Essential role of brain-derived neurotrophic factor in the regulation of serotonin transmission in the basolateral amygdala.

Human and animal model studies have linked brain-derived neurotrophic factor (BDNF) with the etiology of anxiety disorders. This pleiotropic neurotrophin and its receptor, TrkB, promote neuronal survival, differentiation and synaptic plasticity. Here we interrogated the role of BDNF in serotonergic neurotransmission in the basolateral amygdala (BLA), a limbic brain region associated with the neurobiology of anxiety. We found that both GABAergic and pyramidal projection neurons in the wild-type BLA contained TrkB receptors. Examination of BDNF(2L/2LCk-Cre) mutant mice with brain-selective depletion of BDNF revealed mild decreases in serotonin content in the BLA. Notably, whole cell recordings in BLA pyramidal cells uncovered significant alterations in 5-HT(2)-mediated regulation of GABAergic and glutamatergic transmission in BDNF(2L/2LCk-Cre) mutant mice that result in a hyperexcitable circuit. These changes were associated with decreased expression of 5-HT(2) receptors. Collectively, the results indicate a required role of BDNF in serotonin transmission in the BLA. Furthermore, they suggest a mechanism underlying the reported increase in anxiety-like behavior elicited by perturbed BDNF signaling.

The hypothalamic insulin-like growth factor-1 receptor and its relationship to gonadotropin-releasing hormones neurones during postnatal development.

Reproduction in vertebrates is controlled by hypophysiotropic gonadotropin-releasing hormone (GnRH) neurones. Pulsatile GnRH release increases during reproductive development, resulting in the onset and progression of puberty and, ultimately, the acquisition and maintenance of adult reproductive function. These changes in GnRH release are largely due to inputs to GnRH cells from other factors, including the neurotrophic factor, insulin-like growth factor-1 (IGF-1). Here, molecular studies were undertaken to quantify expression of IGF-1 receptor (IGF-1R) mRNA in the preoptic area-anterior hypothalamus (POA-AH) and mediobasal hypothalamus (MBH)-median eminence (ME), the sites of GnRH perikarya and neuroterminals, respectively. Immunocytochemical studies were also carried out to study the anatomical relationship between the IGF-1R and GnRH neurones. Experiments were performed in a developmental context using neonatal (P5), peripubertal ( approximately P30) and adult (P60) male and female mice. We found that IGF-1R mRNA levels in the POA-AH were significantly different among all age groups, with levels higher at P60 then P5 or approximately P30. Levels of IGF-1R mRNA in the MBH-ME were lower at P5 than approximately P30 or P60. Qualitative observations suggested that IGF-1R immunoreactivity in POA-AH increased from P5 through P60. Quantitative double-label immunocytochemistry studies showed that GnRH perikarya expressed IGF-1R. Taken together, the results demonstrate expression of, and developmental changes in, IGF-1R gene and protein in brain regions containing GnRH and other neuroendocrine cells. Moreover, the novel finding that the IGF-1R is expressed on GnRH perikarya in vivo suggests a potential direct anatomical locus where IGF-1 can regulate reproductive development and function.

Neurosecretory and non-neurosecretory parvocellular neurones of the hypothalamic paraventricular nucleus express distinct electrophysiological properties.

Parvocellular neurones of the hypothalamic paraventricular nucleus (PVN) comprise neurosecretory and non-neurosecretory subpopulations. We labelled neurosecretory neurones with intravenous injection of the retrograde tracer, fluoro-gold, and recorded from fluoro-gold-positive and negative PVN parvocellular neurones in hypothalamic slices. Non-neurosecretory parvocellular neurones generated a low-threshold spike (LTS) and robust T-type Ca2+ current, whereas neurosecretory neurones showed no LTS and a small T-current. LTS neurones were located in non-neurosecretory regions of the PVN, and non-LTS neurones were located in neurosecretory regions of the PVN. These findings indicate that neurosecretory and non-neurosecretory subtypes of parvocellular PVN neurones express distinct membrane electrical properties.

Noradrenergic regulation of parvocellular neurons in the rat hypothalamic paraventricular nucleus.

