Central oxytocinergic neurotransmission: a drug target for the therapy of psychogenic erectile dysfunction

A group of oxytocinergic neurons originating in the paraventricular nucleus of the hypothalamus and projecting to extrahypothalamic brain areas (e.g. hippocampus, medulla oblongata and spinal cord) control penile erection. Activation of these neurons by dopamine and dopamine agonists, excitatory amino acids (N-methyl-D-aspartic acid) or oxytocin itself, or by electrical stimulation leads to penile erection, while their inhibition by GABA and GABA agonists or by opioid peptides and opiate-like drugs inhibits this sexual response. The activation of oxytocinergic neurons in the paraventricular nucleus by dopamine, oxytocin and excitatory amino acids is apparently secondary to the activation of nitric oxide (NO) synthase. NO in turn activates, by a mechanism that is as yet unidentified, the release of oxytocin from oxytocinergic neurons in extrahypothalamic brain areas. Several peptide analogues of hexarelin, a growth hormone releasing peptide, also induce penile erection when injected into the paraventricular nucleus and, to a lesser extent, systemically, apparently by acting on a specific receptor to activate oxytocinergic neurons as shown for the above drugs and oxytocin. Paraventricular oxytocinergic neurons and mechanisms similar to those reported above are also involved in the expression of penile erection in physiological contexts, namely when penile erection is induced in the male by the presence of an inaccessible receptive female, which is considered a model for psychogenic impotence in man, as well as during copulation. These findings show that paraventricular oxytocinergic neurons projecting to extra-hypothalamic brain areas and to the spinal cord are a likely target for the treatment of erectile dysfunction of central origin.     

Screening of nutritional status in The Netherlands

BACKGROUND AND AIMS: In 2001, the Dutch Dietetic Association conducted a national screening on malnutrition. The goal of this screening was to determine the prevalence of disease-related malnutrition in The Netherlands in all fields of medical care and to investigate the involvement of the dietitian in the treatment of malnutrition. METHODS: Eight thousand five hundred and twenty nine patients were screened of which data of 7606 patients could be analysed. Eighty one per cent (6150) of the patients were hospital patients. Eleven per cent (808) of the patients lived in a nursing home. Seven per cent (533) of the patients were home-care patients, who were measured at home or at the general practitioner's office. The origin of 115 patients (2%) was not registered. Age, height, weight, unintentional weight loss, kind of illness and intervention by a dietitian were registered. Malnutrition was defined as >10% unintentional weight loss during the past 6 months and risk of malnutrition was defined as 5-10% unintentional weight loss during the past 6 months. RESULTS: Twelve per cent (884) of all patients appeared to be malnourished. Thirteen per cent (962) were at risk of malnutrition and 75% (5760) were well nourished. Fifty four per cent of the malnourished patients were referred to a dietitian.Oncological disease was more associated with malnutrition than non-oncological disease (in particular in the head and neck, lung and intestinal areas). Also, non-oncological gastro-intestinal and lung disease patients were often categorised as malnourished. Elderly patients (>75 years) were more at risk of malnutrition. BMI and unintentional weight loss did not correlate well. CONCLUSION: In this national survey conducted by dietitians, including a convenience sample of mainly institutionalised patients, approximately 25% of patients in all medical fields were categorised as moderately or severely malnourished. About half of these patients were seen by a dietitian.     

Benzoylalanine-derived ketoamides carrying vinylbenzyl amino residues: discovery of potent water-soluble calpain inhibitors with oral bioavailability

Novel benzoylalanine-derived ketoamides were prepared and evaluated for calpain I inhibition. Derivatives carrying vinylbenzyl amino residues in the P(2)-P(3) region inhibited calpain in nanomolar concentrations and thus represent a novel class of nonpeptidic calpain inhibitors. Selected examples exhibited an improved pharmacokinetic profile including improved water-solubility and metabolic stability. In particular, these calpain inhibitors showed oral bioavailability in rats as demonstrated by N-(1-benzyl-2-carbamoyl-2-oxoethyl)-2-[E-2-(4-diethylaminomethylphenyl)ethen-1-yl]benzamide (5d). The closely related derivative N-(1-carbamoyl-1-oxohex-1-yl)-2-[E-2-(4-dimethylaminomethylphenyl)-ethen-1-yl]benzamide (5b) was evaluated for neuroprotective efficacy after experimental traumatic brain injury in a fluid percussion model in rats. When administered after injury, 5b reduced the number of damaged neurons by 41%, and this result would be in line with the suggested neuroprotective efficacy of calpain inhibition.     

