Alzheimer--certitudes and hypotheses.

Alzheimer's disease is a degenerative, progressive and irreversible condition, which affects cognitive functions. It was first described in 1907, by the German physician Alois Alzheimer. Although at the time, it was considered a rare disease, in 2010 in the world were estimated 35.6 million cases of dementia, most of these with the diagnosis of Alzheimer's disease. Typical neuropathologic lesions are represented by the amyloid plaques, neurofibrilar tangles and synapses and neurons losses. It was hypothesized that the amyloid protein has prion-like properties. Even from the first descriptions of the disease, atypical features were observed - the second case described by the physician Alois Alzheimer, had only plaques, the tangles were missing. About 19 % of the healthy old subjects present in the brain the same lesions as Alzheimer's cases, while in 10 % of the cases of disease, in necropsy are present only the plaques or only the tangles. These aspects are even more paradoxical, as the certain diagnosis is established only at necropsy, on anatomopathological lesions. Even so, the international diagnosis criteria, based on clinical aspects, can establish a certain, probable or a possible diagnosis. It exist an early-onset form, as well as a late-onset form of disease (which appears after 80-85 years of life); genes are involved in the genesis of the disease. A lot of money are spent to find an efficient medication in the treatment of the disease (tramiprosate--an amyloid-antagonist, Dimebon, gamma-secretase inhibitors or a vaccine--a synthetic form of the amyloid protein); for the moment the used medication may at its best only to temporary improve the symptoms. Some scientists believe that approx. 30 % of the cases are wrongly diagnosed with Alzheimer, being in fact other forms of dementia, or that we deal with several biologic processes, generating rather an Alzheimer's syndrome, meanwhile others are unsatisfied by a poor diagnosed disease and its popular receipt as a part of the normal aging process.

Posttraumatic stress disorder: neuroendocrine and pharmacotherapeutic approach.

Posttraumatic stress disorder (PTSD) is represented by the development of characteristic symptoms, that appear following direct/indirect exposure to a traumatic event in which physical harm was threatened, witnessed or experienced. PTSD can also occur after the unexpected death of a family member or close friend, following a serious harm or threat of death or injury to a loved one, or in case of divorce or unemplyoement. It occurs in 1%-4% of the population. As neuroendocrine pattern, PTSD is characterized by abnormal low cortisol levels and higher than normal epinephrine and norepinephrine levels. In chronique forms a total decrease of the hippocampal volume, was found, region of the brain involved in processing memories and in the memorization process. Symptoms are grouped in three main categories: re-experiencing the event, accompanied by anxiety, nightmares and flashbacks; persistent avoidance of any reminders of the event, feeling detached or estranged from others; persistent anxiety and/or physical reactivity. As treatment, besides various psychotherapy techniques, various classes of psychotropic drugs are used, such as morphine, antipsychotics, usual or atypical antidepressants, anticonvulsants, to reduce anxiety, avoidance, nightmares and hyperexcitability.

Main neuroendocrine features and therapy in primary sleep troubles.

Insomnia is a sleep trouble in which the patient has difficulties in falling or in staying asleep. There are patients who fall asleep easily, but wake up too early; others have troubles in falling asleep and a third category has troubles with both falling and staying asleep. Independent of the type of insomnia, the final result is a poor-quality sleep, responsible for depressive or irritable mood, loss in concentration, learning and memory capacities. Sleep is essential to emotional and physical health. Inadequate sleep over a period of time is increasing the risks for obesity, diabetes, heart disease and depression. People suffering of chronic insomnia show an increased predisposition for psychiatric problems. People who had sleep troubles reported impaired ability to fulfill tasks involving memory, learning, logical reasoning and mathematical operations. New studies show that insomnia might be a result of the decrease of gamma-aminobutyric acid (GABA), a neurochemical responsible for the decrease of activity in many brain areas. Lower brain GABA levels were also found in people with major depressive disorder and anxiety disorders. Hypnotics, such as benzodiazepines are acting increasing the activity of the GABA neurons. Exposure to stress is associated with a greater risk for insomnia, with individual differences. Stress activates the sympathetic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis. Increased activity of HPA axis is stimulating the secretion of corticotropin-releasing hormone, further inducing sleep disruption. Insomnia is also associated with depression and anxiety disorders, in which the HPA axis is characteristically overactive. People who show predisposition to sleep troubles have a hyperactive sympathetic nervous system, they are usually suffering from hyperarousal and they have a more intense response to stressful events. Primary sleep troubles (insomnia) has no apparent causes, is lasting more than one month, and is affecting approximately a quarter of the adult population. Secondary insomnia is associated with chronic heart and/or lung diseases, medication which interfere with onset or duration of sleep, constant change of the sleep habits, restless leg syndrome, etc. Besides lifestyle changes and cogn itive-behavioral therapy, in the treatment of insomnia are used hypnotic medicines, advised to be prescribed on short-term cures of one or two weeks. Benzodiazepines are inducing and maintaining sleep. Longer use is responsible for severe side effects--dependency and withdrawal syndrome, daytime drowsiness and dizziness, low blood pressure, memory troubles and change in the melatonin secretion during night-time period. For these reasons were created non-benzodiazepines hypnotics--zolpidem, zaleplon, which are as effective as benzodiazepines, but have fewer side effects. Nevertheless the use of these hypnotics is also restricted to 7-10 days. Zopiclone (Imovane) another short-acting non-benzodiazepine hypnotic has a different chemical structure, but a pharmacologic profile similar to that of the benzod iazepines; the treatment should be of maximum four weeks. Besides generally known concerns related to the use of hypnotics (residual sedative effects, memory impairment, rebound insomnia, abuse, dose escalation, dependency and withdrawal problems) it was signaled a risk of death associated with the use of current hypnotic medications.

