Long-term survival of full trisomy 13 in a 14 year old male: a case report.

Long term survival for the cases of trisomy 13 into over a first decade is very rare. We reported here the case of a 14-year-old male karyotype with full type of trisomy 13. In this clinical phenomenon, the case had typical facial, finger and limb anomalies for trisomy 13. Arterial septal defect and patent ductus arteriosus were recognized using ultrasonography after birth. Major cerebral malformation such as holoprosencephaly or cerebellar hypoplasia were also not revealed. After 5 months of his age, artificial ventilation therapy for dyspnea associated with laryngomalacia was required. A tracheotomy was performed at 6 months of his age. After 12 years old, intractable partial epilepsy was recognized. For his partial seizures, a treatment with a combination of two anti-epileptic drugs, valproic acid and levetiracetam, were advised. Now he is alive for 14-years-old and he is the 4th longest surviving patient with full karyotype of trisomy 13.

Drop episodes improved after tracheotomy: a case of Coffin-Lowry syndrome associated with obstructive sleep apnea syndrome.

Some cases of Coffin-Lowry syndrome recognized episodic drops and it tended to be intractable for medical treatment. We reported here a patient with the Coffin-Lowry syndrome associated with obstructive sleep apnea syndrome (OSAS). The patient had epileptic seizures and drop attacks only during night-time and it was not recognized during the daytime. His sleep-induced electroencephalogram was normal. At 12-years old of his age, his OSAS was worse, so we performed a tracheotomy. Notably after the operation, his epileptic episodes were disappeared.

Inhibitory effects of maternal smoking on the development of severe retinopathy of prematurity.

PURPOSE: In this study, the effects of maternal smoking along with other clinical risk factors in developing severe retinopathy of prematurity (ROP) were evaluated. DESIGN: A case-control study. METHODS: Records of newborn infants with an estimated postmenstrual age of 32 weeks or less (n=86) were reviewed. ROP grading was evaluated in accordance with the International Classification of Retinopathy of Prematurity. Severe ROP was diagnosed when it progressed to stage 3 with plus disease. The factors were first evaluated using a univariate logistic regression analysis between the groups of severe and non-severe ROP, followed by a multivariate logistic regression analysis using STATA version 10 and R version 2.71. RESULTS: A low birth weight, a long duration of artificial ventilation and oxygen supplementation, presence of chronic lung disease, and absence of maternal smoking were found to be significantly associated with severe ROP in the univariate logistic regression analysis. In the multivariate logistic regression analysis, maternal smoking was revealed as a significant factor independently associated with the incidence of severe ROP. CONCLUSIONS: An inhibitory effect of maternal smoking against developing severe ROP is suggested. The mechanism by which smoking may reduce the incidence of severe ROP needs to be further investigated.

Preventative effect of exercise against falls in the elderly: a randomized controlled trial.

SUMMARY: The present study was conducted to determine the effect of 5-month exercise program on the prevention of falls in the elderly. The exercise training, which consisted of calisthenics, body balance training, muscle power training, and walking ability training 3 days/week improved the indices of the flexibility, body balance, muscle power, and walking ability and reduced the incidence of falls compared with non-exercise controls. The present study showed the beneficial effect of the exercise program aimed at improving flexibility, body balance, muscle power, and walking ability in preventing falls in the elderly. INTRODUCTION: The present study was conducted to determine the effect of exercise on the prevention of falls in the elderly. METHODS: Sixty-eight elderly ambulatory volunteers were randomly divided into two groups: the exercise and control groups. The daily exercise, which consisted of calisthenics, body balance training (tandem standing, tandem gait, and unipedal standing), muscle power training (chair-rising training), and walking ability training (stepping), were performed 3 days/week only in the exercise group. No exercise was performed in the control group. RESULTS: After the 5-month exercise program, the indices of the flexibility, body balance, muscle power, and walking ability significantly improved in the exercise group compared with the control group. The incidence of falls was significantly lower in the exercise group than in the control group (0.0% vs. 12.1%, P = 0.0363). The exercise program was safe and well tolerated in the elderly. CONCLUSIONS: The present study showed the beneficial effect of the exercise program aimed at improving flexibility, body balance, muscle power, and walking ability in preventing falls in the elderly.

