By P. Mortis. New Mexico Institute of Mining and Technology.
On the whole purchase levitra 10 mg fast delivery erectile dysfunction prescription medications, matters of length buy levitra toronto erectile dysfunction virgin, level of generality purchase genuine levitra on line impotence over 70, and organization similarly have been left to the judgment of the individual contributors. In those cases where the contributors to this book were not themselves highly conversant with interrogation practices, the editors have drawn on their own experience and on research that they have conducted on interrogation in advising the contributors and in editing the chapters. The editors thus actively sought to increase the relevance of the reviews to the realities of interrogation. Lackland Air Force Base, Texas: Air Force Personnel and Training Research Center, December 1956. Effects of Communist indoctrination attempts: Some comments based on an Air Force prisoner-of-war study. Social-psychological needs and "involuntary" behavior as illustrated by compliance in interrogation. Factors used to increase the susceptibility of individuals to forceful indoctrination: Observations and experiments. Are the Cominform countries using hypnotic techniques to elicit confessions in public trials? Communist interrogation, indoctrination and exploitation of American military and civilian prisoners. Introduction When an interrogation is carried out for the purposes of intelligence, we may assume that it is intended to obtain information and not simply to produce compliant behavior on the part of the man being interrogated. One might describe an interrogator as a man who tries to obtain information from another man who may or may not possess it and who is not necessarily motivated to give the information if he does. The interrogator would like to have this man produce his information rapidly, accurately, completely, and without amendments or additions. In the words of the law, he wants "the truth, the whole truth, and nothing but the truth" — and often he wants this as soon as possible because the information that he seeks has perishable qualities. In the urgency of his need, he may interrogate a man who is injured, fatigued, or in pain. In doing so he incurs the risk that his efforts may produce compliant behavior without eliciting accurate information. The information that the interrogator seeks represents what his source still knows about various events, situations, organizations, devices, etc. The most complete and accurate information that he can hope to obtain can be only an approximation of the "true facts of the case" even "under -19- the best circumstances. The term "circumstances" is taken to mean "the condition of the man being interrogated and the situation in which he finds himself at the time. The human brain, the repository of the information that the interrogator seeks, functions optimally within the same narrow range of physical and chemical conditions that limit the functions of human organs in general; and it has, in addition, certain special limitations of its own. Any circumstance that impairs the function of the brain potentially affects the ability to give information as well as the ability to withhold it. Effects of Disturbed Bodily Functions Upon Brain Function Some aspects of the physical and chemical conditions necessary for the normal function of the human brain are rather precisely known. The brain, like other organs of the human body, exists in an "internal milieu" which is maintained in a remarkably steady state by a great number of feedback mechanisms, some quite complex. Any disturbance in the constancy of this milieu brings into play homeostatic responses which may involve the great majority of bodily processes as well as the activities of the man as a whole. When environmental conditions pose a threat, these mechanisms are capable of creating major alterations in the internal economy and in many facets of behavior (59, 129, 130). It is largely in this manner that changes in the condition of the man being interrogated may affect his ability to give accurate information. Some features of the internal milieu may be considered briefly in order to illustrate some of the vulnerabilities of the brain to external influences. A rise in temperature above 44° C (112° F) (10, 33, 121), or a fall below 24° C (75° F) (73, 116) may damage the brain permanently or be fatal. An elevation of body temperature to 41° C (106° F) or above — which may occur during the fever accompanying -20- disease or during heat stroke — nearly always impairs brain function. Similarly, a depression of body temperature to approximately 31° C (88° F) — a level which is sometimes produced artificially during anesthesia or which may occur naturally in men after extreme exposure to cold — also impairs brain function (2, 9, 37, 62, 123). The nature of the impairments of brain function that occur during these and similar disturbances of homeostasis are discussed shortly. These impairments show many points of similarity, regardless of the conditions causing them. The concentration of the fluid in the internal milieu is maintained remarkably close to 310 miliosmols per liter. An increase in its concentration (as may occur after hemorrhage or after injuries that create shock) may impair the function of the brain. A decrease in its concentration (which can take place if a man is forced to drink excessive amounts of water over a short period of time) also may impair brain funtion 1 (38, 134). The internal milieu contains a number of organic and inorganic substances in solution, and the concentration of each of these is also