Drug-induced oral lichenoid reaction during nivolumab therapy.

Oral lichenoid reaction, an immune-related adverse event of immunotherapy, has been reported in very few patients receiving anti-programmed cell death receptor-1 (anti-PD-1) therapy. Here, we describe a case of severe stomatitis (grade ≥3 by the Common Terminology Criteria for Adverse Events, version 4.0) accompanied by pharyngolaryngitis that was observed in a patient receiving nivolumab therapy. The stomatitis was diagnosed as drug-induced lichenoid reaction. Nivolumab therapy was discontinued, and the patient was administered systemic prednisolone (1mg/kg). Most of the patient's mucosal changes in the oral cavity and pharyngolarynx resolved within approximately 3 weeks after starting the prednisolone. Clinicians should be aware that severe oral lichenoid reactions can occur in patients receiving anti-PD-1 therapy.

A two-step hybrid technique for accurately localizing acoustic source in anisotropic structures without knowing their material properties.

Acoustic source localization techniques generally assume straight line propagation of waves from the acoustic source to the sensor. However, it is well-known that in anisotropic plates the acoustic energy does not always propagate in straight lines. Even for isotropic plates containing a cavity or an inclusion between the acoustic source and the sensor the straight line propagation assumption is violated. In such cases only options available in localizing acoustic source is to use relatively expensive distributed sensor systems, or to follow time reversal techniques based on the impulse response functions which is labor intensive and computationally demanding. A two-step hybrid technique is proposed in this paper for predicting acoustic source in anisotropic plates. During the first step it was assumed that the waves propagated along straight lines from the acoustic source to the sensor. The source was localized with this simplifying assumption. Then this first prediction was improved in the second step by solving an optimization problem. Experimental results showed that the second step always moved the estimates towards the actual source location. Thus it always reduced the prediction error irrespective of whether the final prediction coincided with the actual source location or not.

A Novel Therapeutic and Prophylactic Vaccine (HVJ-Envelope / Hsp65 DNA + IL-12 DNA) against Tuberculosis Using the Cynomolgus Monkey Model.

We have developed a novel tuberculosis (TB) vaccine; a combination of the DNA vaccines expressing mycobacterial heat shock protein 65 (HSP65) and interleukin 12 (IL-12) delivered by the hemagglutinating virus of Japan (HVJ)-envelope and -liposome (HSP65 + IL-12/HVJ). An IL-12 expression vector (IL-12DNA) encoding single-chain IL-12 proteins comprised of p40 and p35 subunits were constructed. This vaccine provided remarkable protective efficacy in mouse and guinea pig models compared to the BCG vaccine on the basis of C.F.U of number of TB, survival, an induction of the CD8 positive CTL activity and improvement of the histopathological tuberculosis lesions. This vaccine also provided therapeutic efficacy against multi-drug resistant TB (MDR-TB) and extremely drug resistant TB (XDR-TB) (prolongation of survival time and the decrease in the number of TB in the lung) in murine models. Furthermore, we extended our studies to a cynomolgus monkey model, which is currently the best animal model of human tuberculosis. This novel vaccine provided a higher level of the protective efficacy than BCG based upon the assessment of mortality, the ESR, body weight, chest X-ray findings and immune responses. All monkeys in the control group (saline) died within 8 months, while 50% of monkeys in the HSP65+hIL-12/HVJ group survived more than 14 months post-infection (the termination period of the experiment). Furthermore, the BCG priming and HSP65 + IL-12/HVJ vaccine (booster) by the priming-booster method showed a synergistic effect in the TB-infected cynomolgus monkey (100% survival). In contrast, 33% of monkeys from BCG Tokyo alone group were alive (33% survival). Furthermore, this vaccine exerted therapeutic efficacy (100% survival) and augmentation of immune responses in the TB-infected monkeys. These data indicate that our novel DNA vaccine might be useful against Mycobacterium tuberculosis including XDR-TB and MDR-TB for human therapeutic clinical trials.

