Levodopa-Carbidopa Intestinal Gel Injection for Patient with Severe Parkinson's Disease Followed by Total Hip Arthroplasty: A Case Report and Literature Review.

BACKGROUND: Patients with Parkinson's disease have a high dislocation rate after total hip arthroplasty (THA). This study describes a case with severe Parkinson's disease who developed rapidly destructive coxarthrosis (RDC) and underwent THA using a dual mobility cup after a levodopa-carbidopa intestinal gel (LCIG) infusion. CASE PRESENTATION: The patient is a 59-year-old female with a ten-year history of Parkinson's disease, which was first treated with oral levodopa. The patient developed RDC of the right hip joint. However, THA was difficult owing to Parkinson's disease and its treatment side effects, such as wearing-off, dyskinesia, and freezing of the gait, Thus, LCIG was initiated, and improvement in wearing-off and dyskinesia was observed. Two months after the LCIG therapy, the disease was controlled well. THA was subsequently performed using a dual mobility cup to prevent postoperative dislocation. Postoperatively, LCIG therapy was continuously administered to carefully manage the disease, which was controlled well with no increase in wearing-off and dyskinesia after surgery. At 1 year after surgery, the walking speed, stride length, and the Harris hip score improved compared to preoperatively. The UPDRS III motor score improved to eight without signs of wearing-off or dyskinesia. The Hoehn-Yahr scale was II in the "on" period and remained unchanged 1 year after surgery. The patient could walk without a cane and had satisfactory functional outcomes. CONCLUSION: This case proved that LCIG treatment performed preoperatively, followed by THA using a dual mobility cup, and strict management of Parkinson's disease could result in a satisfactory clinical course without recurrence of wearing-off and dyskinesia. Similar procedures may benefit other patients with Parkinson's disease who have previously been deemed unsuitable for THA.

A novel homozygous mutation of CLCN2 in a patient with characteristic brain MRI images - A first case of CLCN2-related leukoencephalopathy in Japan.

Chloride channel 2 (ClC-2) is one of nine ClC family proteins and is encoded by CLCN2. We report the first patient with a CLCN2 mutation in Japan. A 22-month-old female had generalized tonic-clonic convulsions at the age of 3 months. Brain MRI showed high signals in the bilateral cerebellar white matter including the dentate nucleus, dorsal midbrain, and posterior limbs of the internal capsules in diffusion-weighted images, and apparent diffusion coefficient values were low in the same areas. Antiepileptic drugs were effective, and she had neither intellectual disabilities nor motor disturbance. A homozygous frameshift mutation (c.61dup, p.Leu21Profs∗27) of CLCN2 was identified in the patient. Homozygous mutations of CLCN2 are known to be associated with CLCN2-related leukoencephalopathy (CC2L). The clinical findings of this patient were different from other patients with CC2L. Therefore, mutations in CLCN2 may cause various phenotypes. Further accumulation of cases with CLCN2-mutations is required to explore the clinical spectrum of CC2L.

A novel biosensor with high signal-to-noise ratio for real-time measurement of dopamine levels in vivo.

Fast-scan cyclic voltammetry (FSCV) is an established method for measuring dopamine (DA) levels in the brain in real time. However, it is difficult to discriminate DA from other monoamines such as serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (NE). We report a novel DA-specific biosensor consisting of a carbon-fiber electrode coated with an ion-exchange membrane, a layer containing monoamine oxidase B, and a cellulose membrane. We performed FSCV using the probe to monitor the amount of DA in vitro and in vivo. First, we measured currents in vitro in phosphate-buffered saline as we added one micromole each of DA, 5-HT, and NE. The results confirmed that the biosensor selectively detected DA. Next, we implanted the probe in the striatum of male rats to investigate whether it could selectively detect changes in the DA content in vivo. The probe detected both the tonic change induced by methamphetamine administration and the phasic change induced by electrical stimulation of the medial forebrain bundle. In contrast, the electrode in the 6-hydroxydopamine-lesioned striatum did not respond to systemic selective serotonin or serotonin/norepinephrine reuptake inhibitors, confirming its selectivity. Furthermore, the probe in the striatum could still detect changes in the DA level 1 week after electrode implantation. The results suggest that the novel biosensor can measure real-time changes in DA levels in vivo with a relatively high signal-to-noise ratio.

