On Rhythms in Neuronal Networks with Recurrent Excitation.

We investigate rhythms in networks of neurons with recurrent excitation, that is, with excitatory cells exciting each other. Recurrent excitation can sustain activity even when the cells in the network are driven below threshold, too weak to fire on their own. This sort of "reverberating" activity is often thought to be the basis of working memory. Recurrent excitation can also lead to "runaway" transitions, sudden transitions to high-frequency firing; this may be related to epileptic seizures. Not all fundamental questions about these phenomena have been answered with clarity in the literature. We focus on three questions here: (1) How much recurrent excitation is needed to sustain reverberating activity? How does the answer depend on parameters? (2) Is there a positive minimum frequency of reverberating activity, a positive "onset frequency"? How does it depend on parameters? (3) When do runaway transitions occur? For reduced models, we give mathematical answers to these questions. We also examine computationally to which extent our findings are reflected in the behavior of biophysically more realistic model networks. Our main results can be summarized as follows. (1) Reverberating activity can be fueled by extremely weak slow recurrent excitation, but only by sufficiently strong fast recurrent excitation. (2) The onset of reverberating activity, as recurrent excitation is strengthened or external drive is raised, occurs at a positive frequency. It is faster when the external drive is weaker (and the recurrent excitation stronger). It is slower when the recurrent excitation has a longer decay time constant. (3) Runaway transitions occur only with fast, not with slow, recurrent excitation. We also demonstrate that the relation between reverberating activity fueled by recurrent excitation and runaway transitions can be visualized in an instructive way by a (generalized) cusp catastrophe surface.

Detection of bone marrow-derived fibrocytes in human dental pulp repair.

AIM: To explore the expression profile of CD45+/pro-collagen I+ fibrocytes in intact dental pulps as well as during wound healing in adult dental pulp tissue. METHODOLOGY: A total of 16 healthy permanent teeth were obtained from young patients (18 to 25 years) undergoing orthodontic treatment. Routine pulp capping with mineral trioxide aggregate (MTA) was performed under local anaesthesia to induce a mineralized barrier at the exposed surface. Teeth were extracted from patients after 7, 14 and 35 days. Sections of the extracted teeth were prepared and stained for various markers using indirect immunofluorescence. Fibrocytes were counted, and the data were statistically evaluated using the Dunnett test. RESULTS: In uninflammed pulp tissue, a pro-collagen I-positive reaction was detected in odontoblasts, as well as in perivascular cells. Most of the CD45-positive cells were negative for pro-collagen I in normal pulp tissue, whereas CD45+/pro-collagen I+ fibrocytes were detected 7 days after injury. At day 14, fibrocytes were recognized under the fibrous matrix in contact with MTA and had infiltrated into regions of new capillary formation, where the fibrocytes were positively stained for vascular endothelial growth factor. By 35 days, fibrocytes were few, coincident with the formation of dentine bridges. The number of fibrocytes peaked 7 days post-injury and decreased at 14 days. CONCLUSIONS: The presence of fibrocytes in human pulp wound healing was observed. The spatiotemporal distribution of fibrocytes suggests that fibrocytes are involved in the early stages of pulp wound healing, specifically by contributing to new blood vessel formation.

Phenytoin-induced gingival overgrowth caused by death receptor pathway malfunction.

OBJECTIVE: In this study, we investigated the role of phenytoin (PHT) in death receptor-induced apoptosis of gingival fibroblasts to clarify the mechanism of PHT-induced gingival overgrowth. METHODS: Human gingival fibroblasts were cultured to semiconfluence and treated with PHT (0.025, 0.1, 0.25, and 1.0 µM) for 48 h, and then, the apoptotic cell numbers were relatively determined by absorptiometry. After 24 h of 0.25 µM PHT treatment, caspase activity was measured by absorptiometry, apoptotic and cell cycle phase distribution was analyzed by flow cytometry, expression levels of apoptotic genes were quantified by real-time qPCR, and expression of apoptotic proteins was detected by Western blot analysis. After 48 h of 0.25 µM PHT treatment, appearance of apoptotic cells was detected by TUNEL assay. RESULTS: PHT treatment decreased the proportion of apoptotic cells in gingival fibroblasts compared to a serum-free control culture in response to the protein changes as follows: PHT upregulated c-FLIP and, in turn, downregulated FADD, caspase-8, and caspase-3; PHT upregulated c-IAP2 and downregulated TRAF2; PHT downregulated caspase-9 and caspase-3 via decreased RIPK1 activity and increased Bcl-2 activity. CONCLUSION: PHT-induced gingival overgrowth may result from the above-mentioned mechanisms involving apoptosis inhibition in gingival fibroblasts.