High prevalence of bipolar disorder comorbidity in adolescents and young adults with high-functioning autism spectrum disorder: a preliminary study of 44 outpatients.

BACKGROUND: Psychiatric comorbidity of autism spectrum disorder (ASD) has not been well examined. METHODS: Mood disorders in 44 consecutive outpatients with high-functioning ASD were examined at a university hospital according to DSM-IV. Inclusion criteria were an IQ of 70 or higher on the Wechsler Intelligence Scale and age of 12 years or over. RESULTS: Sixteen patients (36.4%) were diagnosed with mood disorder. Of these 16 patients, four were diagnosed as having major depressive disorder, two patients as bipolar I disorder, six patients as bipolar II disorder, and four patients as bipolar disorder not otherwise specified. Bipolar disorder accounted for 75% of cases. Twelve patients had Asperger disorder and four patients had pervasive developmental disorder not otherwise specified. None of the patients had autistic disorder. LIMITATIONS: The sample size was small. We could not use Autism Diagnostic Interview - Revised. Referral bias could not be avoided in this study. CONCLUSIONS: The major comorbid mood disorder in patients with high-functioning ASD is bipolar disorder and not major depressive disorder. The autistic spectrum may share common vulnerability genes with the bipolar spectrum.

Targeted in vivo expression of nicotinic acetylcholine receptors in mouse brain using lentiviral expression vectors.

Nicotinic acetylcholine receptors (nAChRs) in the brain exhibit diverse functional properties and ubiquitous distribution. Yet, except for providing a receptor for the exogenously applied nicotine of tobacco products, their role in the normal functioning of the brain has remained elusive. We have used a lentiviral expression vector to re-express the beta2 subunit specifically in the ventral tegmental area (VTA) of beta2-/- mice. The viral vector efficiently expresses beta2- subunit protein leading to new nAChR-binding sites. VTA neurons transduced by the lentiviral vector are responsive to intravenous nicotine when analyzed using in vivo electrophysiology. Nicotine-induced dopamine release from the nucleus accumbens (NuAcc) was also restored in re-expressing beta2-/- mice. Intra-VTA injection of nicotine was found to be reinforcing in both wild-type and beta2-subunit re-expressing beta2-/- mice, but not in beta2-/- mice. Furthermore, in the absence of applied nicotine, the spontaneous slow exploratory behavior of the mice was restored, whereas fast navigation did not change. This latter behavioral analysis suggests a role for beta2* nAChR, specifically expressed in the VTA, in mammalian cognitive function.

Application of ligating loops to control bleeding during endoscopic surgery for a highly vascular hypopharyngeal tumour.

Endoscopic treatment of hypervascular lesions of the hypopharynx is challenging because of difficulty in controlling bleeding during surgery. We report a highly vascular hypopharyngeal solitary fibrous tumour treated by endoscopic laser surgery combined with ligating loops. Application of dual ligating loops provided easy and secure haemostasis of the feeding artery before resection. Since the endoscopic approach is less invasive than the external approach, we confirm that it is worthwhile to attempt an endoscopic approach using ligating loops before resorting to the external approach in the treatment of hypervascular hypopharyngeal lesions.

Cervicothoracic malignant peripheral nerve sheath tumor in a 12-year-old girl with neurofibromatosis type 1.

We encountered a 12-year-old girl with neurofibromatosis type 1 (NF1) who developed a low-grade cervicothoracic malignant peripheral nerve sheath tumor (MPNST). Computed tomography of the neck showed an elastic firm tumor measuring 7 x 6 x 4 cm and arising from the upper mediastinum. She had no pain or neurological symptoms, but the tumor enlarged to ca. 8 x 8 x 4 cm over the following 7 months. Although we had diagnosed a neurofibroma by preoperative incisional biopsy, the resected tumor showed low-grade MPNST in the central portion of the tumor. In treating a tumor in a patient with NF1, we must recognize that partial biopsies do not necessarily establish a definitive diagnosis and that a growing tumor may indicate malignant transformation.

