The ontology of craniofacial development and malformation for translational craniofacial research.

We introduce the Ontology of Craniofacial Development and Malformation (OCDM) as a mechanism for representing knowledge about craniofacial development and malformation, and for using that knowledge to facilitate integrating craniofacial data obtained via multiple techniques from multiple labs and at multiple levels of granularity. The OCDM is a project of the NIDCR-sponsored FaceBase Consortium, whose goal is to promote and enable research into the genetic and epigenetic causes of specific craniofacial abnormalities through the provision of publicly accessible, integrated craniofacial data. However, the OCDM should be usable for integrating any web-accessible craniofacial data, not just those data available through FaceBase. The OCDM is based on the Foundational Model of Anatomy (FMA), our comprehensive ontology of canonical human adult anatomy, and includes modules to represent adult and developmental craniofacial anatomy in both human and mouse, mappings between homologous structures in human and mouse, and associated malformations. We describe these modules, as well as prototype uses of the OCDM for integrating craniofacial data. By using the terms from the OCDM to annotate data, and by combining queries over the ontology with those over annotated data, it becomes possible to create "intelligent" queries that can, for example, find gene expression data obtained from mouse structures that are precursors to homologous human structures involved in malformations such as cleft lip. We suggest that the OCDM can be useful not only for integrating craniofacial data, but also for expressing new knowledge gained from analyzing the integrated data.

Transition matrix population model for dust mite Dermatophagoides pteronyssinus (Acari: Pyroglyphidae).

A transition matrix model of the population dynamics of the European house dust mite, Dermatophagoides pteronyssinus (Trouessart) (Acari: Pyroglyphidae), is described. It can model continuously varying conditions by forming transition matrices by interpolation between known transition matrices constructed from experimental data. Finite carrying capacity is modeled by modifying the population distribution vector at each time-step by using a form of the Skellam model, which is derived from the assumption that in competition each successful animal gets all it requires, and the unsuccessful animals get insufficient resources for survival or reproduction. The transition matrix model does not require all mites to have the same survivorship, life-stage durations, fecundity, and so on. Life table data to drive the model is taken from two sources, one source of which requires using the mean and standard deviation of the duration of each stage to synthesize a range of duration times and a range of transition probabilities to the next stage, thus ensuring variability between mites. Where synthesized data are used, significant long-lasting oscillations in dust mite levels are modeled, which does not happen when modeling with unsynthesized data, and is unlikely to occur in the field. Under conditions normally met with in the microenvironment (bedding, base of carpet, soft furnishing) of D. pteronyssinus, finite carrying capacity is essential to prevent unbounded population growth. The model is compared with other workers' field data with fair agreement. It is argued that shortcomings in the available data rather than the model are the principal reasons for differences between field and modeled results.

The Cool Teens CD-ROM for anxiety disorders in adolescents : a pilot case series.

Five adolescents received a multimedia CD-ROM containing a self-help treatment program for young people with an anxiety disorder. Participants used the 8-module Cool Teens CD-ROM over a 12-week period on a home computer. Every 2 weeks, they received a brief telephone call from a clinical psychologist to monitor symptoms and progress and to discuss any problems with understanding content or implementing techniques. Based on structured interviews, two participants (40%) no longer met diagnostic criteria (self-report ADIS) for at least one clinical anxiety disorder immediately following treatment and these same participants no longer met diagnostic criteria for any clinical anxiety disorder at 3-month follow-up. Two other participants failed to make gains based on diagnostic criteria, but showed improvement in anxiety symptoms for one main fear. Participants were generally satisfied with the multimedia content, the modules, and the delivery format of the program.

Development of Dermatophagoides pteronyssinus (Acari: Pyroglyphidae) at constant and simultaneously fluctuating temperature and humidity conditions.

House dust mites are found in almost all dwellings in New Zealand and are a major risk factor in the development of asthma and perennial allergic rhinitis. We studied the longevity, life stage length, and fecundity of a New Zealand strain of European house dust mite, Dermatophagoides pteronyssinus (Trouessart), at constant (23 degrees C, 75% RH) and the fluctuating conditions typically found in dry (18-25 degrees C, 60-38% RH) and damp (18-23 degrees C, 70-55% RH) New Zealand dust mite microhabitats in carpets. All the adult mites placed in the "dry" conditions died within 18 d. Mites in the "da conditions had developmental times, oviposition, and death rates that were not significantly different from constant conditions. These mites are tolerant of fluctuating temperatures, but they are more susceptible to environments that strongly fluctuate in humidity.

