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By P. Jerek. Ashland University.

Neurochemistry has begun to provide techniques for evaluating the nature of these consequences order genuine kamagra gold on-line impotence quoad hoc meaning. Psychoanalysis is another discipline in which interest in these issues is growing buy on line kamagra gold best herbal erectile dysfunction pills. Here, increasing emphasis is placed on the importance of understanding ego functioning and its role in mediating behavior. From this viewpoint, the question may be raised, "If the ego is the executive aspect of personality, enabling the individual to cope with reality, what becomes of ego functions in the absence of an external environment with which to cope? The work of Hartmann (36) in elaborating the theoretical basis of "ego psychology" is important in this development. A second major source of interest in human response to restricted environments has come from the military establishment. Technological developments, as seen in a variety of military applications, have given the pursuit of these questions a new urgency. With the advent of space craft, isolated radar stations, and a generally increased reliance on automated equipment, the problem of efficient functioning in severely restricted, monotonous environments is no longer merely of theoretical or academic interest. The problem of efficient personnel selection and utilization, in a wide variety of these circumstances, has provided marked impetus to the initiation and development of research programs dealing with reactions to limited sensory and social environments. In this connection, the experience of prisoners of war with Communist "thought- reform" has had similar effects. The revelation that isolation may be one factor in the susceptibility of humans to radical changes in customary behavior and beliefs has heightened interest in the study of isolation. The shocked fascination of the general public, not excepting the scientific community, has served to highlight the need for a systematic understanding of the effects of physical and -53- social isolation on behavior. Literature on methods of "thoughtreform" or ideological reform has attempted to place these procedures in a context which emphasizes the fact that they are well known and not the result of new discoveries or magical innovations on the part of the Communists (9, 10, 42, 49, 67). In these procedures, solitary confinement and monotonous, barren surroundings play an important role in making the prisoner more receptive and susceptible to the influence of the interrogator. The use of this technique rests not on laboratory science but is part of the empirical know-how of police and military interrogation. A third major source of interest in these phenomena, although perhaps less dramatic than the foregoing, has come from developments within academic psychology. One such development has taken place in the area of motivation, in which a number of experimenters (14, 34, 58) have attempted to establish the existence and operation of what has been called curiosity or exploratory drive as a primary motive. Attributing a significant role in the determination of behavior to such a drive, we find that this research has arisen in a context which seeks to refute the strongly prevalent view of the organism as a passive receptacle of experience; one which responds only to drive- relevant stimulation. As formulated by Hebb, "Characteristically, stimulus response theory has treated the animal as more or less inactive unless subject to special conditions of arousal. Studying human response to restricted environments may indicate the mode of operation of the "need for experience. Studies of sensory deprivation early in the life of animals, and the effects upon subsequent development and learning, have a relatively long history within psychology. Originally designed to evaluate the relative influence of innate organizational processes (as opposed to learning) on perception, these researches have since been more directly focused on the general effects of early deprivation upon a variety of subsequent behaviors. Although experimental work, because of ethical considerations, has of necessity been confined to animal investigations, clinical and anecdotal evidence such as the reports of Spitz (73, 74, 75) and others (22, 23, 26, 27), and those on "feral man" (70, 71) have supplemented these studies. These reports -54- have highlighted the importance of a full range of early environmental experience to the development of normal adult functioning. The occurrence of serious and irreversible disruptions of normal development and behavior has been reported. Methodological Considerations Before turning to an examination of the experimental findings, it may be well to consider some of the methodological and conceptual problems raised by research in this area. The diversity of variables involved in a systematic study of response to reduced environmental stimulation makes for considerable complexity. It will be useful to take a brief overview of procedures employed by various investigators. In the first of these, efforts were directed toward an absolute reduction of input to the organism from the external world. Lilly (50) immersed two subjects up to three hours in a tank of slowly circulating tepid water, wearing nothing but a head mask that covered eyes and ears. Subjects received an initial set of training exposures to overcome fear of the situation. On the day of the experiment, they were placed in the tank and were instructed to inhibit all movement so far as possible. Although absolute reduction in sensory input is the goal here, this latter method places less of a restriction on motor activity. A second approach to reducing sensory stimulation was used by Bexton, Heron and Scott (8). They reduced patterning of sensory inputwhile retaining levels of input at near normal. In this procedure using twenty-two male college students, the subject wore a pair of translucent goggles that permitted the perception of light but not of objects. Auditory input consisted of the masking sound of fan and airconditioner motors, and tactile experience was reduced through the use of cuffs and gloves that permitted no direct exploration of the immediate surroundings. In this procedure goggles are not used and the subject is exposed to normally patterned vision of a highly restricted environment. Wexler, Mendelson, Leiderman, and Solomon (80) placed seventeen subjects into polio tank respirators with arms and legs in cardboard cuffs. The repetitive drone of the respirator motor provided an auditory masking sound, whereas the visual environment consisted of the front of the respirator and the blank walls of a screen. Since the ports of the respirator were left open, subjects breathed for themselves. This procedure relies on monotony to achieve its effects and is thus similar to situations in which highly repetitive simple tasks are performed. It is also most similar to the environment of the prisoner in solitary confinement as well as other isolation situations as encountered in real life. Without attempting a comprehensive survey of methodological problems and issues, some examination of the choices confronting researchers in this problem area may be helpful. Efforts at the absolute reduction of sensory input are limited by the impossibility completely of doing away with sensory experience in a living conscious organism. Even the most sophisticated instrumentation cannot eliminate sensations and perceptions arising from internal body functions. To the extent to which this goal is relevant to testing a variety of hypotheses, it can only be approximated. Few if any investigators have attempted a rigorous definition of the terms they have employed. Most have used their experimental methods to provide an empirical basis for their conceptions.

