Head and neck cancer patients show poor oral health as compared to those with other types of cancer.

PURPOSE: Several studies have found associations between periodontitis and various types of cancer. Since the site of head and neck cancer (HNC) has contiguity or proximity to the oral cavity, it may be particularly influenced by oral inflammation. This study aimed to determine whether HNC patients have poor oral health as compared to those with other types of cancer. METHODS: This study retrospectively examined oral environmental factors including periodontal inflamed surface area (PISA), a new periodontal inflammatory parameter. A total of 1030 cancer patients were divided into the HNC (n = 142) and other cancer (n = 888) groups. Furthermore, the HNC group was divided into high (n = 71) and low (n = 71) PISA subgroups, and independent risk factors affecting a high PISA value were investigated. RESULTS: Multivariate logistic regression analysis showed that number of missing teeth (odds ratio 1.72, 95% CI 1.15-2.56, P < 0.01), PISA (odds ratio 1.06, 95% CI 1.03-1.06, P < 0.05), and oral bacterial count (odds ratio 1.02, 95% CI 1.01-1.03, P < 0.01) were independent factors related to HNC. In addition, multivariate logistic regression analysis indicated that current smoker (odds ratio 7.51, 95% CI 1.63-34.71, P < 0.01) and presence of untreated dental caries (odds ratio 3.33, 95% CI 1.23-9.00, P < 0.05) were independent risk factors affecting high PISA values in HNC patients. CONCLUSION: HNC patients have higher levels of gingival inflammation and poor oral health as compared to patients with other types of cancer, indicating that prompt oral assessment and an effective oral hygiene management plan are needed at the time of HNC diagnosis.

Mouse maternal odontogenic infection with Porphyromonas gingivalis induces cognitive decline in offspring.

Introduction: Porphyromonas gingivalis (P. gingivalis), a major periodontal pathogen, causes intrauterine infection/inflammation. Offspring exposed to intrauterine infection/inflammation have an increased risk of neurological disorders, regardless of gestational age. However, the relationship between maternal periodontitis and offspring functional/histological changes in the brain has not yet been elucidated. Methods: In this study, we used a gestational mouse model to investigate the effects of maternal odontogenic infection of P. gingivalis on offspring behavior and brain tissue. Results: The step-through passive avoidance test showed that the latency of the acquisition trial was significantly shorter in the P. gingivalis group (p < 0.05), but no difference in spontaneous motor/exploratory parameters by open-field test. P. gingivalis was diffusely distributed throughout the brain, especially in the hippocampus. In the hippocampus and amygdala, the numbers of neuron cells and cyclic adenosine monophosphate response element binding protein-positive cells were significantly reduced (p < 0.05), whereas the number of ionized calcium binding adapter protein 1-positive microglia was significantly increased (p < 0.05). In the hippocampus, the number of glial fibrillary acidic protein-positive astrocytes was also significantly increased (p < 0.05). Discussion: The offspring of P. gingivalis-infected mothers have reduced cognitive function. Neurodegeneration/neuroinflammation in the hippocampus and amygdala may be caused by P. gingivalis infection, which is maternally transmitted. The importance of eliminating maternal P. gingivalis-odontogenic infection before or during gestation in maintenance healthy brain function in offspring should be addressed in near future.

The Urinary Excretion of Magnesium as an Effective Magnesium Deficiency State Indicator: A Controlled Intervention Trial.