Absence of mutations in the Wilms' tumor gene wt1 in de novo non-small cell lung cancers.

We recently demonstrated that the WT1 gene was overexpressed in the majority of de novo lung cancers regardless of cancer subtypes. Here, we examined WT1 genomic DNA in 38 cases of de novo non-small cell lung cancers (NSCLC) for mutations using direct sequencing. The sequencing analysis showed no mutations of WT1 genomic DNA in any of 38 de novo non-small cell lung cancers examined. These results indicated that the non-mutated, wild-type WT1 gene played an important role in de novo NSCLC.

A case of mucopolysaccharidosis IV with lower leg paresis due to thoraco-lumbar kyphoscoliosis.

We treated a patient of type IV mucopolysaccharidosis (Morquio's disease) with lower leg paresis due to kyphoscoliosis. A 65-year-old woman presented with Morquio's disease. A lateral radiograph demonstrated the classic bullet-shaped vertebrae and a 65 degrees thoraco-lumbar kyphosis. After the age of 60, she suffered from numbness in both lower legs and walking disturbance. Bilateral patellae-tendon reflexes were exaggerated. MRI showed compression of the spinal cord around T12 to L2 with a highlighted area of change inside the spinal cord. Myelography and computed tomography after the myelography showed narrowing of the sub-arachnoidal space and deformation of the spinal cord around the T12 to L2 levels. Severe vertebral osteoporosis made it necessary to first perform posterior correction of the kyphosis and fusion. The curve was stabilised with the Luque method from T7 to L4. Her neurological condition markedly recovered, but 1 year after surgery her neurological condition again began to deteriorate, resulting in walking disturbance. For this reason, anterior decompression and fusion through a lateral thoracotomy was undertaken. Decompression of the spinal cord and a bone graft from the iliac crest were attained. The patient's neurological condition again improved, but not as much as immediately after the first operation.

A neurofibromatosis type 1 patient with severe kyphoscoliosis and intrathoracic meningocele.

The patient presented with neurofibromatosis and a dystrophic kyphoscoliosis around the cervico-thoracic junction. When the patient was 59 years old, he started to suffer from dyspnea caused by an intrathoracic meningocele in the upper left thoracic cavity. A wide laminectomy from T2 to T5 was performed and the meningocele was resected. Although the dyspnoea disappeared postoperatively, the patient started to neurologically deteriorate. Laminectomy alone caused instability around the apex of the kyphosoliosis and spinal cord compression. Halo cast was applied and brought remarkable recovery of neurologic deficits. This result encouraged us to perform posterior fusion in situ from C3 to L2 with bone graft from the iliac crests and the Luque technique in conjunction with the Isola system. This resulted in the patient being able to walk again. The removal of the posterior element predisposes the patient to unstable postlaminectomy kyphosis and removes valuable bone stock required for posterior spinal fusion. For this reason, spinal fusion should have been conducted during surgery for the patient's meningocele.

[WHO classification in thymoma].

WHO classification of thymic epithelial tumors have been shown to reflect their oncological behaviors, and type A, AB and B1 tumors have better prognosis than type B2 and B3 tumors, suggesting the significance of this classification in the clinical practice of thymomas. Type B tumors are more invasive than type A and AB tumors. Type B1 and B2 tumors are frequently associated with myasthenia gravis while type A and AB tumors are not. The findings of computed tomography (CT) imaging revealed that type A and AB tumors tend to be round and have the smooth surface while type B1, B2 and B3 tumors are often flat and have irregular surface. Type AB, B1 and B2 tumors possess a significant number of CD4+CD8+ double positive T cells in the tumor. These observations are supposed to be useful for preoperative evaluation of WHO classification of thymomas, and to help the clinicians decide application of preoperative therapy and the method of surgical resection including endoscopic surgery.

