Neuroendocrine signals in the regulation of gonadotropin-releasing hormone secretion

Gonadotropin-releasing hormone (GnRH) is a key hypothalamic peptide that controls the secretion of pituitary gonadotropins, particularly luteinizing hormone (LH), and hence gonadal function. Hypothalamic GnRH is released in a pulsatile manner. In the female, the pattern of GnRH pulses, i.e., pulse frequency and amplitude, varies during different reproductive stages and among different species. Several central and peripheral signals modulate GnRH neuronal activities. Some of these signals are stimulatory to GnRH release, e.g., norepinephrine (NE) and neuropeptide Y (NPY); some are inhibitory, e.g., beta-endorphin and interleukin-1; others are both stimulatory and inhibitory, e.g., estradiol-17 beta (E2). The neuronal structures and chemical interactions that result in pulsatile GnRH release remain unresolved. However, the core of the so-called 'GnRH pulse-generator' likely involves NE and NE transporter (NET, the protein for pre-synaptic re-uptake of NE). Both secretion and re-uptake of NE may determine hypothalamic NE availability. Many of the GnRH-stimulating and GnRH-inhibiting signals may influence the 'pulse-generator' by acting on GnRH neurons as second level signals. Hypothalamic GnRH is also released in a "surge" manner that is triggered either by increasing levels of circulating steroids (E2 and progesterone) during the preovulatory period in spontaneous-ovulating species, or by coitus in induced-ovulating animals. The sequential steps and mechanisms by which the GnRH surge occurs after E2 or coitus are not clear. However, it is unlikely that the E2 or coital stimuli act directly on GnRH neurons; E2 receptors have not been found in GnRH cells whereas coital signals must stop in the brainstem before they reach the hypothalamus. The brainstem may be an extra-hypothalamic site where both E2 and coital stimuli are transformed into GnRH-stimulating signals. One such signal may be NE whose brainstem cell bodies send terminals into the hypothalamus. Evidence from our laboratory suggests that a hypothalamic NE surge occurs at the time of the preovulatory GnRH surge in both the monkey and rabbit. Moreover, gene expression of both tyrosine hydroxylase (the rate-limiting enzyme for NE synthesis) and NET (the rate-limiting factor for synaptic NE transmission) in the brainstem increases after E2 in the monkey and after coitus in the rabbit. Other hypothalamic and/or brainstem signals, i.e., NPY, galanin, beta-endorphin, nitrous oxide and gamma aminobutyric acid, are likely involved in generating, maintaining and/or modulating the GnRH surge process. A better understanding of the up-stream GnRH-regulating signals will help improve treatments for many reproductive disorders associated with stress, obesity, infection and aging.     

The utility of high-resolution magnetic resonance imaging in the evaluation of the triangular fibrocartilage complex of the wrist

This work offers an anthropological analysis of intra-household processes underlying gender- and age-specific differences in individual nutritional and health care allocations and outcomes in particular cultures. Based on recent ethnographic studies in India, Nepal, Madagascar, Mexico, and Peru, correspondences are analyzed between local cultural ("emic") and scientist-policy maker practitioner ("etic") understandings of nutrition, health, and human development, and the relative "values" of females, males, and children of different ages. The data and analyses clarify specific epidemiological and demographic findings on age and gender bias in nutrition and health and highlight the multiple cultural, economic, and biological factors that contribute to gender- or age-based discrimination or neglect. Recent advances in nutrition policy have argued for a broader concept of nutritional security, one that incorporates both food quantity and quality, and of nutrition as "food, health and care" (International Conference on Nutrition, World Declaration and Plan of Action for Nutrition, FAO/WHO, Rome, 1992). These ethnographic findings; lend strong support for such broader nutrition concepts and associated nutrition policies. The studies also suggest ways in which anthropological questions, methods, and data and community-based research can help predict or identify the nutritionally vulnerable within households and help other social and medical scientists design more effective interventions.     

