Risk of colorectal neoplasia associated with the adenomatous polyposis coli E1317Q variant.

BACKGROUND: Reports of the risk of colorectal neoplasia associated with a variant of the adenomatous polyposis coli (APC E1317Q) gene are conflicting. Using a case-control design, we investigated this relationship within a clinic-based cohort followed through the Integrated Cancer Prevention Center and the Tel-Aviv Sourasky Medical Center. MATERIALS AND METHODS: All study subjects were tested for the APC E1317Q variant at enrollment. Subjects underwent colonoscopic evaluation (+/-biopsy and/or polypectomy) and had cancer history and colorectal neoplasia risk factors assessed. The crude and adjusted risks of neoplasia associated with the E1317Q variant were calculated. RESULTS: The prevalence of the E1317Q variant was 1.4% in the entire study sample and 3.2% in Sephardic Jews. E1317Q was more prevalent among cases: 15 of 458 (3.3%) cases were carriers compared with 11 of 1431 (0.8%) controls [odds ratio (OR) 4.4, 95% CI 2.0-9.6]. When stratified by neoplasia type, adenoma risk was significantly elevated in carriers (OR 4.1, 95% CI 1.8-9.4) but colorectal cancer risk was not (OR 2.1, 95% CI 0.8-5.3). After adjustment, the E1317Q variant remained a significant predictor of colorectal adenoma (OR 4.6, 95% CI 2.0-10.8). CONCLUSIONS: The APC E1317Q variant is associated with colorectal neoplasia, particularly colorectal adenomas, but further studies are still needed. Variant prevalence is elevated in Sephardic Jews.

Localization of a ferricyanide-reactive site of cytochrome b-c1 complex, possibly of cytochrome b or ubisemiquinone, at the outer face of submitochondrial particles.

When succinate oxidation by submitochondrial particles is blocked by antimycin, NoHOQnO or funiculosin, addition of ferricyanide restores oxygen uptake coupled to membrane potential generation. The effect of ferricyanide is abolished by mucidin or myxothiazol, as well as by KCN. The data strongly favor a cyclic redox loop mechanism in site 2 and show that either heme of the ferrous cytochrome b or ubisemiquinone formed in the QH2-oxidizing center of complex b-c1 is accessible to ferricyanide at the outer (M) side of the submitochondrial particle membrane.

Mechanical influence and cAMP injection evoke the same reaction of neuron ionic channels.

Intracellular cAMP injection and negative pressure in the patch-electrode increase the interburst closed time of the same potassium ionic channels in the snail neuron membrane. Sodium channels which were registered as change of background noise are activated both by cAMP injection and by negative pressure. These results are considered in connection with data about the unusual biochemistry of the neuron reaction to cAMP.

Unusual biochemistry of changes in neuron membrane permeability evoked by cAMP.

Influence of different metabolic poisons on cAMP-evoked neuron membrane permeability is investigated. Drugs preventing cAMP binding with R subunits of protein kinase decrease the cAMP-evoked current, but the inhibitor of the C subunit. H8, has no effect. The cAMP-dependent current is increased by uncouplers and decreased by inhibitors of glycolysis and oxidative phosphorylation. The mechanism of cAMP action on neuron permeability is discussed.

Cerebrospinal fluid leukocyte aggregation in meningitis.

OBJECTIVE: To evaluate whether the difference in aggregation of cerebrospinal fluid cells from patients with bacterial, viral, aseptic and partially treated meningitis can be used for diagnostic purposes. METHODS: Cerebrospinal fluid samples of 100 patients with meningitis (15 bacterial, 13 partially treated, 10 viral and 62 aseptic) were compared on the basis of the predefined leukocyte aggregation score (LAS). RESULTS: Mean LAS was 56% in the bacterial meningitis group (range, 15 to 90%), 5.8% in the partially treated meningitis group (range, 0 to 27%), 2% in the proven viral meningitis group (range, 0 to 5%) and 2% in the aseptic meningitis group (range, 0 to 15%). All patients with bacterial meningitis had a LAS of > 15%, whereas all those with viral or aseptic meningitis had a score of < 15%. Although most patients with partially treated meningitis had a low LAS, several had higher scores, which may indicate bacterial infection. There was no statistical correlation between number of cells, type of cells (mononuclear or polymorphonuclear) or cerebrospinal fluid protein and glucose concentration and degree of leukocyte aggregation for the different groups. CONCLUSION: Measurement of the LAS may contribute to the immediate differential diagnosis of bacterial or viral meningitis, especially in patients with very high pleocytosis, as sometimes seen in enteroviral meningitis. It may also serve as a guide for the likelihood of bacterial infection in cases of partially treated meningitis. Additional studies are needed to confirm these observations.