With the western influence in our diets, food consumption has changed, and our magnesium (Mg) intake is no longer optimal. Serum Mg (S-Mg) level is currently used as an indicator of Mg deficiency and is strictly regulated via compensatory mechanisms. It is believed that a 24-h urine collection can be used to evaluate potential Mg deficiency. This study aimed to assess whether Mg deficiency state as found in urine Mg (U-Mg) excretion and improving such deficiency with a diet that meets the Recommended Dietary Allowances (RDAs) of Mg for 15 d. Healthy Japanese women were recruited for Study 1 (n=22) and Study 2 (n=10). Study 1 was 1-d balance test, where fasting blood and 24-h urine samples were collected. Study 2 was 15-d diet load test, where fasting blood (days 1, 7, and 15) and 24-h urine (odd days) were collected. All test meals were made certain to have met the RDA for Mg for women in their 20s. In Studies 1 and 2, S-Mg was within the normal range. In Study 1, U-Mg excretion was 67.7±17.0 mg/d, with a large dispersion. In Study 2, U-Mg excretion on days 7 and 15 was significantly higher than on day 1, but have no significant differences in U-Mg excretion between days 7-15. U-Mg excretion can be a valuable indicator to evaluate Mg state. In young women, improvements in Mg deficient state were observed after 7-15 d of taking meals that met the RDAs of Mg.

Experimental tooth loss affects spatial learning function and blood-brain barrier of mice.

OBJECTIVE: This study aims to investigate how experimental tooth loss affected learning, memory function, and brain pathophysiology in mice. MATERIALS AND METHODS: The mice (C57BL/6 J, 2-month-old, male) were divided into tooth loss and control groups. The behavioral test battery was performed at 6 and 12 months after tooth extraction. The protein levels of the tight junctions in the brains of the mice were analyzed. Hippocampal astrocyte was measured using immunohistochemical staining. RESULTS: The results of behavioral tests and biochemical analysis performed during the 6 months observation period did not show significant differences between the groups. However, the escape latency in the tooth loss group was significantly longer than that in the control group at the 12 months after tooth extraction. The level of claudin-5 decreased in the tooth loss group. Additionally, hippocampal astrogliosis was found in the tooth loss group. CONCLUSIONS: Experimental tooth loss reduced the level of claudin-5 and caused astrogliosis in the brains of mice, which was accompanied by deterioration of learning functions. This study may provide a new insight about the association between tooth loss and cognitive dysfunction.

Dental and Occlusal Changes during Mandibular Advancement Device Therapy in Japanese Patients with Obstructive Sleep Apnea: Four Years Follow-Up.

Dentoskeletal changes caused by the long-term use of mandibular advancement devices (MADs) for obstructive sleep apnea (OSA) have rarely been investigated in Japan. We assessed the long-term dentofacial morphological changes in 15 Japanese patients with OSA who used two-piece MADs for an average of 4 years. Lateral cephalography analyses were performed initially and 4 years later (T1). The dental assessment included overjet, overbite, upper anterior facial height, lower anterior facial height (LAFH), total anterior facial height (TAFH), and anterior facial height ratio. Dental casts were digitized and analyzed using a 3D scanner. Changes in the apnea hypopnea index (AHI) and other sleep-assessment indices were assessed using polysomnography and out-of-center sleep testing. Radiography revealed lingual inclination of the maxillary central incisors, labial inclination of the mandibular central incisors, clockwise rotation of the mandible, and an increase in the TAFH and LAFH at T1. In the dental cast analysis, the diameter width and palatal depth tended to decrease and increase, respectively. There was a significant decrease in the AHI and other sleep assessment indices after using the MADs for approximately 4 years. However, these findings do not provide a strong basis and should be interpreted cautiously. Future studies should have a larger sample size and should further investigate the long-term occlusal and dental changes caused by the original MADs in Japanese patients with OSA.

Trehalose Suppresses Lysosomal Anomalies in Supporting Cells of Oocytes and Maintains Female Fertility.