Relationship between physicochemical and osteotropic properties of bisphosphonic derivatives: rational design for osteotropic drug delivery system (ODDS).

PURPOSE: The objective of this investigation is to develop a rational design of Osteotropic Drug Delivery System (ODDS), which we have proposed as a novel method for drug delivery to the skeleton via bisphosphonic prodrug, based on the relationship between physicochemical and pharmacokinetic properties of bisphosphonates. METHODS: The theoretical octanol/water partition coefficients (clog P) of 13 bisphosphonates were calculated by computer software, CLOGP ver. 3.05 (Daylight C.I.S., Inc. Irvine, CA) and related to pharmacokinetic or osteotropic parameters after intravenous injection into rats. On the other hand, to optimize ODDS of diclofenac (DIC-BP), the effects of doses or infusion rates on the in vivo disposition were investigated in relation to solubility product value (Ksp) of DIC-BP-calcium complex. RESULTS: Clog P had good correlations with total plasma clearance, apparent distribution volume and the fraction dose delivered to the whole skeleton after bolus injection into rats (r = -0.868 approximately -0.914). The targetability of bisphosphonates to the skeleton was linearly decreased with an increase in clog P value and the more hydrophilic bisphosphonates were suitable for ODDS in bolus administration. On the other hand, DIC-BP, a relatively lipophilic bisphosphonate, was effectively and selectively delivered to the skeleton only when administered as a slow infusion to keep plasma concentration lower than that calculated from Ksp value where DIC-BP could precipitate with calcium in the plasma circulation. CONCLUSIONS: Our results suggest the possibility of a rational design of ODDS via bisphosphonic prodrugs, after consideration of compound lipophilicity and precipitability of bisphosphonate-calcium complex.

Increased excretion of N-acetyl-beta-D-glucosaminidase and beta2-microglobulin in gestational week 30.

BACKGROUND: Little is known about when the urinary excretion of a combination of N-acetyl-beta-D-glucosaminidase (NAG) and beta2-microglobulin (beta2MG) concentration [relative to creatinine (Cr)] reaches maximal values during uncomplicated normotensive pregnancy. This study was thus designed to analyze when urinary excretion of biochemical parameters was increased during normotensive pregnancy. METHODS: NAG, beta2MG, total protein, albumin, and Cr were simultaneously measured in random (untimed) midstream urine samples from 22 healthy nonpregnant women and from 82 normotensive pregnant women (22 in gestational week 20, 25 in week 30, and 35 in week 37). RESULTS: NAG/Cr and beta2MG/Cr ratios were significantly higher (P < 0.01-0.05) in the normotensive pregnant women in gestational week 30 than in the nonpregnant control subjects and normotensive pregnant women in gestational week 20. The NAG/Cr and beta2MG/Cr ratios showed maximal values in gestational week 30. The total protein/Cr ratio was significantly higher in gestational weeks 20, 30, and 37 than in the control subjects. The albumin/Cr ratio was significantly higher in women in gestational week 30 and 37 than in women in gestational week 20 and in the control subjects. CONCLUSIONS: The excretion of both NAG and beta2MG relative to Cr was increased and showed the maximal values in gestational week 30 during normotensive pregnancy. The increase in a tubular enzyme (NAG) might be caused by renal tubular damage, and that in a low molecular weight protein (beta2MG) might result from decreased renal tubular reabsorption. These findings suggest that renal tubular damage and reabsorption dysfunction were increased in gestational week 30.

N-methyl-D-aspartate receptor antagonist reduces nitrotyrosine formation in caudate-putamen in rat focal cerebral ischemia-reperfusion.