Asp34 of PvuII endonuclease is directly involved in DNA minor groove recognition and indirectly involved in catalysis

The PvuII restriction endonuclease is a homodimer that recognizes and cleaves the DNA sequence 5'-CAGCTG-3' in double-stranded DNA, and the structure of this enzyme has been reported. In the wild-type enzyme, Asp34 interacts with the internal guanine of the recognition sequence on the minor groove side. The Asp34 codon was altered to specify Gly (D34G), and in vitro studies have revealed that the D34G protein has lost binding specificity for the central G.C base-pairs, and that it cuts the canonical sequence with 10(-4)-fold reduced activity as compared to the wild-type enzyme. We have now determined the structure at 1.59 A resolution of the D34G PvuII endonuclease complexed with a 12 bp duplex deoxyoligonucleotide containing the cognate sequence. The D34G alteration results in several structural changes relative to wild-type protein/DNA complexes. First, the sugar moiety of the internal guanine changes from a C2'-endo to C3'-endo pucker while that of the 3' guanine changes from C3'-endo to C2'-endo pucker. Second, the axial rise between the internal G.C base-pairs is reduced while that between the G.C and flanking base-pairs is expanded. Third, two distinct monomeric active sites are observed that we refer to as being "primed" and "unprimed" for phosphodiester bond cleavage. The primed and unprimed sites differ in the conformation of the Asp58 side-chain, and in the absence from unprimed sites of four networked water molecules. These water molecules, present in the primed site, have been implicated in the catalytic mechanism of this and other endonucleases; some of them can be replaced by the Mg2+ necessary for cleavage. Taken together, these structural changes imply that the Asp34 side-chains from the two subunits maintain a distinct conformation of its DNA substrate, properly situating the target backbone phosphates and indirectly manipulating the active sites. This provides some insight into how recognition of the specific DNA sequence is linked to catalysis by the highly specific restriction endonucleases, and reveals one way in which the structural conformation of the DNA is modulated coordinately with that of the PvuII protein.     

Contribution of proteasomal beta-subunits to the cleavage of peptide substrates analyzed with yeast mutants

Proteasomes generate peptides that can be presented by major histocompatibility complex (MHC) class I molecules in vertebrate cells. Using yeast 20 S proteasomes carrying different inactivated beta-subunits, we investigated the specificities and contributions of the different beta-subunits to the degradation of polypeptide substrates containing MHC class I ligands and addressed the question of additional proteolytically active sites apart from the active beta-subunits. We found a clear correlation between the contribution of the different subunits to the cleavage of fluorogenic and long peptide substrates, with beta5/Pre2 cleaving after hydrophobic, beta2/Pup1 after basic, and beta1/Pre3 after acidic residues, but with the exception that beta2/Pup1 and beta1/Pre3 can also cleave after some hydrophobic residues. All proteolytic activities including the "branched chain amino acid-preferring" component are associated with beta5/Pre2, beta1/Pre3, or beta2/Pup1, arguing against additional proteolytic sites. Because of the high homology between yeast and mammalian 20 S proteasomes in sequence and subunit topology and the conservation of cleavage specificity between mammalian and yeast proteasomes, our results can be expected to also describe most of the proteolytic activity of mammalian 20 S proteasomes leading to the generation of MHC class I ligands.     

Biomechanics of injury of the cervical spine

Whiplash injuries of the cervical spine are of special medical and socio-economic importance. Biomechanical studies of the injury have proven, that a hypertranslation of the capito-cervical region takes place first, leading to ligamentous hyperdistension and ruptures, when exceeding elastic deformation, thus possibly resulting in mechanical disturbance and rotatory malpositioning. Diagnosis of so called "functional disorders" bears difficulties concerning objective tests for structural lesions. This demands the definition of diagnostic parameters and clinical signs, which also consider vegetative phenomena. This paper aims at a systematic clinical and radiological check. Adequate therapeutic means have to be concordant to prognosis. Therefore functional parameters should already determine differential diagnosis. This is based on technical feasibilities and needs future scientific efforts.     

