Ultimate Translation: Developing Therapeutics Targeting on N-Methyl-d-Aspartate Receptor.

N-Methyl-d-aspartate receptors (NMDARs) are broadly distributed in the central nervous system (CNS), where they mediate excitatory signaling. NMDAR-mediated neurotransmission (NMDARMN) is the molecular engine of learning, memory and cognition, which are the basis for high cortical function. NMDARMN is also critically involved in the development and plasticity of CNS. Due to its essential and critical role, either over- or under-activation of NMDARMN can contribute substantially to the development of CNS disorders. The involvement of NMDARMN has been demonstrated in a variety of CNS disorders, including schizophrenia, depression, posttraumatic stress disorder, aging, mild cognitive impairment and Alzheimer's dementia, amyotrophic lateral sclerosis, and anti-NMDAR encephalitis. Several targets to "correct" or "reset" the NMDARMN in these CNS disorders have been identified and confirmed. With analogy to aminergic treatments, these targets include the glycine/d-serine co-agonist site, channel ionophore, glycine transporter-1, and d-amino acid oxidase. It is still early days in terms of developing novel therapeutics targeting the NMDAR. However, agents modulating NMDARMN hold promise as the next generation of CNS therapeutics.

[Blood supply topographic features in maxilla and mandible].

Topographic anatomical studies provide data on the characteristics of blood supply to maxilla and mandible. It is established that maxilla is supplied by the large number of major arteries which are commonly anastomosed to each other. Mandible intraosseous blood supply is by one major lower alveolar artery and a large number of small extraosseous arteries that supply blood to the bone, masticatory and facial muscles.

[Blood supply in maxilla after segmental osteotomy].

Anthropometric measurements allowed us to obtain anatomical data on the topography of large and small palatine canals, sprouts sphenoid bone pterygoid, pterygopalatine and pterygomaxillary sutures. These structures are important because they contain blood vessels and nerves located in the area of jaw osteotomy. A study of maxilla blood supply sources after segmental osteotomy found that the descending palatine artery, the pterygopalatine artery, the upper posterior alveolar and infraorbital arteries usually remain intact by osteotomy. There are numerous anastomoses between all the arteries supplying the maxilla.

Targeted disruption of serine racemase affects glutamatergic neurotransmission and behavior.

A subset of glutamate receptors that are specifically sensitive to the glutamate analog N-methyl-D-aspartate (NMDA) are molecular coincidence detectors, necessary for activity-dependent processes of neurodevelopment and in sensory and cognitive functions. The activity of these receptors is modulated by the endogenous amino acid D-serine, but the extent to which D-serine is necessary for the normal development and function of the mammalian nervous system was previously unknown. Decreased signaling at NMDA receptors has been implicated in the pathophysiology of schizophrenia based on pharmacological evidence, and several human genes related to D-serine metabolism and glutamatergic neurotransmission have been implicated in the etiology of schizophrenia. Here we show that genetically modified mice lacking the ability to produce D-serine endogenously have profoundly altered glutamatergic neurotransmission, and relatively subtle but significant behavioral abnormalities that reflect hyperactivity and impaired spatial memory, and that are consistent with elevated anxiety.

[Computer modelling and topographo-anatomic substantiation of TMJ ankylosis surgical treatment].

Results of topographo-anatomic research of lateral and deep area of face with the use of three-dimensional computer modelling was presented. Application of the received data at operations of patients with ankilosis of the temporomandibular joint gave good results. It allows to draw a conclusion of possibility of this technique in a wide clinical practice.

[Side face part computer modelling use as background for low invasive access for TMJ puncture].

Computer modelling of the anatomic structures of different parts of maxillofacial region helps to widen surgeon's possibilities when planning and carrying out operative interventions, to improve doctor's training and to optimize students education in medical institutions. The use of 3D computer modeling for side face parts as the background for low invasive access for TMJ puncture. Results of the practical use of the worked off access (on 3D modell) to the upper part of TMJ confirm the practical efficacy of computer modelling.

Early embryonic death of glutamate carboxypeptidase II (NAALADase) homozygous mutants.