Galanin-like peptide as a link between metabolism and reproduction.

Galanin-like peptide (GALP) is a hypothalamic neuropeptide that binds and activates galanin receptors in vitro. Following the discovery of GALP, researchers have attempted to properly place it in the context of galanin receptor physiology. Central injections of GALP have revealed some common actions with galanin, such as acutely increased food intake and suppression of the thyroid axis. Other actions are unique to GALP, such as long-term inhibition of food intake and stimulation of luteinizing hormone (LH) secretion in male rats. GALP and galanin also produce differential effects on expression of the immediate early gene product Fos in the brain. Determining which of these actions are dependent on galanin receptors (versus a putative GALP-specific receptor), as well as which actions represent the authentic physiology of endogenous GALP will require continued experimentation. GALP gene expression is positively regulated by several hormones involved in the control of energy balance and metabolism, namely leptin, insulin and thyroid hormone. Based on current evidence, GALP neurones may serve as a hypothalamic relay, transmitting information from the periphery to circuits within the brain involved in the physiological control of metabolism and reproduction.

Predicting psychrometric conditions in biocontaminant microenvironments with a microclimate heat and moisture transfer model -- description and field comparison.

UNLABELLED: A numerical model is described that is designed to model psychrometric conditions in biocontaminant microenvironments, such as in bedding and the base of carpets for dust-mites, and on the surface of linings for molds. The model is very general and can include room air, other room components, other zones including the outdoors, other rooms and any subfloor space. Mechanical plant can be modeled. Good agreement between modeled and field results are reported for the complex case of an occupied bed and for the microclimate in the base of a carpet, before and after its timber floor above a crawl space was retrofitted with insulation. PRACTICAL IMPLICATIONS: Biocontaminants such as dust-mites and molds can pose serious health problems. Understanding microclimates in biocontaminant microhabitats, when coupled with biologic models, will make it possible to predict how the life cycles of these biocontaminants are affected as these conditions change. In turn, this will suggest which interventions that modify indoor climate and microclimate are likely to control these biocontaminants. Furthermore such interventions might include indoor humidity control, changing building insulation and ventilation levels, covering mattresses, use of electric blankets, use of carpet heating, etc. Such models will provide a fast way for screening for interventions that are likely to be effective in the control of biocontaminants.

A role for kisspeptins in the regulation of gonadotropin secretion in the mouse.

Kisspeptins are products of the KiSS-1 gene, which bind to a G protein-coupled receptor known as GPR54. Mutations or targeted disruptions in the GPR54 gene cause hypogonadotropic hypogonadism in humans and mice, suggesting that kisspeptin signaling may be important for the regulation of gonadotropin secretion. To examine the effects of kisspeptin-54 (metastin) and kisspeptin-10 (the biologically active C-terminal decapeptide) on gonadotropin secretion in the mouse, we administered the kisspeptins directly into the lateral cerebral ventricle of the brain and demonstrated that both peptides stimulate LH secretion. Further characterization of kisspeptin-54 demonstrated that it stimulated both LH and FSH secretion, at doses as low as 1 fmol; moreover, this effect was shown to be blocked by pretreatment with acyline, a potent GnRH antagonist. To learn more about the functional anatomy of kisspeptins, we mapped the distribution of KiSS-1 mRNA in the hypothalamus. We observed that KiSS-1 mRNA is expressed in areas of the hypothalamus implicated in the neuroendocrine regulation of gonadotropin secretion, including the anteroventral periventricular nucleus, the periventricular nucleus, and the arcuate nucleus. We conclude that kisspeptin-GPR54 signaling may be part of the hypothalamic circuitry that governs the hypothalamic secretion of GnRH.

Regulation of galanin-like peptide gene expression by pituitary hormones and their downstream targets.