Noradrenergic projections to the hypothalamic paraventricular nucleus have been implicated in the secretory regulation of several anterior pituitary hormones, including adrenocorticotropin, thyroid-stimulating hormone, growth hormone and prolactin. In an attempt to elucidate the effects of norepinephrine on the central control of pituitary hormone secretion, we looked at the actions of norepinephrine on the electrical properties of putative parvocellular neurons of the paraventricular nucleus using whole-cell current-clamp recordings in hypothalamic slices. About half (51%) of the putative parvocellular neurons recorded responded to norepinephrine with either a synaptic excitation or a direct inhibition. Norepinephrine (30-300microM) caused a marked increase in the frequency of excitatory postsynaptic potentials in about 36% of the parvocellular neurons recorded. The increase in excitatory postsynaptic potentials was blocked by prazosin (10microM), but not by propranolol (10microM) or timolol (20microM), indicating that it was mediated by alpha(1)-adrenoreceptor activation. It was also blocked by ionotropic glutamate receptor antagonists, suggesting that the excitatory postsynaptic potentials were caused by glutamate release. The increase in excitatory postsynaptic potentials was completely abolished by tetrodotoxin, indicating the spike dependence of the norepinephrine-induced glutamate release. In a separate group comprising 14% of the parvocellular neurons recorded, norepinephrine elicited a hyperpolarization (6.2+/-0.69mV) that was blocked by the beta-adrenoreceptor antagonists, propranolol (10microM) and timolol (20microM), but not by the alpha(1)-receptor antagonist, prazosin (10microM). This response was not blocked by tetrodotoxin (1.5-3microM), suggesting that it was caused by a direct postsynaptic action of norepinephrine. The topographic distribution within the paraventricular nucleus of the norepinephrine-responsive and non-responsive parvocellular neurons was mapped based on intracellular biocytin labeling and neurophysin immunohistochemistry. These data indicate that one parvocellular subpopulation, consisting of about 36% of the paraventricular parvocellular neurons, receives an excitatory input from norepinephrine-sensitive local glutamatergic interneurons, while a second, separate subpopulation, representing about 14% of the parvocellular neurons in the paraventricular nucleus, responds directly to norepinephrine with a beta-adrenoreceptor-mediated inhibition. This suggests that excitatory inputs to parvocellular neurons of the paraventricular nucleus are mediated mainly by an intrahypothalamic glutamatergic relay, and that only a relatively small subset of paraventricular parvocellular neurons receives direct noradrenergic inputs, which are primarily inhibitory.

Noradrenergic excitation of magnocellular neurons in the rat hypothalamic paraventricular nucleus via intranuclear glutamatergic circuits.

Noradrenergic projections to the hypothalamus play a critical role in the afferent control of oxytocin and vasopressin release. Recent evidence for intrahypothalamic glutamatergic circuits prompted us to test the hypothesis that the excitatory effect of noradrenergic inputs on oxytocin and vasopressin release is mediated in part by local glutamatergic interneurons. The voltage response to norepinephrine (30-300 microM) was tested with whole-cell recordings in putative magnocellular neurons of the paraventricular nucleus (PVN) in hypothalamic slices (400 micrometers). Norepinephrine elicited an alpha1 receptor-mediated direct depolarization in 23% of the magnocellular neurons tested; however, the most prominent response, seen in 42% of the magnocellular neurons, was an alpha1 receptor-mediated increase in the frequency of EPSPs. The norepinephrine-induced increase in EPSPs was blocked by tetrodotoxin and by ionotropic glutamate receptor antagonists, suggesting that norepinephrine excited presynaptic glutamate neurons to cause an increase in spike-mediated transmitter release. The increase in EPSPs also was observed in a surgically isolated PVN preparation (64% of cells) and with microdrop applications of norepinephrine (1 mM, 33% of cells) and glutamate (0.5-1 mM, 28%) in the PVN, indicating that the norepinephrine-sensitive presynaptic glutamate neurons are located within the PVN. Biocytin injection and subsequent immunohistochemical labeling revealed that both oxytocin and vasopressin neurons responded to norepinephrine. Our data indicate that magnocellular neurons of the PVN receive excitatory inputs from intranuclear glutamatergic neurons that express alpha1-adrenoreceptors. These glutamatergic interneurons may serve as an excitatory relay in the afferent noradrenergic control of oxytocin and vasopressin release under certain physiological conditions.