Pentax Airway Scope® vs Macintosh laryngoscope for tracheal intubation in adult patients: a systematic review and meta-analysis.

The Pentax Airway Scope(®) is a single-use optical videolaryngoscope designed to assist with difficult tracheal intubation. We systematically reviewed the efficacy of the Pentax Airway Scope with that of a conventional laryngoscope for tracheal intubation in adults with 'normal' and 'difficult' airways. We included 17 randomised controlled trials with a total of 1801 participants. We used the DerSimonian and Laird random-effects model to calculate pooled relative risk or weighted mean differences. The relative risk (95% CI) of a Cormack-Lehane grade-1 laryngeal view was 2.40 (1.76-2.49) with the Pentax Airway Scope compared with the Macintosh laryngoscope, p < 0.00001. We found no other differences between the two laryngoscopes. Despite a superior laryngeal view, the Pentax Airway Scope provides little clinical benefit over the conventional laryngoscope.

Self-assessed approach to improving school health in Niger.

INTRODUCTION: Award schemes and self-evaluation systems have been developed to implement the 'Health-Promoting School (HPS)' concept in European and Asian countries. While there have been many successes in these regions, the implementation of HPS in African countries has been minimal. This study evaluated the impact of a self-evaluation system on school health in Niger. METHODS: A school health activity guide was developed and distributed to 1999 primary schools in the Niger Tahoua region to raise awareness and solve problems related to school health and hygiene. The number of schools that planned or implemented health-related activities, and the budget and implementation status of their activities was compared over 3 years (before, soon after, and 1 year after distribution). Focus group discussions (FGDs) were also conducted targeting Conseillers Pédagogiques (CPs), who supervise primary schools and teachers, primary school principals and members of Comité de Gestion des Etablissement Scolaire (COGES), which is a type of school steering committee. RESULTS: The number of schools planning at least one health-related activity increased from 47% to 79% soon after distribution of the guide (p <0.001).The number of schools implementing activities increased from 44% to 65% one year after distribution (p <0.001). Health-related budget per school also increased after distribution (p <0.0001) and increases were maintained 1 year after the intervention (p=0.8414). Fulfilment or partial fulfilment rates for health-related activities were lower compared with other (non-health) activities in all three years (80%, 77% & 84% in health-related activities vs 88%, 90% & 91% in others; p <0.001, p <0.001, & p=0.004, respectively). Most FGD participants expressed a positive impression of the program and noted the usefulness of the guide. However, some respondents reported difficulties, especially in relation to budget. CONCLUSION: The introduction of a health activity guide for self-assessment was effective in increasing health-related activities in primary schools in Niger, where a simple monitoring system should be introduced to establish the HPS concept.

Navigated opening wedge high tibial osteotomy improves intraoperative correction angle compared with conventional method.

PURPOSE: The correction angle after high tibial osteotomy (HTO) depends on an accurate preoperative planning and an accurate intraoperative technique. We hypothesized that the use of a navigation system in opening wedge HTO would improve the intraoperative target angles in the coronal and sagittal planes. METHODS: Postoperative femoro-tibial angle (FTA) and tibial posterior slope (TPS) in 28 knees with navigated opening wedge HTO were compared to those in 31 knees with the conventional method. Intraoperative correction angle was determined by the predicted medial opening width in the conventional group, and by the change of hip-knee-ankle angle in the navigated group. We defined lateral unstable knee as the knees with lateral cortex breakage or lateral tibial plateau fracture. RESULTS: Mean postoperative FTA was higher in the conventional group than in the navigated group (P < 0.037). In the conventional group, 4 lateral unstable knees were corrected to 174.6°. In the navigated group, 5 lateral unstable knees were corrected to 170.3° and no knees showed FTA > 173°. Mean change in TPS was greater in the conventional group than in the navigated group (P = 0.001). CONCLUSION: The navigation system in opening wedge HTO might reduce undercorrection in the knees with lateral cortex breakage or lateral tibial plateau fracture, and provide the better intraoperative FTA and TPS. LEVEL OF EVIDENCE: III.