[Relation between intraoperative salvaged blood transfusion and postoperative infection after cardiac surgery].

In cardiac surgery, several studies have shown bacterial contamination rates of intraoperative salvaged blood ranging from 12.7 to 96.8%. We evaluated the relation between intraoperative salvaged blood transfusion produced by the Cell Saver 5 device (Haemonetics Corp., Braintree, MA, USA) and postoperative infection determined by bacteriological study and the postoperative clinical course after cardiac surgery. Seven cases of cardiac surgery were investigated by bacteriological study. Although bacteria were cultured from all salvaged blood, no bacteria were cultured from the patients' blood 24 hours after salvaged blood infusion. Another 26 patients who underwent cardiac surgery, were divided into groups: group CS (n = 15) with salvaged blood transfusion after operation and group N (n = 11) without salvaged blood transfusion, and were evaluated in relation to the postoperative clinical course. There were no statistically significant differences between group CS and group N in the data of WBC, CRP and maximum body temperature. One case of deep sternal wound infection and 2 cases of local wound infection were observed in group CS, but none in group N (p = 0.18). These complications were treated by primary closure without muscle flaps. We conclude that salvaged blood autotransfusion was not related to postoperative infections in cardiac surgery.

Epidemiological transition of tuberculosis and future agenda of control in Japan: results of the Ad-Hoc National Survey of Tuberculosis 2000.

SETTING: In Japan, the incidence of tuberculosis (TB), which had improved continuously from 1951, has shown an upturn since 1997. OBJECTIVE: An Ad-Hoc National Survey was conducted to review the issues of TB control in Japan and to discuss the future direction of change. METHODS: TB registries kept at health centres in all prefectures were reviewed for the year 1998. Vital statistics and BCG vaccination records were reviewed separately. RESULTS: The survey revealed a 34.7% under-estimation of TB deaths in TB registers, and a 11.2% over-estimation of TB cases registered due to a change in diagnosis after registration. For treatment, the four-drug regimen advocated for smear-positive cases was used in only 54.8% of indicated cases, and treatment duration was very long; for example, 18.4% of first-time hospitalised cases over 15 years of age received in-patient care for more than 6 months and 29.8% continued treatment for more than 12 months. Apart from an increasingly elderly population, other factors contributing to an increase in TB included underlying health risk factors for increased susceptibility to TB and socio-economic risk factors for treatment failure. Regarding preventive measures, active case finding by health screening contributed to detection of only 8.7% of new cases aged over 60 years, but BCG vaccination appeared to be preventive among infants under 1 year of age. CONCLUSION: The National Survey revealed a changing profile of TB in Japan and suggested a need to review and revitalise the TB control programme.

Detection of nerve action potentials under low signal-to-noise ratio condition.

We propose a method for detection of action poten. tials (APs) under low signal-to-noise ratio condition. It is based on multiresolution analysis. Three parameters are used for detection. Two of them are for determining if there is an AP or not, and the other is for the estimation of waveforms. Our method provides better estimated waveforms than the conventional de-noising approach.

[Bacterial contamination of salvaged blood in open heart surgery: is that an airborne contamination or a normal skin flora contamination?].

We investigated sources of bacterial contamination of intraoperative salvaged blood producted by autologous transfusions device (CS; CELL SAVER 5, Heamonetics Corp., Braintree, MA). Eleven patients undergone open heart surgeries including 2 emergency operations with a median sternotomy enrolled in this study. Blood samples were drawn from salvaged blood bags. Airborne contaminants (AB) were collected by a blood agar plate put besides the operation bed for 30 minutes. The median wounds samples were collected by a swab. Bacterial growth was detected in 81.8% of salvaged blood samples. Twenty-nine bacterium were isolated from CS, 72.4% of those were Staphylococci. 9.1% of sample was positive in wound swabs. Forty bacterium were isolated from plate cultures. 65% of them were Staphylococci. Staphylococcus epidermidis and coagulase negative Staphylococcus isolated both CS and AB in the 2 cases had the same identify codes, and incubated from several AB cultures. Corynebacterium sp. is also isolated from both CS and AB cultures in other 2 same cases. In 7 out of 8 cases (87.5%), from which Staphylococci isolated in CS, the Staphylococci were cultured from AB in not the same but the other cases. In conclusion, highly incidence of the identification in identical code of Staphylococci indicated that the main source of CS contamination was highly suspected to AB.