The first report of Japanese patients with asparagine synthetase deficiency.

BACKGROUND: Asparagine synthetase (ASNS) deficiency was recently discovered as a metabolic disorder of non-essential amino acids, and presents as severe progressive microcephaly, intellectual disorder, dyskinetic quadriplegia, and intractable seizures. METHODS: Two Japanese children with progressive microcephaly born to unrelated patients were analyzed by whole exome sequencing and novel ASNS mutations were identified. The effects of the ASNS mutations were analyzed by structural evaluation and in silico predictions. RESULTS: We describe the first known Japanese patients with ASNS deficiency. Their clinical manifestations were very similar to reported cases of ASNS deficiency. Progressive microcephaly was noted during the prenatal period in patient 1 but only after birth in patient 2. Both patients had novel ASNS mutations: patient 1 had p.L145S transmitted from his mother and p.L247W which was absent from his mother, while patient 2 carried p.V489D and p.W541Cfs*5, which were transmitted from his mother and father, respectively. Three of the four mutations were predicted to affect protein folding, and in silico analyses suggested that they would be pathogenic. CONCLUSION: We report the first two Japanese patients with ASNS deficiency. Disease severity appears to vary among patients, as is the case for other non-essential amino acid metabolic disorders.

A case of a teenage boy with eosinophilic gastroenteritis with esophageal involvement developing a hemorrhagic duodenal ulcer.

A boy in his early teens visited our hospital with chief complaints of hematemesis and tarry stools. Upper gastrointestinal endoscopy identified a hemorrhagic duodenal ulcer, for which hemostasis was performed using a clip. Proton pump inhibitor (PPI) administration diminished the ulcer but relapse occurred after PPI discontinuation. The esophagus showed concentric rings and longitudinal linear furrows considered to be characteristic of eosinophilic esophagitis. Biopsies of the duodenal ulcer and the esophagus revealed marked infiltration of eosinophils, leading to a diagnosis of eosinophilic gastroenteritis with esophageal involvement. Steroid treatment was initiated, and the duodenal ulcer and esophagitis resolved. Endoscopic findings characteristic of eosinophilic esophagitis were key to the diagnosis of eosinophilic gastroenteritis.

Postobstructive pulmonary edema that developed immediately after the removal of an endobronchial foreign body.

The patient was a 5-year-old boy who was transported to our hospital for a paroxysmal cough, disturbance of consciousness, tonic-clonic convulsions and labored breathing. The patient's respiratory failure persisted after the convulsions remitted, and the presence of an endobronchial foreign body was suspected based on the findings of chest CT performed the following day. A peanut was subsequently removed from the right main bronchus using a bronchoscope with tracheal intubation and bag valve mask ventilation. Immediately after removal, the patient rapidly developed exacerbated hypoxemia, and a reduction in right lung lucency was noted on chest radiography. He was therefore diagnosed with type II postobstructive pulmonary edema, and his condition improved within a short period of time.

Infantile Cases of Sitosterolaemia with Novel Mutations in the ABCG5 Gene: Extreme Hypercholesterolaemia is Exacerbated by Breastfeeding.

Few data exists regarding the clinical impact of breastfeeding in infantile sitosterolaemic cases. We report four Japanese infantile cases of sitosterolaemia, an extremely rare inherited disease characterised by increased serum levels of plant sitosterol, presenting with severe hypercholesterolaemia and systemic xanthomas exacerbated by breastfeeding. In these four cases, genetic analyses were performed for low-density lipoprotein (LDL) receptor, proprotein convertase subtilisin/kexin type 9 (PCSK9), LDL receptor adaptor protein 1 and ATP-binding cassette (ABC) subfamily G member 5 and 8 (ABCG5 and ABCG8) genes. We assessed their clinical manifestations, including responsiveness to a variety of treatments, especially to weaning from breastfeeding and use of ezetimibe. Two pairs of mutations in the ABCG5 gene in each case, including two novel mutations (c.130C>T or p.Ser44Ala and c.1813_1817delCTTTT or p.Pro558GlufsX14) and two known mutations (c.1306G>A or p.Arg389His and c.1336C>T or p.Arg446X), were identified. Significant reductions in cholesterol levels were obtained by means of weaning from breastfeeding alone. Substantial reductions in sitosterol levels, without any apparent side effects, were observed with ezetimibe. In conclusion, we have identified infantile Japanese sitosterolaemic subjects with extreme hypercholesterolaemia exacerbated by breastfeeding. Their unique response to weaning from breastfeeding, as well as to use of ezetimibe, could provide insights into the metabolic basis of sterols in humans.