Cross-cultural adaptation and validation of the Oxford 12-item knee score in Japanese.

INTRODUCTION: With the high incidence of knee osteoarthritis (OA) in Japan, there is a strong need not only for surgical therapies, but also for validated outcome measures. For this study, we completed cross-cultural adaptation, testing and validation of the Oxford knee score (OKS) for prospective use in national and international clinical studies involving Japanese patients. MATERIALS AND METHODS: The Japanese version of the OKS was developed according to the standard cross-cultural adaptation guidelines. For validation, the OKS was tested on 54 patients diagnosed with OA, osteonecrosis, ligament or meniscus injury. Reliability was tested using the intraclass correlation coefficient (ICC). Internal consistency or homogeneity was assessed using Cronbach's alpha. The correlation between the Japanese OKS, WOMAC and SF-36 questionnaires was used to assess construct validity. RESULTS: No major difficulties were encountered with the translation and pre-testing stages. For reliability and validity, the Japanese OKS was completed without any missed responses by 53 (98.15%) and 52 (96.30%) patients at the first and second distribution, respectively. The total OKS showed good reliability with an ICC of 0.85. Internal consistency was strong (Cronbach's alpha = 0.90). Strong construct validity (ICC values of 0.51-0.84) was obtained against the WOMAC and SF-36 (physical functioning, role-physical, bodily pain, and social functioning subscales) scores. Notable "ceiling" effects of the OKS were reported for 11 of the 12 questionnaire items. CONCLUSION: The Japanese OKS has proven to be a reliable and valid instrument for the self-assessment of knee pain and function in Japanese speaking patients with knee OA and other knee complaints.

[Usefulness of the thoracoscopic surgery under local anesthesia and irrigation for the patient with Bacillus cereus empyema; report of a case].

The case was 54-year-old male with some risks such as chronic heart failure, atrial fibrillation, and liver chirrhosis. He was admitted because of severe back pain and diagnosed as empyema by preoperative thoracentesis. By thoracoscopic procedures under local anesthesia, fibrinopurulent tissues were cleaned as much as possible and 3 of chest tubes were replaced. The final diagnosis was Bacillus cereus pyothorax by bacterial cultures of pleural effusion. Intrathoracic cavity was cleaned with physiological saline solution. The patient made favorable progress and recovered. Thoracoscopic surgery under local anesthesia with thoracic irrigation was so effective and safe methods to control the infection.

Possible pharmacotherapy for nifedipine-induced gingival overgrowth: 18α-glycyrrhetinic acid inhibits human gingival fibroblast growth.

BACKGROUND AND PURPOSE: This investigation aimed to establish the basis of a pharmacotherapy for nifedipine-induced gingival overgrowth. Gingival overgrowth has been attributed to the enhanced growth of gingival fibroblasts. In this study, we investigated the effects of 18-α-glycyrrhetinic acid (18α-GA) on growth, the cell cycle, and apoptosis and on the regulators of these processes in gingival fibroblasts isolated from patients who presented with nifedipine-induced gingival overgrowth. EXPERIMENTAL APPROACH: Gingival fibroblasts were cultured in medium containing 1% FBS with/without 10 µM 18α-GA for 24 or 48 h, and the cell number, cell cycle phase distribution, relative DNA content, apoptotic cell number and morphological characteristics of the cells undergoing apoptosis were measured together with the levels of proteins that regulate these processes and the level of caspase activity. KEY RESULTS: 18α-GA significantly decreased cell numbers and significantly increased the percentage of cells in the sub-G1 and G0 /G1 phases of the cell cycle and the number of apoptotic cells. Nuclear condensation and fragmentation of cells into small apoptotic bodies appeared in the fibroblasts treated with 18α-GA. In addition, 18α-GA significantly decreased the protein levels of cyclins A and D1, CDKs 2 and 6, phosphorylated Rb (ser(780) and ser(807/811)), Bcl-xL and Bcl-2 and increased the protein levels of p27, cytosolic cytochrome c, pro-caspase-3, and cleaved caspase-3 and the activities of caspases 3 and 9. CONCLUSIONS AND IMPLICATIONS: 18α-GA inhibited gingival fibroblast growth by suppressing the G1 /S phase transition and inducing apoptosis. In conclusion, 18α-GA may be used as a pharmacotherapy for nifedipine-induced gingival overgrowth.

