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Background The MEHMO (mental retardation, epileptic seizures, hypogonadism and hypogenitalism, microcephaly, and obesity) syndrome, which is caused by a hemizygous variant in the EIF2S3 gene on chromosome Xp22, is associated with significant morbidity and mortality. Refractory epileptic seizures and glucose dysregulation are characteristic manifestations of the MEHMO syndrome, which can often diminish patients’ quality of life. Case A 5-year-old boy was referred to our hospital because of profound intellectual disability, micropenis, cryptorchidism, central hypothyroidism, and microcephaly. He had neonatal hypoglycemia at birth and later experienced refractory epileptic seizures and developed obesity and insulin-dependent diabetes. A diagnosis of MEHMO syndrome was established on the basis of the patient’s clinical manifestations and de novo novel missense variant in the EIF2S3 gene (NM_001415.3:c.805 T > G) that was detected through whole-exome analysis. Although the patient’s refractory seizures and diabetes had been well controlled with a combination of ketogenic diet (KD) therapy and insulin therapy, acute fatal necrotizing pancreatitis occurred at the age of 68 months. Moreover, despite intensive care, his condition rapidly deteriorated to multiple organ failure and acute respiratory distress syndrome, resulting in death. Conclusion The pathophysiology of glucose intolerance in MEHMO syndrome remains to be elucidated; however, recent studies have suggested that EIF2S3 gene variants could lead to glucose dysregulation and β-cell damage in the pancreas. We suspect that in the present case, KD therapy led to an abnormal load on the beta cells that were damaged owing to eIF2γ dysfunction. Therefore, the adverse effects of KD in patients with MEHMO syndrome should be considered.

Background: Although the incidence of cerebral infarction is higher in Duchenne muscular dystrophy (.75 per 100) than in the general population (7.5-11.4 per 100 000), only 18 cases have been reported, and prevention and management guidelines for infarction in this disorder remain lacking. Patients and Methods: We encountered 2 cases of Duchenne muscular dystrophy with cerebral infarction. To clarify risk factors for such infarction in Duchenne muscular dystrophy, we reviewed 20 cases, including our 2 patients. Results: Age at onset of infarction ranged from 4 to 31 years (n = 19). Most patients were 16-21 years old (14 of 19; 73.7%). Eighteen patients (90%) had dilated cardiomyopathy (DCM), showing a higher frequency than in the age-matched general Duchenne muscular dystrophy population. Left ventricular ejection fraction (LVEF) ranged from 10.2% to 42% (median, 20%; n = 9). Detectable cardiac thrombus and atrial fibrillation were rare (2 of 17; 11.8%, and 1 of 17; 5.9%, respectively). Conclusions: Presence of DCM with low LVEF seems to be the strongest risk factor for cerebral infarction in Duchenne muscular dystrophy.

Left ventricular noncompaction cardiomyopathy (LVNC) is characterized by prominent trabecular meshwork, and it is thought to result from arrest of the normal compaction process during embryogenesis. Patients with LVNC may be asymptomatic or have symptoms ranging from heart failure to stroke, life-threatening arrhythmias, or sudden death. The frequency of LVNC in children has increased with longer clinical courses. About 80% of patients with trisomy 13 have a congenital cardiac abnormality, but a clinical description of LVNC with trisomy 13 is lacking because of its poor prognosis and lack of awareness about LVNC. We described a patient with trisomy 13 who was diagnosed with LVNC-dilated phenotype and died suddenly, as well as two additional patients with LVNC. All three patients had chronic heart failure without congenital heart disease and were treated with diuretics. To manage trisomy 13 with or without congenital heart disease, cardiac disease such as LVNC may present at any ages, and therefore cardiac evaluation should be considered as a part of their appropriate management.

Nerve transfer involves the use of a portion of a healthy nerve to repair an injured nerve, and the process has been used to alleviate traumatic brachial plexus injuries in humans. Study of the neural mechanisms that occur during nerve transfer, however, requires the establishment of reliable experimental models. In this study, we developed an ulnar-musculocutaneous nerve-transfer model wherein the biceps muscle of a mouse was re-innervated using a donor ulnar nerve. Similar muscle action potentials were detected in both the end-to-end suture of the transected nerve (correctrepair) group and the ulnar-musculocutaneous nerve-transfer group. Also, re-innervated acetylcholine receptor (AChR) clusters and muscle spindles were observed in both procedures. There were fewer re-innervated AChR clusters in the nerve transfer group than in the correct repair group at 4 weeks, but the numbers were equal at 24 weeks following surgery. Thus, our ulnar-musculocutaneous nerve-transfer model allowed physiological and morphological evaluation for re-innervation process in mice and revealed the delay of this process during nerve transfer procedure. This model will provide great opportunities to study regeneration, re-innervation, and functional recovery induced via nerve transfer procedures.

Cutis laxa (CL) syndromes are connective tissue disorders characterized by redundant, sagging, inelastic and wrinkled skin, with organ involvement. Here, we describe a patient with ALDH18A1-related CL who developed cyclic vomiting. The patient was a 12-year-old boy who presented with poor postnatal growth, hypotonia, short stature, joint hyperlaxity, microcephaly, strabismus, bilateral cataracts, facial dysmorphism and severe mental retardation. Bone radiographs showed osteopenia and osteoporosis, and magnetic resonance angiography showed marked kinking and tortuosity of the brain vessels. These findings were clinically compatible with ALDH18A1-related CL. Molecular analysis revealed a de novo heterozygous mutation (p.R138Q) in ALDH18A1. No mutations were found in PYCR1 gene. The patient developed cyclic vomiting with decreased blood levels of ornithine, citrulline, arginine and proline without hyperammonemia and other hypoaminoacidemias were also found. ALDH18A1 encodes Δ(1)-pyrroline-5-carboxylate synthase, which is related to the biosynthesis of ornithine, citrulline, arginine, and proline. Cyclic vomiting has never been reported in other ALDH18A1-related CL patients. This is the first case report of ALDH18A1-related CL with cyclic vomiting associated with amino acid abnormalities.