Galanin-like peptide (GALP) mRNA is expressed in neurones of the hypothalamic arcuate nucleus and within pituicytes in the neurohypophysis. Several neuropeptides that are expressed in the arcuate nucleus participate in the neuroendocrine regulation of pituitary hormone secretion. Our objective was to determine the extent to which GALP might be a target for regulation by pituitary hormones or their downstream targets in the rat. The expression of GALP mRNA in the arcuate nucleus was reduced by hypophysectomy as determined by in situ hybridization. However, this did not appear to be attributable to the loss of either gonadal or adrenal steroids because castrated, ovariectomized and adrenalectomized rats had GALP mRNA expression that was indistinguishable from their respective controls. Next, we investigated the effects of growth hormone deficiency on GALP mRNA expression by studying dwarf rats and found that GALP gene expression was not different between dwarf rats and controls. We found that thyroidectomy led to a significant reduction in GALP mRNA expression compared to intact controls, and thyroidectomized rats implanted with thyroxine pellets had GALP mRNA expression that was similar to intact controls. Thus, the reduction of GALP mRNA expression seen in hypophysectomized animals may reflect, in part, a selective loss of thyroid hormone. We also found that the expression of GALP mRNA was increased in the neurohypophysis of lactating rats compared to nonlactating rats, whereas GALP mRNA expression in the arcuate nucleus was unaffected by lactation. This suggests that the induction of GALP gene expression in pituicytes is physiologically associated with activation of oxytocin and vasopressin secretion during lactation.

Distribution and regulation of galanin-like peptide (GALP) in the hypothalamus of the mouse.

Galanin-like peptide (GALP) is a newly discovered molecule whose expression in the brain is confined to the arcuate nucleus and median eminence. In the rat, cellular levels of GALP mRNA are reduced by fasting and reversed by peripheral administration of leptin. The purpose of this investigation was 1) to clone and map the distribution of GALP mRNA in the brain of the mouse; 2) to compare the pattern and magnitude of GALP mRNA expression in the leptin-deficient obese (ob/ob) mouse with that of wild-type controls; and 3) to examine the effects of leptin delivered into the brain on the expression of GALP mRNA in the ob/ob mouse. We report the sequence of a mouse GALP cDNA and show that GALP mRNA is expressed in the arcuate nucleus, median eminence, infundibular stalk, and the neurohypophysis of this species. The expression of GALP mRNA in the brain was markedly reduced in the ob/ob mice, compared with wild-type animals. Intracerebroventricular infusion of leptin to ob/ob mice increased both the number of GALP mRNA-expressing neurons and their content of GALP mRNA, compared with vehicle-treated controls. These observations demonstrate that GALP mRNA is induced by leptin through a direct action on the brain.

Serotonergic neurons are targets for leptin in the monkey.

Leptin is a secretory product of adipocytes that has been shown to affect food intake, metabolism, and reproduction. One site of leptin's action is the central nervous system, where the leptin receptor (Ob-R) messenger ribonucleic acid (mRNA) and protein are expressed in discrete areas. In both the rat and monkey, Ob-R mRNA has been localized in the Raphe nuclei of the brainstem. Neurons in the Raphe nuclei are the primary source of serotonin in the brain. Serotonergic pathways influence both feeding and reproduction, and these cells are plausible direct targets for leptin's action. We used double label in situ hybridization and computerized image analysis to determine whether serotonergic neurons in the brainstem of the female pigtailed macaque (Macaca nemestrina) express Ob-R mRNA. We observed that many cells in the Raphe nuclei express serotonin transporter mRNA, a marker of serotonergic cells, and Ob-R mRNA. Based on quantitative analysis, the highest number of cells that express both serotonin transporter and Ob-R mRNAs were found in the caudal dorsal Raphe and median Raphe nuclei; fewer double labeled cells were situated in the caudal linear nucleus and rostral median Raphe, whereas double labeled cells occurred infrequently in the rostral dorsal Raphe. These observations suggest that leptin may act on serotonergic cells to mediate some of its effects on ingestive behavior, metabolism, and reproduction.

Gene expression microarray data analysis for toxicology profiling.

When dealing with thousands of genes, all potentially interesting, it is desirable to rank the genes according to their degree of participation in a physiological process. Therefore, genes with the highest Shannon entropy and ERL can be selected as the best toxicity target candidates, permitting preclinical scientists to focus their research and resources on those genes.