Determination of lingual myoarchitecture in whole tissue by NMR imaging of anisotropic water diffusion.

The muscular anatomy of the tongue consists of a complex three-dimensional array of fibers, which together produce the variations of shape and position necessary for deglutition. To define the myoarchitecture of the intact mammalian tongue, we have utilized NMR techniques to assess the location and orientation of muscle fiber bundles through measurement of the direction-specific diffusional properties of water molecules. Whole sheep tongues were excised and imaged with a slice-selective stimulated-echo diffusion sequence in the midline sagittal plane, and three-dimensional diffusion tensors were determined for each voxel. The derived diffusion tensors were depicted graphically as octahedra whose long axes indicate local muscle fiber orientation. Two distinct groups of midline fibers were identified: 1) in-plane sagittal fibers originating in the posteroinferior region of the tongue, radiating with a fanlike projection anteriorly and superiorly and merging with vertically oriented fibers, and 2) cross-plane (transverse) fibers, oriented at right angles to the vertically aligned fibers, predominantly in the anterior and superior regions of the tongue. Regional comparison of diffusion anisotropy revealed uniform and parallel alignment (high anisotropy) in the posteroinferior region of the tongue, corresponding to the base of the genioglossus, and less uniform, orthogonally aligned fibers (low anisotropy) in the anterosuperior region of the tongue, corresponding to the core intrinsic muscles. These data indicate that lingual myoarchitecture, determined through direction-dependent mobility of water molecules, can be depicted as discrete regions of muscle fibers, whose orientation and extent of diffusion anisotropy predict local contractility.

Patterns of lingual tissue deformation associated with bolus containment and propulsion during deglutition as determined by echo-planar MRI.

Disordered lingual function is a common clinical attribute of patients with oropharyngeal dysphagia. To determine physiologic patterns of lingual tissue motion during swallowing, we imaged the actively deforming tongue during water bolus swallows with sequential single-slice sagittal orientation echo-planar imaging. At rest, with the bolus contained in the oral cavity before swallow initiation, the tongue displayed a characteristic curved configuration consisting of a convex surface (anterior to the bolus) in continuity with a concave surface (containing the bolus) and a posterior-located convex surface (comprising the tongue base). With swallow initiation, the previously deformed tongue underwent rapid biphasic displacement: (a) superior displacement of the anterior tongue and deepening of the midposterior-located bolus-containing concavity, resulting in a laterally beveled surface encompassing the bolus; and (b) retrograde displacement of the configured tissue, resulting in clearance of the bolus from the oral cavity to the oropharynx. These findings indicate that deglutitive tongue action can be depicted by echo-planar imaging as a series of deformative surface modifications, which are related to the activity of intrinsic and extrinsic lingual muscles.

Echo-planar magnetic resonance imaging of deglutitive vocal fold closure: normal and pathologic patterns of displacement.

Abnormalities of vocal fold closure during deglutition predispose to aspiration due to impairment of airway protection. Conventional assessment of deglutitive vocal fold motion with laryngoscopy does not permit visualization through a complete adduction-abduction cycle. We determined spatiotemporal patterns of deglutitive vocal fold adduction through echo-planar magnetic resonance imaging in 15 normal volunteers and 6 patients with vocal fold paralysis. In normal volunteers, deglutitive vocal fold adduction was synchronized with laryngeal elevation, with complete vocal fold closure at the apex. Patients with unilateral vocal fold paralysis demonstrated reduced elevation and medial movement of the involved vocal fold. At maximal laryngeal elevation the uninvolved vocal fold attained a position superior to the paralyzed fold, resulting in level differences and an interglottic gap. Patients with bilateral vocal fold paralysis demonstrated reduced elevation and medial movement of both vocal folds. These findings indicate that normal and abnormal patterns of vocal fold displacement can be distinguished noninvasively through the use of echo-planar imaging.

The Hay's flexion rotation obstetric forceps: reestablishing relevance in modern obstetrics.