As examples buy kamagra gold on line amex erectile dysfunction blood pressure medication, amino acids serine and threonine each possesses an alcoholic hydroxy group buy generic kamagra gold from india erectile dysfunction doctors in colorado springs. However, certain compounds, such as lidocaine and ketamine, may undergo rapid dealkylation. The reactivity of aromatic and heterocyclic amines, hydrazines, hydrazones, and amidines to metabolic acetylation and oxidation seems to be proportional to their pKa values. In other words, their signifcance in metabolic deactivation is related to their pKa values. Issues with metabolic transformations and conjugations can be addressed by further improving on the structure of the peptide drug. To further greatly reduce the risk of glucuronidation at the P2 position, the P2 phenol moiety was replaced by a 3-amino-2-chlorobenzoate moiety. It was also found that a slight bulk increase by a ′ P2 2,6-dimethylbenzyl moiety could improve stability against glucuronidation. Peptide drugs are more susceptible to degradation by peptidases than other classes of drugs. In order to avoid recognition and premature degradation of the peptide drug by peptidases in the body, our research group often exchange the natural amino acids found in the peptide drug with their isosteres. These isosteres have similar physi- cal or chemical properties that hopefully impart similar or higher biological activity to the parent drug. These replacements are intended to lower the risk of unexpected metabolism by peptidases without lowering the potency of the peptide drug. During the drug-optimization process of our β-secretase inhibitors, isosteres of the carboxy- late function were evaluated of which the 1H-tetrazol-5-yl isostere is depicted in Figure 8. To sum up, natural amino acid residues in a peptide drug can be exchanged for their respective isosteres to reduce the risk of premature digestion by peptidases. Other than modifying the peptide drug to reduce its risk of enzymatic degrada- tion, enzyme inhibitors can be added to the formulation. These enzyme inhibitors can either directly inhibit the peptidases, or indirectly remove ions that are needed for peptidase hydrolysis. Keeping these key points in mind, other routes of administration can also be exam- ined. For simplicity, we will refer to the routes of administration as parenteral, topical, and enteral. The parenteral route involves piercing the skin or mucous membrane for the drug to reach the bloodstream, mean- ing injectable drugs. The topical route refers to ear, eye, hair, nail, rectal, skin, and vaginal products. The enteral route would include all medications that would pass by the throat including orally inhaled, nebulized, oral, and sublingal medications. Our dis- cussion on solubilizing agents is applicable to all routes of administration, namely, parenteral, topical, and enteral. Even with the parenteral routes where several physi- cal barriers have been bypassed, the peptide drug may need to be internalized into the target cells. Several drugs are currently available on the pharmaceutical market as transder- mal patches as a noninvasive entry of drugs into the systemic circulation through the skin. Such drugs include estrogen in hormone replacement therapy, nicotine as a smoking cessation aid, and antimuscarinic scopolamine for the management of nau- sea and motion sickness. However, because normal skin is permeable only to small lipophilic molecules, peptide drugs, being hydrophilic and macromolecular, do not readily penetrate the skin. To facilitate the permeation of peptide drugs into the skin, chemical permeation enhancers and enzyme inhibitors, which are meant to prevent hydrolysis of the peptide drug, are under investigation. Phonophoresis or sonophore- sis may assist the transport of peptide drugs under the infuence of ultrasound. A promising technique is iontophoresis, in which a constant low level electric current is used to push a charged peptide drug through the skin. A combination of the above techniques may one day be able to reliably deliver peptide drugs across the skin to the systemic blood circulation in human. In mucosal drug delivery, it can be generalized that the intrinsic membrane perme- ability for a hydrophilic peptide drug follows the order of intestinal, nasal, bronchial, tracheal, vaginal, rectal, corneal, buccal, sublingual, and skin, ranked from highest to lowest permeability where absorptions through the intestinal and nasal surface are comparable. The two most favored mucosal surfaces for nonoral peptide drug delivery are the nasal and bronchial mucosa. The pharmacokinetic profles of the same drug delivered through different routes are different and adjustments to therapeutic levels are defnitively needed. As with all route of drug delivery, intersubject variability, that is, physiological differences from one person to the other will play a key factor and dosage regimens will need to be tailored to the patient. To lessen the risk of enzymatic degradation, enzyme inhibitors are incorporated in the formulation. These broad-spectrum pepti- dase inhibitors competitively bind to the active sites of proteolytic enzymes to prevent enzymatic hydrolysis of the peptide drug. Mucosal proteolytic enzymes are com- posed of exopeptidases, such as mono and diaminopeptidases, and endopeptidases, such as serine, cysteine, and aspartic peptidases. Examples of common peptidase inhibitors include amastatin, aprotinin, bestatin, boroleucine, borovaline, leupeptin, pepstatin, and trypsin inhibitors. Antibacterial agents, such as azelaic acid, fusidic acid, and puromycin, exhibit activity against peptidases. Other enzyme inhibitors, such as