Supporting cells of oocytes, i.e., cumulus cells, control oocyte quality, which determines fertilization success. Therefore, the transformation of mature and immature cumulus cells (MCCs and ICCs, respectively) into dysmature cumulus cells (DCCs) with dead characteristics deteriorates oocyte quality. However, the molecular basis for this transformation remains unclear. Here, we explored the link between autophagic decline and cumulus transformation using cumulus cells from patients with infertility, female mice, and human granulosa cell-derived KGN cell lines. When human cumulus cells were labeled with LysoTracker probes, fluorescence corresponding to lysosomes was enhanced in DCCs compared to that in MCCs and ICCs. Similarly, treatment with the autophagy inhibitor chloroquine elevated LysoTracker fluorescence in both mouse cumulus cells and KGN cells, subsequently suppressing ovulation in female mice. Electron microscopy analysis revealed the proliferation of abnormal lysosomes in chloroquine-treated KGN cells. Conversely, the addition of an autophagy inducer, trehalose, suppressed chloroquine-driven problematic lysosomal anomalies and ameliorated ovulation problems. Our results suggest that autophagy maintains the healthy state of the supporting cells of human oocytes by suppressing the formation of lysosomes. Thus, our results provide insights into the therapeutic effects of trehalose on female fertility.

Masticatory Function Assessment of Adult Patients With Cleft Lip and Palate After Orthodontic Treatment.

OBJECTIVE: To determine whether orthodontically treated patients with cleft lip and palate (CLP) possess a different masticatory function than those of untreated patients with normal occlusion. DESIGN: Occlusal contact area, occlusal force, as well as masseter and anterior temporal muscular activity were measured during maximum voluntary clenching (MVC) tests. Mandibular left and right lateral movements during mastication were also assessed. To further elucidate the nature of masticatory function, especially to determine the rate of abnormal jaw movement patterns, a parametric error index (EI) was set. Finally, masticatory efficiency was evaluated with a glucose sensitive measuring device. PARTICIPANTS: Fifteen patients with CLP who had previously completed the orthodontic treatments required to achieve an acceptable and more harmonious occlusion accepted to volunteer in this study along with 21 untreated patients who already possessed a normal occlusion. RESULTS: Patients with CLP showed a significantly lower occlusal force, reduced occlusal contact area, and decreased masticatory efficiency as well as significantly higher EI value when compared with controls. However, there was no significant difference when analyzing muscle activity, although masticatory efficiency was significantly different between the 2 groups. Despite this result, the scores obtained by the patients with CLP in the masticatory efficiency tests were still in the normal range. CONCLUSIONS: Orthodontic treatment for adult patients with CLP provides a satisfactory result for the patients' masticatory ability albeit significantly less ideal compared with untreated patients with normal occlusion.

Elimination of Porphyromonas gingivalis inhibits liver fibrosis and inflammation in NASH.

AIM: Non-alcoholic steatohepatitis (NASH) is a critical liver disease showing potential progression to liver cirrhosis/cancer. Previously, we had reported that odontogenic infection of Porphyromonas gingivalis (P. gingivalis), a major periodontal pathogen, exacerbates fibrosis in NASH through the production of fibrosis mediators such as transforming growth factor-ß1 (TGF-ß1) and galectin-3. In this study, we determined the effects of therapeutic interventions using antibiotics on NASH progression induced by P. gingivalis odontogenic infection. MATERIALS AND METHODS: To eliminate P. gingivalis infection, the macrolide antibiotic [azithromycin (AZM)] was applied locally and/or systemically to a high-fat-diet-induced NASH mouse model with P. gingivalis odontogenic infection. After treatment with AZM, liver and periodontal tissues were analysed with focus on inflammation markers such as tumour necrosis factor-α (TNF-α)/Tnf-α and interleukin-1ß (IL-1ß)/Il-1ß, and fibrosis markers such as galectin-3, phosphorylated Smad2 (pSmad2; key signalling molecule of TGF-ß1), and the number of hepatic crown-like structures (hCLSs). Further, Non-alcoholic Fatty Liver Disease Activity Score (NAS), a common histological scoring system, and fibrosis area were evaluated. RESULTS: P. gingivalis odontogenic infection significantly increased the expression of Tnf-α, Il-1ß, galectin-3, and pSmad2, the number of hCLSs, and NAS score, whereas the elimination of P. gingivalis odontogenic infection, especially local with or without systemic application, significantly inhibited them. CONCLUSION: This study suggests that elimination of P. gingivalis odontogenic infection inhibited NASH progression induced by the infection.