Neuron generator potentials evoked by intracellular injection of cyclic nucleotides and mechanical distension.

Depolarization of neuron membrane was shown to occur during cAMP injection by means of both iontophoresis and pressure. Distension of the neuron by means of blowing with large volumes of solution without cAMP can produce reversible responses. The time course can be made similar to that of the cAMP effect and the responses can be repeated many times in the same neuron. The effect of cAMP can be differentiated from the mechanical response by injecting small volumes of concentrated solutions. The delay in this depolarization response to cAMP is only 0.1-0.3 s. The calculated time of diffusion from the electrode tip to the membrane is about 10 times greater. The similarity of cAMP and mechanical responses and the short delay of the cAMP effect suggests that a cAMP effect may be mediated by mechanical signals in the cytoskeleton.

Papillary and follicular neoplasms of the thyroid gland. Differential immunohistochemical staining with high-molecular-weight keratin and involucrin.

The morphologic distinction between papillary and follicular neoplasms of the thyroid gland can be difficult, especially on small biopsy specimens or in fine-needle aspirations. To determine whether immunohistochemistry could help in achieving the correct diagnosis, we characterized the staining pattern for a series of papillary and follicular neoplasms of the thyroid gland. A pilot study was performed using a panel of antibodies, including high-molecular-weight keratin (HMWK, 34 beta E12), cytokeratin (CK) 5/6, CK7, CK13, CK14, CK20, AE1/AE3, CAM5.2, involucrin, and villin. Of these antibodies, involucrin and HMWK showed strong differential staining between follicular and papillary neoplasms. HMWK stained 91% of papillary carcinomas, including follicular variants, with a median of 53% positive cells, and involucrin stained 72.5% of papillary neoplasms with a median of 45% positive cells. HMWK stained only 20% of follicular neoplasms, whereas involucrin stained 29% of cases. Papillary neoplasms showed strong, although patchy, staining with HMWK and involucrin, whereas those follicular neoplasms that did have staining showed a weak, diffuse pattern of staining. We believe that HMWK, and involucrin to a lesser degree, could be useful in differentiating papillary from follicular neoplasms, especially for cytologic cell block material or for cases in which the architectural pattern is follicular.

Transmucosal fine-needle aspiration diagnosis of intraoral and intrapharyngeal lesions.

OBJECTIVES: The effectiveness of fine-needle aspiration biopsy (FNAB) for the diagnosis of neck, thyroid, and salivary gland masses is well documented. Very few reports explore the potential of an intraoral FNAB approach for the diagnosis of submucosal lesions. We describe our technique and present case examples of pertinent differential diagnostic entities. We recommend an expanded role for FNAB of the oral cavity and oropharynx. STUDY DESIGN: Retrospective review. METHODS: A uniform technique was employed for transmucosal FNAB of 76 patients with intraoral masses. In applicable cases, cytology results were compared with traditional biopsy methods and permanent histopathologic specimens for accuracy. RESULTS: Our experience demonstrates the high sensitivity (93%) and specificity (86%) of intraoral FNAB when compared with biopsy by conventional means. FNAB provides distinct advantages for the cytologic diagnosis of submucosal lesions, which may be difficult to reach and adequately sample through conventional biopsy. FNAB of the tonsil and tonsillar fossa provides a safe and effective means of diagnosing both lymphoma and squamous cell cancer. Transmucosal FNAB via the mouth led to rapid diagnosis of a number of benign and malignant lesions. Applying this uniform FNAB technique, we had no significant complications. CONCLUSION: We recommend transmucosal FNAB as an effective means for highly accurate diagnosis of submucosal lesions of the oral cavity and oropharynx. CLINICAL RELEVANCE: Traditional biopsy techniques in the oral cavity may require anesthesia and may have diagnostic difficulties, particularly for submucosal lesions. Transmucosal FNAB overcomes these shortcomings by providing a minimally invasive means to rapid diagnosis of intraoral lesions.

Increase in leukocyte adhesiveness and aggregation with stress: a model of human congestive heart failure.

Stress has a significant influence on the function of the human organism. A simple, rapid, inexpensive, and reliable marker for stress would therefore be of great value. We have recently noted that stress increases the state of leukocyte adhesiveness and aggregation in the peripheral blood. We evaluated 64 patients who had various degrees of congestive heart failure, a condition known to induce a state of physiologic stress, to verify whether a relation exists between the intensity of the stress response and the magnitude of leukocyte adhesiveness. Included in the 64 were 53 patients without congestive heart failure, 23 with compensated failure, 22 with significant congestive heart failure, and 19 with florid pulmonary edema. The percentage of aggregated leukocytes in these four group was 6% +/- 4%, 6% +/- 4%, 10.5% +/- 5%, and 15% +/- 14%. Values for the third and fourth group differed in a statistically significant way. Thus, with further investigation into additional stress-inducing conditions, the state of leukocyte adhesion and aggregation may prove to be a reliable marker for the detection of stress and an inexpensive tool for quantifying its severity.

