Reduced Frontal Glutamate + Glutamine and N-Acetylaspartate Levels in Patients With Chronic Schizophrenia but not in Those at Clinical High Risk for Psychosis or With First-Episode Schizophrenia

Changes in brain pathology as schizophrenia progresses have been repeatedly suggested by previous studies. Meta-analyses of previous proton magnetic resonance spectroscopy (¹H MRS) studies at each clinical stage of schizophrenia indicate that the abnormalities of N-acetylaspartate (NAA) and glutamatergic metabolites change progressively. However, to our knowledge, no single study has addressed the possible differences in ¹H MRS abnormalities in subjects at 3 different stages of disease, including those at ultrahigh risk for psychosis (UHR), with first-episode schizophrenia (FES), and with chronic schizophrenia (ChSz). In the current study, 24 patients with UHR, 19 FES, 25 ChSz, and their demographically matched 3 independent control groups (n = 26/19/28 for the UHR, FES, and ChSz control groups, respectively) underwent ¹H MRS in a 3-Tesla scanner to examine metabolites in medial prefrontal cortex. The analysis revealed significant decreases in the medial prefrontal NAA and glutamate + glutamine (Glx) levels, specifically in the ChSz group as indexed by a significant interaction between stage (UHR/FES/ChSz) and clinical status (patients/controls) (P = .008). Furthermore, the specificity of NAA and Glx reductions compared with the other metabolites in the patients with ChSz was also supported by a significant interaction between the clinical status and types of metabolites that only occurred at the ChSz stage (P = .001 for NAA, P = .004 for Glx). The present study demonstrates significant differences in ¹H MRS abnormalities at different stages of schizophrenia, which potentially correspond to changes in glutamatergic neurotransmission, plasticity, and/or excitotoxicity and regional neuronal integrity with relevance for the progression of schizophrenia.Key words: anterior cingulate cortex, at-risk mental state, biomarkers, frontal lobe, magnetic resonance imaging, neurochemical abnormality     

Nationwide survey of Arima syndrome: Revised diagnostic criteria from epidemiological analysis

Aim: We have never known any epidemiological study of Arima syndrome since it was first described in 1971. To investigate the number of Arima syndrome patients and clarify the clinical differences between Arima syndrome and Joubert syndrome, we performed the first nationwide survey of Arima syndrome, and herein report its results. Furthermore, we revised the diagnostic criteria for Arima syndrome. Methods: As a primary survey, we sent out self-administered questionnaires to most of the Japanese hospitals with a pediatric clinic, and facilities for persons with severe motor and intellectual disabilities, inquiring as to the number of patients having symptoms of Arima syndrome, including severe psychomotor delay, agenesis or hypoplasia of cerebellar vermis, renal dysfunction, visual dysfunction and with or without ptosis-like appearance. Next, as the second survey, we sent out detailed clinical questionnaires to the institutes having patients with two or more typical symptoms. Results: The response rate of the primary survey was 72.7% of hospitals with pediatric clinic, 63.5% of national hospitals and 66.7% of municipal and private facilities. The number of patients with 5 typical symptoms was 13 and that with 2–4 symptoms was 32. The response rate of the secondary survey was 52% (23 patients). After reviewing clinical features of 23 patients, we identified 7 Arima syndrome patients and 16 Joubert syndrome patients. Progressive renal dysfunction was noticed in all Arima syndrome patients, but in 33% of those with Joubert syndrome. Conclusion: It is sometimes difficult to distinguish Arima syndrome from Joubert syndrome. Some clinicians described a patient with Joubert syndrome and its complications of visual dysfunction and renal dysfunction, whose current diagnosis was Arima syndrome. Thus, the diagnosis of the two syndromes may be confused. Here, we revised the diagnostic criteria for Arima syndrome.     

Five pediatric cases of ictal fear with variable outcomes

Purpose: Ictal fear is an uncommon condition in which fear manifests as the main feature of epileptic seizures. The literature has suggested that ictal fear is generally associated with poor seizure outcomes. We wanted to clarify the variability in seizure outcome of children with ictal fear. Subjects and methods: We identified five pediatric patients with ictal fear who were followed up on at Okayama University Hospital between January 2003 and December 2012. We retrospectively reviewed their clinical records and EEG findings. Results: The onset age of epilepsy ranged from 8 months to 9 years and 10 months. The common ictal symptoms were sudden fright, clinging to someone nearby, and subsequent impairment of consciousness, which were often accompanied by complex visual hallucinations and psychosis-like complaints. Ictal fear, in four patients, was perceived as a nonepileptic disorder by their parents. Ictal electroencephalograms (EEG) of ictal fear were obtained in all patients. Three showed frontal onset, while the other two showed centrotemporal or occipital onsets. Two patients were seizure free at last follow-up, while seizures persisted in the other three. A patient with seizure onset during infancy had a favorable outcome, which was considered to be compatible with benign partial epilepsy with affective symptoms. Conclusion: Ictal fear is not always associated with a symptomatic cause or a poor seizure outcome. It is quite important to make a correct diagnosis of ictal fear as early as possible to optimize treatment.     