The health impact of chronic recurrent rhinosinusitis in children.

OBJECTIVES: To report and quantify the health-related quality of life of children who require surgical intervention for chronic recurrent rhinosinusitis and to assess the perspective of the child vs that of the parent. DESIGN: Prospective, observational. PATIENTS AND INTERVENTION: Twenty-one of a consecutive sample of 35 children undergoing endoscopic sinus surgery for infectious indications completed, along with their parents, the Child Health Questionnaire. The Child Health Questionnaire measures in parallel both child and parent perceptions of health by means of separate parent proxy report (Child Health Questionnaire-Parent Form 50) and child self-report (Child Health Questionnaire-Child Form 87) questionnaires concerning physical and psychosocial functioning. MAIN OUTCOME MEASURES: Tabulated scores from both the Child Health Questionnaire-Parent Form 50 and Child Health Questionnaire-Child Form 87 were compared with published data from age-matched normative populations and several pediatric chronic disease groups. RESULTS: Significant decrements in the general health of children with chronic recurrent rhinosinusitis compared with a normative sample were observed for both child- and parent-reported data, particularly in the physical domains. Children with rhinosinusitis were perceived by their parents to have significantly more bodily pain (P<.001)and to be more limited in their physical activities (P<.05)than children with asthma, juvenile rheumatoid arthritis, and other chronic disorders. Parent-child perceptions did vary, with parents reporting more pain and general behavioral effects relative to their children's reports in these areas. CONCLUSION: The health impact of chronic recurrent rhinosinusitis as reported by the subjective evaluations of pediatric patients and their parents is severe.

An unusual pterygopalatine meningocele associated with neurofibromatosis type 1. Case report.

The authors describe an unusual meningocele of the lateral wall of the cavernous sinus and the anterior skull base in a young patient with typical stigmata of neurofibromatosis Type 1 (NF1). This lesion was discovered during evaluation for recurrent meningitis. It represented an anterior continuation of Meckel's cave into a large cerebrospinal fluid space within the lateral wall of the cavernous sinus, extending extracranially through an enlarged superior orbital fissure into the pterygopalatine fossa adjacent to the nasal cavity. It was successfully obliterated, via an intradural middle fossa approach, with fat packing and fenestration into the subarachnoid space. This meningocele most likely represents a variant of cranial nerve dural ectasia occasionally seen in individuals with NF1. It has as its basis the same mesodermal defect responsible for the more common sphenoid wing dysplasia and spinal dural ectasias identified with this condition. Involvement of the trigeminal nerve with expansion of the lateral wall of cavernous sinus has not been reported previously. The authors surmise, however, that it may be present in some cases of orbital meningocele associated with sphenoid wing dysplasia.

Cytokeratin expression in the odontogenic keratocyst.

PURPOSE: This study attempted to identify differential cytokeratin expression in cystic jaw lesions using immunohistochemical staining. PATIENTS AND METHODS: The charts from selected patients treated between 1983 and 1994 for jaw cysts were evaluated. Twenty-four paraffinized specimens were selected randomly for investigation with 5 immunohistochemical stains. The 4 diagnostic categories included ameloblastoma, dentigerous cyst, odontogenic keratocyst (OKC), and recurrent odontogenic keratocyst in patients with nevoid basal cell carcinoma (NBCC) syndrome. The 5 immunohistochemical stains included antibodies to cytokeratins 13, 17, and 18; CAM 5.2; AE 1/3; and carcinoembryonic antigen (CEA). RESULTS: Differential staining of OKCs from patients with and without NBCC syndrome was found only with the antibody to cytokeratin 17. Furthermore, staining of OKCs in syndromic patients appeared to be stronger and more uniform than in nonsyndromic patients. CONCLUSIONS: These findings suggest that immunohistochemical staining for cytokeratin 17 may aid in the diagnosis of OKCs and may be used to further subdivide these lesions based on the presence or absence of NBCC syndrome.

Physician experience with an optical image guidance system for sinus surgery.