Background In Japan, adrenocorticotropic hormone (ACTH) therapy has been the mainstay of treatment of West syndrome. Conventional ACTH therapy is administered short-term with efficacy, yet the relapse rate is high. Relapse after initial ACTH therapy is a poor prognostic factor for long-term seizure control and outcome of cognitive function. Here, we report successful long-term weekly ACTH therapy for relapsed WS in a tuberous sclerosis complex (TSC) child after conventional ACTH therapy. Patient The patient had a series of epileptic spasms (ES) and hypsarrhythmia at age 3 months. She was diagnosed with WS associated with TSC, and was treated with conventional ACTH therapy at age 4 months, and a second course of ACTH therapy at age 8 months. Both courses of therapy were transiently effective. A third course of ACTH therapy was started at age 1 year and 2 months, and long-term weekly ACTH therapy was continued thereafter. During this therapy, both ES and hypsarrhythmia remained completely resolved. Therapy was continued, and dose reduction was started when the patient was 2 years and 10 months old. No serious adverse events had occurred during this therapy. Conclusion This case demonstrated that long-term weekly ACTH may be safe and effective. Although at present, this therapy may only be considered for relapsed symptomatic WS patients, it may be a good alternative therapy when frequent relapses occur after favorable response to conventional ACTH therapy.

To understand the neural mechanisms underlying the therapeutic effects of crossing nerve transfer for brachial plexus injuries in human patients, we investigated the cortical responses after crossing nerve transfer in mice using conventional and tomographic optical imaging. The distal cut ends of the left median and ulnar nerves were connected to the central cut ends of the right median and ulnar nerves with a sciatic nerve graft at 8 weeks of age. Eight weeks after the operation, the responses in the primary somatosensory cortex (S1) elicited by vibratory stimulation applied to the left forepaw were visualized based on activity-dependent flavoprotein fluorescence changes. In untreated mice, the cortical responses to left forepaw stimulation were mainly observed in the right S1. In mice with nerve crossing transfer, cortical responses to left forepaw stimulation were observed in the left S1 together with clear cortical responses in the right S1. We expected that the right S1 responses in the untreated mice were produced by thalamic inputs to layer IV, whereas those in the operated mice were mediated by callosal inputs from the left S1 to layer II/III of the right S1. To confirm this hypothesis, we performed tomographic imaging of flavoprotein fluorescence responses by macroconfocal microscopy. Flavoprotein fluorescence responses in layer IV were dominant compared to those in layer II/III in untreated mice. In contrast, responses in layer II/III were dominant compared to those in layer IV in operated mice. The peak latency of the cortical responses in the operated mice was longer than that in the untreated mice. These results confirmed our expectation that drastic reorganization in the cortical circuits was induced after crossing nerve transfer in mice.

Summary Background Multiple-branch reconstruction is required in order to attain facial reanimation for extensive facial nerve defects. We previously reported that end-to-side nerve grafting, with the use of a single nerve graft for defect reconstruction, was easy to perform. We have also demonstrated the efficacy of end-to-side nerve suture of the recipient nerve to the donor graft nerve, in experimental rat models and clinical cases. The regenerating axons, which extended into the nerve graft, were "distributed" to multiple recipient nerves via end-to-side nerve-suture sites. Methods Thirty-two patients who underwent facial nerve reconstruction (five to 10 branches) had a single sural nerve graft coapted to the proximal stump of the facial nerve in an end-to-end manner, followed by end-to-side nerve suture of the recipient nerve stumps to the side of the nerve graft. In 19 patients who were expected to undergo postoperative radiotherapy and/or chemotherapy, the distal end of the graft was connected to the side of the hypoglossal nerve for "axonal supercharging," to enhance the recovery of the facial muscles. Results Initial facial movements were noted at 5–12 months postoperatively, and good recovery (House–Brackmann grade III/IV) was observed during long-term follow-up in most patients. Conclusion End-to-side nerve suture of the recipient nerve stumps to the nerve graft requires less graft nerve material and less technical mastery to reconstruct multiple branches of the facial nerve. We also described the concept of "axonal supercharging," namely the connection of double-donor neural sources to the graft, and "axonal distribution," namely the reinnervation of multiple recipient nerve stumps connected to the graft in an end-to-side manner. This combination of axonal supercharging and distribution can be a useful option in facial nerve reconstruction.

Meckel's diverticulum (MD) is the most prevalent congenital anomaly of the gastrointestinal tract and often presents a diagnostic challenge. Patients with trisomy 18 frequently have MD, but the poor prognosis and lack of consensus regarding management for neonates has meant that precise information on the clinical manifestations in infants and children with MD is lacking. We describe the cases of three children with trisomy 18 who developed symptomatic MD. Intussusception was diagnosed in Patient 1, intestinal volvulus in Patient 2, and gastrointestinal bleeding in Patient 3. All three patients underwent surgical treatment and only the Patient 1 died due to pulmonary hypertensive crisis. The other two patients experienced no further episodes of abdominal symptoms. In patients with trisomy 18, although consideration of postoperative complications and prognosis after surgical treatment is necessary, symptomatic MD should carry a high index of suspicion in patients presenting with acute abdomen.

A patient with complex regional pain syndrome type II was successfully treated using free anterolateral thigh flap transfer with digital nerve coaptation to the cutaneous nerve of the flap. Release of the scarred tissue and soft tissue coverage with targeted sensory nerve coaptation were useful in relieving severe pain.