p-chloromercuribenzoate, phenylmethylsulfonyl fuoride, thiomersal, and chelate metal ions, are essential for proteolytic activity. The bioavailabil- ity of mucosal delivered peptide drugs can be dramatically improved by solubilizing the drug with permeation enhancers that improve solubility, enhance membrane fu- idity, or open tight junctions [24]. Tight junctions are the gaps between the margins of adjacent endothelial cells with several transmembrane proteins that project into and seal the gaps. The need for an adjuvant to enhance the penetration of peptide drugs in order to obtain adequate absorption for practical use is especially true for larger molecules and those having relatively high water solubility. However, most absorption enhancers can potentially damage the mucosa, especially when used con- tinuously or chronically, because the increase in membrane permeability may cause unpleasant sensations or local irritation [25]. Mucolytic agents, such as amino acid N-acetyl-l-cysteine, reduce the viscosity and tenacity of mucus, the frst layer, to allow surfactant molecules to diffuse more effciently onto the endothelial membrane, the second layer, to increase membrane fuidity and mucosal permeability. This mucolytic peptide drug is admin- istered to the lungs of cystic fbrosis patients through a nebulizer. Fatty acids, such as palmitic acid and oleic acid, as well as lipids are used to moisturize and soften the cell layers, thereby increasing membrane fuidity. Signal transduction substances, such as enzyme pro- tein kinase C, regulates the tight junctions, as junction modulating peptides to permit the entry of the drug into the bloodstream. The use of a mixed solvent system, that is, cosolvent, could facilitate drug sol- ubilization but has not shown any clear advantage when one considers the higher risk of mucosal irritability [26]. In developing a salt form, one should ascertain that the salt form of the peptide drug would not cause intolerable mucosal irritation.

To generate unique representations cheap kamagra gold online amex erectile dysfunction causes medscape, the algorithm dictates a strict kamagra gold 100mg low cost erectile dysfunction treatment nhs, depth-first traversal of the subgraph lattice, hence the name ‘depth-first search’ code (dfs-code). Since the string of concatenated edge/vector representations resembles the sequence of letters in a word, graph representations are compared in the same way, that is, lexicographically. The elements of the string are sequentially compared until a mismatch is found or if one string ends. Lower edge/vector labels precede higher ones; if all labels match, the shorter string precedes the longer. The dfs-code of a fragment determines which nodes can be extended, thereby restricting the number of refinements for that fragment. Appearance lists are used instead of embeddings; hence, subgraph isomorphism tests are still necessary for the graphs in these appearance lists. By concatenating all entries of the matrix, a string is formed that is used for lexicographic ordering of the graphs. In this way, embeddings are rapidly created for new fragments made from joining or extension. As stated before, finding subgraph isomorphisms is a laborious task compared to other search problems, and therefore time consuming. Gaston stores all embeddings, in 34 Computational Approaches order to restrict generation of fragment refinements to those that actually appear in the database, and for isomorphism testing. Comparison of four frequent substructure-mining algorithms in terms of a performance. The runtime per fragment found is also provided to correct for the runtime overhead due to the higher number of fragments at lower support values. Benchmarks were carried out on a comprehensive set of graph databases, including molecular databases. For example, a support value of 4% resulted in 37,727 fragments of which the largest had 22 bonds. For this, molecules were 35 Chapter 2 randomly divided into sets of various sizes. Sample measurements are provided for illustrating the quantitative comparison of the algorithms. Size and contents of the database, the minimum support value, as well as implementation details and even the underlying hardware architecture may influence performance of the algorithm. The data in Table 1 are indicative for the overall outcome of the quantitative comparison. For all algorithms, lower support values resulted in an exponential rise in runtime. This is probably due to the runtime overhead caused by the exponential rise in found fragments at lower support values. MoFa, which stores only one subgraph embedding per node in the search tree, was also memory efficient. Gaston needed most memory, since with this method embedding lists for new fragments are based on those of ‘parent’ fragments. Embedding lists are not used in gSpan, which, in fact, speed up testing, especially for larger fragments. Some memory architectures penalize the memory-intensive 36 Computational Approaches operations of Gaston. Although MoFa was the slowest in all tests, it offers more functionality for molecular databases, e. This can be useful for the exploration of biochemical 16 reactions where this length is less important. Interestingly, the four fragment miners mentioned above have been made available as 17 a single package named ParMol (Parallel Molecular Mining). Other algorithms for frequent fragment mining that are more database-centric include 18 19 18 Molfea and Warmr. Molecules are encoded as basic facts, and queries result in a combination of facts. The fragments that can be searched for or result from queries, are linear sequences of non-hydrogen atoms and bonds. The fact that Molfea only finds