Foamy macrophages in acquired immunodeficiency syndrome cholangiopathy with Encephalitozoon intestinalis.

Acquired immunodeficiency syndrome (AIDS) cholangiopathy is a clinical syndrome characterized by right upper quadrant pain, low-grade fever, and bile duct dilatation or papillary stenosis. Cryptosporidia and cytomegalovirus have been most commonly reported as causes of AIDS cholangiopathy, but recently microsporidia have also been recognized as a causative agent. We here report an additional case of AIDS cholangiopathy with the microsporidian Encephalitozoon (Septata) intestinalis. Because this microsporidial species can disseminate throughout the body and is susceptible to treatment by albendazole, it is important to identify and separate this organism form other causes of AIDS cholangiopathy. A key histologic feature seen in this case, which has not been observed in AIDS cholangiopathy caused by other parasitic organisms, is the presence of numerous foamy macrophages in the lamina propria, which contain the microsporidial organisms, as seen by electron microscopy. The presence of these foamy macrophages may be an important histologic clue to the presence of infection by Encephalitozoon intestinalis.

Increased adhesiveness of white blood cells in patients with unstable angina: additional evidence for an involvement of the immune-inflammatory system.

BACKGROUND: Data are being accumulated on the presence of inflammatory response in patients with acute coronary syndromes. HYPOTHESIS: The study was undertaken to confirm that the adhesive state of the peripheral blood leukocytes can provide information on an inflammatory process in patients with unstable angina pectoris. METHODS: The study included 21 patients with unstable angina, 32 patients with stable angina, and 13 patients with chest pain and no evidence of coronary artery disease. RESULTS: The percentage of aggregated leukocytes in patients with unstable angina (5.8 +/- 3.2%) was significantly (p < 0.02) increased compared with that of patients with no evidence of active coronary disease (3.2 +/- 2.6%). CONCLUSION: Additional evidence for an existing smoldering inflammatory process in unstable angina pectoris can be provided by testing the percentage of aggregated leukocytes in peripheral blood.

Analog-digital molecular cell computer.

The living cell is controlled by a molecular stochastic computer of parallel-successive action. MCC may be equivalent to the universal computer. MCC operates with molecule-words (DNA, RNA, proteins) according to the programme recorded in DNA and RNA. Operations are produced by molecular devices (RNA- and DNA-polymerases, ligases, proteinases and so on). Molecular devices operating with molecule-words are recorded on molecules themselves, and they are read off by ribosomes. Therefore the programme of the reorganization of the programme itself may be recorded on the molecule-words. MCC operates with molecular words having definite addresses. The words and the operators collide by Brownian movement and combine if the molecular surface of address segment is complementary and properly oriented. It is possible to reproduce not only the programmes but also the operators of MCC. The molecular computer operates with word-molecules according to the programme, recorded in DNA, with the aim of predicting an outer situation in the next time-moment and selecting of a correct answer by synthesis of suitable proteins and other substances and also by macroscopic motion. Each step of directed calculation is needed of the consumption of minimally necessary portion of free energy and search is due to the Brownian movement without free energy loss. Cyclic nucleotides are intraneuron membrane potential controlling systems which can be described as molecular diffusional analog computers, well fitted to solve mathematical physics equations if there are high frequency generators and regulators of cyclic nucleotides sources and sinks. It is suggested that molecular proton channels in an electric field are such generators of 10(11)-10(12) Hz. Biophysics cannot use the ordinary laws of physics and must take into account the influence on the phenomena to be studied, not only of a measurement but also of a calculation process in the real device predicting the future.

Molecular quantum computer of neuron.

Living cells are controlled by quantum regulators in which the price of action of elementary operations approaches Planck's constant. The description of such systems is based on four principles: (1) minimal price of action principle for control; (2) principle of optimality; (3) minimum irreversibility principle; and (4) the principle of causality.

Cell molecular computers and biological information as the foundation of nature's laws.

It is proposed to unite the principles of new science mathematics, physics and biology for the description of living creatures. Such description is based on four principles: minimal price of action, optimum prediction, minimal irreversibility, and causality. In this new knowledge of nature not only the molecular biological experimental aspects have to be considered, but also the profound 'meaning' of molecular texts of DNA.

Quantum molecular computer model of the neuron and a pathway to the union of the sciences.