[Relevance of L-type calcium channels for the non-genomic effects of estradiol and aldosterone upon contractile activity in isolated arteries]. / Relevanta canalelor de calciu de tip L pentru efectele non-genomice ale estradiolului si aldosteronului asupra activitatii contractile în artere izolate.

UNLABELLED: Non-genomic vascular effects of steroids are incompletely understood, despite progress made regarding some aspects, such as the mechanism of endothelium-dependent relaxation by estrogens. AIM: To investigate the involvement of certain mechanisms in the rapid, non-genomic effects of estradiol (EST) and aldosterone (ALD) on endothelium-dependent and -independent vasomotor responses. MATERIAL AND METHODS: Isometric myography of rings from aorta, mesenteric arch, and first order mesenteric branches isolated from male Wistar rats was used. RESULTS: We found that L-type calcium channels (Cav1.2) are important for endothelium-independent relaxation induced by EST, while ALD reduces the involvement of Cav1.2 in phenylephrine-induced contraction and potentates both NO- and EDHF-mediated endothelium-dependent relaxation. To further examine the relevance of Cav1.2 for the vascular effects of EST and ALD, we were using rings with and without functional endothelium, precontracted by direct activation of Cav1.2 (Bay K 8644), high extracellular K+, phenylephrine, and under complete Cav1.2 block (nifedipine). Data suggest that EST, which directly inhibits Cav1.2 in transfected HEK cells, uses mainly this path to induce endothelium-independent relaxation, and that ALD may induce a rightward shift in the voltage-dependence of Cav1.2.

[Resolution of inflammation--pharmacological aspects]. / Rezolutia inflamatiei--implicatii farmacologice.

Inflammation is a fundamental biologic process evolutionally preserved by a germ line code. The interplay of the epigenetic with the environment directs the code to temporally distinct inflammatory responses, which can be acute or chronic. The aim of this study is to present new aspects regarding the resolution of inflammation. Acute inflammation normally resolves by mechanisms still somewhat elusive. Current evidence suggests that an active coordinated program initiated the first few hours after the inflammatory response begins and its failure lead to chronic inflammation. This process is essential for appropriate host responses, tissue protection and the return to homeostasis. Prostaglandins and leukotrienes are lipid mediators that play important roles in host defense and acute inflammation. Granulocytes promote the switch of arachidonic acid-derived prostaglandins and leukotrienes to lipoxins, active antiinflammatory and pro-resolution mediators. The apoptosis of the neutrophils coincides with the biosynthesis of resolvins and protectins from omega-3 polyunsaturated fatty acids and releases anti-inflammatory and reparative cytokines. This information could lead to new treatments for inflammatory diseases.

[Intentional poisoning with ACE inhibitors. Emergeny Hospital Iasi]. / Toxicitatea acuta a inhibitorilor enzimei de conversie a angiotensinei. Experienta clinicii de medicina interna si toxicologie, spitalul clinic de urgente "SF Ioan" Iasi.

UNLABELLED: Regarding angiotensin-converting enzyme inhibitors (ACEI) poisoning, only few data are available in the last decade literature. In the previous couple of years especially isolated case reports were published. MATERIAL AND METHOD: We analyzed retrospectively all the patients with acute ACEI poisoning admitted in Iasi Internal Medicine and Toxicology Clinic between 2004 and 2009. RESULTS: 17 cases of poisoning were recorded (enalapril-9 cases, captopril-3 cases, perindopril-3 cases, lisinopril-2 cases). All the poisonings were intentional. A favorable outcome was consistently observed, and were recorded no sequelae or death in this study. The main complain was hypotension, required fluid administration, only one case with 500 mg enalaprilum and severe hypotension required injection of vasopressive amines. No abnormal renal function and no angioedema were noted.