<Emphasis Type="Bold">Reproductive Endocrinology:</Emphasis> Uterine Perfusion and Hormonal Pattern in Patients with Polycystic Ovary Syndrome

Purpose: To evaluate whether polycystic ovary syndrome (PCOS) patients with different pulsatility index (PI) of uterine artery showed differences in their hormonal pattern. Methods: Eighty-eight PCOS-affected patients and 15 controls were submitted to Doppler flow measurement of uterine artery; LH, FSH PRL, estradiol, and androgens concentration determination; and BMI evaluation during early follicular phase. Results: The mean PI of uterine artery of PCOS patients was significantly higher than control group (2.97 ± 0.9 vs. 1.89 ± 0.2 respectively). The distribution of the PI'values was significantly different in the PCOS-affected patients and in control group. The plasma levels of DHEAS and BMI were significantly higher in PCOS patients with PI 3 than in PCOS patients with PI < 3. Conclusion: High resistance in the uterine artery is present in PCOS patients, but a wide range PI values of uterine artery is present. BMI and DHEAS seem to be factors interfering with uterine perfusion.     

Differences in autonomic physiological responses between good and poor inductive reasoners

We investigated individual- and task-related differences in autonomic physiological responses induced by time limited figural and verbal inductive reasoning tasks. In a group of 52 participants, the percentage of correctly responded task items was evaluated together with nine different autonomic physiological response measures and respiration rate (RR). Weighted multidimensional scaling analyses of the physiological responses revealed three underlying dimensions, primarily characterized by RR, parasympathetic, and sympathetic activity. RR and sympathetic activity appeared to be relatively more important response dimensions for poor reasoners, whereas parasympathetic responsivity was relatively more important for good reasoners. These results suggest that poor reasoners showed higher levels of cognitive processing intensity than good reasoners. Furthermore, for the good reasoners, the dimension of sympathetic activity was relatively more important during the figural than during the verbal reasoning task, which was explained in terms of hemispheric lateralization in autonomic function.     

The vestibulospinal reflex in humans: effects on paraspinal muscle activity

OBJECTIVE: To elucidate the electromyographic (EMG) patterns elicited in the superficial paraspinal muscles (sacrospinalis, ileocostalis lomborum, longissimus dorsi and splenium cervicis). MATERIAL AND METHODS: In normal subjects adapted to the dark and standing on a force platform, EMG patterns were elicited in the superficial paraspinal muscles by means of unilateral cold caloric stimulation of the labyrinth. RESULTS: Almost concomitantly with the occurrence of postural derangement of the subject's trunk and head, the EMG patterns of the paraspinal muscles on both sides showed significant and consistent changes. In particular, the paraspinal muscles ipsilateral to the stimulated side showed a significant reduction in activity, while the homologous muscles of the contralateral side markedly increased their activity, with a consistent delay in comparison to the contralateral muscles. Moreover, the EMG changes occurred in a hierarchic fashion in the caudal-rostral direction. In fact, the more powerful and longer-lasting effects were consistently observed in the more caudal muscles, i.e. the sacrospinalis and ileocostalis, while the effects on the longissimus dorsi and splenium cervicis muscles were weak and inconsistent. CONCLUSION: These results suggest a possible use for the EMG patterns resulting from unilateral cold caloric stimulation for clinical evaluation of the vestibulospinal reflex.     