The aim of this study is to determine experimentally whether N-methyl-D-aspartate (NMDA) receptor is involved in nitrotyrosine formation in rat brain subjected to focal ischemia-reperfusion, by using the NMDA receptor antagonist MK-801. Halothane-anesthetized and artificially ventilated rats were given MK-801 (5 mg/kg, i.p.) or vehicle prior to 2 h of focal cerebral ischemia followed by 0.5 h of reperfusion. The brain was then removed and divided into four sections, cortical ischemic core, peri-ischemic cortex, lateral caudate-putamen and non-ischemic cortex. Tissue nitrotyrosine was measured by means of hydrolysis/HPLC. MK-801 significantly attenuated nitrotyrosine formation in the lateral caudate-putamen. We conclude that nitrotyrosine formation required activation of NMDA receptors, at least in part.

Bone-specific delivery and sustained release of diclofenac, a non-steroidal anti-inflammatory drug, via bisphosphonic prodrug based on the Osteotropic Drug Delivery System (ODDS).

We have newly synthesized osteotropic diclofenac with bisphosphonic moiety (DIC-BP) based on the concept of Osteotropic Drug Delivery System (ODDS) and investigated its potency of site-specific and controlled delivery of diclofenac to the bone in rats. After intravenous injection into rats, DIC-BP was predominantly distributed in the skeleton. DIC-BP once incorporated in the bone was gradually eliminated (t(1/2)=9.7 days), releasing diclofenac into the bone compartment. As a result, the bone concentration of regenerated diclofenac was apparently constant over 28 days. Furthermore, we evaluated the anti-inflammatory effects of DIC-BP compared with diclofenac (sodium salt) in adjuvant-induced arthritic rats. The mean effective doses (ED(50)) were 0.55 mg/kg and 1.3 mg/kg for daily oral administration of diclofenac and weekly intravenous injection of DIC-BP, respectively. Considering the frequency of medication of 17 times for diclofenac and 4 times for DIC-BP in the experimental period, ED(50) was corrected to 9.4 and 5.2 mg/kg (per experimental period) for diclofenac and DIC-BP, respectively. Moreover, DIC-BP exhibited no side effects of gastrointestinal damage, typical of non-steroidal anti-inflammatory drugs. Thus, ODDS of diclofenac shows promise as an approach for highly potent and non-toxic therapy of diclofenac, with less frequent medication.

Role of infection in the development of acquired subglottic stenosis in neonates with prolonged intubation.

OBJECTIVE: To examine whether clinically diagnosed infection correlates with subsequent development of subglottic stenosis in intubated neonates. METHODS: Sixty-two neonatal infants intubated for more than 14 days were examined. Several risk factors for subglottic stenosis, including infection, duration of intubation, frequency of intubation, the size of the endotracheal tube etc., were evaluated by multiple logistic regression analysis. RESULTS: Infection that occurred within 14 days of intubation showed a positive correlation with subsequent subglottic stenosis. The duration of intubation, frequency of intubation and the size of the endotracheal tube did not affect the development of subglottic stenosis. The majority of infections were considered to be respiratory tract infections, including pneumonia. CONCLUSIONS: Infection occurring within 14 days of intubation is considered to be a risk factor for acquired subglottic stenosis in neonates intubated for more than 14 days. Prevention of infection within 14 days of intubation may reduce the incidence of subglottic stenosis in neonates.

[A surgical case of growing cavernous angioma at the pontomedullary junction].

We described a surgical case of growing cavernous angioma located at the pontomedullary junction. This 52-year-old woman presented with symptoms caused by a small hemorrhage in the right cerebellopontine angle. Magnetic resonance images (MRI) suggested cavernous angioma as the underlying pathology. 9 months after the first episode, the second hemorrhage occurred with a deteriorated neurological state that disappeared under conservative treatment except for right facial paresis and hearing disturbance. During careful observation for 1 year, the size of the lesion gradually increased on MRI and additional neurological deficits including left hemiparesis and right abducent nerve palsy were diagnosed. The first operation was carried out through the right lateral suboccipital approach, but only partial removal of the cavernous angioma was accomplished due to the overlying seventh and lower cranial nerves. After more than 4 months, a third hemorrhagic episode was presented with a sudden onset of right cerebellar signs and facial numbness. The cavernous angioma grew in size to reach the ventrolateral corner of the 4th ventricle with dense hemosiderin deposition around the core lesion on MRI. An enhancement inside the lesion was also demonstrated after gadolinium-diethylenetriaminepenta-acetic acid administration. The second operation through the midline suboccipital approach was selected for the complete resection of the residual cavernous angioma. The lesion was too hard to resect without internal decompression. The pontine part of the lesion was almost totally resected, but manipulation for the medullary part to create a discrete layer between the lesion and surrounding neural tissues was unsuccessful and generated severe bradycardia, so this part of the cavernous angioma had to be left. The problems for the management of cavernous angioma in the brain stem should be discussed, especially focussing on the surgical indication in reference to our experience and previous literatures.