Glutamate carboxypeptidase II (EC 3.4.17.21) catalyzes the hydrolysis (Km = 0.2 microM) of the neuropeptide N-acetylaspartylglutamate to yield N-acetylaspartate and glutamate and also serves as a high-affinity folate hydrolase in the gut, cleaving the polyglutamate chain to permit the absorption of folate. N-acetylaspartylglutamate is an agonist at the mGluR3 metabotropic receptor and a source of extracellular glutamate through hydrolysis by glutamate carboxypeptidase II. Given the important role of glutamate in brain development and function, we were interested in the effects of a null mutation of glutamate carboxypeptidase II that would potentiate the effects of N-acetylaspartylglutamate. The PGK-Neomycin cassette was inserted to delete exons 9 and 10, which we previously demonstrated encode for the zinc ligand domain essential for enzyme activity. Successful germline transmission was obtained from chimeras derived from embryonic stem cells with the targeted mutation of glutamate carboxypeptidase II. Homozygous null mutants did not survive beyond embryonic day 8. Folate supplementation of the heterozygous mothers did not rescue the homozygous embryos. Mice heterozygous for the null mutation appeared grossly normal and expressed both mutated and wild-type mRNA but the activity of glutamate carboxypeptidase II is comparable to the wild-type mice. The results indicate that the expression of glutamate carboxypeptidase II is upregulated when one allele is inactivated and that its activity is essential for early embryogenesis.

Mapping of brain stem neuronal circuitry active during swallowing.

A poorly understood neural circuit in the brain stem controls swallowing. This experiment studied the swallowing circuit in the rat brain stem by means of fos immunocytochemistry. The fos protein is a marker of activated neurons, and under experimental conditions, repetition of a behavior causes the fos protein to be produced in the neurons involved in that behavior. The fos technique has been successfully used to delineate neural circuits involved in reflex glottic closure, cough, and vocalization; however, the technique has not been used to map the swallowing circuit. Nine rats were used in this study. Swallows were evoked in anesthetized rats for 1 hour, then, after a 4-hour delay to allow maximum fos production, the rats were painlessly sacrificed by perfusion. The brain stems were removed and sectioned in the frontal plane, and every fourth section was immunoreacted for fos protein. All sections were examined by light microscopy, and cells positive for fos were marked on drawings of brain stem structures for different levels throughout the brain stem. Control animals underwent sham experiments. After subtraction of the areas of fos labeling seen in controls, all experimental rats showed fos-labeled neurons in very discrete and localized areas, including practically all regions implicated by prior neurophysiology studies of swallowing. The distribution of labeled neurons was more dispersed through the brain stem than current theories of swallowing would suggest. Specifically, recent studies of swallowing control have focused on the nucleus of the solitary tract (NST) and the region surrounding the nucleus ambiguus (periambigual area) just rostral to the obex. These areas contained fos-labeled neurons, but unexpectedly, heavy labeling was found in the same areas caudal to the obex. Areas containing the heaviest labeling were specific subnuclei of the NST and surrounding reticular formation; the periambigual area; and the intermediate reticular zone in the pons and caudal medulla. Interestingly, none of these anatomic structures had uniform fos labeling; this finding suggests that the unlabeled areas are involved in other oromotor behaviors, or that the specific protocol did not activate the full population of swallowing-related neurons. A notable finding of this study is a candidate for the central pattern generator (CPG) of swallowing. Careful lesioning studies in cats strongly suggest that a region in the rostral-medial medulla contains the CPG for swallowing, although the exact location of the CPG was never pinpointed. In the homologous region of the rat brain stem, fos labeling was only found in a small group of neurons within the gigantocellular reticular formation that may be a candidate for the CPG. In summary, correlation with prior physiology experiments suggests that this experiment appears to have delineated many, if not all, of the components of the swallowing circuit for the first time in any mammal. In addition, other areas were found that might also be swallowing-related. One notable example is a small group of fos-labeled cells that may be the CPG for swallowing. Further studies are required to clarify the specific roles of the fos-labeled neurons seen in this study.

Thymic hyperplasia in a patient with Graves' disease.

Hyperplastic changes of the thymus may be found in patients with Graves' disease. However, this rarely presents as an anterior mediastinal mass, particularly among adults. In this report, we describe a 32-year old woman with Graves' disease and hyperthyroidism. During medical evaluation and treatment for her hyperthyroidism, a large anterior mediastinal mass was incidentally discovered. A cytological study of the lesion via computed tomogram-guided fine needle biopsy could not make a definitive diagnosis and suggested the possibility of a thymoma, which led to a surgical exploration. However, the final pathological diagnosis of the surgically removed tissue was thymic hyperplasia. The relationship between Graves' disease and thymic changes is discussed.

The development and validation of the Taiwanese Ethnic Identity Scale (TEIS): a "derived etic" approach.

The purpose of this study was to design a multidimensional measure of ethnic identity (EI) that would be appropriate for research on acculturating and modernizing cultural groups. Four qualitative approaches were utilized: in-depth interviews, free-listing exercise, card-sorting technique, and cognitive interviews. Qualitative interviews conducted with Taiwanese American subjects identified ten major domains related to EI. Fifty items were generated from the four qualitative approaches and the psychometric properties of the Taiwanese Ethnic Identity Scale (TEIS) were tested with two samples: 305 Taiwanese American (TA) and 354 Taiwanese (T) women. Factor analysis yielded a 26-item TEIS with six factors. The six factors and the percentage of variance accounted for by each factor were: rituals and traditions (22.8%), language (10.3%), family dynamics/good child (7.1%), parental opinion (6.0%), individualism (4.5%), and collectivism (4.5%). Components of content, construct, and known groups validity were assessed, as well as reliability.