chains of atoms limits its usefulness 19 since almost all molecules have rings or branching points. It has been successfully applied to chemical data, for instance to find frequent substructures in carcinogenic compounds. Examples and background knowledge are encoded as a facts and rules in a relational database. Logic programming is used to represent examples, background knowledge, and hypotheses, in a uniform way. Warmr searches the available patterns in a breadth-first manner, starting from the most general relations, and gradually increasing the level of complexity, to find patterns that are more specific. Candidates that are more specific are generated by pruning non-frequent patterns from the next level. Second, the complexity of relations queried, places high demands on computing 19 resources 2. For a pair of molecules, a number of substructures/fragments may exist that occur in both structures. Corresponding atoms should have the same atom type and the same topological distance to other common atoms, in both molecules. The topological distance is the number of bonds that form the shortest path between two atoms. Scores are based on the number of common atoms, and are corrected with a penalty for discontinuous pieces. Despite the high level of detail of these approaches, exhaustive study of all possible fragments can be costly, however. A more restrictive, still sensible, approach may be to focus on chemically meaningful fragments only, instead of including every single fragment in a study. This method splits molecules into non-overlapping structural parts according to a predefined set of breaking rules. This approach yields (chemically) more intuitive fragments such as rings/ring systems, linkers, side chains, functional groups, etc. A typical compound (Figure 6-a) is fragmented into 28 molecular parts, according to the method described by Bemis et al. Three ring systems (Figure 6-d) are at the core of this compound, which are connected by two linkers (Figure 6-e). Attached to this framework are the five side chains (Figure 6-b), yielding the complete molecule. There are many variations to this method; most methods differ in the precise definition of building blocks. By removing (b) the side chains from this structure, (c) the molecular framework is revealed. The connection point to the framework or rings is indicated by a rectangular label composed of the letter B and the atom type that it is connected to.

By the summer of 189 the direct collaboration between Behring and Wernicke had already ceased after a vehement quarrel that was probably as much personal as it was professional discount 100mg kamagra gold erectile dysfunction joke. Eine medizinhistorische Untersuchung zur Entwicklung der Serumtherapie am Beispiel des Diphtherieantitoxins unter Berücksichtigung der Bioergographie des Geheimen Medizinalrates Professor Dr buy kamagra gold on line erectile dysfunction over 40. The second trial was carried out in the Children’s Medical Unit of the Charité in June 189 (Behring, Boer and Kossel 189 , p. Although these trials were therapeutically dissatisfying, they proved that the serum was not dangerous for humans (Eduard Henoch, “Kurzbericht in der Sitzung der Berliner medicinischen Gesellschaft am 1. On the nineteenth of December he presented the dog-serum to the Berlin scientifc community. In light of the positive clinical evaluation (made possible with the help of Wernicke’s dog-serum), Farbwerke Hoechst supplied Behring with additional money for his work. Based on the experiments of his colleague Ehrlich at the Institute for Infectious Diseases in the summer of 189 , Behring adopted a method of increasing immunity through injections of pure diphtheria toxin of a constant high potency:69 in experiments on the prophylactic potential of milk taken from immunized dairy animals, Ehrlich had successfully tested this method, although he had used bacteria cultures instead of toxin to achieve immunity. He thus fnally dismantled the antitoxin- concept and stood frmly on the side of phagocytosis-theory: „The preventive sera are stimulating and not antitoxic”. Roux’s recognition of Behring’s work led to a situation, in which priority-quarrels were avoided: while he presented the clinical success of the French diphtheria serum at the Congress of Hygiene and Demography in Budapest in September 1894, Behring did not attend the congress. The French press thus took it for granted that Roux was the father of the therapeutic diphtheria 72 Emil Behring, „Die Gewinnung der Blutantitoxine und die Classifcirung der Heilbestrebungen bei ansteckenden Krankheiten. As Roux’s assistant for these courses in 1893 Martin kept full notes: For the thirty-second lesson on „Diphtérie“ he had outlined: „Immunité donnée aux animaux contre la diphtérie. The notes for the thirty-ninth lesson on „Virulence & Immunité“ included a passage on „antitoxines“ and „phagocytosis“: „Pouvoir bactéricide des humeurs chez les animaux réfractaires. Pouvoir atténuant des humeurs chez les animaux qui ont l’immunité acquise; différences entre les actions in-vitro & dans l’organisme vivant. Appuis fournit à la théorie phagocytaire par la découverte des toxines microbiennes & de la sensibilité chimique des leucocytes. L’immunité est une sorte d’accoutumance des leucocytes aux poisons microbiens“ (Ibid. Theoretical differences did not prevent him to beneft from practical experience gained in Berlin. The same holds true for Behring, as shown by his correspondence with Metschnikoff beginning in the autumn of 1891, thus right after the International Congress of Hygiene and Demography in London. The prelude to the dispute was Metschnikoff’s offer to collaborate scientifcally in