A case of Coffin-Lowry syndrome with premature exfoliation of primary teeth.

We present a case of a 5-year-old boy with premature exfoliation of primary teeth. All eight primary incisors had exfoliated by the age of 3 years, and three canines and one primary first molar were subsequently lost when he was 4 years old. None of the exfoliated teeth exhibited caries. The boy also showed characteristic facial changes, tapering of the fingers, and mental and motor retardation. Based on these findings, he was diagnosed as having Coffin-Lowry syndrome. Premature exfoliation of primary teeth in Coffin-Lowry syndrome has been described in a few reports. This manifestation of the disease would be helpful for diagnosis at an early stage as those previous reports suggested.

Inhibition of inflammatory and bone-resorption-inhibitory effects of alendronate by etidronate.

Among the bisphosphonates (BPs), the aminobisphosphonates (aminoBPs) have much stronger bone-resorption-inhibitory activities (BRIAs) than nonaminobisphosphonates (nonaminoBPs). However, aminoBPs have inflammatory effects. We previously reported that in mice: (i) all aminoBPs tested (10-40 micromol/kg) induced various inflammatory reactions (including induction of histidine decarboxylase), whereas clodronate (a non-aminoBP) (10-160 micromol/kg) inhibited these reactions; and (ii) a clear sclerotic line (tentatively called the BP line) was detectable in the tibia by radiography a few weeks after a single injection of either alendronate (a typical aminoBP) (1.6 micromol/kg) or clodronate (160 micromol/kg), and this BP-line formation (a marker for the BRIAs of BPs) was not reduced in mice given both alendronate and clodronate. In this study, using this murine model, we compared clodronate, etidronate (another typical non-aminoBP), alendronate, etidronate + alendronate, and clodronate + alendronate in terms of their inflammatory effects and/or BP-line formation. For BP-line formation, 480 micromol/kg etidronate was needed (single injection). At 160 micromol/kg, etidronate inhibited the histidine decarboxylase induction, but not the other inflammatory reactions induced by alendronate. However, etidronate (unlike clodronate) also inhibited alendronate-induced BP-line formation (even at 40 micromol/kg). Etidronate (160 micromol/kg) also inhibited the physicochemical changes in the tibia induced by six, weekly injections of alendronate. Therefore, depending on the dose, etidronate can inhibit alendronate's inflammatory actions and its BRIA. These results, together with those reported previously, suggest that a strategy utilizing clodronate (but not etidronate) plus an aminoBP might prevent or reduce the inflammatory side effects induced by aminoBPs while preserving their powerful BRIAs. We discuss the mechanisms underlying the antagonism between aminoBPs and non-aminoBPs.

Effects of weekly administrations of alendronate+clodronate on young mouse tibia: localized action at the proximal growth plate.

Alendronate (A), a typical aminobisphosphonate (aminoBP), has a strong bone-resorption-inhibitory activity (BRIA). However, like other aminoBPs it has inflammatory side effects. In contrast, the BRIA of clodronate (C), a non-aminoBP, is much weaker, and in animal experiments it suppresses aminoBP-induced inflammatory reactions. In the present study, we examined the effects of weekly administrations of A (1.6 micro mol/kg) + C (160 micro mol/kg) on the tibias in young mice and compared them to those induced by A or C alone. Radiophotography showed that A increased bone density at a selective site in the tibia. Indeed, one week after the final injection of A (given alone), clear sclerotic lines (tentatively called BP-lines) were visible at sites corresponding to the location of the growth plate at the time of the each injection. C also produced BP-lines, although they were weaker than those produced by A. Combined administration of A and C produced similar BP-lines as seen in mice given A alone. These results together with other physicochemical effects of A on the tibia suggest that (1) each injection of A and C inhibits bone resorption selectively and transiently at the tibial growth plate in young mice, although minor effects on other sites cannot be excluded, and (2) the combination of A and C keeps still a strong BRIA. Our findings may suggest a strategy for the prevention or reduction of some inflammatory side effects of A or other aminoBPs.

Determination of isatin, an endogenous monoamine oxidase inhibitor, in urine and tissues of rats by HPLC.