[Production of chemoattractant-induced reactive oxygen species in human neutrophils--role of protein kinase C isoforms]. / Productia de specii reactive ale oxigenului indusa de chemoatractanti in neutrofile umane. Rolul isoformelor protein-kinazei C.

UNLABELLED: The aim of our study was to characterize the priming effect of extracellular nucleotides on reactive oxygen species (ROS) production induced by formyl-methionyl-leucyl-phenylalanine (fMLP), interleukin-8 (IL-8), leukotriene B4 (LTB4), and platelet activating factor (PAF). Also, we investigated the roles played by different protein kinase C (PKC) isoforms in nucleotide-induced priming. ROS production was determined by an isoluminol-based assay. MATERIAL AND METHOD: Nucleotide-induced priming was concentration- and time-dependent. The concentration of UTP able to cause maximal priming was 10 microM. When UTP (10 microM) was administered prior the agonist, the increase of the amplitude of the response reached the maximum at 1 minute of preincubation with the nucleotide. RESULTS: Calcium depletion of neutrophil caused significant inhibition of ROS production induced by all agonists tested, but did not affect the priming effect of the nucleotides. We tested the effect of several PKC inhibitors on the nucleotide-induced priming. GF 109203X (5 microM), an inhibitor of all neutrophil's PKC isoforms, or RO 31-8220 (5uM), an inhibitor of classical and novel PKC isoforms, abolished the responses induced by fMLP (10 nM) IL-8 (10 nM), LTB4 (100 nM) or PAF (100 nM). Go 6976 (100 nM), a selective inhibitor of classical PKC isoforms, had no effect on nucleotide-induced priming, suggesting that activation of these PKC isoforms does not play a role in the priming effect. Rottlerin (5 microM), a PKC delta inhibitor, almost abolished the effect of fMLP in the absence or in the presence of UTP, indicating that PKC delta is essential for the fMLP-induced effect; rottlerin also caused inhibition of ROS production induced by IL-8, LTB4 or PAF, however the priming effect of UTP was not affected for these chemoattractants. Our data suggest that classical PKC isoforms do not play a role in chemoattractant-induced ROS production. CONCLUSION: Although fMLP induced effect appears to be highly dependent on PKC delta activation, other chemoattractants are able to cause ROS production through PKC delta-independent mechanisms.

[The neutrophil in human pathology]. / Neutrofilul in patologia umana.

The aim of this paper is to present few aspects of neutrophil role in some human diseases. New clinical and experimental findings and challenging hypothesis are briefly reviewed. The major role of neutrophils in host defense is a rapid response to invading microorganisms. To select their targets, neutrophils do not differentiate well between strange and host antigens without the support of soluble components of the immune system. The powerful weapons of neutrophils and the nonspecific response are the two major mechanisms by which they may damage normal tissue. The host-harming potential of the neutrophils is restricted by elimination of the primary event that initiates inflammatory response and by means that inactivate neutrophils. Inactivation of mediators and temporal adjustment in the pattern of chemokines production lowers the neutrophil influx; apoptosis provide safe clearance of dying neutrophils from the inflammatory site. Neutrophils become the major factor for tissue injury if these regulatory mechanisms are disturbed or if the acute episode cannot be resolved.

New technical approaches in stereotaxic catheterization of cerebral ventriculi: implications for the L-arginine/NO synthase/nitric oxide cascade.

In order to study the actions of certain substances at cerebral level, a stereotactic device for ensuring a precise catheterization of points in certain cerebral areas was used. For the operation technique was used a stereotaxic atlas specifically designed for rat brain (G. Paxinos, C. Watson, 1998), which offers all the necessary information for the identification of the trepanation. Stereotaxic implantation of cannules in the brain is useful for microinjecting solutions containing various substances (in amounts of microl), directly and targeted in the anatomical structures of the brain. The technique described can use either metalic or silastic cannules, that have variable lumen (usually for adapting a Hamilton syringe). The cannules can be implanted at cerebroventricular level, having the possibility to target all the cerebral ventricles. The intracerebroventricular (icv) administration of L-arginine induces a significant increase of response latency for mechano-algesic test. The most obvious changes are induced following the administration of the association of L-NAME with L-arginine, situation when is manifested an important increase of the response latency, starting with 5 minutes post-administration and continuing up to 45 minutes determination. The increase is significantly higher compared with the results obtained with L-arginine alone. A similar evolution is registered in the case of the plantar test.

Experimental data regarding the implications of certain minimum structure enkephalin-like peptides in nociceptive processing.