November 1891. In his letter he wrote: „We can only support each other just like phagocytes and bacteria“. In an article that appeared in March 1892 along with the one he had written with Wernicke in the Zeitschrift für Hygiene, Behring presented his „humoral” hypothesis, which emphasized the decisive and direct role played by the „cell-free blood“ in immunization and healing. In this article, he claimed that, unlike the „cellular“ hypothesis, his humoral one had been empirically confrmed. By May of 1894 Metschnikoff had already reassured Behring that Roux viewed him as the true „discoverer” of the serotherapy treatment against diphtheria (Metschnikoff to Behring, 14. In December 1895, both Behring and Roux were also awarded a prestigious prize of the French Academy of Science (Metschnikoff to Behring, 4. For a recent discussion of the debate on immunology between Behring and Metschnikoff see also Linton (Derek S. Unlike my assessment, Linton states that Behring, although „partial to the humoral theory, … refused to take sides or be drawn into the debates between the warring advocates of humoral immunity and cellular immunity“ (ibid. In my opinion, the fact that Behring distanced himself from Hans Buchner’s special humoral theory of „alexines“ even more than from the phagocytosis-theory (ibid. Etwas derartiges glauben wir für diejenige Immunität annehmen zu dürfen, welche wir mit dem Diphtheriegift zu Wege bringen. Vielmehr haben immer erneute Experimente ergeben, dass es direct das Serum ist, welches Immunität und Heilung gewährt“ (Behring and Wernicke 189 , 18). Roux thus transformed assertions about actively acquired immunity against toxin into assertions about immunity induced by the serum. Metschnikoff was more aware of a potential misreading of this passage, as well as the potential of such a misreading to guide Behring towards adopting the cellular or phagocytosis theory. In his next letter to Behring, Metschnikoff cited the relevant passage and suggested that Behring had discreetly disavowed the antitoxin theory. At the same time, Metschnikoff mentioned that in the meantime he had become convinced that the antitoxins could not possibly make a substantial contribution to the phenomenon of immunization. In a letter to Metschnikoff at the end of March 1892, he declared that he was now in a position to identify the antitoxin as an excretion contained in urine. Moreover, his latest experiments on immunization against tetanus would soon prove that the acquisition of immunity against the toxin was also due to a chemical process induced by the poison’s action on the cell-free blood serum. In one letter, Behring wrote: „Esteemed colleague, if for the present we two, as representatives of two contrary standpoints, still seem to work against each other, if we actually still wage a war, then I nevertheless wish that you, like me, never loose sight of the possibility of establishing common ground for a peace agreement“. And Roux obliged, describing how to prepare a very powerful toxin within a few weeks by constantly aerating the diphtheria cultures. In later years, Behring even publicly acknowledged the validity of phagocytosis, although he did point out that it was not as vitally important as the toxin-antitoxin reaction as a mechanism in immunity. Serum Evaluation On several different occasions in the beginning of his research on diphtheria serum, Behring had insisted that the antitoxin theory was mainly of „heuristic value” for him, both in extracting the therapeutic serum and in measuring its effcacy. Behring carefully elaborated his evaluation techniques parallel to the diphtheria serum research, as can easily be surmised from his publications: in 1891, he adopted one of Ehrlich’s methods,93 which he completely changed in 189 in collaboration with Wernicke94 and again in 1893, this time working together with Oscar Boer,95 before a partnership with Ehrlich gave rise to a refned and standardized method at the end of 1893. The serum was injected 24 hours before the guinea pigs were infected with a dose of diphtheria culture strong enough to kill an untreated animal. The quality of the serum was now no longer measured by its capacity to prevent symptoms, but by its capacity to prevent 89 On this issue, see the letters between Behring and Metschnikoff from May 1894 (Behring to Metschnikoff, 5. Medicinisch- chirurgisches Handwörterbuch für praktische Aerzte, edited by Albert Eulenburg, vol. Furthermore, the strength of a serum being tested now had to be specifed in relation to a so called „normal serum“ defned by Behring as a therapeutically effective dose for humans. Its actual strength was assessed against a toxin of confrmed high potency that Behring had extracted from two-years-old diphtheria cultures. The standard toxin was now made and defned by Behring and Ehrlich, and they asserted that no one had the right to reference their „titer“ without express permission. Secondly, a network of strategic cooperation between bacteriological research, clinicians, pharmaceutical enterprises, and state authorities developed around the serum: the concept of the serum’s „value” bridged the differences between these diverse interest groups because it was broad and fexible enough to be translated from a laboratory to a therapeutic measure and because it assumed an economic and a public health value. Indeed, Behring was enough of a businessman to recognize the advantages of having a metric for the „value” of the serum and of course the Farbwerke Hoechst were eager to have such a useful accounting tool. Thus, it was probably no accident that Behring redefned the evaluation method at the same time that Wernicke and Aronson were presenting their dog-sera.

