge and for biomedical application. We applied surface enhanced infrared absorption spectroscopy (SEIRA) of nucleic acids on gold substrate and essentially increased the sensitivity of IR spectroscopy. We observed numerous changes in infrared spectra of DNA from sensitive and resistant cells that reflect drastic changes in molecular structure of DNA from tumour cells. The DNA from resistant cancer cells could be characterised as rigid structure, the structure of DNA from sensitive cancer strain seems to be flexible and after application of anticancer drugs drastically changes and approaches to the structure of helix forms. The molecular structure of lipids from resistant and sensitive cancers after application of anti-tumour drugs is also modified. Thus, we observed a disordering in the lipid chain packing from resistant cells after application of cisplatin and, in some cases, formation of phospholipid-Pt complex.

Comparative in vitro study of the effects of the new antitumor drug Ukrain and several cytostatic agents on the thiol groups in the tissue of Guerin carcinoma and its resistance to cisplatin variant.

A comparative in vitro study between the effects of Ukrain (a new synthetic thiophosphoric acid derivative of great celandine alkaloids) and alkylating antitumor drugs cyclophosphamid and cisplatin on total thiol content in Guerin carcinoma, Guerin/cis-DDP carcinoma, and in animal livers was carried out. It is shown that Ukrain action on thiol groups in Guerin carcinoma tissue does not differ from that of cyclophospamid and cisplatin to both of which Guerin carcinoma is very sensitive. Once tumor resistance to cisplatin has developed, cisplatin does not react with tumor thiol groups and cyclophosphamid reactions with tumor thiol groups decrease. Reactions of Ukrain with thiol groups of cisplatin resistant tumors increase. This indirectly indicates the increase of tumor sensitivity to this drug. Therefore, the cytotoxicity of Ukrain is similar to that of known antitumor drugs and can probably overcome the cisplatin resistance of the tumor.

Study of acute toxicity of Ukrain in rats after intravenous injection.

The acute toxicity of i.v. Ukrain injection in rats was studied. The interrelation between toxicity (death of animals) and dosage was determined by nonlinear regression method. White blood count (WBC) in peripheral blood, weight of animals, and weight of major organs were determined in animals during all stages of investigation. Morphological studies of toxic changes in 40 different organs of rats were performed on macro- and microscopic levels.

[Comparative evaluation of the action of cis-dichlorodiammineplatinum and oxoplatinum on hemopoiesis un mice]. / Sravnitel'naia otsenka deistviia tsis-dikhlordiamminoplatiny i oksoplatina na gemopoéz u myshei.

Myelosuppressive effects of cis-dichlorodiamminoplatinum (DDP) and oxoplatinum have been revealed. The administration of these drugs leads to early and deep depletion of CFU compartment. The most rapid rate of reduction was registered during 24-48 hours after DDP administration and within first three hours after oxoplatinum administration. Reduction of the total bone marrow cellularity caused mainly by a decrease of erythroid cells and, to a less extent, by a decrease of lymphoid and myeloid cells is observed. Leukopenia and anemia have developed during the treatment. Myelosuppressive effects are more pronounced with the oxoplatinum administration. A strict correlation is established between the haemopoietic tissues damage and the level of platinum content in the animal organism.

[Adaptation of the body to alkylating anti-tumor substances]. / Adaptatsiia organizma k alkiliruiushchim protivoopukholevym preparatam.

It is determined that the organism may adapt in principle to alkylating antitumour preparations, to thiophosphamide in particular, being administered for a long time. The development of cell adaptation reactions in the systems of hemopoiesis and microsomal oxidation of hepatocytes is studied. An increase in the activity of enzymes of the microsomal liver oxidation system is found as accompanied by a lower concentration of 35S-thiophosphamide in the studied tissues and blood serum. The reactivity of tissue and serum SH-groups is observed to decrease with the organism adaptation to the preparation.

[Modification of the determination of the quantitative characteristics of an experimental tumor process]. / Modifikatsiia opredeleniia kolichestvennykh kharakteristik éksperimental'nogo opukholevogo protsessa.

Modifications of the main quantitative characteristics of experimental tumour processes are proposed for the optimal assessment and comparison of various antitumoural effects.

[Modification of the toxic effects of cis-dichlorodiammineplatinum]. / Modifikatsiia toksicheskikh éffektov tsis-dikhlordiamminoplatiny.

It is established that the preparation K-2-9 being administered in combination with cis-dichlorodiaminoplatinum (DDP) lowers the DDP toxic effects, in particular nephrotoxicity and enterotoxicity, increases the activity of the enzymes participating in microsomal liver oxidation, the activity of kidney transamidinase, the quantity of SH-groups of the liver and kidney tissue, intensifies the antitumour effect of DDP.

[Nonspecific oxidase activity in the liver of rats undergoing chemotherapy with cis-dichlorodiammineplatinum]. / Aktivnost' nespetsificheskikh oksidaz pecheni krys pri khimioterapii tsis-dikhlordiaminoplatinoi.

A combined administration of cis-dichlorodiaminoplatinum (DDP) and phenobarbital increases the activity of nonspecific oxidases, decreases the toxic effect of DDP especially its nephrotoxic action, but does not decrease the antiblastic action of DDP in rats. On the basis of experimental data the optimum regime of DDP repeated administrations is suggested.

[The mechanisms of a decrease in the toxic action of cisplatin when administered jointly with preparation K-2-9 to mice with melanoma B16]. / O nekotorykh mekhanizmakh snizheniia toksicheskogo deistviia tsisplatina pri sovmestnom vvedenii s preparatom K-2-9 mysham s melanomoi B-16.

The K-2-9 preparation was determined to change cis-platinum pharmacokinetics, that resulted in its pharmacodynamics alterations. The higher Pt concentrations in the blood of animals which were given the K-2-9 preparation provided selectivity of cytostatic accumulation in the tumour tissue, that was accompanied by more prolonged inhibition of the DNA synthesis. A decrease in the toxicity of cis-platinum is associated with a change in the elimination pathway and acceleration of its removal from the organism.

[Changes in the contents of epidermal growth factor and EGF-like polypeptides in the liver tissue of rats in N-nitrosodiethylamine-induced hepatocarcinogenesis]. / Izmenenie soderzhaniia épidermal'nogo faktora rosta i podobnykh emu polipeptidov v tkani pecheni krys pri gepatokantserogeneze, indutsirovannom N-nitrozodiétilaminom.

It has been determined that concentration of EGF-like substances in the liver of rats with N-diethylnitrosamine-induced hepatocarcinogenesis increases and reaches its maximum in tumours (50-150 ng/mg protein). In the regenerating liver the amount of these peptides does not exceed 10 ng/mg protein. High pressure gel-filtration of appropriate extracts has revealed EGF-competing substances with m. w. about 20-30 kD in the liver carcinomas. The presented data confirm that registered EGF-like substances belong to TGF-alpha peptides.