Ataxia-telangiectasia-like disorder (ATLD) is a rare autosomal recessive disorder, and has symptoms similar to ataxia-telangiectasia (AT). ATLD is caused by mutations in the MRE11 gene, involved in DNA double-strand break repair (DSBR). In contrast to AT, ATLD patients lack key clinical features, such as telangiectasia or immunodeficiency, and are therefore difficult to be diagnosed. We report a female ATLD patient presenting with hypergonadotropic hypogonadism and hypersegmented neutrophils, previously undescribed features in this disorder, and potential diagnostic clues to differentiate ATLD from other conditions. The patient showed slowly progressive cerebellar ataxia from 2 years of age, and MRI revealed atrophy of the cerebellum, oculomotor apraxia, mild cognitive impairment, writing dystonia, hypergonadotropic hypogonadism with primary amenorrhea, and hypersegmented neutrophils. Western blot assay demonstrated total loss of MRE11 and reduction of ATM-dependent phosphorylation; thus, we diagnosed ATLD. Genetically, a novel missense mutation (c.140C>T) was detected in the MRE11 gene, but no other mutation was found in the patient. Our presenting patient suggests that impaired DSBR may be associated with hypergonadotropic hypogonadism and neutrophil hypersegmentation. In conclusion, when assessing patients with ataxia of unknown cause, ATLD should be considered, and the gonadal state and peripheral blood smear samples evaluated.

Takeshi Yoshida , Takeo Kato *, Tomonari Awaya , Minoru Shibata , Keiko Saito , Minako Ide , Masao Matsuhashi , Toshio Heike a,1 Department of Pediatrics, Kyoto University Graduate School of Medicine, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan Human Brain Research Center, Kyoto University Graduate School of Medicine, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan

Background and aims Newborns admitted to the neonatal intensive care unit are repeatedly subjected to painful or stressful procedures; therefore, objective assessment of their pain is essential. An increasing number of scales for neonatal pain assessment have been developed, many of which are based on physiological and behavioral factors. Recently, salivary biomarkers have been used to assess stress in adults and older infants. This study aimed to determine whether salivary biomarkers can be useful objective indices for assessing newborn pain. Study design A total of 47 healthy newborns were enrolled 3–4 days after birth. Heel lancing was performed to collect blood for a newborn screening test. Before and after heel lancing, saliva was collected to analyze hormone levels, a video was recorded for behavioral observations, and heart rate was recorded. Two investigators independently assessed newborn pain from the video observations using the Neonatal Infant Pain Scale (NIPS). Salivary chromogranin (sCgA) and salivary amylase (sAA) levels were measured using an enzyme-linked immunosorbent assay kit and a dry chemistry system, respectively. Results No definite changes in salivary biomarkers (sCgA or sAA) were detected before and after heel lancing. However, newborn sCgA levels were markedly higher than reported adult levels, with large inter- and intra-subject variability, whereas newborn sAA levels were lower than adult levels. NIPS score and heart rate were dramatically increased after heel lancing. Conclusions NIPS score (behavioral assessment) and heart rate are useful stress markers in newborns. However, neither sCgA nor sAA is suitable for assessing newborn pain.

BACKGROUND The high incidence of glucocorticoid-responsive complications in extremely preterm infants suggests the immaturity of their adrenal function; however, knowledge of the hypothalamus-pituitary-adrenal (HPA) axis in extremely preterm infants is limited. METHODS To clarify the characteristics of the HPA axis in preterm very low birthweight (VLBW) infants, we performed CRH tests repeatedly: at about 2 weeks of age and at term (37-41 weeks of postmenstrual age) for 21 VLBW infants with a gestational age (GA)

Histological changes were observed in peripheral nerves following end-to-side nerve coaptation to determine the effects of perineurial opening and deliberate donor nerve injury during surgery. Twenty rats were randomised into four groups as follows: group 1, end-to-side nerve coaptation without perineurial opening; group 2, end-to-side nerve coaptation with simple perineurial opening; group 3, end-to-side nerve coaptation with partial crush injury after perineurial opening; group 4, end-to-side nerve coaptation with partial neurotomy after perineurial opening. Seven days after coaptation of the musculocutaneous (recipient) nerve to the ulnar (donor) nerve, the nerves were immunohistochemically analysed using antibodies against neurofilament-H (RT97) and phosphorylated GAP-43 (p-GAP-43). The former labels all axons, including regenerating axons and degenerated axonal debris, while the latter only labels regenerating axons. Results demonstrated no regenerating nerves in the recipient nerve of group 1. In group 2, because nerve herniation from the perineurial opening partially injured donor nerve fibres, some regenerating axons extended proximally and distally along the partially injured fibres in the donor nerve; some of these regenerating axons also extended into the recipient nerve via the perineurial opening. In groups 3 and 4, thin regenerating axons were more prominent in recipient and donor nerves compared with group 2. Statistical evaluation revealed increased efficacy of perineurial opening and deliberate donor nerve injury in end-to-side nerve coaptation, suggesting that partial nerve fibre herniation with partial axonotmesis or neurotomesis was important for effective axonal regeneration in end-to-side nerve coaptation.