Why are some patients with severe neglect able to copy a cube? The significance of verbal intelligence.

Cube-copying is often used to assess constructional ability of brain-damaged patients and the influence of unilateral spatial neglect is often pointed out in patients with right hemisphere lesions. However, some patients with severe neglect perform cube-copying satisfactorily. The aim of the present study is to identify the factors that affect the performance of cube-copying in patients with left unilateral spatial neglect. Constructional performance was investigated in 100 patients with unilateral spatial neglect using a task to copy the Necker cube. The relationship of the patients' cube-copying performance to the severity of their neglect, as well as other factors (verbal intelligence, age, duration after onset of the disease, educational level, lesion site, piecemeal approach, and side of starting to copy) was analyzed. Twenty-two normal subjects also participated in this study as controls. Among many factors adopted for analysis, neglect severity and verbal intelligence were found to be primary factors affecting the cube-copying performance of the patients with unilateral spatial neglect. The effect of neglect severity on cube-copying performance was apparent in the patients whose verbal intelligence was deteriorated, but was not observed in the patients with preserved verbal intelligence. Similarly, the effect of verbal intelligence on cube-copying performance was apparent in the patients with severe neglect, but not in the patients with mild neglect. We conclude that constructional ability in the copying of a cube is determined by verbal intelligence, as well as by the severity of unilateral spatial neglect.

Effect of stimulation of the dorsal aspect of the cervical spinal cord on local cerebral blood flow and EEG in the cat.

Currently there is considerable interest in electrical stimulation of the dorsal aspect of the cervical spinal cord as a potentially effective therapy for persistent vegetative patients. The authors assessed change in the local cerebral blood flow (LCBF) and electroencephalogram (EEG) in the cat following spinal cord stimulation (SCS). In 31 adult cats under isoflurane anesthesia, an electrode for SCS was introduced epidurally to the midline of the C2-C3 segment. Stimulation was performed at 25 Hz and 0.1 msec for 30 min. These animals were divided into five groups by the voltage: (1) 2V (n = 7), (2) 4V (n = 7), (3) 6V (n = 7), (4) 4V with intravenous injection of muscarinic cholinergic agents--atropine sulfate (n = 5), and (5) sham-operated control (n = 5) without stimulation. LCBF was measured by laser Doppler flowmetry through bilateral small burr holes at the parietal area during and 60 min after stimulation. At 2V, LCBF increased only during SCS, then returned to the pre-stimulated level, while the increase continued until the end of the experiment at 4V and 6V. The increase in LCBF was not affected by atropine sulfate. EEG showed spike and wave or polyspikes after SCS in two animals of the 6V group, but not in the 2V and 4V groups, and moreover a moderate increase of the background activity at only 4V. The present data suggested that SCS at 4V can provide the appropriate microcirculatory enhancement with less harmful influence which continues to increase 30 min after SCS, although the exact mechanism should be elucidated continuously. Within the limitation of animal experiments, this study could provide the logical basis for determining the condition of SCS.

Nitrotyrosine generation via inducible nitric oxide synthase in vascular wall in focal ischemia-reperfusion.