A prospective evaluation of 140 forceps deliveries with the Hay's flexion rotation obstetric forceps was undertaken over a 5-year period. The Hay's forceps was used for a variety of indications and included outlet forceps application in 35.7%, low or midforceps application in 29.3% with forceps rotation in 16.4%, 19.3% of applications for an aftercoming head and 19.3% applications at caesarean section. Outlet forceps deliveries had maternal and neonatal outcomes comparable with the Wrigley's short obstetric forceps. Midforceps applications were compared to the Simpson's long forceps, with maternal morbidity at 21% being significantly less, blade marks being the only neonatal morbidity and the Apgar scores being significantly higher with the Hay's forceps. Every forceps application at caesarean section resulted in an easy delivery. Thus the Hay's forceps with innovations such as parallelism and flexion potential could revalidate the role of the forceps in contemporary obstetrics.

Evaluation of two methods employed for cervical ripening.

The study evaluates breast stimulation and oxytocin infusion as methods for cervical ripening in patients where an obstetric indication for induction of labour exists. Forty patients with a Bishop score of 5 or 6 were randomly selected for either breast stimulation or oxytocin infusion. In a similar group of 20 cases, no method was employed. The Bishop score improved in 41.2% of cases where breast stimulation was used as compared to 75% where an oxytocin infusion was given. Three foetal deaths in the breast stimulation group brought the study to a stop after 17 cases. Cervical ripening with an oxytocin infusion drip appears to be a better method since infusion dosage can be precisely controlled making the technique more predictable and reliable. Though breast stimulation is effective in ripening the cervix, it may be used only in cases of intrauterine foetal death as it may otherwise adversely affect foetal outcome.

Essential fatty acid deficiency associated with the use of a medium-chain-triglyceride infant formula in pediatric hepatobiliary disease.

Serum phospholipid fatty acid patterns were determined by gas chromatography in four infants with hepatobiliary disease receiving a formula with a high content of medium-chain-triglyceride (MCT) oil. All four infants demonstrated signs of essential fatty acid deficiency, characterized by decreased arachidonic acid and increased palmitoleic and oleic acids. All had substantial concentrations of the pathologic triene 5,8,11-eicosatrienoic acid. Three of four had decreased linoleic acid concentrations and abnormal ratios of triene to tetraene (5,8,11-eicosatrienoic acid: arachidonic acid), greater than 0.38. One patient may have experienced growth failure due to abnormal essential fatty acid status. Infants with the potential for fat malabsorption should only receive MCT-oil feedings with well above the generally recommended requirements for linoleic acid (3% of total caloric intake).

Outcome of teenage pregnancy.

Two hundred consecutive cases up to 19 years of age admitted for confinement at The Nowrosjee Wadia Maternity Hospital, Bombay, were studied. Out of these 200 girls, 6 were unmarried, 51 were anaemic, 20 had toxaemia of pregnancy. Six girls (43%) in the age group 15-17 years delivered prematurely as compared to only 26 girls (14%) in the age group of 17-19 years. This difference is statistically significant. Also, only, 4 girls (29%) in the age group of 15-17 years had full term normal delivery as compared to 113 girls (61%) in the age group of 17-19 years signifying that the outcome of pregnancy becomes worst in girls below the age of 17 years. Ten babies (71%) of mothers in the age group of 15-17 years were LBW as compared to 75 babies (44%) of mothers in the age group of 17-19 years signifying that the incidence of LBW babies is inversely proportional to maternal age. Teenage pregnant girls needed more attention for prevention and treatment of preeclampsia eclampsia, anaemia, prematurity and LBW.

Familial occurrence of trophoblastic disease - report of recurrent molar pregnancies in sisters in three families.

Three families are described in which trophoblastic desease occurred in one or more pregnancies in two or more sisters. The possible role of genetic factors in the etiopathogenesis of hydatidiform mole is reviewed in light of these data. We believe this to be the first report of familial occurrence of molar pregnancies.

A controlled comparison of dipyrone and paracetamol in post-episiotomy pain.

A double-blind, placebo-controlled trial was carried out in 299 patients suffering from post-episiotomy pain to compare the analgesic effectiveness and tolerance of single doses of 500 mg dipyrone and 500 mg paracetamol. Assessments of pain relief over a 6-hour period showed that dipyrone produced significantly better results than placebo within half an hour of intake and maintained this superiority throughout the 6 hours. It also afforded consistently better pain relief than paracetamol and was significantly more effective at the 6-hour assessment. Side-effects were few and mild.