Odontogenic infection by Porphyromonas gingivalis exacerbates fibrosis in NASH via hepatic stellate cell activation.

Odontogenic infection of Porphyromonas gingivalis (P.g.), a major periodontal pathogen, exacerbates pathological progression of non-alcoholic steatohepatitis (NASH). In this study, we aimed to clarify the detailed mechanism in which P.g. induced hepatic stellate cells (HSCs; key effector cells in liver fibrosis) activation. In the liver of high fat diet-induced NASH mouse model with P.g. odontogenic infection, immunolocalization of P.g. was detected. The number of hepatic crown-like structure, which was macrophage aggregation and related to liver fibrosis, was drastically increased and fibrosis area was also increased through upregulating immunoexpression of Phosphorylated Smad2 (key signaling molecule of TGF-ß1) and Galectin-3. P.g.-secreted trypsin-like enzyme [gingipain; an activator of protease-activated receptor 2 (PAR2)] stimulated HSC proliferation and differentiation through Smad and ERK signaling induced by TGF-ß1 produced from HSCs with P.g.-infection. Further, Galectin-3 produced from HSCs with P.g. infection and P.g.-derived LPS/lipoprotein stimulation stabilized TGFß-receptor II resulting in increasing sensitivity for TGF-ß1, finally leading to HSC differentiation via activating Smad and ERK signaling. In addition to them, hepatocytes (main component cells of liver) contributed to HSC activation through TGF-ß1 and Galectin-3 production in paracrine manner. Collectively, P.g.-odontogenic infection exacerbates fibrosis of NASH by HSC activation through TGF-ß1 and Gal-3 production from HSCs and hepatocytes.

Advanced paternal age alone does not adversely affect pregnancy or live-birth rates or sperm parameters following intrauterine insemination.

PURPOSE: This study aimed to evaluate the effect of advanced paternal age on pregnancy outcomes and sperm parameters following intrauterine insemination (IUI). We used IUI data rather than assisted reproductive technology data, which might mask the effects of sperm impairments. METHODS: We retrospectively analyzed 1576 IUI cycles in women under 40 years old between April 2012 and May 2016 at the National Center for Child Health and Development in Japan. The main outcomes were clinical pregnancy and live birth. RESULTS: The mean male age was significantly lower in cycles that resulted in pregnancy compared with those without pregnancy (38.0 vs 39.1 years; P < 0.001), with a similar trend for live-birth cycles. However, there was no relationship between advanced paternal age and pregnancy outcomes after adjusting for confounding factors and correlations within patients using generalized estimating equations, and the age of the female partner was the only factor affecting pregnancy rate. Furthermore, advanced paternal age had no effect on sperm parameters. CONCLUSIONS: Advanced paternal age alone does not adversely affect pregnancy or live-birth rates or sperm parameters following IUI.

Autophagy-disrupted LC3 abundance leads to death of supporting cells of human oocytes.

Autophagic recycling of cell parts is generally termed as the opposite of cell death. Here, we explored the relation between cell death and autophagy by examining granulosa cell layers that control oocyte quality, which is important for the success of fertilization. Granulosa cell layers were collected from infertile women and morphologically divided into four types, viz., mature (MCCs), immature (ICCs), and dysmature cumulus cells (DCCs), and mural granulosa cells (MGCs). Microtubule-associated protein light chain 3 (LC3), which is involved in autophagosome formation, was expressed excessively in DCCs and MGCs, and their chromosomal DNA was highly fragmented. However, autophagy initiation was limited to MGCs, as indicated by the expression of membrane-bound LC3-II and autophagy-related protein 7 (ATG7), an enzyme that converts LC3-I to LC3-II. Although pro-LC3 was accumulated, autophagy was disabled in DCCs, resulting in cell death. Our results suggest the possibility that autophagy-independent accumulation of pro-LC3 proteins leads to the death of human granulosa cells surrounding the oocytes and presumably reduces oocyte quality and female fertility.