OBJECTIVES/HYPOTHESIS: Intraoperative guidance systems have been developed which use infrared tracking technology to assist with anatomical localization during sinus surgery. Although the introduction of this technology is intended to increase the safety and efficacy of sinus surgery, little is known about its actual impact in the clinical setting. The objective of this report was to study the application and utilization of an image guidance system shared by multiple sinus surgeons in a specialty hospital. STUDY DESIGN: Combined prospective case study and retrospective analysis of physician surveys. METHODS: An optical-based image guidance system (LandmarX, Xomed, Inc., Jacksonville, FL) was used by 34 physicians to perform 754 sinonasal surgeries over a 2.5-year period at Massachusetts Eye and Ear Infirmary. In 19 cases, system registration was repeated during surgery to measure the effect of fiducial placement on system accuracy. RESULTS: The measured accuracy of anatomical localization at the start of surgery (mean value, 1.69 +/- 0.38 mm) was comparable to the perceived accuracy of 1 to 3 mm that was reported by 79% of surgeons surveyed. Operating room time (mean period, 130.6 +/- 41.1 min) correlated with the surgical procedure performed (P < .05), but not with the disease stage or revision rate. According to a majority of surgeons, use of the image guidance equipment increased operating room time by 15 to 30 minutes during initial cases and by 5 to 15 minutes once experience with the equipment had been acquired. More than 90% of surgeons anticipated their continued use of the image guidance equipment for sinus surgery at a similar or greater level in the future. CONCLUSION: An optical-based image guidance system can be successfully integrated into a multisurgeon operating room environment. Use of the system provides accurate anatomical localization during sinus surgery and results in a relatively high level of physician satisfaction.

Galanin-like peptide (GALP) is a target for regulation by leptin in the hypothalamus of the rat.

Galanin-like peptide (GALP), which was recently isolated from the porcine hypothalamus, shares sequence homology with galanin and binds with high affinity to galanin receptors. To study the distribution and regulation of GALP-expressing cells in the brain, we cloned a 120 base-pair cDNA fragment of rat GALP and produced an antisense riboprobe. In situ hybridization for GALP mRNA was then performed on tissue sections throughout the forebrain of adult ovariectomized female rats. We found GALP mRNA-containing cells in the arcuate nucleus (Arc), caudal dorsomedial nucleus, median eminence and the pituitary. Because GALP mRNA in the Arc appeared to overlap with the known distribution of leptin receptor mRNA, we tested the hypothesis that GALP expression is regulated by leptin. Using in situ hybridization, we compared the number of GALP mRNA-containing cells among groups of rats that were fed ad lib or fasted for 48 h and treated with either leptin or vehicle. Fasting reduced the number of identifiable cells containing GALP mRNA in the Arc, whereas the treatment of fasted animals with leptin produced a 4-fold increase in the number of cells expressing GALP message. The presence of GALP mRNA in the hypothalamus and pituitary and its regulation by leptin suggests that GALP may have important neuroendocrine functions, including the physiological regulation of feeding, metabolism, and reproduction.

Impact of tympanostomy tubes on child quality of life.

BACKGROUND: The objective benefits of tympanostomy tubes for otitis media are well established, but the subjective impact of surgery on child quality of life (QOL) has not been systematically studied. OBJECTIVES: To determine the subjective impact of tympanostomy tubes on child QOL, and to compare the variability in QOL before surgery with that observed after surgery. DESIGN: Prospective, observational, before-and-after trial. SETTING: Fourteen referral-based pediatric otolaryngology practices in the United States. PATIENTS: Consecutive (64%) and convenience (36%) sample of 248 children (median age, 1.4 years) with otitis media scheduled for bilateral tympanostomy tube placement as an isolated surgical procedure. INTERVENTION: Tympanostomy tubes were inserted as part of routine clinical care. Validated measures of QOL (OM-6 survey), satisfaction with health care decision (Satisfaction With Decision Scale), and satisfaction with office visit; surveys were completed at baseline (visit 1), at surgery (visit 2), and after surgery (visit 3). MAIN OUTCOME MEASURES: Short-term changes in QOL before surgery (visit 1 to visit 2) and after surgery (visit 2 to visit 3). RESULTS: Changes in QOL before surgery were mostly trivial, and were smaller than changes observed after surgery (P<.001). Large, moderate, and small improvements in QOL occurred after surgery in 56%, 15%, and 8% of children, respectively. Physical symptoms, caregiver concerns, emotional distress, and hearing loss were most improved, but significant changes were also seen for activity limitations and speech impairment. Trivial changes occurred in 17% of children, and 4% had poorer QOL. Predictors of poorer QOL were otorrhea 3 or more days (10% of variance) and decreased satisfaction with surgical decision (3% of variance). Hearing status, child age, type of otitis media (recurrent vs chronic), and office visit satisfaction were unrelated to outcome. CONCLUSIONS: Tympanostomy tubes produce large short-term improvements in QOL for most children. The best outcomes occur when postoperative otorrhea is absent or minimal, and when parents are satisfied with their initial decision to have surgery. Further research is needed to document the long-term impact of tubes on child QOL.