maintained at a remarkably steady level. Disturbances in the concentration of any of these substances, upward, downward, or in their relative proportions, may impair brain function. This impairment may be produced directly by the effect of these changes on the brain, or indirectly through the impairment of the function of other vital organs, which in turn produce a disturbance of the internal milieu. It would not be profitable to attempt to list the limits of the various elevations, depressions, or relative disproportions of these substances beyond which an impairment of brain function may occur. In practice no single change occurs, but rather a disturbance of the concentration of several. Among these are excessive sweating, deprivation of water, diets deficient in salt, ingestion of excessive amounts of water or other nonsalty beverages over a short period of time, ingestion of excessive amounts of salt in food when water is restricted, ingestion of sea water in the absence of other water, poison- 1 The awkward term “brain function” is used here because there is no other that denotes all of the complex activities that the higher centers of the brain make possible. Even very rapid breathing, which sometimes occurs in people who are anxious or afraid, may lead to chemical changes in the blood that cause disturbances of brain function (17, 36, 77, 96). Many of the crude procedures that interrogators have utilized from time to time to make informants "tractable" and to "make them talk" have an adverse effect upon the composition of body fluids: the "hot box" or "sweat box"; the deprivation of water; the salty diet; the "water treatment"; the use of emetics to produce vomiting; and the use of cathartics such as castor oil to produce diarrhea. These procedures have been used by both European and Oriental interrogators in the historical past. They were also in use quite recently in Communist countries, and perhaps still are. The brain, like other organs, maintains its functions by constant metabolic activity. The basis for this activity is energy obtained by the oxidation of the organic chemicals available from food. Thus, a constant supply of oxygen must be brought to the brain by the blood in the amount of approximately 50 cc per minute (40, 66, 102). The most common way by which the brain becomes deprived of oxygen is by failure of the circulation (65), which may be brought about by loss of blood from hemorrhage, by shock resulting from injury (which has an effect on the circulation quite similar to that of hemorrhage), or by illness. Such failure of the circulation may occur also when a man is forced to stand still in a fixed position for a long time. It is responsible for the common phenomenon of the soldier who faints while standing at attention (20, 22, 89, 90, 107). Transient circulatory failure is also involved in "emotional fainting," which occurs as a result of an acute fall in blood pressure produced by an "emotional" stimulus.
Whether one performs ex vivo or in vivo gene therapy purchase levitra australia erectile dysfunction only with partner, important focal points are duration of expression of the gene or therapeutic protein and speciﬁcity in deliv- ering the gene to the site of action with minimal adverse effects (1–3) order levitra 20mg without prescription erectile dysfunction proton pump inhibitors. Currently discount levitra 10mg fast delivery erectile dysfunction protocol reviews, genes packaged in viral vectors, such as retrovirus, adenovirus, adeno-associated virus, and herpes simplex virus, remain the leading therapeutic candidates for gene therapy, as they have produced functional improvements in several animal models of previously mentioned genetic diseased states. However, because of the risk fac- tors (pathogenicity, immunogenicity) associated with viral vectors, a major empha- sis has been placed on the formulation of nanoparticulate drug delivery vehicles for gene delivery (3). The term “nanometer” in the metric scale of linear measurement refers to one- billionth of a meter. According to National Nanotechnology Initiative, nanotechnol- ogy is deﬁned as research and technology resulting in “the controlled creation and usage” of unique small particles, varying from 1 to 100 nm in length. Looking at the biological systems, it is evident that they are composed of inherent “nanoblocks. This chapter focuses on the formulation of nanoparticulate drug delivery systems for gene delivery. The gene-loaded gold nanoparticles target the cells at a critical velocity that can puncture the cell membrane, and ultimately release the genes into the cell nucleus (9). This method, which involves physical transfer of genes, has the potential to replace the traditional transfection techniques characterized by dismal efﬁciency rates and immunotoxicity (9). It is to be noted, however, that original gene gun suffers from lack of precision and can crush the cells due to “sticking of gold par- ticles (pit damage)”. To overcome these pitfalls, Pui and Chen’s laboratory, at Uni- versity of Minnesota, devised a similar gene gun by using the patented technique called “continuous gene transfection” (9). As reported by Pui and Chen, the gold particle–coated gene composite is loaded into a capillary with the help of a syringe. The applied electric ﬁeld forces the gene suspension or spray out of the capillary at a constant velocity. The suspension is a complex mixture of “highly charged and dispersed gene-coated particles” (9). As mentioned before, the unusually high repelling velocity of similarly charged particles tear the cell membrane and “unload the genes into the cells” (9). Also, there is