Insulin sensitivity is inversely correlated with plasma intact parathyroid hormone level.

Abnormal glucose metabolism and a high prevalence of diabetes have been reported in patients with primary and secondary hyperparathyroidism. We hypothesize that plasma intact parathyroid hormone (iPTH) level is a determinant of either insulin sensitivity or beta-cell function. The study included 52 normotensive, healthy subjects with glucose tolerance. Insulin sensitivity and beta-cell function were assessed using a hyperglycemic clamp. Fasting plasma iPTH was determined. The relationships between its level and insulin sensitivity index and beta-cell function were examined. Insulin sensitivity index was inversely correlated with plasma iPTH level (r2 = .104, P = .020). The first phase insulin response was positively correlated with plasma iPTH level (r2 = .098, P = .023), but no correlation existed with the second phase insulin response. After adjusting for age, gender, ethnicity, and waist-to-hip ratio, plasma iPTH level was an independent determinant of insulin sensitivity index (P = .019). However, no independent relationship between plasma iPTH level and beta-cell function (the first phase and second phase insulin response) was found. In normotensive, glucose-tolerant, and healthy subjects, plasma iPTH level accounts for 10.4% of the variation in insulin sensitivity index. For each pg/mL increment in plasma iPTH level, there is a decrease of 0.247 micromol/L/m2/min/pmol/L in insulin sensitivity index. Although the molecular basis of this relationship is not clear, our results indicate that plasma iPTH level is inversely correlated with insulin sensitivity index.

The I27L amino acid polymorphism of hepatic nuclear factor-1alpha is associated with insulin resistance.

Mutations of the hepatic nuclear factor-1alpha (HNF-1alpha) gene have been found in patients with maturity-onset diabetes of the young. We examined the relation between the I27L polymorphism of HNF-1alpha and insulin sensitivity and beta-cell function assessed by a hyperglycemic clamp. This study included 52 healthy glucose-tolerant and normotensive subjects (age, 19-40 yr; body mass index, 17.58-35.61 kg/m2; waist/hip ratio, 0.65-1.03). We identified 19 LL subjects, 24 IL, and 9 II subjects. No difference was noted in the demographic features among the three genotypes. The LL group had the highest postchallenge insulin levels at 30 and 90 min (P = 0.038 and P = 0.015, respectively) and also the highest insulin area under curve (P = 0.009) among the three genotypes. The LL group was more insulin resistant than the IL and II groups (P = 0.042 for insulin sensitivity index). After adjusting for age, gender, obesity, and ethnicity, the I27L polymorphism was an independent determinant of the insulin sensitivity index (P = 0.001). However, it had no impact on either the first or second phase insulin response. Therefore, we conclude that the I27L polymorphism is associated with insulin resistance, but not beta-cell function. The mechanism of this association is unclear, but HNF-1alpha may play a role in regulating hepatic glucose metabolism.

Antibacterial activity of a chitooligosaccharide mixture prepared by cellulase digestion of shrimp chitosan and its application to milk preservation.

The antibacterial activity of a chitooligosaccharide mixture prepared by digestion of shrimp chitosan with cellulase at 50 degrees C for 14 h was evaluated. Sugars with 1 to 8 degrees of polymer (DP) were found in this chitooligosaccharide mixture, and the weight percentage of sugars with DP > or = 6 was 44.3%. Minimal lethal concentrations of this mixture against Aeromonas hydrophila, Escherichia coli, Listeria monocytogenes, Pseudomonas aeruginosa, Salmonella Typhimurium, Shigella dysenteriae, Staphylococcus aureus, Vibrio cholerae, and Vibrio parahaemolyticus in nutrient broth were 5 to 29 ppm, which were much lower than those of the chitosan reactant (50 to 1,000 ppm). The antibacterial activity of this mixture in the sterilized milk against E. coli O157, L. monocytogenes, Salmonella Typhimurium, and S. aureus was much stronger at 4 degrees C than at 37 degrees C. When raw milk was supplemented with either 0.24% or 0.48% (wt/vol) of this oligosaccharide mixture and stored at 4 degrees C for 12 days, its mesophilic and psychrotrophic counts were reduced by at least 3 log cycles, and there was very little change in pH. In addition, this mixture retarded the growth of Salmonella species and caused quicker reduction of Staphylococcus species in raw milk. Accordingly, the shelf life of raw milk at 4 degrees C was extended by at least 4 days.