Effect of levetiracetam in acute encephalitis with refractory, repetitive partial seizures during acute and chronic phase.

AIM: To clarify the effect of levetiracetam (LEV) for acute and chronic seizure control in acute encephalitis with refractory, repetitive partial seizures (AERRPS). METHODS: We retrospectively reviewed the clinical course of six AERRPS cases treated with LEV, and explored the acute phase termination by withdrawal from barbiturate-induced coma under artificial ventilation, and the reduction in seizure frequency during the chronic phase. LEV was administrated orally or via nasogastric tubes as an add-on agent during acute (n=3; age 8-10 years) and chronic (n=3; age 19-30 years) AERRPS. RESULTS: In the acute phase, administration of LEV (50-60 mg/kg/d) in combination with phenobarbital (n=3; peak 57.9-76.1 µg/ml) and potassium bromide (n=2; 30-36 mg/kg/d)) resulted in successful reduction of intravenous barbiturate dosage and withdrawal from artificial ventilation. In the chronic phase, seizure frequency reduced by >75% for 5-18 months with LEV 750-1500 mg/d. CONCLUSION: LEV may affect seizure control in AERRPS, particularly during the chronic phase, through its unique action of inhibition of excitatory neurotransmitter release. The regimen of oral barbiturate, potassium bromide and LEV would be worth for trial during the acute phase of AERRPS.

Postoperative atypical hemolytic uremic syndrome associated with complement c3 mutation.

Atypical hemolytic uremic syndrome (aHUS) can be distinguished from typical or Shiga-like toxin-induced HUS. The clinical outcome is unfavorable; up to 50% of affected patients progress to end-stage renal failure and 25% die during the acute phase. Multiple conditions have been associated with aHUS, including infections, drugs, autoimmune conditions, transplantation, pregnancy, and metabolic conditions. aHUS in the nontransplant postsurgical period, however, is rare. An 8-month-old boy underwent surgical repair of tetralogy of Fallot. Neurological disturbances, acute renal failure, thrombocytopenia, and microangiopathic hemolytic anemia developed 25 days later, and aHUS was diagnosed. Further evaluation revealed that his complement factor H (CFH) level was normal and that anti-FH antibodies were not detected in his plasma. Sequencing of his CFH, complement factor I, membrane cofactor protein, complement factor B, and thrombomodulin genes was normal. His ADAMTS-13 (a disintegrin-like and metalloprotease with thrombospondin-1 repeats 13) activity was also normal. However, he had a potentially causative mutation (R425C) in complement component C3. Restriction fragment length polymorphism analysis revealed that his father and aunt also had this mutation; however, they had no symptoms of aHUS. We herein report a case of aHUS that developed after cardiovascular surgery and was caused by a complement C3 mutation.

Na(+)-K(+)-2Cl(-) cotransporter-mediated fluid secretion increases under hypotonic osmolarity in the mouse submandibular salivary gland.