Tactile sensation, which is one of the earliest developing sensory systems, is very important in the perception of an individual's body and the surrounding physical environment, especially in newborns. However, currently, only little is known about the response of a newborn's brain to tactile sensation. The objective of the present study was to determine the response of a newborn's brain to tactile sensation and to compare the brain responses to various sensory stimuli. Ten healthy newborns, 2-9 days after birth, were enrolled. A multichannel near-infrared spectroscopy system was used to measure brain responses. The probe array covered broad cortical areas, including the parietal, temporal, and occipital areas. We measured cortical hemodynamic changes in response to three different types of stimuli: tactile, auditory, and visual. Activated areas were analyzed by t-tests, and the number of activated channels among the three different stimuli was compared by χ²-tests. The results showed that when the brain responded to each type of stimulation, the corresponding primary sensory area was activated, and tactile stimuli induced broader areas of brain activation than the other two types of stimuli (auditory or visual). Thus, broad brain areas, including the temporal and parietal areas, were activated by tactile stimuli in early newborn periods. These results suggest that there are differences in newborns' reactions to various types of sensory stimuli, which may reflect the importance of tactile sensation in the early newborn period.

We tested a hypothesis that the spinal plasticity induced within a few hours after nerve injury may produce changes in cortical activities and an initial phase of neuropathic pain. Somatosensory cortical responses elicited by vibratory stimulation were visualized by transcranial flavoprotein fluorescence imaging in mice. These responses were reduced immediately after cutting the sensory nerves. However, the remaining cortical responses mediated by nearby nerves were potentiated within a few hours after nerve cutting. Nerve injury induces neuropathic pain. In the present study, mice exhibited tactile allodynia 1–2 weeks after nerve injury. Lesioning of the ipsilateral dorsal column, mediating tactile cortical responses, abolished somatic cortical responses to tactile stimuli. However, nontactile cortical responses appeared in response to the same tactile stimuli within a few hours after nerve injury, indicating that tactile allodynia was acutely initiated. We investigated the trigger mechanisms underlying the cortical changes. Endogenous glial cell line-derived neurotrophic factor (GDNF), found in the Meissner corpuscles, induced basal firing ∼0.1 Hz or less in its Aβ tactile afferents, and disruption of the basal firing triggered the potentiation of nontactile cortical responses. Application of 10 nmLY341495 [(2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid], a specific antagonist of group II metabotropic glutamate receptors (mGluRs), on to the surface of the spinal cord also induced the potentiation of nontactile cortical responses. Together, it is suggested that low-frequency afferent firing produced by GDNF in touch-sensitive nerve fibers continuously activated spinal group II mGluRs and that failure of this activation triggered tactile allodynia.

Diagnosis of autoimmune hepatitis (AIH) may be challenging. However, early diagnosis is important because immunosuppression is life-saving. Diagnostic criteria of the International Autoimmune Hepatitis Group (IAIHG) were complex and purely meant for scientific purposes. This study of the IAIHG aims to define simplified diagnostic criteria for routine clinical practice. Candidate criteria included sex, age, autoantibodies, immunoglobulins, absence of viral hepatitis, and histology. The training set included 250 AIH patients and 193 controls from 11 centers worldwide. Scores were built from variables showing predictive ability in univariate analysis. Diagnostic value of each score was assessed by the area under the receiver operating characteristic (ROC) curve. The best score was validated using data of an additional 109 AIH patients and 284 controls. This score included autoantibodies, immunoglobulin G, histology, and exclusion of viral hepatitis. The area under the curve for prediction of AIH was 0.946 in the training set and 0.91 in the validation set. Based on the ROC curves, two cutoff points were chosen. The score was found to have 88% sensitivity and 97% specificity (cutoff ≥6) and 81% sensitivity and 99% specificity (cutoff ≥7) in the validation set. Conclusion: A reliable diagnosis of AIH can be made using a very simple diagnostic score. We propose the diagnosis of probable AIH at a cutoff point greater than 6 points and definite AIH 7 points or higher. (HEPATOLOGY 2008.)

症例は48歳, 男性. 前日夕方より嘔気出現し食事が摂取できなかった. 翌朝トイレで意識レベルが低下しているところを発見された. 血液データで貧血を認め, 上部消化管出血によるショックを疑い胃内視鏡検査施行. 胃内に黒色の凝血塊を多量に認めたが, 明らかな出血源は不明だった. 翌日胃内視鏡検査を再度施行した所, 胃角部対側に中心に潰瘍がある腫瘤を認め, 粘膜下腫瘍の潰瘍形成による出血と診断した. 腫瘤切除のため腹腔鏡補助下胃部分切除術を施行. 腫瘤の大きさは3×2cmで中心に陥凹を形成されていた. 粘膜下層から漿膜下層に相当する部位にランゲルハンス島, 腺房細胞, 導管を有するHeinrich I型の異所性膵組織を認めた. 悪性所見はなかった.胃の迷入膵は稀に出血性ショックをおこす程出血することを考慮して治療に当たらなければならないと考えた.

症例は49歳,女性. 2週間前から左乳腺腫瘤を自覚し来院.左乳房C領域に2cm程の境界不明瞭な腫瘤を触知.マンモグラフィにてカテゴリー3, 乳房超音波検査では乳頭腺管癌を疑った.穿刺吸引細胞診でclassV乳頭腺管癌と診断.乳頭より22mm離れていたため,乳房温存手術を施行. Level IIIのリンパ節腫脹を触知したため, Level IIIまでリンパ節を郭清した.術後の病理診断では癌の拡がりは4×1.5cmでscirrhous+invasive micropapillary carcinoma (IMP), ly3, リンパ節転移3/16, 断端(-), ER(-), PR(-), HER2(1+) だった.術後AC 4クール, weekly paclitaxel 12クール施行後,放射線療法を残存乳腺および鎖骨上窩に施行した.