Sonographic Optic Nerve Sheath Diameter: A Simple and Rapid Tool to Assess the Neurologic Prognosis After Cardiac Arrest.

BACKGROUND AND PURPOSE: The early prediction of hypoxic encephalopathy after cardiac arrest is challenging. Measurement of the optic nerve sheath diameter (ONSD) by using sonography is a straightforward, noninvasive technique to detect an increased intracranial pressure, which can even be conducted at the bedside. However, it remains unknown whether or not sonographic ONSD measurement is valuable as a prognostic indicator of hypoxic encephalopathy. METHODS: Seventeen patients after cardiac arrest were retrospectively enrolled in this study. ONSD measurements 3 mm behind the papilla were recorded. A Glasgow Outcome Scale score of 4 or above was considered to indicate a favorable prognosis. RESULTS: The mean ONSD associated with a favorable prognosis was 5.0 mm (4.4-6.1 mm). The ONSD associated with a poor prognosis was 6.1 mm (5.4-7.2 mm). ONSD less than or equal to 5.4 mm was an indicator of a favorable prognosis, with a sensitivity of 83%, specificity of 73%, positive likelihood ratio of 3.1, and negative likelihood ratio of .23. CONCLUSIONS: Sonographic ONSD measurement is a simple, rapid technique to assess the neurological prognosis after cardiac arrest.

Indirect Fist Percussion of the Liver Is a More Sensitive Technique for Detecting Hepatobiliary Infections than Murphy's Sign.

Background. Murphy's sign and Charcot's triad are established clinical findings of acute cholecystitis and cholangitis, respectively, but both show low sensitivity and limited clinical application. We evaluated if indirect fist percussion of the liver improves the efficiency of diagnosing cholecystitis and cholangitis when used as a diagnostic adjunct. Methods. The presence/absence of right upper quadrant (RUQ) tenderness, Murphy's sign, and pain induced by indirect fist percussion of the liver was assessed, and the results were compared with the definite diagnosis based on ultrasound and additional examinations in patients aged over 18 who visited our outpatient clinic with suspected hepatobiliary diseases. Results. Four hundred and eight patients were investigated, and 40 had hepatobiliary infection (acute cholecystitis: 10, acute cholangitis: 28, liver abscess: 1, and hepatic cyst infection: 1). The sensitivity of indirect fist percussion of the liver for diagnosing hepatobiliary infection was 60%, being significantly higher than that of RUQ tenderness (33%) and Murphy's sign (30%), and its specificity was 85%. There was no significant improvement in sensitivity or diagnostic accuracy when Murphy's sign was combined with indirect fist percussion of the liver. Conclusion. Indirect fist percussion-induced liver pain is a useful clinical finding to diagnose hepatobiliary infection, with high-level sensitivity.

Neuronal ceroid lipofuscinosis with early-onset dementia and periventricular leukoencephalopathy in which a skin biopsy was diagnostically useful.

Neuronal ceroid lipofuscinosis (NCL) is a rare disease with onset typically during childhood; however, that developing during adulthood can lead to early-onset dementia. We report a 54-year-old man whose onset coincided with speech impairment, amnesia and dyscalculia. On brain MRI, marked diffuse leukoencephalopathy with periventricular predominance was observed. On a skin biopsy, characteristic fingerprint images were noted, and the patient was diagnosed with NCL. The differential diagnosis of cognitive impairment with leukoencephalopathy is wide ranging; however, when marked symmetrical periventricular-predominant leukoencephalopathy is prevalent and no peripheral neuropathy or gait disorders are evident, a diagnosis of NCL should be suspected and a skin biopsy should be performed.

Attenuation of axonal injury and oxidative stress by edaravone protects against cognitive impairments after traumatic brain injury.