Respiratory syncytial virus infection of human respiratory epithelial cells enhances inducible nitric oxide synthase gene expression.

The induction kinetics of the mRNA of interferon regulatory factor 1 (IRF-1), inducible nitric oxide synthase (iNOS), and proinflammatory cytokines in respiratory syncytial virus (RSV)-infected human type 2 alveolar epithelial cells (A549 cells) were analyzed semiquantitatively by RT-PCR. RSV enhanced IRF-1 and iNOS mRNA expression as early as 4 h after RSV infection and this enhancement lasted several hours. No IFN-gamma gene expression was observed during the whole course of the infection. Expression of IFN-beta, IL-1beta, and TNF-alpha genes was observed slightly at 4 h and became marked 7 h after infection. Addition of neutralizing antibodies to these cytokines to the culture had no effect on the induction of iNOS mRNA. The iNOS transcriptional activity in RSV-infected cells was significantly enhanced by an exogenous cytokine mixture (IL-1beta, TNF-alpha, and IFN-gamma). An apparent nitric oxide (NO) production was identified only when cytokines were added together with RSV infection. A significant increase of iNOS gene expression was observed in nasopharyngeal exudate cells obtained from infants during the acute phase of RSV bronchiolitis. These observations suggest that RSV infection of human respiratory epithelial cells induces the iNOS gene both in vitro and in vivo; this induction may occur rather promptly and involves transcriptional activator IRF-1 induced by the RSV infection itself. The iNOS gene, which is initially induced by RSV infection, may be further enhanced in a paracrine fashion by proinflammatory cytokines released by infection-activated inflammatory cells.

Enhanced cytokine production by milk macrophages following infection with respiratory syncytial virus.

Paired samples of milk and serum collected 3 days postpartum from 20 women were tested for the presence and level of interleukin (IL)-1, IL-6, IL-12, tumor necrosis factor alpha (TNF-alpha), and interferon-gamma (IFN-gamma) by enzyme immunoassay. The expression of these cytokine mRNAs in milk macrophages from eight donors were semiquantitatively analyzed by reverse transcriptase-polymerase chain reaction. The effects of respiratory syncytial virus (RSV) infection on cytokine production were determined in five samples of milk macrophages. Over 90% of the milk samples tested exhibited detectable levels of IL-1beta, IL-6, and TNF-alpha. No IL-12 or IFN-gamma activity was detected in the milk. IL-6 activity was weakly detected in about 45%, and TNF-alpha activity in about 10% of the serum samples tested. However, no IL-1beta, IL-12, or IFN-gamma activity was demonstrated in any of the serum samples. Milk macrophages from eight subjects all exhibited mRNA for IL-1beta, TNF-alpha, and IL-6, and IFN-gamma mRNA in six of eight subjects, although no IFN-gamma was detected in any of the 20 samples of milk tested. RSV exposure resulted in a 2- to 100-fold increase in the expression of IL-1beta, IL-6, and TNF-alpha mRNA as well as cytokine protein. Although RSV infection enhanced the expression of IFN-gamma mRNA, no detectable IFN-gamma was produced by the milk macrophages. These observations suggest that the milk macrophages are actively engaged in the physiological production of IL-1beta, IL-6, TNF-alpha, and IFN-gamma in the mammary gland and continue to possess the capacity to increase production of these cytokines in response to RSV and possibly other viral infections.

Human parathyroid hormone-related peptide-(107-111) does not inhibit bone resorption in neonatal mouse calvariae.