A retrospective cohort study involving 29 Japanese patients with autoimmune hepatitis (AIH) was performed to clarify factors that predict the efficacy of prednisolone and the occurrence of various serious adverse effects. Independent predictors were identified by logistic analysis and with use of the Cox proportional hazard model. Responses to prednisolone were noted in 28 patients, who were classified into the complete remission group (52%) or the relapse group (48%). Multivariate analysis identified alanine aminotransferase, alkaline phosphatase, and immoglobulin G levels as independent predictors of relapse. The adverse effects most frequently observed were diabetes mellitus (37.9%), psychiatric/ neurologic symptoms (34.5%), and circulatory symptoms (34.5%). Predictive factors included lactate dehydrogenase, albumin, and fasting blood glucose levels for diabetes mellitus, alkaline phosphatase and C-reactive protein for psychiatric/ neurologic symptoms, and autoimmune hepatitis score and lactate dehydrogenase for circulatory symptoms. Selection of an optimal treatment method for individual patients may be possible after the risks of relapse and adverse effects have been estimated.

Diagnosing autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis, and other autoimmune liver diseases remains an imperfect process. We need a more accurate, evidence-based diagnostic system.We conducted a national survey and identified 988 cases of liver disease which did not satisfy the inclusion criteria for any liver disease of known etiology. We expected these cases to include autoimmune liver disease (AILD) and its variant forms. We selected 269 prototype cases for which histological re-evaluation of liver biopsy by independent expert hepatopathologists and the original diagnosis coincided. We did a multiple logistic regression analysis to determine explanatory variables that would distinguish cases of AIH and PBC from those of non-AIH and non-PBC, respectively. We constructed a multivariable diagnostic formula that gave AIH and PBC disease probabilities and validated it in a study of an additional 371 cases (validation group).Based on the results of the statistical analysis, we selected three laboratory tests and four histological features as independent variables correlated to the diagnosis of both AIH and PBC. For the validation group, assuming that the original diagnosis was correct, the sensitivity and specificity for AIH were 86.3% and 92.4%, respectively. For PBC the sensitivity and specificity were 82.5% and 63.7%, respectively. A detailed analysis of inconsistent cases showed that the diagnosis based on the formula had given the correct diagnosis, for either AIH or PBC, except for 5 cases (1.3%) in which disease probability was low for both.A seven-variable formula based on three laboratory tests and four histological features gives significant information for the diagnosis of AILD.

Background: The natural history of short-segment Barrett's esophagus (SSBE) is not fully understood. We, thereby, conducted a retrospective cohort study to provide further information about chronological change of SSBE. Materials and methods: A total of 174 cases undergoing upper gastrointestinal endoscopy from April 1980 to October 2002 were diagnosed to have SSBE based on the definition of Barrett's esophagus proposed by the Japanese Society for Esophageal Diseases. A cohort of 100 patients with SSBE less than 3 cm was enrolled in the present study. The mean follow-up period was 76.2 ± 59.9 months and 4.27 ± 2.66 endoscopic examinations were performed on each patient. The cumulative probability of elongation of SSBE to 3 cm or longer was estimated by the Kaplan-Meier method. Then, independent contributing factors to its elongation were determined using Cox's proportional hazard model. Results: Elongation of SSBE to 3 cm or longer occurred in 30 patients (30%) during the follow-up period. The cumulative 5-year probability of elongation of SSBE to 3 cm or longer was 18.4%. Hiatal hernia, severe reflux esophagitis and SSBE 1 cm or longer at initial diagnosis were proven to be independent contributing factors to its elongation. Conclusions: The present study demonstrated that SSBE has a tendency to increase its length over time especially when it is accompanied by hiatal hernia or by severe reflux esophagitis.

In Japan, the incidence of liver cirrhosis caused by hepatitis viruses is higher, and cirrhosis is more likely to be complicated by hepatocellular carcinoma, than in Western countries. The aim of this study was to predict the outcome in liver cirrhosis with ascites with and without hepatocellular carcinoma.The subjects were 146 patients with liver cirrhosis complicated by ascites. Forty-six factors were evaluated concerning clinical laboratory parameters and extracted prognostic factors using the Cox proportional hazards model.The mean duration of the follow-up period was 634.9 days, during which 89 (61%) of the patients died, 27 (18.5%) survived, and 30 (20.6%) were lost to follow-up. The cumulative survival rate after the onset of ascites was 59.7% after 1 year, 44.5% after 2 years, and 29.5% after 5 years. Multivariate analysis indicated 9 factors, i.e. age, total bilirubin (T-Bil), alkaline phosphatase (ALP), blood urea nitrogen (BUN), alpha-fetoprotein (AFP), mean arterial pressure (MAP), gastrointestinal bleeding, infection, and portal vein tumor thrombosis (PVTT), as independent prognostic factors. The prognostic index (PI) was calculated by the following formula using these 9 factors. PI = 0.045 x age + 0.180 x T-Bil + 0.088 x ALP + 0.020 x BUN + 0.467 x AFP + (-0.022 x MAP) + 0.662 x gastrointestinal bleeding + 0.521 x infections + 0.882 x PVTT.Prediction of the outcome using PI based on the 9 factors provides additional information for the determination of the therapeutic approach in cirrhotic patients with ascites with and without hepatocellular carcinoma.

A retrograde method of nerve tracing using a recombinant adenovirus was applied to experimental regeneration of peripheral nerves to study the sprouting position of the regenerating axon. This enabled us to see the entire length of the axons on a whole-mount neural specimen. The peroneal nerve was transsected and infected with this virus, and the tibial nerve was transsected and sutured in eight Wistar rats. Four to five weeks later, labelled axons appeared in the tibial nerve, some of which could be traced from the tibial nerve to the spinal cord without making a connection with other labelled fibres. Control experiments negated the possibilities of transneuronal immigration or contamination of the virus. When the peroneal and tibial nerves were double-labelled with fluorescent tracers four weeks after their transsection, double-labelled motor neurons appeared. Based on these findings, we conclude that regenerating branches do sprout in the spinal cord after axotomy.