Dose Oral Adult- Vitamin-B12 defciency of dietary origin: 50 to 150 µg daily between meals discount kamagra gold 100mg with amex erectile dysfunction 60784. Intramuscular injecton Initally 1 mg repeated 10 tmes at intervals of 2 to 3 days cheap 100 mg kamagra gold fast delivery biking causes erectile dysfunction, maintenance 1 mg every month. Dose may be increased at 4 weekly intervals in increments of 25 U/kg 3 tmes weekly untl a target haemoglobin concentraton of 9. Usual maintenance dose: <10 kg: 225-450 U/ kg/week; 10-30 kg: 180-450 U/kg/week and >30 kg: 90-300 U/kg/week. Subcutaneous Anaemia related to non-myeloid malignant disease chemotherapy Adult: As epoetn alfa or zeta: Initally, 150 U/kg 3 tmes weekly. Stop treatment if response is stll inadequate afer 4 week of treatment using this higher dose. Intravenous Increase yield of autologous blood Adult: As epoetn alfa or zeta: 600 U/kg over 2 minutes twice weekly for 3 week before surgery; in conjuncton with iron, folate and B12 supplementaton. Contraindicatons Hypersensitivity to mammalian cell products and human albumin, uncontrolled hypertension. Precautons Ischaemic heart diseases, chronic renal failure, hypertension, seizures, liver dysfuncton, pregnancy (Appendix 7c) and lactaton, interactons (Appendix 6c). Adverse Efects Nausea, vomitng, increased risk of hypertension, myalgia, arthralgia, rashes and urtcaria, headache, confusion, generalized seizures, thrombosis specifcally during dialysis, fever, diarrhoea, tssue swelling, fu- like syndrome, paraesthesia, constpaton, nasal or chest congeston, immunogenicity leading to Pure Red Cell Aplasia. Dose Oral Adult- Iron-defciency anaemia: elemental iron 100 to 200 mg daily in divided doses. Preventon of iron defciency anaemia (in those at partcular risk): for woman- elemental iron 60 mg daily. A-Z track technique (displacement of the skin laterally prior to injecton) is recommended to avoid injecton or leakage into subcutaneous tssue. Contraindicatons Haemosiderosis, haemochromatosis; any form of anaemia not caused by iron defciency; evidence of iron overload; patents receiving repeated blood transfusions; parenteral iron therapy. Adverse Efects Nausea, vomitng, metallic taste; constpaton, diarrhoea, dark stools, epigastric pain, gastrointestnal irritaton; long-term or excessive administraton may cause haemosiderosis; allergic reacton; back pain; staining of teeth. Folic Acid* Pregnancy Category-A Indicatons Treatment of folate-defciency megaloblastc anaemia; preventon of neural tube defect in pregnancy. Dose Oral Adult- Treatment of folate-defciency, megaloblastc anaemia: 5 mg daily for 4 months (up to 15 mg daily may be necessary in malabsorpton states). Preventon of frst occurrence of neural tube defect: 400 to 500 µg daily before concepton and during the frst twelve weeks of pregnancy. Preventon of recurrence of neural tube defect: 5 mg daily (reduced to 4 mg daily, if suitable preparaton available) from at least 4 weeks before concepton untl twelfh week of pregnancy. Contraindicatons Should never be given without vitamin B12 in undiagnosed megaloblastc anaemia or other vitamin B12 defciency states because risk of precipitatng subacute combined degeneraton of the spinal cord; folate- dependent malignant disease. Precautons Women receiving antepileptc therapy need counselling before startng folic acid; pernicious anaemia; folate dependent tumor; interactons (Appendix 6c); pregnancy (Appendix 7c). Hydroxocobalamin Pregnancy Category-C Indicatons Megaloblastc anaemia due to vitamin B12 defciency, congenital intrinsic factor disease. Dose Intramuscular injecton Adult and Child- Megaloblastc anaemia without neurological involvement: initally 1 mg 3 tmes a week for 2 weeks, then 1 mg every 3 months. Megaloblastc anaemia with neurological involvement: initally 1 mg on alternate days untl no further improvement occurs, then 1 mg every 2 months. Tobacco amblyopia and Leber optc atrophy: 1 mg daily for 2 weeks, then 1 mg twice weekly untl no further improvement, then 1 mg every 1 to 3 months. Precautons Except in