Cyclic nucleotide injection in neurons shows that cAMP controls a new type of membrane permeability. The neuron response to cAMP has a short delay, unusual bioenergetics and is blocked by drugs binding with the regulatory subunit of protein kinase. These data are interpreted in terms of the hypothesis that the controlling system of the living cell is a molecular (DNA, RNA, protein operators with complementary addresses), holographic (quick changeable lattice--cytoskeleton), quantum (each phonon examines whole lattice), hypersound (with wave length 100-10,000 A that does not destroy molecules) system with an inner point of view (molecular coding of questions and answers about quantum processing). Neither an electron, nor a macroscopic computer has an inner point of view.

Microinjection of cyclic nucleotides provides evidence for a diffusional mechanism of intraneuronal control.

Cyclic 3',5'-AMP and cyclic 3',5'-GMP injected into large neurons of the snail Helix lucorum altered neuron activity. The effect of cAMP is usually depolarizing and that of cGMP hyperpolarizing. The results are specific for 3',5'-cyclic nucleotides. The experiments support the hypothesis that reaction-diffusion processes involving cyclic nucleotides form the basis of an intraneuronal system of information processing.

Differentiation between major and milder acute mental stress by means of the leukocyte adhesiveness/aggregation test.

Following previous observations that the adhesive state of white blood cells in the peripheral blood increases during stress, we examined 645 volunteers in various conditions of anticipatory anxiety. The volunteer subjects included 465 controls in whom stress was related solely to impending venipuncture, 149 persons under moderate stress (students before delivering a graded lecture, patients before dental treatment, etc), as well as 31 individuals under major stress (eg, before induction of anesthesia in the operating room). The respective values of aggregated leukocytes in the peripheral blood were 5.2 +/- 3.8, 6 +/- 4.2, and 19.3 +/- 9.3% of aggregated cells, with a significant difference (p < .0001) between the third and the other two groups. In both discriminant analysis and multiple regression, the leukocyte adhesiveness/aggregation test (LAAT) was shown to be superior to the white blood cell count for the detection of major stress. The LAAT had a sensitivity of 0.8, compared with only 0.35 for leukocyte count for that purpose. We concluded that the LAAT could be a powerful tool for the diagnosis of major acute mental stress and for discrimination between conditions causing major stress and those conditions that are less stressful.

Time course analysis of the state of leukocyte adhesiveness/aggregation in patients with ischaemic heart disease.

OBJECTIVE: To determine the state of leukocyte adhesiveness/aggregation (LAA), in the peripheral blood of patients with ischaemic heart disease. METHODS: All the patients were examined during their hospitalization in the Chaim Sheba Medical Center Intensive Coronary Care Unit. The patients were divided into four diagnostic categories according to the clinical picture, electrocardiographic and echocardiographic findings, as well as enzyme levels. The white blood cell count (WBCC), the erythrocyte sedimentation (ESR) and the state of LAA were measured daily for a maximum of six days. RESULTS: The LAA in ten patients with acute anterolateral myocardial infarction, increased from 5 +/- 5% day one to 13 +/- 6% at day five; the respective values for ten patients with a diaphragmatic MI were 2 +/- 2% and 5 +/- 3% respectively. Normal LAA values were noted in ten patients with myocardial ischaemia, and no evidence for infarction, as well as in ten controls. The increases LAA correlated significantly with the erythrocyte sedimentation rate (r = 0.53, p < 0.0001), raising the possibility that fibrinogen is involved in induction and/or maintenance of an increased LAA. CONCLUSIONS: Our findings suggest that the state of LAA increases during the evolution of the infarction/inflammation process. Considering that sticky leukocytes may contribute to capillary flow retardation, the results of the present study would be relevant if optimal timing for anti-adhesive therapy is considered.

[Molecular computer. Biological physics and physics of the real world]. / Molekuliarnaia vychislitel'naia mashina. Biologicheskaia fizika real'nogo mira.

Any mind (man or computer) using Physical laws is a part of physical world, and thus it is necessary to correct physical laws for taking into account influence of the work of real limited computer on the predicted result. If we suppose that univerce was constructed to be supreme regular for mind, then this correction is negligible and on principle there is possibility to calculate relation between fundamental physical and biophysical constants. Two main principle are proposed: 1. The principle of minimum action and uncontrole influence of mind. 2. The maximum asymmetry of elementary particles, which are allowed by first principle. The first principle requires the upper and the lower limits for all physical values, and first of all the upper limit for velocity (c) and the lower limit for action (h). The second principle allows to construct the minimal physical elements for mind.

[Bioenergetics and proton-electron membrane systems]. / Bioénergetika i protonno-élektronnye sistemy membran.

Measurements of potential difference on energy producing subcellular particles by the methods of penetrating ions and of association of these particles with the planar membrane are described as well as some other studies of cell electrical energetics in which the author took part.