reduced or no risk of immunotoxicity and the cells can be transfected with plasmids as often as desired. Another added advantage is the possibility of incorporating multiple genes encoded by different plasmids (10). The potential problem of nons- electivity can be addressed by tagging the gold particles with speciﬁc antibodies. However, translat- ing this potential into reality is difﬁcult, as it is extremely tricky to deliver these short nucleotides to the site of action without degradation. Although, in nascent stage, polycation-based gene delivery shows promise in vitro and in vivo studies. However, these systems usually suffer from low sol- ubility and poor bioavailability (8). To circumvent these problems, scientists have developed a new class of nanoparticulate-based drug delivery systems known as nanocochleates (13). Originally developed by Papahadjopoulos in 1974 as an inter- mediate in the preparation of large unilamellar vesicles, the modiﬁed versions of nanocochleates (diameter range, 30–100 nm) are stable drug delivery vehicles for gene and drug delivery whose structure and properties differ enormously from those of liposomes (13). It comprises a puriﬁed calcium (or any other divalent cation, such as zinc, magnesium, or barium)–soy-based phospholipid, with lipids accounting for three- fourths of the weight. Different lipids that make up the nanocochleates include phosphotidyl serine, dioleoylphosphatidylserine, phosphatidic acid, phosphatidy- linositol, phosphatidyl glycerol, phosphatidyl choline, phosphatidylethanolamine, diphosphotidylglycerol, dioleoyl phosphatidic acid, distearoyl phosphatidylser- ine, and dimyristoyl phosphatidylserine, dipalmitoyl phosphatidylgycerol, or a mixture of one or more of these (13). Scanning electron microscopy reveals that nanocochleates have a unique solid lipid bilayer structure folded into a sheet and devoid of any aqueous internal space unlike a typical phospholipid (13). The divalent cations maintain the sheet structure by electrostatic interaction of its positive charge with the negatively charged lipid head groups in the bilayer (13). Nanocochleates can be formulated by any of the following techniques: hydrogel method, trapping method, liposomes before cochleates dialysis method, direct calcium dialysis method, or binary aqueous–aqueous emulsion system (13). The unique structure (which is extremely stable) protects the associated or encochleated drug or nucleotides from harsh conditions, enzymes, and digestion in the stomach (13). This feature also makes them an ideal vehicle for the oral and systemic delivery of drugs and polynucleotides, with the possibility of increasing oral bioavailibity of the delivered species such as drugs or genes (13). However, a major impediment in using them in vivo stems from their tendency to agglomerate or dissociate when challenged with salt and serum (14). Using biocompatible and biodegradable polymeric micelles as drug or gene deliv- ery vehicles can solve this problem. Amphiphilic block copolymers organize into “micelles of mesogenic size in aqueous milieu owing to differences in solubility between hydrophobic and hydrophilic segments” (15). These copolymer micelles can be differentiated from surfactant micelles in that they have low critical micelle concentration and low dissociation constants (15). These features enhance the reten- tion time of drugs or genes in polymeric micelles, ultimately “loading a higher concentration of genes into the target sites” (15). The polymeric entity is a copolymer containing two hydrophilic groups, one neutral and other charged. Block ionomer complex between poly(ethylene oxide)-[b]-polymethacrylate anions and cetylpyridinium cations produce nanoparticles in the size range from 30 to 40 nm (8). Despite neutralization of the charges of the polyion and the surfactant, this complex is soluble and stable, unlike the regular polyelectrolyte– surfactant complexes that are usually water insoluble. Researchers have demonstrated increased stability, transport, and efﬁciency of antisense oligonucleotides both in vitro and vivo, using cationic copolymers as gene-delivering vehicles (8). For example, Professor Sayon Roy (Boston University) demonstrated the reduction of ﬁbronectin expres- sion by intravitreal administration of antisense oligonucleotides, using block ionomer complexes (8). Nanogels represent miniature hydrogel particles that were formulated by using an emulsiﬁcation/solvent evaporation technique by chemically cross- linking polyethyleneimine with double-end–activated poly(ethylene oxide) (7,8,16). Polynuceotides can be easily entrapped in this system by mixing with nanogel sus- pensions. Oligonucleotide-loaded nanogel particles are small (<100 nm in diam- eter), stable in aqueous dispersions, show no agglomeration with time, cross the intestinal cell layers, and affect gene transcription in a sequence-speciﬁc manner (8,16). The nanogels form a protective coating around the oligonucleotides and pre- vent their degradation. They are composed of three func- tional units: the inner core, the internal shell containing the repetitive units, and the terminal functional groups (18). They can be synthesized by divergent approach (starting from the central core and proceeding toward the outermost periphery), a reverse convergent approach, or by covalent attachment or self-assembly of dendrons (18,19). Apparent similarities of dendrimer architecture with “rigidiﬁed micelles” make them attractive candidates for drug and gene delivery. Smaller drug moieties can be encapsulated in the inner core, whereas oligonucleotides can form complex with cationic surface groups (19).