The aim of this study was to investigate the importance of the amino acidic sequence at N-terminal end of certain minimum structure enkephalin-like peptides for the analgesic activity. Different groups of mice or rats were treated with 1) L-tyrosine (i.p. 200 mg/kg), 2) Tyr-Phe (i.t. 0.5 mg/rat), 3) Tyr-Pro-Phe (i.t. 0.5 mg/rat), 4) Gly-Tyr (i.t. 0.5 mg/rat), 5) Tyr-Gly-Gly (i.t. 0.5 mg/rat). Different tests were utilized to evaluate the antinociceptive effect of the substances tested: thermal nociception (hot plate test, plantar test), mechanical nociception (analgesymeter test). Tyr-Pro-Phe, Tyr-Gly-Gly, Tyr-Phe, but not Gly-Tyr, elicited analgesic activity. So, the presumption made in the case of atypical opioid peptides that opioid-like activity in case of peptides presumes a tyrosine residue at the N-terminal sequence, applies for shorter peptides. It appears also that minimal structure brain peptides with an N-terminal Tyr-Pro, rather than the Tyr-Gly-Gly-Phe sequence typical of other endogenous opioids, can provide better affinity for the opioid receptors and stronger analgesic activity. The inhibition of their analgesic effect by previous administration of naloxone proves that this effect is mediated through the endogenous opioid system.

[Opioid tolerance and dependence--pharmacological aspects]. / Toleranta si dependenta la opioide--implicatii farmacologice.

Prolonged opioids administration leads inevitably to tolerance and dependence, a phenomenon we meet more often in healthy people than in ill patients. Tolerance means a hypersensibility of neuronal membranes as well as changes in the number and affinity of opioid receptors, which implies intake of larger doses to obtain the initial effect. Physical dependence, quite different of the psychological one, is the appearance of abstinence syndrome on sudden interruption of opioid administration or on administration of an antagonist. There is usually cross-tolerance in opioids, but it can also be incomplete, when the initial opioid can be replaced with another one that produces a milder abstinence syndrome. Classically, metadone is used in long time therapy, after detoxification with an antagonist is performed (naloxon, naltrexon). Modern pharmacological alternatives are levo-alpha-acetyl-methadol (LAAM) and agonists-antagonists (butorphanol, buprenorphine, pentazocine, nalbuphine). An antagonist can also be used if associated with an alpha--stimulant (clonidine), in order to remove noradrenergic manifestations of abstinence syndrome. Now other therapeutical principles are being studied: enkephalinaze inhibitors to reduce the abstinence syndrome, NMDA receptor antagonists, NO sintetasis inhibitors, that facilitates opioid analgesia and hinders tolerance development; colecystokinin-receptors agonists or antagonists to reduce tolerance on morphine. A recent study showed that the concomitant administration of an opioid agonist (sufentanil) and a calcium channels blocker (nimodipine) not only prevents from tolerance development but also triggers hypersensibility to analgesic effects of the opioid.

[Experimental data on pharmacological effects of new phenothiazine derivatives]. / Données expérimentales concernant les effets pharmacologiques de quelques nouveaux dérivés phénothiaziniques.

A variety of triazoles and thiadiazoles linked to the N-atom of the phenothiazine through a two carbon atoms chain have been submitted to preliminary toxicological screening (DL50 and DMT). Two derivatives have been selected for the specific pharmacological evaluation. It has been noted a diminution of the exploratory capacity without the muscle tonus, the balance and the capacity of becoming normal again of the tested animals (mice and rats) being affected.

[The role of the experiment in evaluating psychotropic substances]. / Câteva consideratii privind rolul experimentului în evaluarea substantelor psihotrope.

Designing new experimental models on animals for testing psychotropic drugs encounter important difficulties. The criteria for choosing a certain model, some pharmacokinetic aspects and few examples of models used in psychotropic drug testing are briefly presented.

[The clinicopsychological and therapeutic significance in the depression-pain relationship]. / Semnificatii clinico-psihologice si terapeutice în relatia depresie-durere.

The frequency of depression-pain association, gives the authors the opportunity of evaluating the actual pattern of managing pain according to its sensory-discriminatory, affective-emotional, cognitive and behavioral features. The neurophysiologic, affective and psychologic factors generally correlate in the induction and evolution of pain, being dependent on the individual reactivity environmental and socio-cultural relations. The efficacy of antidepressive drugs in the therapy of pain, explained by their action on the serotoninergic systems, advocates the clinical relationship depression-pain, but also their analgesic properties independent from the thymoanaleptic effect. The results of the clinical essays the authors have carried on some antidepressants (Imipramine, Amitryptyline, Mianserine, Maprotyline) evidenced their effect on the various forms of manifestation and localizations of pain complains. The amelioration of pain, certified by the use in dynamics of Hamilton's depression scale, occurs earlier than the improvement of depressive symptoms, thus attesting the analgesic properties of the antidepressants. The preservation and merging of these effects during the investigation interval, at the same time with an improvement in the depressive symptoms support the clinical correlation depression-pain, emphasizing the complex character of the algopathic syndrome, both somatically and mentally.