emergencies, should not be given before diagnosis confrmed; monitor serum potassium levels-arrhythmias secondary to hypokalaemia in early therapy; pregnancy (Appendix 7c). Adverse Efects Itching, exanthema, fever, chills, hot fushes, nausea, dizziness; rarely, acneiform and bullous eruptons, anaphylaxis; hypersensitvity; headache; diarrhoea. Iron Dextran* Pregnancy Category-C Schedule H Indicatons Iron defciency anaemia, preventon of iron defciency before, during or afer pregnancy, to make up iron defciency afer pregnancy and during lactaton. While deciding on parenteral therapy, oral therapy should be stopped at least 24 h before. Contraindicatons History of allergic disorders including asthma and eczema; infecton; actve rheumatoid arthrits; liver disease. Precautons Oral iron not to be given until 5 days after last injection; hepatic impairment; renal impairment; pregnancy (Appendix 7c); interactions (Appendix 6d). Anaphylactc reactons can occur with parenteral iron and a test dose is recommended before each dose; the patent should be carefully observed for 60 min afer the frst test dose and for 15 min afer subsequent test doses (subsequent test doses not necessary for intramuscular administraton). Facilites for cardiopulmonary resuscitaton must be at hand; risk of allergic reactons increased in immune or infammatory conditons. Adverse Efects Less commonly nausea, vomitng, abdominal pain, fushing, dyspnoea, anaphylactc reactons (see Anaphylaxis above), numbness, cramps, blurred vision, pruritus and rash; rarely, diarrhoea, chest pain, hypotension, angioedema, arrhythmias, tachycardia; dizziness, restlessness, fatgue; seizures, tremor, impaired consciousness, myalgia, arthralgia and sweatng; injecton-site rea ctons also reported, thrombophlebits; peripheral vascular fushing; taste disturbances; syncope. Precautons Interactons (Appendix 6c); pregnancy (Appendix 7c); long term administraton of high dose may cause severe peripheral neuropathies. Adverse Efects Sensory neuropathy reported with high doses given for extended periods, numbness; neurotoxicity; hyperesthesia; muscle weakness. It is estmated that 70-80% of prescriptons for antmicrobials are probably advised unnec- essarily by the health professionals. Inspite of the fact that most common colds and diarrhoeal episodes are viral in origin, yet, antmicrobials are used indiscriminately. Reasons for over prescribing are ofen lack of confdence, peer pres- sure, patent pressure and pharmaceutcal company pressure. Poverty and inadequate access to antbiotcs consttute a major factor in the development of resistance. In many instances death of an adequately equipped diagnostc laboratory in the vicinity compels the physician to prescribe antbiotcs empiri- cally, thus, increasing the likelihood of the patent receiving a wrong antbiotc. Furthermore, ready availability of antbi- otcs over-the-counter and sales promoton schemes by the pharmaceutcal manufacturers also leads to the promoton of indiscriminate use, thus, increasing the likelihood of devel- opment of resistance. These contain either the wrong ingredient, or lesser amount of the actve ingredient. In some instances, the medicaton poisons are capable of causing disability or even death. Patents ofen demand antbiotcs for their ailment on the basis of advertsements read or seen. Unwitng use of more actve drugs at sub therapeutc doses leads directly to the development of mult drug resistance. The bacterial infectons which contribute most to human mortality and morbidity are also those in which emerging antmicrobial resistance is most obvious: diarrhoeal diseases, respiratory infectons, meningits, sexually transmited diseases, and hospital-acquired infectons. Thus, bacterial resistance to an antmicrobial agent can occur due to three general mechanisms: The drug does not reach its target In Gram negatve bacteria, many antbiotcs enter the cell through protein channels called porins. Mutatons or loss of these channels can prevent/slow the rate of antbiotc entry into a cell, efectvely reducing drug concentraton at the target site.