1. We have previously identified isatin as one of the endogenous monoamine oxidase (MAO) inhibitors in the urine and the brain of stroke-prone spontaneously hypertensive rats (SHRSP), using gas chromatography-mass spectrometry (GC-MS). 2. In this study, we attempted to develop a convenient assay to determine isatin using high performance liquid chromatography with an ultraviolet detector (HPLC-UV). The standard curve for authentic isatin was linear at a range from 2 to 20 nmol per ml. The coefficient of variance was within 3% for both intra-assay and inter-assay. The sensitivity was 20 pmol per 10 microl of urine sample. 3. Isatin concentration correlated significantly and positively with endogenous MAO activity (tribulin-like activity) in both urine (r=0.924, P<0.001) and kidney extracts (r=0.862, P<0.01). There was a significant difference in urinary isatin between Wistar Kyoto rats (WKY) and SHRSP. Oral administration of isatin increased urinary isatin concentration and systolic blood pressure in WKY. 4. Determination of isatin using HPLC-UV may be useful for elucidating role of isatin in various conditions of stress and disease.

Antiemetic effects of sendide, a peptide tachykinin NK1 receptor antagonist, in the ferret.

The antiemetic activity of sendide, a new peptide tachykinin NK1 receptor antagonist, against cisplatin-induced emesis was investigated using ferrets. The frequency of cisplatin (10 mg/kg, i.p.)-induced retching (104.6 +/- 14.3/6 h) and vomiting (19.0 +/- 3.0/6 h) was significantly reduced by pretreatment with sendide (3.0 mg/kg, s.c.) (14.0 +/- 8.1/6 h and 1.8 +/- 1.2/6 h, respectively). Intravenous bolus injection of substance P (1-10 microg/kg) or 5-hydroxytryptamine (5-HT) (10-50 microg/kg) produced a dose-dependent increase in the abdominal afferent vagus nerve activity. The change from pre-injection level in the afferent nerve activity induced by substance P (1 microg/kg, i.v.) (453.7 +/- 51.5%) was significantly reduced by pretreatment with either sendide (100 microg/kg, i.v.) (276.1 +/- 50.1%, P < 0.05) or granisetron, a 5-HT3 receptor antagonist (1 mg/kg, i.v.) (146.3 +/- 14.0%, P < 0.01). The amount of 5-HT released into the solution during a 1-h exposure to 2-methyl-5-HT (10(-6) M), a 5-HT3 receptor agonist, was significantly increased (317.9 +/- 46.7%, P < 0.05) compared with that of the control tissues (160.4 +/- 8.1%). The 2-methyl-5-HT-induced 5-HT release was significantly inhibited by administration of sendide (10(-6) M) (174.0 +/- 21.6%, P < 0.05) or granisetron (10(-6) M) (186.6 +/- 27.3%, P < 0.05). Since sendide does not penetrate the central nervous system, these results suggest that the antiemetic effects of sendide are due to the inhibition of NK1 and 5-HT3 receptors on the emetic peripheral detector sites.

Effects of dietary docosahexaenoic acid on survival time and stroke-related behavior in stroke-prone spontaneously hypertensive rats.

1. Dietary docosahexaenoic acid (DHA) suppressed the age-dependent increase in systolic blood pressure and prolonged the average survival time of stroke-prone spontaneously hypertensive rats (SHRSP). 2. Dietary DHA (1% and 5% in diets) altered the circadian rhythm of SHRSP, causing significant increases in ambulatory activity during the dark period. At the onset of stroke, desynchronization with light and dark phases and new biological rhythms were noted in all of the control SHRSP (DHA 0%). DHA treated SHRSP did not show such behavioral changes. 3. These effects were accompanied by the increase of DHA and the decrease of AA levels in plasma and brain cortex. 4. It was concluded that dietary DHA suppresses the development of hypertension and stroke-related behavioral changes, resulting in prolongation of the SHRSP's life span.

In vitro inactivation of herpes simplex virus by a biological response modifier, PSK.