Oblique aortic valve replacement and coronary artery bypass grafting for severely calcified narrow aortic root with unstable angina.

We report an 84-year-old woman diagnosed with aortic stenosis and regurgitation with a severely calcified narrow aortic root and left main coronary artery trunk stenosis with triple-vessel coronary artery disease. Emergency aortic valve replacement and triple coronary artery bypass grafting were successful. The aortic annulus was small and heavily calcified, and the ascending aorta, the sinus of valsalva and the anterior leaflet of the mitral valve were severely calcified. A St. Jude Medical valve 19A (St. Jude Medical Inc., St. Paul, MN) was inserted obliquely along the noncoronary sinus. This technique is a useful alternative in cases where the patient's life is at risk in situations involving severe extensive calcification of a narrow aortic root.

[Maze procedure for atrial fibrillation associated with aortic valve disease in an elderly patient: report of a case].

The choice of a valve substitute in elderly patients remains controversial. Moreover, the combined use of the maze procedure in elderly patients raises further discussion. We report a case of bioprosthetic aortic valve replacement concomitant with the maze procedure in a 74-year-old man. With symptom of orthopnea and short of breath, he was diagnosed as aortic stenosis and regurgitation with atrial fibrillation. We performed the bioprosthesis aortic valve replacement and the maze procedure in this patient. He was extubated next day and discharged on the fifteenth day after the operation without any complications. Postoperatively he gained a sinus regular rhythm and A wave of transmitral flow was detected by Doppler echocardiography. Now, he enjoys his better quality of life without any drugs including warfarin. Although combined aortic valve replacement and maze procedure are more invasive for elderly patients, these procedures provides better quality of life after the operation.

Analysis of glycosidase-catalyzed transglycosylation reaction using probabilistic model.

General mechanism of transglycosylation reaction by glycosidases contains branched paths to form and destroy the glycosylated intermediate. The probabilistic model was applied for the simulation and analysis of the transglycosylation mechanism. The model is composed of a single enzyme molecule and finite amounts of substrates and water molecules mimicking the possible smallest enzyme-catalyzed reaction system in a microcompartment. Using random numbers and probabilities, progress of distribution of reactants and products can be simulated and predicted with minimum adjustable parameters. Experimental data of beta-xylosidase and beta-glucosidase reactions were quantitatively analyzed with the simple scheme. Since the algorithm and simulation procedures are simple, the model is applicable to related complicated enzyme mechanisms containing many branched reaction paths.

Left vocal cord paralysis associated with long-standing patent ductus arteriosus.

SUMMARY: Left vocal cord paralysis in association with patent ductus arteriosus is unusual. We report a patient with long-standing patent ductus arteriosus (PDA) in whom CT studies obtained before and after paralysis developed showed an interval increase in size of the pulmonary trunk. The pathogenesis of left vocal cord paralysis in association with long-standing PDA is discussed.

Axonal projection of olfactory sensory neurons during the developmental and regeneration processes.

We have studied the projection of olfactory sensory neurons (OSNs), during the developmental and regeneration processes, using the transgenic mouse carrying the differently tagged odorant receptor genes, MOR28. We have found that the axon terminals of the two sets of MOR28-positive OSNs, one expressing the lacZ tag and the other expressing the green fluorescent protein gene, are dispersed and intermingled at early developmental or regeneration stages. Projection areas become more distinct and separated at later stages, however, two sets of axon fibers are not typically bundled or segregated during pathfinding. It appears that segregation of axons mainly occurs when they target at the olfactory bulb to form the glomerular structure.