Entanglement of guide wires by vena cava filters during central venous catheter insertion: report of three cases and a review of the literature.

Since 1993, 14 cases of central line guide wires becoming entangled with vena cava filters have been reported. We present three additional cases and review the 14 cases in the literature. Obtaining a detailed patient history is important in identifying patients with a vena cava filter. A low threshold of suspicion is needed and immediate radiograph obtained. Entangled guide wires required fluoroscopic manipulation and or retrieval of the dislodged filter. Of all reported cases, only one sustained an arrhythmia. With no signs and symptoms, conservative management of the dislodged filter is a viable option.

Eating disorders in the Far East.

OBJECTIVE: To investigate eating disorders (EDs) prevalence rates among Asian populations and identify characteristics that distinguish them from their Western counterparts. METHOD: Potential references were identified through an English-language literature search using Medline, Psychinfo, Dissertation Abstracts (1966 to 1999) and through extensive manual searching of textbooks, reviews and reference lists. RESULTS: The majority of studies related to EDs were conducted in Japan and China and a few were conducted in Singapore, Malaysia, Taiwan, and Korea whereas there was none in the Philippines, Laos, Vietnam, Cambodia, Myanmar, Indonesia and Thailand. Prevalence rates in Japan range from 0.025 to 0.030% for anorexia nervosa (AN) and from 1.9 to 2.9% for bulimia nervosa (BN). Community studies in China have found the AN prevalence to be 0.01% and BN rates ranging from 0.5% to 1.3%. These rates are lower than ED rates in the West (particularly the U.S. and Britain). Body dissatisfaction (BD) and dieting rates, however, were similar to those in the West. BD rates ranged from 68% (Taiwan) to 81% (Korea) and dieting rates ranged from 34% (Taiwan) to 68% (Japan). Sociocultural and developmental risk factors were relevant to this population. CONCLUSIONS: EDs in Asian populations have received little attention because they have been predominantly viewed as associated with Western culture. Classified by many as a "culture-bound syndrome" of the West, they may really be a culture-change syndrome.

D-serine added to clozapine for the treatment of schizophrenia.

OBJECTIVE: D-Serine is a full agonist at the glycine site on the N-methyl-D-aspartate (NMDA) receptor. Previous administration of D-serine to schizophrenic patients taking nonclozapine antipsychotics improved positive, negative, and cognitive symptoms, whereas the partial agonist D-cycloserine improved negative symptoms of patients taking conventional antipsychotics but worsened symptoms in clozapine-treated patients. To study the difference between full and partial agonists at the NMDA receptor glycine site, the clinical effects of adding D-serine to clozapine were assessed. METHOD: In a 6-week double-blind trial, 20 schizophrenic patients received placebo or D-serine (30 mg/kg per day) in addition to clozapine. Clinical efficacy, side effects, and serum levels of D-serine were determined every other week. RESULTS: The patients exhibited no improvement with D-serine, nor did their symptoms worsen, as previously reported with D-cycloserine. CONCLUSIONS: The results suggest either that clozapine may have an agonistic effect on the NMDA system or that clozapine-treated patients do not respond to D-serine.

Central nervous pathway for acupuncture stimulation: localization of processing with functional MR imaging of the brain--preliminary experience.

PURPOSE: To characterize the central nervous system (CNS) pathway for acupuncture stimulation in the human brain by using functional magnetic resonance (MR) imaging. MATERIALS AND METHODS: Functional MR imaging of the whole brain was performed in two groups of nine healthy subjects during four stimulation paradigms: real acupuncture at acupoints ST.36 (on the leg) and LI.4 (on the hand) and control stimulations (minimal acupuncture and superficial pricking on the leg). Stimulations were performed in semirandomized, balanced order nested within two experiments. Psychophysical responses (pain, De-Qi effect [characteristic acupuncture effect of needle-manipulation sensation], anxiety, and unpleasantness) and autonomic responses were assessed. Talairach coordinates-transformed imaging data were averaged for a group analysis. RESULTS: Acupuncture at LI.4 and ST.36 resulted in significantly higher scores for De-Qi and in substantial bradycardia. Acupuncture at both acupoints resulted in activation of the hypothalamus and nucleus accumbens and deactivation of the rostral part of the anterior cingulate cortex, amygdala formation, and hippocampal complex; control stimulations did not result in such activations and deactivations. CONCLUSION: Functional MR imaging can demonstrate the CNS pathway for acupuncture stimulation. Acupuncture at ST.36 and LI.4 activates structures of descending antinociceptive pathway and deactivates multiple limbic areas subserving pain association. These findings may shed light on the CNS mechanism of acupuncture analgesia and form a basis for future investigations of endogenous pain modulation circuits in the human brain.