Segmental nerve defects have been repaired with nerve grafts. However, regenerating fibers must go through two coaptation sites, and donor site morbidities are inevitable. We elongated the distal nerve segment using a tissue expander and reconnected the nerve. We compared these results with those of nerve grafting. Nerve injury models were created in the median nerves of both forelimbs in 27 rabbits. The right nerve was repaired by elongation, and the left by tibial nerve grafting. The length of the elongation was the same as that of the graft in each animal. Eight rabbits had a 10-mm segment repaired, 9 had a 15-mm segment repaired, and 10 had a 20-mm segment repaired. Evaluated outcomes were nerve conduction velocity, contractile force of the flexor muscle, axons number, and fiber diameter. The elongated and grafted groups did not differ substantially on any outcome. Distal nerve elongation could be an alternative to nerve grafting for repairing large nerve defects.

A patient with hepatitis C virus (HCV)-related liver cirrhosis and hepatocellular carcinoma (HCC) was treated successfully with an orthotopic liver transplantation (OLT) followed by interferon therapy. The 36-year-old Japanese man was diagnosed as having liver cirrhosis in 1983. HCC was detected in 1991, and by 1994, jaundice and ascites had developed. The patient underwent OLT in June 1995, after which hepatitis C recurred, with elevated aminotransferases. His liver biopsy specimen showed chronic active hepatitis. He was given interferon-alpha three times weekly for 24 weeks in 1999. Six months after the end of the interferon treatment, the patient's serum HCV RNA became negative, with normalization of aminotransferases, and his liver histology exhibited amelioration of fibrosis and inflammation. At the present time, he remains free of HCC (more than 6.5 years after the OLT) and free of HCV RNA (more than 2.5 years since interferon therapy was completed). This is the first Japanese patient whose HCC was cured by OLT and HCV was eradicated by interferon therapy.

Primary biliary cirrhosis (PBC) sera contain antibodies which recognize various nuclear envelope proteins of which antibody against gp210 has been proven to be diagnostic for disease. In contrast, the clinical significance of another nuclear envelope antibody, anti-p62 antibody has not been well investigated. In the present study, we have analyzed anti-nuclear envelope antibodies by indirect immunofluorescence and immunoblot using rat liver nuclear envelope proteins and wheat germ agglutinin-bound fraction. Test sera were obtained from 175 patients with PBC and from 120 controls. Anti-gp210, anti-lamina associated polypeptide 2, anti-lamin B receptor, and anti-p62 complex antibodies were detected with a frequency of 26% (46 of 175), 6% (11 of 175), 9% (16 of 175), and 13% (15 of 115), respectively. The confirmation of Scheuer's stage IV was made with a frequency of 27% (4 of 15) in PBC patients with anti-p62 complex antibody, in contrast to only 2% (2 of 100) in PBC patients without anti-p62 complex antibody. This difference was found to be statistically significant. The presence of anti-p62 complex antibody may be related with the progressive or advanced state of PBC.

Patients with liver cirrhosis (LC) frequently have complications with bacterial infections, and these infections increase the mortality rate. However, a detailed analysis of infections associated with LC patients has not yet been performed. Methods: We analyzed 325 patients with LC with and without hepatocellular carcinoma (HCC) who were hospitalized between 1997 and 1999. Results: Infections developed in 70 (21.5%) patients and 48 (68.6%) of these developed infections during hospitalization. The mortality rate of 28.6% (20/70) in patients with infectious complications was higher than that of 12.5% (32/255) in patients without infectious complications. Forty (57.1%) of the 70 patients had infections of unknown causes; 11 (15.7%) had sepsis; 6 (8.6%) had intravenous hyperalimentation (IVH) infection; 3 (4.3%) each had spontaneous bacterial peritonitis (SBP), liver abscess, and cholecystitis; and 4 (5.7%) had other infections. Bacterial cultures of blood were prepared from 73 of the 325 patients (22.5%), and were positive in 22 of the 73 patients (30.1%). Of these 22 culture-positive patients, 11 had sepsis, 6 had IVH infection, 2 had liver abscess, 1 had cholecystitis, 1 had pneumonia, and 1 had decubitus ulcer. Gram-positive bacterial strains were detected most frequently, in 16 of the 24 strains isolated. Univariate analysis revealed significant differences between the groups with and without infectious complications with regard to hepatitis B virus infection, Child-Pugh classification, ascites, esophageal varices, survival rate, total-bilirubin (T-Bil), albumin (Alb), lactate dehydrogenase (LDH), total cholesterol (T-chol), and prothrombin time (PT). On multivariate analysis, the Alb level was selected as a significant independent factor contributing to the development of infections. Conclusions: Patients with advanced cirrhosis with low Alb levels should be carefully treated, and the administration of broadspectrum antibiotics covering gram-positive bacteria needs to be considered in the treatment of infections.

An 81-year-old man who had previously shown high levels of alkaline phosphatase (ALP), γ-glutamyltransferase (GTP), and total bilirubin presented with acute liver damage. He was positive for serum anti-gp210 and anti-p62 antibodies, but negative for serum antimitochondrial antibody. A liver biopsy revealed massive interstitial fibrosis and pseudolobulus, which were compatible with a diagnosis of primary biliary cirrhosis (PBC) at Scheuer's stage 4. He was given ursodeoxycolic acid at 600 mg/day. However, his condition deteriorated, and he eventually died of hepatic insufficiency in a state of malnutrition. We hypothesize that the presence of anti-gp210 and anti-p62 complex protein antibodies, rather than that of antimitochondrial antibodies, was correlated with the progression of PBC in this particular case.