Neurofibroma of the larynx in neurofibromatosis: preoperative computed tomography and magnetic resonance imaging.

Neurofibromas of the larynx are extremely rare. They occur in association with neurofibromatosis less frequently than solitary neurofibromas. However, most laryngeal tumors in neurofibromatosis are neurofibromas. This disorder has 2 histological subtypes, which require different surgical approaches because of their biological differences. Few cross-sectional imaging studies have been performed in neurofibroma of the larynx. We describe a 44-year-old man with neurofibromatosis and nonplexiform neurofibroma of the larynx and discuss the role of preoperative computed tomography and magnetic resonance imaging in this case. The tumor was removed completely using an endolaryngeal approach without an external incision. It was possible to distinguish subtypes preoperatively on cross-sectional imaging. Magnetic resonance imaging provided more sensitive information in the diagnosis of this tumor than computed tomography. Preoperative cross-sectional imaging should be performed to help the surgeon diagnose and choose an appropriate surgical approach for this disorder.

Monoallelic expression of the odourant receptor gene and axonal projection of olfactory sensory neurones.

BACKGROUND: We have previously generated transgenic mice carrying the murine odourant receptor gene, MOR28, tagged with lacZ. In this animal, the endogenous MOR28 is differently tagged with GFP. It was found that the transgenic and endogenous MOR28 genes are expressed in a mutually exclusive manner and that the two sets of olfactory sensory neurones (OSNs), each expressing either the transgenic or the endogenous MOR28, project their axons to separate glomeruli. RESULTS: Our fluorescent in situ hybridization (FISH) revealed that the two endogenous alleles of MOR28 are also mutually excluded for their transcriptional activation. Therefore, we studied whether there would be any segregation in the projection of the two subsets of OSNs: one set expressing the paternal and the other expressing the maternal allele. It was found that the OSNs for both alleles shared the same glomerulus for their projection, but the projection targets were segregated within the glomerular structure. CONCLUSION: Two subsets of neurones expressing either the transgenic or the endogenous MOR28 target their axons to two separate glomeruli based on the differences in the genetic backgrounds, nature of tagging, and chromosomal locations. In contrast, neurones expressing a maternal or paternal allele share the same glomeruli, but tend to target to segregated areas within the glomerular structure. The segregation was more prominent with increased differences in the genetic background between the two alleles.

[Is open heart surgery clean: bacteriologic analysis of salvaged blood].

In this prospective study, we evaluated contamination of surgical fields in open heart operations by salvaged blood culture used in autologous transfusions device (Cell Saver 5, Heamonetics Corp., Braintree, MA, USA). And also, we prospectively investigated an efficacy of pre- and intra-operative prophylactic antibiotics administrations (cefazolin). Thirty patients undergone open heart surgeries with median sternotomy enrolled in this study. The patients were divided into two groups, group A (n = 15); without prophylactic antibiotics administration, group B (n = 15); with pre- and intra-operative prophylactic antibiotics administrations. Blood samples were drawn through the right atrium after the discontinuation of CPB and from salvaged blood bags. Bacterial growth was detected in 80.0% of salvaged blood samples in group A, 86.7% in group B (p = 0.62). Whereas no bacterial growth detection in blood samples though the right atrium. Quantitative estimates of contaminations showed 1.06 +/- 1.41, 0.90 +/- 1.24 cfu/ml, respectively (p = 0.22). Although bacterial growth rate were not statistically significant difference between groups, detective rate of Staphylococci was remarkably decreased (p = 0.005) in group B. Pre- and intra-operative prophylactic antibiotics administrations were effective for Staphylococci, but not whole microorganisms. In conclusion, salvaged blood used in autologous transfusions was highly contaminated and it suggests that surgical fields were not clear. Prophylactic antibiotics administrations were effective especially for Staphylococci.