Herpes simplex virus (HSV) causes herpes genitalis, primary gingivostomatitis and recurrent herpes labialis. In order to elucidate in vivo mechanisms by which PSK, a biological response modifier, exerts a protective effect against HSV infection, we used an in vitro system to study whether PSK inactivated infectivity of HSV-type 1 (HSV-1) and HSV-type 2 (HSV-2) isolated from patients with herpes genitalis in addition to a laboratory-cultured strain of HSV type 1 (HSV-1-GC+). It was found that HSV-1-GC+ was inactivated by PSK in a dose dependent fashion of concentrations of PSK and virus titers. Concentrations of PSK as low as 0.31 mg/ml was shown to inactivate the infectivity of HSV-1-GC+. Inactivation required at least 30 min of incubation at 37 degrees C with maximal inactivation observed at 60 min incubation time. Similar to HSV-1-GC+, clinically isolated strains of HSV-2 were inactivated by PSK although clinically isolated strains of HSV-1 were resistant to PSK, compared with HSV-2. It was also shown that PSK-treated HSV retained the ability to adsorb to the cell membrane, but did not synthesize viral protein(s). These data illustrate that there is a biological difference in the sensitivity to PSK between HSV type 1 and type 2, and also suggest that PSK could inactivate HSV in lesions at peripheral sites of recurrent herpes.

Antiemetic effects of N-3389, a newly synthesized 5-HT3 and 5-HT4 receptor antagonist, in ferrets.

The antiemetic activity of N-3389 (endo-3,9-dimethyl-3,9-diazabicyclo[3,3,1]non-7-yl-1 H-indazole-3-carboxamide dihydrochloride), a new 5-HT3 and 5-HT4 receptor antagonist, against cisplatin-, cyclophosphamide- and copper sulfate-induced emesis was investigated using ferrets. We also examined the effects of these agents on abdominal afferent vagus nerve activity in anesthetized ferrets. Both intraperitoneal (0.1-1.0 mg/kg) and oral (0.1-1.0 mg/kg) administration of N-3389 produced dose-dependent antiemetic effects. The time-course of cisplatin (10 mg/kg, i.p.)-induced emesis in another group of ferrets paralleled the increase in abdominal afferent vagus nerve activity induced by cisplatin (10 mg/kg, i.p.) and was inhibited by pretreatment with N-3389 (1.0 mg/kg, i.v.). Furthermore, the cisplatin (10 mg/kg, i.p.)-induced increase in abdominal afferent vagus nerve activity was markedly reduced by an additional injection of N-3389 (0.1-1.0 mg/kg, i.v.) in a dose-dependent manner. The antiemetic effects exhibited by N-3389 are probably due to the inhibition of 5-HT3 and 5-HT4 receptors on the abdominal afferent vagus nerves.

Highly virulent strains of herpes simplex virus fail to kill mice following infection via gingival route.

Virulence of herpes simplex virus (HSV) in mice has been demonstrated to be dependent on the site of infection. In this experiment, pathogenesis of HSV was studied in 2 different routes of infection in a mouse model system. When BALB/c mice were infected with 5 x 10(3) plaque-forming units (PFU) of virulent HSV type 1 Miyama GC+ strain (HSV-1-GC+) intraperitoneally, all mice were dead in 6 to 9 days. HSV-1-GC+ was recovered from organs such as the cerebrum, cerebellum, brainstem, and spleen 2 to 5 days after infection, but not from other organs such as trigeminal ganglia. However, if mice were infected in the maxillary gingiva with 1.0 x 10(7) PFU of HSV-1-GC+, all mice survived. HSV-1-GC+ was recovered from the trigeminal ganglia and brainstem 2 to 5 days after infection, but not from other organs tested. When mice were infected in maxillary gingiva with HSV-1-GC+, followed by the intraperitoneal injection of 6 mg of cyclophosphamide 72 hrs after virus infection, all mice were dead within days. Immunofluorescent and hematoxylin-eosin staining of gingival tissue sections revealed that when mice were infected in maxillary gingiva with HSV-1-GC+, 3 times as many gamma delta T-cells and 5 times as many polymorphonuclear cells can be detected in sections of maxillary gingiva when compared with non-infected mice. These data show that the gingiva of mice is considerably more resistant to infection with HSV, compared with the peritoneal cavity, and suggest the possible presence of an oral defense mechanism which might be different from that in the peritoneal cavity.