Water-handling epithelia are sensitive to the osmotic environment. In this study, the effects of a hypo-osmotic challenge on carbachol (CCh)-induced fluid secretion was investigated using an ex vivo submandibular gland perfusion technique and intracellular pH and Ca(2+) measurements. The osmolality of the perfusion solution was altered to examine the response of the gland to a hypotonic challenge. The flow rate was increased by 34% with a 30% hypotonic solution (225 mosmol/kgH2O), although the Ca(2+) response was unchanged. The lowering of the external Cl(-) by 50% abolished this increase in the 30% hypotonic solution. Furthermore, bumetanide, an inhibitor of the Na(+)-K(+)-2Cl(-) cotransporter (NKCC1), completely inhibited the fluid secretion increase caused by the 30% hypotonic solution, and both the total amount of fluid and the flow rate were identical to those of the isotonic solution. This finding was confirmed by measuring the NKCC1 bumetanide-dependent NH4 (+) transport; Na(+)-K(+)-2Cl(-) transport was upregulated >40% by a 30% hypotonic challenge. Therefore, the increase in CCh-induced fluid secretion in response to hypotonic conditions can be attributed, to a large extent, to the specific activation of the NKCC1.

Genetic variations of immunoregulatory genes associated with Rasmussen syndrome.

OBJECTIVE: To elucidate the genetic predisposition of Rasmussen syndrome (RS). METHODS: In 29 Japanese patients, we examined the genome sequences of cytotoxic T-lymphocyte-associated protein 4 (CTLA4), programmed cell-death 1 (PDCD1), and T-bet (TBX21) genes by direct sequencing, and evaluated the significance of SNPs (single nucleotide polymorphism) by comparison with Hap Map data. RESULTS: In all patients, no disease-causative mutations were found in CTLA4, PDCD1, and T-bet. However, rs231775 SNP in exon 1 of CTLA4 showed significant positive genotypic (p=0.0363) and allelic associations (p=0.0137) with onset of RS compared with Japanese controls, as did rs231779 SNP in intron 1 of CTLA4 (p=0.0467 and 0.0188, respectively). Also, rs2227982 SNP in exon 5 of PDCD1 showed significant positive genotypic and allelic associations with RS (p=0.0145 and 0.0114, respectively). Poor cognitive outcome (IQ below 50) was found in 0% of wild type (C/C), 9% of heterologous (C/T) and 25% of homologous (T/T) genotype of rs2227982. Quadriplegia was found only in homologous (T/T) genotype, and hemiplegia was in heterologous (C/T) and homologous (T/T) genotype of rs2227982. No association between SNPs of T-bet and RS onset was found. Regarding SNPs in promoter regions (rs4794067 and rs17250932) of T-bet, however, IQ below 50 was found in 19% of wild type (T/T) and 0% of heterologous (T/C) genotype of rs4794067, and in 19% of wild type (T/T) and 0% of heterologous (T/C) genotype of rs17250932. Quadriplegic patients were found only in wild-type patients (rs4794067 and rs17250932). CONCLUSIONS: We identified three SNPs (rs231775, rs231779, rs2227982) as some of the SNPs associated with onset of Japanese RS. We need further studies in other populations to confirm these genetic predispositions in RS.

Endothelial nitric oxide synthase plays a main role in producing nitric oxide in the superacute phase of hepatic ischemia prior to the upregulation of inducible nitric oxide synthase.

BACKGROUND: The aim of this study was to determine the intrahepatic kinetics of different types of nitric oxide (NO) synthase, such as endothelial nitric oxide synthase (eNOS) and inducible NOS (iNOS), during repeated ischemia/reperfusion (I/R). METHODS: Three different protocols of hepatic I/R in rats were designed as follows: 60 min of ischemia and 30 min of reperfusion (I/R 60/30); 5 min of ischemia and 5 min of reperfusion (I/R 5/5); and repeating 15 min of ischemia and 5 min of reperfusion for four cycles (I/R 15/5 × 4). Intrahepatic NO levels were measured using a selective NO sensor. Changes in hepatic microcirculation during I/R 5/5 were investigated using intravital microscopy. Hepatic expression of eNOS, phospho-eNOS, and iNOS were evaluated during repeated I/R by Western blot, reverse transcription polymerase chain reaction, and immunohistochemistry. RESULTS: During I/R 60/30, intrahepatic NO levels gradually increased and then reached a plateau approximately 15 min after starting ischemia. During I/R 5/5, the sinusoids after 5 min reperfusion were dilated compared with the sinusoids before ischemia. The expression of phospho-eNOS during I/R 15/5 × 4 markedly increased during the first ischemia, and then the levels attenuated during the subsequent repeating I/R cycles; however, the expression of iNOS gradually increased, as observed by Western blot, reverse transcription polymerase chain reaction, and immunohistochemical analysis. An impact of NO production by phospho-eNOS activation during the superacute phase of I/R was also confirmed using pharmacologic NOS inhibitors. CONCLUSION: Our results firstly demonstrated an altered activation of the phospho-eNOS system and iNOS over the course of repeated hepatic I/R.