On the other hand cheap 100 mg kamagra gold effexor xr impotence, when he is lying there are circumstances which arouse in him the tendency to denial buy genuine kamagra gold erectile dysfunction diabetes. In the Indiana studies one experiment was based explicitly on this principle, but with the plan of distinguishing the two response tendencies by different sorts of muscular activity. The experiment gave good results, but not because it was possible to distinguish the two reaction tendencies. A better plan might have been to associate a "yes" answer with one hand and a "no" answer with the other. The purpose may be served, however, if the two response tendencies merely summate in the same place, and this could well be the mechanism by which the usual detection test works. On the conflict hypothesis, both reaction tendencies would probably need to be strong for good results. This suggestion again leads to a paradoxical recommendation: the situation must be so ordered that S makes a strong effort to conceal the infor- -162- mation. This strategy, opposite to that which might encourage admissions, may in fact be favorable to instrumental detection. The experiment, already described, which showed better detection when S was encouraged to think he might "beat the instrument" lends itself to this interpretation. If conflict is the basis of the large reactions that signify deception, then there is some danger of confusion with large reactions produced by strictly personal emotional problems. It is an established fact (see the preceding) that words touching on emotionally sensitized areas will produce large reactions, regardless of deception. A question touching on such an area might provoke a reaction greater than that produced by a mild conflict. A third possible basis of detection is the punishment, or better, threat-of-punishment principle. According to this idea a person will give a large physiologic response during lying because he anticipates serious consequences if he fails to deceive. In common language it might be that he fails to deceive the machine operator for the very reason that he fears he will fail. The physiologic reaction would be the consequence of an avoidance reaction which has a low probability of reinforcement, but not too low. If the theory has any validity at all it must be supposed that the physiologic reaction is associated with a state of uncertainty. It does seem that a lie told with a complete certainty of its acceptance would be unlikely to produce much reaction; and on the other hand we have the experimental evidence already mentioned that a lie told with no prospect of success whatever is also poorly detected. For good detection a situation may be necessary where S is willing to gamble on a rather long chance with some hope of success. To make this punishment theory cover the experimental results one needs to take "punishment" in a broad sense, since in experiments S quite often suffers no serious loss if he is detected. He does, nevertheless, lose the game which he is playing and possibly this is -163- countable as a punishment. Once again there seems to be all opposition between procedures designed to secure information and those that would lead to the best instrumental detection. Present knowledge is not sufficient to lead to a decision on which, if any, of these three theories is correct. Since the theories here discussed are not mutually contradictory, it is quite possible that all the conditions referred to are actually operative in some degree in the detection situation. In that event detection would be best when critical questions are associated with somewhat traumatic past events, when S is threatened with possible but not certain punishment as a result of lying, and when critical questions, perhaps by reason of the uncertain consequences, arouse conflicting reactions in S. Although direct, practical experience is lacking, some general findings of laboratory experiments are applicable. The relevance of many of the experiments for the criminal detection problem suffers from the fact that they involved no "crime. From their success, we may conclude that crime is not essential for lie detection. Studies directed specifically to these distinctive problems would be required for more reliable conclusions regarding the applicability of findings from previous experimentation to practical employments in intelligence interrogations. One may suppose that the person questioned, typically, will have little personal involvement in information sought. The questions frequently will not be about something he has done or for which he feels responsible or guilty. Perhaps he is not very deeply motivated to conceal the specific items or information, but loyalties and threatened penalties may dispose him -164- to do so. If the source regards the matter as unimportant, the motivational aspects of the situation would be rather like those in the common demonstration of detecting which card has been picked from a deck, a trick not difficult to do as a parlor game when a "lie detector" is available. However, if the source is highly motivated toward concealment and anticipates reprisals if he "breaks," the situation is rather like crime detection. Special considerations also arise in the intelligence interrogation situation because of the kinds of people to be interrogated, their physiologic condition, their emotional state, and their attitudes. They differ from both the suspected criminals and the normal individuals or college students used in most experiments. The effect of factors like these is scarcely known for the groups already studied. One naturally speculates about the possibility of devising a few recording instruments that would need no attachment to S and might be concealed from him. Considering the complex problems attending overt electrodes and recorders, the information gained from hidden instruments is likely to be quite meager and unreliable. Furthermore, it is not certain that an S who is not aware of the process would actually respond in the same way as one who is. It would seem necessary that interrogators use the ordinary type of instrument and rely on persuasion or coercion to get subjects into it. There is still the possibility that sophisticated subjects would, under coercion, introduce confusion by moving about and controlling breathing. Nevertheless, on the basis of the facts known from laboratory and field work one might expect that the physiologic methods can be applied to intelligence interrogations with reasonable success. Summary In spite of the early scientific foundations of lie detection in the work of Benussi, Marston, Larson, and Summers (2, 22, 23, 29, 33, 34) there is at present a rather broad gap between current practice and -165- scientific knowledge. There is, on the one hand, some information from the laboratory, which could be applied, and there are procedures of questioning, developed in field work, which await experimental testing. Although variation in procedure and in selection of cases makes present field data quite difficult to evaluate, it does seem probable that a significant amount of detection is being secured by physiologic methods. Laboratory science can make some immediate contributions to the improvement of detection methods. Developments have made possible better instrumentation for the recording and analysis of variables which currently figure in criminal detection, and suggest the possibility of recording various others which could increase the accuracy of detection. For some of these additional variables, experimental evidence is already available, others have yet to be tested. Experiments have also yielded certain results that could be applied to interrogation procedures, of which the following are illustrative. The factor of adaption, differential to particular responses, could be allowed for systematically. The attitude of the examinee influences results considerably; they are better when he does not believe the instrument is infallible.

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