[A case of pulmonary tuberculosis associated with tuberculous fistula of anus].

A 39-year old male visited the hospital complaining of perianal pain, swelling and redness. Under the diagnosis of an anal abscess, drainage was performed repeatedly. As the wound failed to heal and fistulae were detected, excision of entire tract was performed. On histopathological examination of the resected fistulae, caseous necrosis, Langhans giant cells, and epithelioid cell infiltration were found and diagnosed as anal tuberculosis. Chest X-ray showed cavitary lesion with infiltrative shadow in right upper lobe. Acid-fast bacilli were positive in sputum, and the diagnosis of pulmonary tuberculosis was confirmed. Anti-tuberculosis therapy was immediately started with good response to treatment. As tuberculosis of anal region is so rare recently and there is no characteristic clinical picture, it is very difficult to diagnose it pre-operatively. In some cases such as ours, pulmonary or other tuberculosis is accompanied with anal tuberculosis. Therefore, accurate diagnosis of anal tuberculosis is needed to find other tuberculosis early. As anal tuberculosis is rarely diagnosed correctly before operation on the basis of the clinical picture, the histopathological examination of the excised fistula is mandatory for the correct diagnosis of anal tuberculosis.

The protective effect of 4-hydroxy-2-methyl-N-[2-(tetrazol-5-yl)- phenyl]-2H-1, 2-benzothiazine-3-carboxamide-1, 1-dioxide monosodium salt (HX-1920) on cisplatin-induced toxicity in rats.

The protective effect of 4-hydroxy-2-methyl-N-[2-(tetrazol-5-yl)-phenyl]-2H-1, 2-benzothiazine-3-carboxamide-1, 1-dioxide monosodium salt (HX-1920) on the nephrotoxicity of cisplatin was studied in rats. Effects of HX-1920 on antitumor activity and emesis induced by cisplatin were also examined using mice and ferrets, respectively. All 10 rats injected with both HX-1920 and LD50 of cisplatin survived for 14 days. After 24 hr, co-administration of HX-1920 significantly increased the urinary excretion of cisplatin in rats. HX-1920 also significantly inhibited the cisplatin-induced elevation of urinary N-acetyl-beta-D-glucosaminidase, blood urea nitrogen and plasma creatinine concentrations in rats. HX-1920 had no effect on the number of white blood cell. HX-1920 tended to reduce the emesis induced by cisplatin in ferrets. Furthermore, there was no difference in the survival curve between the cisplatin group and the HX-1920 plus cisplatin group in mice inoculated with P 388 leukemia cells. Thus, HX-1920 did not modify the antitumor activity of cisplatin. These results suggest that HX-1920 has a protective effect on the nephrotoxicity of cisplatin without inhibiting its antitumor activity.

Emesis-related biochemical and histopathological changes induced by cisplatin in the ferret.

Cisplatin is an effective antineoplastic agent that causes severe vomiting due to unknown mechanism. The ferret, an animal model useful in the determination of emetic activity, was used to clarify the emesis-related biochemical and histopathological changes that were induced by cisplatin. Cisplatin (5 to 10 mg/kg) was administered intraperitoneally and a 7-10 mg/kg i.p. dose evoked dose-dependent emesis in the ferret. Almost all cisplatin-vomiting episodes occurred within a 6 hour observation period. All ferrets receiving cisplatin in this study died within 3-5 days. Significant increases in ileal mucosal levels of serotonin and norepinephrine were observed in cisplatin-treated ferrets. There were no significant changes in the levels of serotonin and dopamine in the gastric mucosa. Also, karyorrhexis was observed in the epithelial cells of the ileum and in the lymph follicles of the spleen of cisplatin-treated ferrets. These significant biochemical and pathological changes in the ileum may play an important role in cisplatin-induced emesis.

Protective effects of adrenoceptor-blocking agents on myocardial injury induced by epinephrine in mice.