Late delirious behavior with 2009 H1N1 influenza: mild autoimmune-mediated encephalitis?

Delirious behavior associated with influenza usually has an onset within a few days after fever and lasts <24 hours. As we encountered several patients with 2009 H1N1 influenza who presented with late-onset and long-standing delirious behavior, we retrospectively evaluated the clinical, radiologic, and laboratory features to elucidate the possible pathophysiology. This information was collected on 5 previously healthy patients (2 boys and 3 girls, aged 10-15 years) with 2009 H1N1 influenza who presented with late onset (>3 days after fever) and long-standing (>48 hours) delirious behavior. Each exhibited mild to moderate drowsiness between the episodes of delirious behavior. Electroencephalography was normal except for 1 patient with high voltage and slow activity bilaterally in the occipital regions. Brain MRI was normal. The outcome was excellent with no neurologic sequel in 4 of the 5 patients. In all 5 patients, autoantibodies against N-methyl-D-aspartate type glutamate receptor were elevated or positive in cerebrospinal fluid or serum; the autoantibody levels normalized in the 3 patients who had follow-up studies. This study indicates that 2009 H1N1 influenza has a tendency to cause late-onset and long-standing delirious behavior, at least in Japanese children. Mild autoimmune-mediated encephalitis should be considered as an underlying cause.

Novel deletion at Xq24 including the UBE2A gene in a patient with X-linked mental retardation.

By using an in-house bacterial artificial chromosome-based X-tilling array, we detected a 0.4 Mb novel deletion at Xq24 that included UBE2A in a 4-year-old and 10-month-old boy with mental retardation and various other characteristics inherited from his mother; for example, marked developmental delay, synophrys, ocular hypertelorism, esotropia, low nasal bridge, marked generalized hirsutism and seizure. Although additional nine transcripts around UBE2A were also defective, a phenotypic similarity with a recently reported X-linked familial case involving a novel X-linked mental retardation syndrome and a nonsense mutation of UBE2A indicates a functional defect of UBE2A to be responsible for most of the abnormalities in these cases. Because some characteristics, such as congenital heart disease and proximal placement of the thumb, were not described in the family reported previously, suggesting genes other than UBE2A within the deleted region to be responsible for those abnormalities.

Differences in the time course of splenial and white matter lesions in clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS).

Two patients with clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) exhibiting lesions in the white matter and entire corpus callosum (type 2) are reported. The time course differed between the splenial lesion and other lesions in the white matter and corpus callosum other than the splenium; the latter disappeared earlier than the former. These findings strongly suggest that MERS type 2 resolves completely through MERS type 1 exhibiting an isolated splenial lesion, and MERS types 1 and 2 have the same pathophysiology. The possible prior white matter lesions in patients with MERS type 1 may explain the neurological symptoms or EEG abnormalities.

Surgical Control of a Primary Hepatic Carcinoid Tumor: A Case Report.

We report a primary hepatic carcinoid tumor occurring in a 47-year-old man. The patient consulted our hospital complaining of epigastralgia. Abdominal ultrasonography, computed tomography scanning, and magnetic resonance imaging showed a large mass in the right lobe of the liver. FDG-PET revealed 18F-FDG uptake by the right hepatic lobe. The tumor was a solid mass with cystic components, approximately 15 cm in diameter. We conducted an extended right lobectomy of the liver. The resected specimen was a solid tumor with cystic components and hemorrhagic lesion. Microscopic findings showed that the tumor cells had round nuclei and formed trabecular patterns. Immunohistologically, tumor cells were stained positive for chromogranin A, neuron specific enolase, CD56, and S-100. Careful examinations before and after the operation revealed no other possible origin of the tumor. Based on these findings, the tumor was diagnosed as a primary hepatic carcinoid. This is a report of a rare case of a primary hepatic carcinoid tumor with a discussion of several other relevant reports.