The incidence of hepatocellular carcinoma (HCC) in patients with primary biliary cirrhosis (PBC) is not well known. The aims of this study are to determine HCC incidence and survival, and to identify risk factors associated with these outcomes in patients with PBC. We collected information on 396 patients with PBC at enrollment and followed-up from 6 to 271 months. They were all negative for hepatitis B and C virus markers. HCC was detected by scanning with ultrasonography, computed tomography, or both every 4 to 6 months. Life expectancy (LE) was approximated with the declining exponential approximation of LE. A total of 14 patients developed HCC. The cumulative appearance rate of HCC in patients with advanced-stage PBC (Scheuer's stage III or IV) was significantly higher than that for patients with early-stage (stage I or II) (12.3% and 7.7% by the tenth year, respectively. P = .021). Proportional hazards analysis showed 3 factors are independently associated with the development of HCC: age at the time of diagnosis, male gender, and history of blood transfusion. Age, male gender, and advanced-stage PBC were associated with survival, but HCC development was not. The disease-specific annual mortality rate was estimated to be 0.008 for women and 0.028 for men with advanced-stage PBC. In conclusion, HCC develops in old patients with advanced-stage PBC, but HCC does not affect the patients' survival.

Summary Local flaps and composite grafting are the procedures of choice for reconstructing relatively small soft tissue defects. However, despite their limited conveyable volume, local flaps sometimes require a wide dissection area and long new incisions. Composite grafts also have serious limitations and require a well-vascularized recipient bed. To overcome these limitations, we used a free vascularized perivascular tissue flap based on the descending branch of the lateral femoral circumflex artery. Using this method, we performed reconstructions for seven patients (four cases in head and neck region and three cases in lower limb) with various soft tissue defects (ranged from 4.0 cm 3 to 40.0 cm 3 ). This flap was easily elevated, without the need for precise preoperative flap design, and the flap volume was adjustable regardless of whether deep fascia and muscle were included. The flap has a rich vascular supply, which allows bone and cartilage tissue to be combined with the transfer of soft tissue, and satisfactorily treats chronic wounds with poor blood supply.

We report here a patient with chronic active hepatitis who had no markers for hepatitis viruses and no hyper-gamma-globulinemia, but had high titers of antimitochondrial antibody. Serum levels of alkaline phosphatase were normal, and antinuclear antibody, antismooth muscle antibody, and antiliver kidney microsome antibody tested negative. The titers of antimitochondrial antibody exceeded 1:640, and the positivity for anti-M2 was ascertained by using both ELISA and immunoblot with beef-heart mitochondria and a recombinant pyruvate dehydrogenase E2 subunit as antigens. This patient responded to ursodeoxycholic acid (UDCA) therapy in the beginning, but her hepatitis flared up during UDCA therapy. In contrast, she responded completely to corticosteroid therapy. The clinical course and histological findings of this patient strongly suggest that this patient has autoimmune hepatitis.

The authors present a case in which a free circumferential fasciocutaneous flap from the forearm and hand, after radical tumor resection and forequarter amputation, was used successfully to cover the large soft-tissue defect on the chest wall.

Hepatocellular carcinoma (HCC) commonly develops in patients with chronic hepatitis or cirrhosis of the liver caused by hepatitis-C-virus (HCV) infection. We prospectively studied whether irregular regeneration of hepatocytes is a risk factor for HCC in these patients.242 patients were enrolled after liver biopsy and followed up by ultrasonographic scanning every 3 months. We examined age, sex, platelet count, the diagnosis of cirrhosis or chronic hepatitis, liver-cell dysplasia, and irregular regeneration. We classified irregular regeneration as slight or severe, based on histological expression of pleiomorphism, anisocytosis, bulging, and map-like distribution of hepatocytes.37 of 63 patients with cirrhosis and 26 of 179 with chronic hepatitis were judged to have severe irregular regeneration. HCC was diagnosed in 33 of 63 patients with cirrhosis (29 had severe irregular regeneration) and 12 of 179 patients with chronic hepatitis (11 had severe irregular regeneration) during mean follow-up of 5.5 years (SD 4.1; range 1-16). Multivariate analysis with a proportional-hazards model showed severe irregular regeneration (relative risk 15.1 [95% CI 5.6-40.7], p0.0001) and a diagnosis of cirrhosis (3.8 [1.7-8.2], p=0.0008) to be significant risk factors for HCC. Within the diagnostic categories, irregular regeneration was also significant (cirrhosis 6.8 [2.1-21.9], p=0.0014; chronic hepatitis 28.5 [2.9-276.4], p=0.0038).We recommend that liver biopsy to look for irregular regeneration should be done in patients with HCV-related chronic liver diseases. Those with severe irregular regeneration should be followed up carefully.

The posterior interosseous cutaneous flap is characterized by its thinness and the adjustable length of its vascular pedicle. This flap can be used both as a free and reversed vascular pedicled flap. We applied the free flap mostly for reconstruction of the digits, and the reversed vascular pedicled flap for soft-tissue defects of the proximal hand. Of 17 free flaps, 16 survived completely, and 1 developed partial necrosis. Eleven flaps were elevated as reversed vascular pedicled flaps, three of which were combined with the lateral arm flap to cover large defects. In these three combined flaps, the posterior radial collateral artery was anastomosed to an artery in the recipient site to enhance circulation; all three flaps survived completely. Operative time was 30 to 40 minutes shorter for the reversed vascular pedicled flaps. Two of the remaining eight reversed vascular pedicled flaps developed partial necrosis. The flap success rate was thus higher in the free flaps than in the reversed vascular pedicled flaps.