Employing propranolol as a non-selective beta-blocker, atenolol, acebutolol and metoprolol as selective beta 1-blockers, butoxamine as a selective beta 2-blocker, labetalol as an alpha- and beta-blocker, and phentolamine as an alpha-blocker, we compared the effects of these adrenoceptor-blocking agents to reduce the degree of the myocardial injury induced by epinephrine in mice. Epinephrine in a single dose of 4 mg/kg/day, s.c., daily for 7 days, caused widely extended lesions, necrosis and fibrosis in the myocardial fibers, and degeneration in the residual myocardial fibers. The adrenoceptor-blocking agents in a dose of 10 mg/kg/day, s.c., given 30 minutes prior to epinephrine to each mouse daily for 7 days, had reduced the degree of the myocardial injury induced by epinephrine. The blockers, all, effectively suppressed the injury. Although metoprolol and butoxamine were less effective on the protection of the cardiotoxicity than phentolamine, the other blockers prevented the cardiotoxicity with the same degree as phentolamine did. These findings suggest that not only alpha- but also beta 1- and beta 2-adrenoceptors play critical roles in producing the myocardial injury.

Establishment of latent ganglionic infection with herpes simplex virus via maxillary gingiva and viral re-activation in vivo after trauma.

Herpes simplex virus can remain latent for months or years in sensory and automatic ganglia of animals and man, and can be re-activated in vivo by several procedures such as neurectomy, irritation of epithelial surfaces, and administration of immunosuppressive agents. The objective of this study was to determine whether dental stimuli can cause re-activation of the latent herpes simplex virus. Homogenization and explanation of ganglia from mice showed that herpes simplex virus (type 1) traveled from maxillary gingiva to trigeminal ganglia, and remained latent. It was also shown that mice passively immunized with rabbit antibody to herpes simplex virus, following the inoculation of herpes simplex virus by the maxillary gingiva route, developed a latent infection in the trigeminal ganglia. Neutralizing antibody was cleared from the circulation and could not be detected in most of these animals after five weeks. A neutralizing test showed that antibody-negative mice with latent infection were able to produce antibody to re-infection with herpes simplex virus, suggesting that re-activation can be identified by measurement of serum antibody. By use of this mouse model system, it was shown that when maxillary gingiva was traumatized with dry ice, viral re-activation occurred in 58% of these animals, as demonstrated by the appearance of neutralizing antibody. Irradiation by a Stomalaser beam had no effect on the re-activation of latent herpes simplex virus. Our mouse model system may serve as a useful model for obtaining new information on re-activating or inhibitory factors in dentistry.

[Clinical evaluation of low viscosity composite resin].

This study was to evaluate clinically low viscosity composite resin. The subjects of the present study were 121 children aged 2 to 10 years who visited the Pedodontic clinic of Tohoku University Dental Hospital and 53 children aged 2 to 8 years who visited the clinic of the general practitioners in Sendai. A total of 451 cavities (343 at the clinic of the University Hospital, 108 at the clinic of the general practitioners) were treated with Clearfil SC-II (Kuraray). The observation period varied from 1 month to 33 months after treatment. The restorations were examined with regard to spacing or stepped abrasion in the marginal region of the fillings, fracture, loss, attrition and discoloration of the fillings, and recurrent caries and/or pulpal involvement of the treated teeth. The following findings were obtained. 1) The restoration cases treated at the clinic of the University Hospital were evaluated as clinically acceptable in 254 cases (74.1%), while those treated at the clinic of the general practitioners in 76 cases (70.4%). 2) Of the 343 restorations treated at the clinic of the University Hospital, 73 (21.3%) exhibited poor restorative conditions, while of the 108 restorations treated at the clinic of the general practitioners, 15 (13.9%) showed such conditions. 3) The incidences of poor restorative conditions for anterior restorations were 39.7% and 8.3% respectively at the clinics of the University Hospital and general practitioners. 4) The incidences of poor restorative conditions for posterior restoration were 16.9% and 17.7% respectively at the clinics of the University Hospital and general practitioners. 5) Among the poor restorative conditions, the spacing or stepped abrasion and recurrent caries in the marginal region of the restorations occurred more frequently. 6) The incidences of spacing or stepped abrasion and recurrent caries in the marginal region of the restorations increased in the cases of class II and III cavities.