Traumatic axonal injury (TAI), a feature of traumatic brain injury (TBI), progressively evolves over hours through impaired axonal transport and is thought to be a major contributor to cognitive dysfunction. In spite of various studies suggesting that pharmacologic or physiologic interventions might reduce TAI, clinical neuroprotective treatments are still unavailable. Edaravone, a free radical scavenger, has been shown to exert neuroprotective effects in animal models of several brain disorders. In this study, to evaluate whether edaravone suppresses TAI following TBI, mice were subjected to weight drop injury and had either edaravone (3.0mg/kg) or saline administered intravenously immediately after impact. Axonal injury and oxidative stress were assessed using immunohistochemistry with antibodies against amyloid precursor protein, a marker of impaired axonal transport, and with 8-hydroxy-2'-deoxyguanosine, a marker of oxidative DNA damage. Edaravone significantly suppressed axonal injury and oxidative stress in the cortex, corpus callosum, and hippocampus 24h after injury. The neuroprotective effects of edaravone were observed in mice receiving 1.0, 3.0, or 10mg/kg of edaravone immediately after impact, but not after 0.3mg/kg of edaravone. With treatment 1h after impact, axonal injury was also significantly suppressed and this therapeutic effect persisted up to 6h after impact. Furthermore, behavioral tests performed 9 days after injury showed memory deficits in saline-treated traumatized mice, which were not evident in the edaravone-treated group. These results suggest that edaravone protects against memory deficits following TBI and that this protection is mediated by suppression of TAI and oxidative stress.

Identification and functional characterization of glioma-specific promoters and their application in suicide gene therapy.

Suicide gene therapy has been shown to be effective in inducing tumor regression. In this study, a human brain tumor-specific promoter was identified and used to develop transcriptionally targeted gene therapy. We searched for genes with brain tumor-specific expression. By in silico and reverse-transcription polymerase chain reaction screening, MAGE-A3 and SSX4 were found to be expressed in a tumor-specific manner. SSX4 gene promoter activity was high in human brain tumor cells but not in normal human astrocyte cells, whereas the MAGE-A3 promoter showed activity in both tumor and normal cells. A retrovirus vector carrying a suicide gene, the herpes simplex virus thymidine kinase gene controlled by the SSX4 promoter, was constructed to evaluate the efficacy of the promoter in tumor-specific gene therapy. Glioma and human telomerase catalytic subunit-immortalized fibroblast BJ-5ta cell lines transduced with retrovirus vectors were assayed for killing activity by ganciclovir. Glioma cell lines were effectively killed by ganciclovir in a concentration-dependent manner, whereas BJ-5ta cells were not. By contrast, MAGE-A3 promoter failed to induce cytotoxicity in a brain tumor-specific manner. In addition, mouse glioma RSV-M cells transduced with retrovirus vector also showed suppressed tumor formation activity in syngeneic mice in response to ganciclovir administration. Therefore, the SSX4 promoter is a candidate for brain tumor-specific gene therapy and supports the efficacy and safety of suicide gene therapy for malignant brain tumors.

[Long-term disease-free survival following multimodal treatment in a patient with curatively unresectable advanced gastric cancer with metachronous liver metastasis].

A case was a 57-year-old man. Despite a diagnosis of cStage IV gastric cancer (cN2, cH0, cM0, cT3 (SE), cP1), we preferentially performed a non-curative surgery to avoid stenosis or bleeding by tumor invasion. Since no evidence of peritoneal metastasis was found at surgery, distal gastrectomy with D2 lymph node dissection was performed, and lymph nodes anterior to the pancreatic head were sampled. The pathological diagnosis was pT3 (SE), pN2, sH0, pM1 (LYM), pStage IV. After the surgery, S-1 was administered. One year and 9 months later, a solitary metastasis was found in S6 of the liver, and the patient underwent radiofrequency ablation (RFA) followed by adjuvant S-1. Currently, 5 years and 10 months after the surgery, the patient is under follow-up, and remains alive with recurrence-free. We speculate that in the presence of N or M (LYM) factors for stage IV gastric cancer, surgery with lymphadenectomy, which does not prevent the completion of adjuvant chemotherapy, followed by multimodal treatments such as continued chemotherapy and RFA, led to the long-term survival.