Probabilities for singleton and multiple pregnancies after in vitro fertilization

OBJECTIVE: To help physicians provide risk estimates for specific pregnancy outcomes. DESIGN: Computation of exact binomial probabilities for singleton and multiple pregnancies as a function of two inputs: the number of embryos transferred and the implantation rate. Inputs were varied over the range of values reported in the literature. MAIN OUTCOME MEASURE(S): Probabilities for a singleton pregnancy (none), a multiple pregnancy (Pmult), and no pregnancy (Pnone) after one IVF cycle. RESULT(S): Given a 30% implantation rate and three embryos transferred, Pone=.44, Pmult=.22, and Pnone=.34. Although further increasing the number of embryos transferred increases the chance of pregnancy, it also raises the probability of a multiple pregnancy and lowers the chance of a singleton pregnancy. Although varying the implantation rate changes the specific probability estimates, the same trade-off persists. CONCLUSION(S): Those who consider an IVF "success" to be a singleton pregnancy should be attentive to the number of embryos transferred. Infertility therapy may be one area in medicine where more is not necessarily better.     

Predicting personality pathology among adult patients with substance use disorders: effects of childhood maltreatment

The purpose of this study was to examine predictive relationships between types of childhood maltreatment and personality disorders in a substance-abusing population. Three hundred thirty-nine drug- or alcohol-dependent patients completed a reliable and valid retrospective measure of childhood trauma, the CTQ, and a self-report inventory that assesses the entire range of DSM-III-R personality disorders, the PDQ-R. As a preliminary step, factor analyses were used to group personality disorders into the three DSM-III-R Axis II clusters (Clusters A, B, and C), although some diagnostic subclusters were also found. Structural equation modeling analyses revealed several significant paths between types of maltreatment and personality disorder clusters (and subclusters). Physical abuse and physical neglect were related to a subcluster of "psychopathic" personality disorders consisting of childhood and adult antisocial personality traits and sadistic traits. Emotional abuse emerged as a broad risk factor for personality disorders in Clusters A, B, and C. Emotional neglect was related to the traits of schizoid personality disorder, which formed its own subcluster. Finally, sexual abuse, which had been expected to predict borderline personality disorder traits, was unrelated to any personality disorder cluster. These findings support the view that child maltreatment contributes to the high prevalence of co-morbid personality disorders in addicted populations.     

Nonlinear multi-output regression on unknown input manifold

Consider unknown smooth function which maps high-dimensional inputs to multidimensional outputs and whose domain of definition is unknown low-dimensional input manifold embedded in an ambient high-dimensional input space. Given training dataset consisting of ‘input-output’ pairs, regression on input manifold problem is to estimate the unknown function and its Jacobian matrix, as well to estimate the input manifold. By transforming high-dimensional inputs in their low-dimensional features, initial regression problem is reduced to certain regression on feature space problem. The paper presents a new geometrically motivated method for solving both interrelated regression problems.     

Fast, Exact, Linear Booleans

We present a new system for robustly performing Boolean operations on linear, 3D polyhedra. Our system is exact, meaning that all internal numeric predicates are exactly decided in the sense of exact geometric computation. Our BSP-tree based system is 16-28× faster at performing iterative computations than CGAL's Nef Polyhedra based system, the current best practice in robust Boolean operations, while being only twice as slow as the non-robust modeler Maya. Meanwhile, we achieve a much smaller substrate of geometric subroutines than previous work, comprised of only 4 predicates, a convex polygon constructor, and a convex polygon splitting routine. The use of a BSP-tree based Boolean algorithm atop this substrate allows us to explicitly handle all geometric degeneracies without treating a large number of cases.     

Speech-evoked activity in primary auditory cortex: effects of voice onset time

Neural encoding of temporal speech features is a key component of acoustic and phonetic analyses. We examined the temporal encoding of the syllables /da/ and /ta/, which differ along the temporally based, phonetic parameter of voice onset time (VOT), in primary auditory cortex (A1) of awake monkeys using concurrent multilaminar recordings of auditory evoked potentials (AEP), the derived current source density, and multiunit activity. A general sequence of A1 activation consisting of a lamina-specific profile of parallel and sequential excitatory and inhibitory processes is described. VOT is encoded in the temporal response patterns of phase-locked activity to the periodic speech segments and by "on" responses to stimulus and voicing onset. A transformation occurs between responses in the thalamocortical (TC) fiber input and A1 cells. TC fibers are more likely to encode VOT with "on" responses to stimulus onset followed by phase-locked responses during the voiced segment, whereas A1 responses are more likely to exhibit transient responses both to stimulus and voicing onset. Relevance to subcortical speech processing, the human AEP and speech psychoacoustics are discussed. A mechanism for categorical differentiation of voiced and unvoiced consonants is proposed.