Time-dependent changes in plasma levels of cationic electrolytes produced by hypertonic solutions of low potent substance intraperitoneally administered to rats.

In order to investigate interrelations of plasma levels of potassium with those of the other electrolytes in case of intraperitoneal administration of hypertonic solution consisting of low potent substance, each of the three hypertonic solutions (2,800 mOsm/L), i.e., 50% glucose, 8.12% sodium chloride, and 13.16% sodium sulphate, was intraperitoneally injected to rats in a dose of 3.5 ml/kg body weight. Blood was sampled from the femoral artery at 0, 5, 10, 20, 30 and 45 min after the administration and at the time-point of death. In all cases of the three administered groups, the plasma levels of magnesium was observed to start increasing from 5 min, and, then, the potassium levels from 10 min. The phosphorus levels did not show a significant increase until 20 min, showing later an abrupt increase until the death. Calcium, on the other hand, did not show any significant change in the plasma level until the death. These findings denote that a high osmotic pressure moves first intracellular water and magnesium ion to the outside of the cell, and , with a time delay, intracellular potassium ion is forced to move slowly to the outside. Finally, intracellular phosphorus seems to be released into the extracellular space as a result of damages by suppression of mitochondrial oxidative phosphorylation and by activation of phospholipase both of which were caused directly or indirectly by a critical osmotic force.

[A study on the renal action of beta 1- and beta 2-adrenoceptors in rats].

The present experiments were designed to study urine volume and urinary sodium excretion effects of beta-antagonists and beta-agonists with reference to beta 1- and beta 2-adrenoceptors in rats. The beta-antagonists used were atenolol as a selective beta 1-antagonist, butoxamine as a beta 2-antagonist and propranolol as a non-selective beta-antagonist. The beta-agonist used were salbutamol as a beta 2-agonist and isoproterenol as a non-selective beta-agonist. Beta-antagonists increased the urine volume and urinary sodium excretion, but beta-agonists decreased the urine volume and urinary sodium excretion. With regards to these effects, atenolol increased the urine volume more than urinary sodium excretion, isoproterenol decreased the urine volume more than urinary sodium excretion, and salbutamol decreased the urinary sodium excretion more than urine volume. When beta-antagonists were infused with a beta-agonist, the original diuretic effects of these beta-antagonists were inhibited by the beta-agonist. In these effects, beta-antagonists infused with isoproterenol inhibited urine volume more than urinary sodium excretion, but beta-antagonists infused with salbutamol inhibited urinary sodium excretion more than urine volume. These results indicate that the urine volume is related to beta 1-adrenoceptors, while the urinary sodium excretion is related to beta 2-adrenoceptors, although there is no selectivity towards either beta 1-adrenoceptors or beta 2-adrenoceptors as far as diuresis or antidiuresis is concerned.

[A study on the mechanism of the antiasthmatic effect of labetalol on experimental histamine-induced asthma].

The effect of labetalol (alpha- and beta- adrenoceptor blocking agent) on the respiratory organs of guinea pig was investigated in vivo and in vitro. The asthmatic symptoms which were induced by inhalation of histamine were relieved by pretreatment with labetalol (1-5 mg/kg, i.p.) in most cases. Propranolol, on the contrary, aggravated distinctly the histamine-induced asthma, although phentolamine and diphenhydramine relieved the asthma. Experiments carried out in vitro showed that labetalol relaxed the tonus of isolated tracheal preparation, shifting the histamine dose-response curve to the right and downward. The down shifting by labetalol was dose-dependent and much more sensitive than that by papaverine, and it disappeared after pretreatment of propranolol. Thus, it was considered that labetalol exerted a relaxing action on the tracheal preparation by a beta 2-adrenoceptor partial agonist action (intrinsic sympathomimetic activity, ISA). Since labetalol in high concentration also shifted the histamine dose-response curve parallel to the right as seen with phentolamine or diphenhydramine, it was considered that labetalol exerted not only an alpha-blocking action but also an antihistaminic action.