EP 91073 prevents EP 80661-induced penile erection: new evidence for the existence of specific EP peptide receptors mediating penile erection

The effect of EP 91073, EP 51389, EP 70555 and EP 51216, peptide analogues of the growth hormone releasing peptide hexarelin, on penile erection induced by EP 80661 or EP 60761 injected into the paraventricular nucleus of the hypothalamus, was studied in male rats. Of the above peptides only EP 91073 (0.2-1 microg) was found capable of reducing penile erection induced by EP 80661 or EP 60761, when given into the paraventricular nucleus. Despite its ability to prevent EP peptide-induced penile erection, EP 91073 (1 microg) was unable to prevent penile erection induced by the dopamine receptor agonist apomorphine (50 ng), oxytocin (30 ng) and N-methyl-D-aspartic acid (50 ng), when given into the paraventricular nucleus 10 min prior to the above substances. The EP 91073-induced prevention of penile erection occurred with a reduction in the increase in nitric oxide production that occurs in the paraventricular nucleus concomitant to penile erection induced by EP 80661 and EP 60761, as measured by intracerebral vertical microdialysis. The present results are in line with the hypothesis that EP 80661 and EP 60761 induce penile erection by activating specific receptors in the paraventricular nucleus, located possibly in oxytocinergic neurons mediating penile erection, and show that EP 91073 acts as an antagonist of these EP peptide receptors mediating penile erection.     

Frequency-dependent LTP/LTD in guinea pig Deiters' nucleus

Synaptic plasticity was studied in the lateral vestibular nuclei (LVN) of the guinea pig in vivo. High frequency stimulation (HFS) of increasing or decreasing frequencies was applied to the ipsilateral vestibular nerve. Vestibular field potentials (VFPs) and extracellular single unit activity evoked in the LVN by electrical stimulation of the ipsilateral vestibular nerve, were analyzed before and after the application of different protocols of HFS. Results show that the monosynaptic component of the VFPs undergo long-term potentiation (LTP) with stimulation of 100 Hz applied for 20 s lower frequencies, applied for shorter periods, induce only a transient post-tetanic potentiation. This potentiation, although long lasting, is not permanent since it is susceptible of a reversal or cancellation by opposite patterns of HFS that determine a depression or depotentiation of the previously acquired potentiation. The results demonstrate that the plasticity phenomena that take place at the level of the LVN neurons are not steady but undergo continuous adjustment of their sign and gain depending on the variable flow of vestibular information that reach the nuclei from the labyrinthine receptors.     

Role of pH as a regulator of vaginal physiological environment

In the vagina there are several microorganisms. Their survival is fundamental to have a physiological environment in the vagina (ecosystem). The same vaginal environment playg a fundamental role to guarantee tho survival of resident microorganisms. Several factors, like changes of temperature and oxygenation, can interfere on vaginal ecosystem, but the resident vaginal microorganisms are the main factors to stabilize the vaginal ecosystem. The Doderlein's lactobacillus is the predominant vaginal microorganism. It is capable of fermenting the glycogen deriving from the decline of the eutrophic vaginal mmucosa, to lactic acid with release of hydrogen ions. The final result of that metabolism is an acid pH with values between 4-4.5. Vaginal pH undergoes physiologically changes from birth to menopause, according to changes of ovarian steroids occurring during woman's life. Adequate levels of estrogens play a fundamental role in the trophism of vaginal mucosa. In fact, estrogens increase the cellular content of glycogen. Exogenous acbvities on vaginal pH can be exerted by several factors, such as sexual activily, oral contraceptives, systemic diseases, vaginal infections (candidosis, thrichomonias, vaginosis), systemic or local therapies. They incrcase vaginal pH by acting through different mechanisms. The increase of vaginal pH is detrimental for the survival of Doderlein's lactobacillus, but not for the pathogenetic microorganisms whose replication, on the contrary, is favored by the absence of contraction exerted by Doderlein's bacillus. It has been showed that local acidifying substances (lactic acid, lactobacillus and substances recently synthesized like alpha-aminovalerianic acid, policarbophil and carbopol 934) are useful in restoring the biological and chemical characteristics of the vaginal ecosystem.