We report the case of a 48-year-old man with familial adenomatous polyposis (FAP) who was found to have ampullary carcinoma 6 years after undergoing total colectomy. The patient was examined periodically after colorectal surgery except for duodenoendoscopy because he had also previously undergone distal gastrectomy with gastrojejunal anastomosis for a duodenal ulcer at 27 years of age. An ampullary lesion was suspected on blood chemistry and detected by computed tomography scan and ultrasonography although the patient showed no clinical symptoms. A pancreatoduodenectomy was performed and the histological examination revealed well-differentiated adenocarcinoma with no metastasis to the regional lymphnodes. Long-term periodic surveillance of the upper gastrointestinal tract including the papilla of Vater is therefore important for FAP patients who have undergone prophylactic colectomy.

We report a new type of locomotive robot which is able to avoid standing obstacles and to ascend and descend a flight of stairs. This locomotive robot is of the self-contained navigation type. The structures are composed of three portions : a main element attached to steering gears, the front and rear body. Thus, they are connected by the coupling rod. Each portion has some legs on both sides which are attached to wheels. Fundamentally, ascending/descending, level and steering motions allow the robot to ascend and descend spiral stair cases. Minimum turning radius is small compared to the previous type. We call this structure the leg-vehicle type. Our results show that stable locomotion of the robot can be attained.

We report a 2-year-old Japanese boy with acute necrotizing encephalopathy (ANE) triggered by human herpes virus-6, who presented insightful magnetic resonance imaging (MRI) findings. He was admitted due to impaired consciousness and a convulsion, 2 days after the onset of an upper respiratory infection. At admission, cranial MRI showed marked gadolinium enhancement at the bilateral thalami, brainstem and periventricular white matter without abnormal findings in noncontrast MRI sequences. On the following day, noncontrast computed tomography demonstrated homogeneous low-density lesions in the bilateral thalami and severe diffuse brain edema. The patient progressively deteriorated and died on the 18th day of admission. The pathogenesis of ANE remains mostly unknown, but it has been suggested that hypercytokinemia may play a major role. Overproduced cytokines cause vascular endothelial damage and alter the permeability of the vessel wall in the multiple organs, including the brain. The MRI findings in our case demonstrate that blood–brain barrier permeability was altered prior to the appearance of typical neuroradiological findings. This suggests that alteration of blood–brain barrier permeability is the first step in the development of the brain lesions in ANE, and supports the proposed mechanism whereby hypercytokinemia causes necrotic brain lesions. This is the first report demonstrating MRI gadolinium enhancement antecedent to typical neuroradiological findings in ANE.

According to a recent nationwide survey in Japan, a significant proportion of very low birth weight infants (VLBWI) develop late-onset circulatory collapse after the first week of life. Small doses of glucocorticoid are very effective in these patients, and relative adrenal insufficiency is suspected to be the main cause of the condition. Although the CRH test is required to evaluate the hypothalamic-pituitary-adrenal axis, obtaining multiple blood samples is invasive.The present study was carried out to validate the consistency of the cortisol profiles of matched serum and saliva samples collected as part of the CRH test from VLBWI.In 23 VLBWI with a gestational age of less than 29 wk, we performed CRH tests at 2 wk after birth and at term. Their cortisol values were measured at the baseline and 30 min after the administration of a single dose of human CRH (1 μg/kg) using matched serum and saliva samples.In 26 CRH tests in 19 infants, we were able to measure both serum and salivary cortisol. Significant correlations were detected between the infants' serum and salivary cortisol values (r=0.78; P0.0001), the increases in these values induced in response to the CRH test (r=0.81; P0.0001), and their peak serum and salivary cortisol values (r=0.68; P=0.0001).This study indicated that using salivary cortisol measurements for the CRH test could be a reliable method for evaluating the hypothalamic-pituitary-adrenal axis in VLBWI with gestational age of less than 29 wk.

A nephrotic patient with membranoproliferative glomerulonephritis type II (MPGN II) was treated with cyclosporin A (CSA) and alternate-day low-dose prednisolone. This patient developed the nephrotic syndrome twice. The second episode of the nephrotic syndrome was steroid resistant, and therefore this patient was treated with a CSA regimen. During treatments with alternate-day low-dose prednisolone and CSA, this patient recovered from the nephrotic syndrome. We conclude that CSA therapy may be effective for patients with the steroid-resistant nephrotic syndrome caused by MPGN II.

A 54 year- old man was admitted to our hospital because of general fatigue and marked hepato -splenomegaly. Laboratory findings revealed marked leukocytosis including atypical lymphocytosis and abnormalities in the hepatic function tests. A diagnosis of acute stage of adult T-cell leukemia (ATL) was made from his positive serum anti-ATL (HTLV-1). Since the complication of alcoholic liver disease could not be ruled out because of his heavy consumption of alcohol, hepato - splenomegaly and abnormal liver function tests, a laparoscopic examination was performed. The laparoscopic findings of the liver revealed it was yellow / brown in color, and showed swelling of both lobes, granular unevenness and diffuse white markings on the surface. Histological findings of the liver biopsy specimen revealed an enlargement of the portal areas with diffuse infiltration of ATL cells but no evidence of alcoholic liver diseases. It is suggested that the white markings on the liver surface, which showed slight elevation unlike those seen in chronic hepatitis, might reflect an infiltration of ATL cells.

The photorefractive effect of a ferroelectric liquid crystal doped with a photoconductive compound was investigated. The photorefractive effect appeared only at the temperature at which the sample exhibits ferroelectricity. The refractive index grating formation time was measured to be ∼30 ms. In the ferroelectric phase, reorientation of the spontaneous polarization vector was found to be induced by the internal space-charge field.