Nitrotyrosine produced by NO-mediated reaction is a possible marker for cytotoxicity in brain ischemia. In this study, we aimed to determine whether iNOS is responsible for the nitrotyrosine formation and which type of cell is predominantly nitrated. Fifty-eight wild-type and 28 iNOS knockout male mice were used. Under halothane anesthesia the left middle cerebral artery was occluded for 2 h and reperfused for 0.5 or 15 h. The ratio of nitrotyrosine to total tyrosine (%NO2-Tyr) was measured by means of a hydrolysis/HPLC. After 0.5-h reperfusion, %NO2-Tyr in the ischemic cortex of wild-type and knockout mice amounted to 0.037 +/- 0.040% (n = 8) and 0.064 +/- 0.035% (n = 6), respectively, being significantly higher than that in the sham operation group (n = 7) (P < 0.05). After 15-h reperfusion, nitrotyrosine was detected only in wild-type mice (0.039 +/- 0.025%, n = 7), not in knockout or sham-operated mice (P < 0.05). Immunohistochemical reaction for nitrotyrosine was seen predominantly in the vascular wall in the peri-infarct region of the cerebral cortex in wild-type mice after 15-h reperfusion, but not in corresponding knockout mice. Our data suggest that iNOS is responsible for nitrotyrosine formation in the later phase of reperfusion, and that vascular endothelium is the major site of this reaction, at least in the case of 15-h reperfusion.

7-Nitroindazole attenuates nitrotyrosine formation in the early phase of cerebral ischemia-reperfusion in mice.

The purpose of this study was to evaluate the role of neuronal nitric oxide synthase (nNOS) in nitrotyrosine (NO2-Tyr) formation in the early phase of ischemia-reperfusion in mouse brain. Using a hydrolysis/high pressure liquid chromatography (HPLC) procedure (0.6 microM detection limit), we measured %NO2-Tyr (ratio of NO2-Tyr to total tyrosine) in 23 male C57Black/6J mice subjected to 2-h middle cerebral artery occlusion followed by 0.5-h reperfusion, in the presence (25 or 50 mg/kg) and absence of 7-nitroindazole (7-NI), a relatively specific nNOS inhibitor. At 25 mg/kg, 7-NI reduced NO2-Tyr formation to about a half of that in the vehicle-treated group (0.10 +/- 0.07 vs. 0.18 +/- 0.05%), while 50 mg/kg suppressed NO2-Tyr formation to below the limit of detection, indicating that nNOS is responsible for most of the NO2-Tyr formation in the early phase after reperfusion.

Dynamics of nitrotyrosine formation and decay in rat brain during focal ischemia-reperfusion.

The purpose of this study was to establish the dynamics of nitrotyrosine (NO2-Tyr) formation and decay during the rise of NO2-Tyr in rat brain subjected to 2-hour focal ischemia-reperfusion, and to evaluate the role of inducible nitric oxide synthase in the rise. The authors first determined the half life of NO2-Tyr in rat brain at 24 hours after the start of reperfusion by blocking NO2-Tyr formation with N(G)-monomethyl-L-arginine and after the decay of NO2-Tyr by means of a hydrolysis/HPLC procedure. The values obtained were approximately 2 hours in both peri-infarct and core-of-infarct regions. Using the same hydrolysis/HPLC procedure, the ratio of nitrotyrosine to tyrosine from the 2-hour occlusion to as much as 72 hours after the start of reperfusion was measured in the presence and absence of aminoguanidine (100 mg/kg intraperitoneally twice a day). In the absence of aminoguanidine, the ratio of NO2-Tyr in the peri-infarct and core-of-infarct regions reached 0.95% +/- 0.34% and 0.52% +/- 0.34%, respectively, at 1 hour after the start of reperfusion. The elevated levels persisted until 48 hours, then declined. The peri-infarct region showed the highest percent NO2-Tyr level, followed by the core of infarct, then the caudoputamen. Aminoguanidine significantly reduced NO2-Tyr formation (up to 90% inhibition) during 24 to 48 hours. The authors conclude that inducible nitric oxide synthase is predominantly responsible for NO2-Tyr formation, at least in the late phase of reperfusion. These results have important implications for the therapeutic time window and choice of nitric oxide synthase inhibitors in patients with cerebral infarction.