Recent analysis of the structure-function relationship of human PTH-related peptide (hPTHrP) has led to the discovery that its direct inhibitory activity on osteoclastic bone resorption resides fully in the 107-111 sequence of the peptide, as assessed by a bone resorption assay using isolated rat osteoclasts. Here we report that hPTHrP-(107-111) is inactive in neonatal mouse calvariae in culture. hPTHrP-(107-111), at doses of 10(-12)-10(-6) M and incubation periods up to 96 h, did not affect either basal or agonist-stimulated 45Ca release from prelabeled neonatal mouse calvariae, while salmon calcitonin was a potent and powerful inhibitor of both basal and stimulated 45Ca release from bone. Moreover, salmon calcitonin, but not hPTHrP-(107-111), inhibited the increase in osteoclast number in hPTHrP-(1-34)-treated bones. Furthermore, hPTHrP-(107-139) also failed to inhibit 45Ca release and the hPTHrP-(1-34)-induced increase in osteoclast number in this organ culture model when tested under conditions identical to those for hPTHrP-(107-111). The addition of indomethacin to hPTHrP-(107-111)- or hPTHrP-(107-139)-treated bones was without effect, excluding the possibility that the direct inhibitory activity of these peptides on osteoclasts is ablated by a prostaglandin-mediated mechanism. Although the mechanism underlying the apparent inability of the carboxyl-terminal PTHrP fragments to inhibit osteoclastic bone resorption in neonatal mouse calvariae is unknown, it may involve the complex microenvironment of osteoclasts in intact bone, which contains a large variety of cell types other than osteoclasts.

Thyrotropin receptor antibodies in hypothyroid Graves' disease.

To clarify the relation of TSH receptor antibody (TRAb) to Graves' ophthalmopathy and thyroid function, the activities of TSH binding inhibitor immunoglobulins, thyroid-stimulating antibodies, and thyroid stimulation-blocking antibodies were measured in five patients with hypothyroid Graves' disease. The diagnosis was based on the presence of Graves' ophthalmopathy and either permanent or transient hypothyroidism without a history of treatment for hyperthyroid Graves' disease. TSH binding inhibitor immunoglobulins and thyroid-stimulating antibodies were detected in all five patients. Thyroid stimulation-blocking antibodies results indicated that a blocking type of TRAb was not a cause of hypothyroidism. Destructive changes in the thyroid were probably responsible for hypothyroidism, since 1) high antibody titers against thyroglobulin and thyroid microsomal antigen, 2) diffuse hypoechogenicity of the thyroid on ultrasonography, 3) absent or impaired responses of serum T3 after TRH or TSH stimulation, and 4) histological findings similar to those in Hashimoto's thyroiditis were observed. In all patients except one, thyroid function was changeable, with euthyroid and even subclinical hyperthyroid episodes occurring during the course of the illness. It is conceivable that such unstable thyroid function may be attributable to subtle changes in the balance between the effects of destructive changes in the thyroid and the stimulatory effects of TRAb. In conclusion, all patients had TRAb, suggesting a possible relationship between such antibodies and Graves' ophthalmopathy. Patients develop euthyroidism or subclinical hyperthyroidism during the course of the illness with high frequency.

Noninvasive quantitative measurements of regional cerebral blood flow using technetium-99m-L,L-ECD SPECT activated with acetazolamide: quantification analysis by equal-volume-split 99mTc-ECD consecutive SPECT method.

Resting- and acetazolamide (Acz)-activated-regional cerebral blood flow (rCBF) measurements were performed by consecutive single-photon emission computed tomography (SPECT) studies before and after Acz administration using equal-volume-split technetium-99m-L,L-ethyl cysteinate dimer. Quantitative rCBF images were converted from qualitative axial SPECT images by the application of Patlak plot graphical analysis with radionuclide angiography and Lassen's linearization correction. Total time span required for this study was 53 minutes. The unaffected side of 37 studies with unilateral vascular lesions and 45 studies without apparent vascular lesions showed 132 +/- 17% and 140 +/- 15% increase of mean CBF (mCBF), respectively, under Acz administration. Comparing these values, the Acz-activated rCBF increases of less-affected and affected hemispheres of 23 studies with bilateral vascular lesions (116 +/- 13% and 113 +/- 12%, respectively) was lower with high statistical significance (P < 0.001). For the other 20 cases, physiologic saline was administered instead of Acz. This group showed no changes in mCBF under placebo administration (after placebo/baseline; 100 +/- 6%). Acetazolamide-activated rCBF increase was recognized clearly and easily using quantitative images. This noninvasive method is easy to perform and may be helpful to detect regional abnormalities of hemodynamic reserve in cerebrovascular diseases.

Stimulation of nerve growth factor synthesis/secretion by 1,4-benzoquinone and its derivatives in cultured mouse astroglial cells.