The application of shannon entropy in the identification of putative drug targets.

A major challenge in the field of functional genomics is the development of computational techniques for organizing and interpreting large amounts of gene expression data. These methods will be critical for the discovery of new therapeutic drug targets. Here, we present a simple method for determining the most likely drug target candidates from temporal gene expression patterns assayed with reverse-transcription polymerase chain reaction (RT-PCR) and DNA microarrays.

Galanin's functional significance in the regulation of the neuroendocrine reproductive axis of the monkey.

Galanin stimulates the neuroendocrine reproductive axis in the rat, but whether galanin acts similarly in primate species is unknown. To test the hypothesis that galanin acts within the hypothalamo-hypophyseal axis to stimulate luteinizing hormone (LH) and gonadotropin-releasing hormone (GnRH) secretion in the primate, galanin was administered either systemically or directly into the arcuate nucleus-median eminence of ovariectomized macaques (pigtailed or rhesus, respectively) that were maintained on estradiol. The mean plasma levels of LH were significantly elevated in pigtailed macaques after peripheral injection of galanin (2 mg) as compared with vehicle treatment. In rhesus monkeys, galanin (80 microM) administered by push-pull perfusion into the arcuate nucleus-median eminence did not significantly alter either GnRH or LH release. To determine whether in the monkey, as in the rat, subpopulations of medial forebrain GnRH neurons coexpress galanin mRNA, we used single- and double-label in situ hybridization and computerized imaging techniques. GnRH mRNA-containing cells were identified in both the medial and lateral forebrain of the female pigtailed macaque. No galanin mRNA expression was detectable in GnRH neurons located in either the medial preoptic area or mediobasal hypothalamus; however, within the substantia innominata a subset of GnRH mRNA-expressing neurons did coexpress galanin mRNA. Taken together, these results suggest that galanin induces LH release in primates, but galanin may not act directly on hypothalamic GnRH neurons. Presently, we have confirmed in another primate species the existence of GnRH gene expression in the lateral forebrain and discovered that a small subset of these neurons coexpress galanin. These particular cells may have a unique and as of yet undefined physiological function that is distinct from those GnRH neurons serving a hypophysiotropic function.

Genomics and proteomics: the new millennium of drug discovery and development.

One of the most pressing issues facing the pharmaceutical and biotechnology industry is the tremendous dropout rate of lead drug candidates. Over the last two decades, several new genomic technologies have been developed in hopes of addressing the issues of target identification and lead candidate optimization. Gene expression microarray is one of these technologies and this review describes the four main formats, which are currently available: (a) cDNA; (b) oligonucleotide; (c) electrokinetic; and (d) fiberoptic. Many of these formats have been developed with the goal of screening large numbers of genes. Recently, a high-throughput array format has been developed where a large number of samples can be assayed using arrays in parallel. In addition, focusing on gene expression may be only one avenue in preventing lead candidate failure. Proteomics or the study of protein expression may also play a role. Two-dimensional polyacrylamide gel electrophoresis (2-DE) coupled with mass spectroscopy has been the most widely accepted format to study protein expression. However, protein microarrays are now being developed and modified to a high-throughput screening format. Examples of several gene and protein expression studies as they apply to drug discovery and development are reviewed. These studies often result in large data sets. Examples of how several statistical methods (principal components analysis [PCA], clustering methods, Shannon entropy, etc.) have been applied to these data sets are also described. These newer genomic and proteomic technologies and their analysis and visualization methods have the potential to make the drug discovery and development process less costly and more efficient by aiding to select better target and lead candidates.