Unsuspected gallbladder cancer diagnosed during or after laparoscopic cholecystectomy.

BACKGROUND: The long-term prognosis of laparoscopic cholecystectomy (LC) for patients with unsuspected gallbladder carcinoma (GBC) remains unclear. We investigated retrospectively the role of examination of frozen sections and the prognosis of patients with unsuspected GBC detected during or after LC. METHODS: LC was performed on 1,793 consecutive patients. If a suspicious lesion was found, intraoperative frozen section examination was performed. RESULTS: Of all these patients, 38 (2.1%) were histopathologically diagnosed as having a GBC during (28) or after LC (10). The tumor stages of the 28 diagnosed during LC were: pT1a (17), pT1b (2), pT2 (8), and pT3 (1). The sensitivity and specificity of intraoperative frozen section examination were 90 and 100%, respectively. On the other hand, those 10 cases diagnosed after LC had pT1a (1) and pT2 (9) tumors. Survival rates were not significantly affected by whether the patient was diagnosed with GBC during or after LC. CONCLUSIONS: The survival with unsuspected GBC was related to stage and it was confirmed that a carefully performed LC is adequate treatment for Stage 1A and B cancer. The LC procedure does not adversely affect the prognosis of unsuspected GBC, regardless of whether it is detected during or after LC.

Vaccination and infection as causative factors in Japanese patients with Rasmussen syndrome: molecular mimicry and HLA class I.

Rasmussen syndrome is an intractable epilepsy with a putative causal relation with cellular and humoral autoimmunity. Almost half of the patients have some preceding causative factors, with infections found in 38.2%, vaccinations in 5.9% and head trauma in 8.9% of Japanese patients. In a patient with seizure onset after influenza A infections, cross-reaction of the patient's lymphocytes with GluR epsilon 2 and influenza vaccine components was demonstrated by lymphocyte stimulation test. Database analyses revealed that influenza A virus hemagglutinin and GluR epsilon 2 molecules contain peptides with the patient's HLA class I binding motif (HLA - A*0201). The relative risks of HLA class I genotypes for Rasmussen syndrome are 6.1 (A*2402), 6.4 (A*0201), 6.3 (A*2601) and 11.4 (B*4601). The relative risks of HLA class I-A and B haplotypes are infinity (A*2601 + B*5401), 21.1 (A*2402 + B*1501), 13.3 (A*2402 + B*4801) and 5.1 (A*2402 + B*5201). Some alleles and haplotypes of HLA class I may be the risk factors in Japanese patients. Cross-reactivity of cytotoxic T lymphocytes may contribute to the processes leading from infection to the involvement of CNS.

Recurrent hepatitis C after living donor liver transplantation detected by Tc-99m GSA liver scintigraphy.

Recurrence of hepatitis C virus (HCV) after living donor liver transplantation was investigated using technetium-99m- diethylenetriaminepentaacetic acid-galactosyl human serum albumin (Tc-99m-GSA) liver scintigraphy. Four patients with decompensated cirrhosis due to HCV infection were retrospectively reviewed in this study. Scintigraphy was performed to determine the hepatic uptake ratio of the tracer corrected for disappearance from the blood, as well as the maximal removal rate of the tracer by hepatocytes, as parameters of hepatic functional reserve. In all patients, serum HCV ribonucleic acid (RNA) was detected 3 months after transplantation. The corrected hepatic uptake ratio and removal rate showed little change after transplantation in two patients without the recurrence of HCV infection. In another two patients, these levels were decreased at 3 months after transplantation. In one patient, recurrent HCV infection was diagnosed by confirmatory histologic examination at 12 months after transplantation. In the other patient, both levels declined further at 8 months. Although treatment was initiated with a combination of interferon plus ribavirin, this patient died of progressive hepatic failure. In conclusion, a decrease in scintigraphic parameters at 3 months after transplantation suggests recurrent HCV infection affecting the graft. Tc-99m-GSA liver scintigraphy is a useful noninvasive method for evaluating graft functional reserve.