Previously we reported that astroglial cells cultured from mouse brain synthesize and secrete nerve growth factor (NGF) and that, in quiescent cells, catecholamines markedly increase the NGF content in the conditioned medium (CM). We wished to further assess the structural properties required for exhibition of such effect of compounds containing a ring structure analogous to that of catechol on astroglial NGF synthesis. During our study, we found that hydroquinone, which was confirmed not to stimulate NGF synthesis in mouse fibroblast cells in another of our investigations, is a potent stimulator of NGF synthesis in astroglial cells and that 1,4-benzoquinone, an oxidized form of hydroquinone, is a more effective stimulator than hydroquinone itself. In addition, the results of experiments with 1,2-benzoquinone derivatives indicated that the presence of a long aliphatic side chain in the molecule eliminates the stimulatory effect of 1,4-benzoquinone on NGF synthesis in astroglial cells.

beta(2)-glycoprotein I deficiency: prevalence, genetic background and effects on plasma lipoprotein metabolism and hemostasis.

beta(2)-glycoprotein I (beta(2)-GPI=apolipoprotein H) is an important autoantigen in patients with the antiphospholipid syndrome. It also plays a role in lipoprotein metabolism, such as anti-atherogenic property, triglyceride removal, and enhancement of lipoprotein lipase. Serum beta(2)-GPI concentration of 812 apparently healthy Japanese individuals was measured by sandwich EIA. Two families with complete beta(2)-GPI deficiency were identified. In one family, all affected had increased serum LDL-cholesterol levels or smaller particle sizes of LDL, while the other had no apparent abnormality in lipid metabolism. Individuals investigated had no history of thrombosis or overt abnormalities in hemostatic tests. A thymine corresponding to position 379 of the beta(2)-GPI cDNA was deleted in every beta(2)-GPI deficient individual. The incidence of this heterozygous deficiency determined by RFLP was 6. 3% in Japanese and none in Caucasians. Heterozygotes had significantly lower concentrations of serum beta(2)-GPI than did those without the mutation, yet no significantly different lipid profiles, such as total cholesterol, triglyceride, HDL-cholesterol, LDL-cholesterol, apoA-I, apoB and Lp(a), were observed. A low concentration of beta(2)-GPI seemed not to be associated with apparent abnormality in lipoprotein metabolism.

Diffuse bony uptake of thallium-201-chloride in the granulocyte colony-stimulating factor-producing lung carcinoma.

Diffuse uptake of 201TI in the axial bone is reported in a patient with large cell carcinoma of the lung who showed leukocytosis and an increased concentration of granulocyte colony-stimulating factor (G-CSF) in plasma. The abnormal bony uptake of 201TI disappeared in association with normalization of the elevated plasma G-CSF level after complete tumor resection. The production of G-CSF was confirmed by immunoperoxidase staining of the tumor tissue.

Radioiodine uptake by squamous-cell carcinoma of the lung.

A patient with a history of total thyroidectomy for papillary carcinoma showed a solitary hot spot in the chest on post-therapy radioiodine imaging. Subsequent evaluation demonstrated that this lesion was a primary squamous-cell lung cancer. Our case illustrates a rare but important differential diagnosis from lung metastasis of thyroid cancer in 131I scintigraphy. Alternatively, this "aberrant uptake" might be a rather common phenomenon for lung neoplasms, although the underlying mechanism is not yet known. Future experimental studies might lead to a new application of radioiodine imaging in pulmonary oncology.

Resting and acetazolamide-challenged technetium-99m-ECD SPECT in transient global amnesia.

Regional resting cerebral blood flow and vascular reserve in a patient with transient global amnesia (TGA) were evaluated during and after a TGA episode using 99mTc-ethyl cysteinate dimer (ECD). The patient had consecutive SPECT studies before and after acetazolamide (ACZ) administration with adjunctive radionuclide angiography using equal-volume-split 99mTc-ECD. SPECT study during TGA episode showed poor vasodilatory reactivity to ACZ in the left medial temporal region involving the hippocampus and resting hypoperfusion in the regions bilaterally. The resting hypoperfusion with reserved vasodilatory reactivity to ACZ also was seen in the bilateral thalami. Abnormal findings in these regions disappeared on the follow-up SPECT study 15 days after the onset. No previous SPECT evaluation of regional abnormalities of both hemodynamic reserve and resting perfusion during and after an episode of TGA has been reported.