Different patterns of cerebellar abnormality and hypomyelination between POLR3A and POLR3B mutations

Background

Mutations of POLR3A and POLR3B have been reported to cause several allelic hypomyelinating disorders, including hypomyelination with hypogonadotropic hypogonadism and hypodontia (4H syndrome). Patients and methods: To clarify the difference in MRI between the two genotypes, we reviewed MRI in three patients with POLR3B mutations, and three with POLR3A mutations. Results: Though small cerebellar hemispheres and vermis are common MRI findings with both types of mutations, MRI in patients with POLR3B mutations revealed smaller cerebellar structures, especially vermis, than those in POLR3A mutations. MRI also showed milder hypomyelination in patients with POLR3B mutations than those with POLR3A mutations, which might explain milder clinical manifestations. Conclusions: MRI findings are distinct between patients with POLR3A and 3B mutations, and can provide important clues for the diagnosis, as these patients sometimes have no clinical symptoms suggesting 4H syndrome.     

Quantitative evaluation of ventricular dilatation using computed tomography in infants with congenital cytomegalovirus infection

Background

Infants with congenital cytomegalovirus infection (CCMVI) may develop brain abnormalities such as ventricular dilatation, which may potentially associate with sensorineural hearing loss. There is currently no recognized method for quantitative evaluation of ventricle size in infants with CCMVI. Our objectives were to establish a method for quantitative evaluation of ventricle size using computed tomography (CT) in infants with CCMVI, and determine a cut-off value associated with abnormal auditory brainstem response (ABR) early in life.

Design/Subjects

This study enrolled 19 infants with CCMVI and 21 non-infected newborn infants as a control group. Infants with CCMVI were divided into two subgroups according to ABR at the time of initial examination: normal ABR (11 infants) or abnormal ABR (8 infants). Ventricle size was assessed by calculating Evans’ index (EI) and lateral ventricle width/hemispheric width (LVW/HW) ratio on brain CT images, and was compared among groups. A cut-off ventricle size associated with abnormal ABR was determined.

Results

EI and LVW/HW ratio were significantly higher in the CCMVI with abnormal ABR group than the control and CCMVI with normal ABR groups. Cut-off values of 0.26 for EI and 0.28 for LVW/HW ratio had a sensitivity of 100% and 100%, respectively, and a specificity of 73% and 91%, respectively, for association with abnormal ABR.

Conclusions

We established a method for quantitative evaluation of ventricle size using EI and LVW/HW ratio on brain CT images in infants with CCMVI. LVW/HW ratio had a more association with abnormal ABR in the early postnatal period than EI.     

Aberrant Glycosylation and Localization of Polycystin-1 Cause Polycystic Kidney in an AQP11 Knockout Model

We previously reported that disruption of the aquaporin-11 (AQP11) gene in mice resulted in cystogenesis in the kidney. In this study, we aimed to clarify the mechanism of cystogenesis in AQP11(−/−) mice. To enable the analyses of AQP11 at the protein level in vivo, AQP11 BAC transgenic mice (Tg^AQP11) that express 3×HA-tagged AQP11 protein were generated. This AQP11 localized to the endoplasmic reticulum (ER) of proximal tubule cells in Tg^AQP11 mice and rescued renal cystogenesis in AQP11(−/−) mice. Therefore, we hypothesized that the absence of AQP11 in the ER could result in impaired quality control and aberrant trafficking of polycystin-1 (PC-1) and polycystin-2 (PC-2). Compared with kidneys of wild-type mice, AQP11(−/−) kidneys exhibited increased protein expression levels of PC-1 and decreased protein expression levels of PC-2. Moreover, PC-1 isolated from AQP11(−/−) mice displayed an altered electrophoretic mobility caused by impaired N-glycosylation processing, and density gradient centrifugation of kidney homogenate and in vivo protein biotinylation revealed impaired membrane trafficking of PC-1 in these mice. Finally, we showed that the Pkd1(+/−) background increased the severity of cystogenesis in AQP11(−/−) mouse kidneys, indicating that PC-1 is involved in the mechanism of cystogenesis in AQP11(−/−) mice. Additionally, the primary cilia of proximal tubules were elongated in AQP11(−/−) mice. Taken together, these data show that impaired glycosylation processing and aberrant membrane trafficking of PC-1 in AQP11(−/−) mice could be a key mechanism of cystogenesis in AQP11(−/−) mice.Aquaporin-11 (AQP11) is a membrane-channel protein. Although AQP11 is reported to be permeable to the water molecule,^1–3 the permeability of AQP11 to other solutes remains unclear. AQP11(−/−) mice die in the neonatal period because of renal failure and retarded growth.^4,5 Moreover, AQP11(−/−) mice develop renal cysts, suggesting that AQP11 can play a role in cystogenesis.^4,5 However, the mechanisms of cystogenesis in AQP11(−/−) mice have yet to be clarified. One of the reasons for the difficulties in investigating AQP11 has been the lack of a good antibody for detecting endogenous AQP11 in mouse tissues.Autosomal dominant polycystic kidney disease (PKD) is the most common inherited renal disorder, occurring in 1:400 to 1:1000 live births. It is characterized by gradual renal cyst development and expansion, ultimately resulting in massive kidney enlargement and ESRD. Among autosomal dominant PKD patients, 85%–90% of cases result from mutations in the PKD1 gene, whereas another 10%–15% of cases are accounted for by mutations in the PKD2 gene. PKD1 encodes polycystin-1 (PC-1), a 462-kD, 4303–amino acid integral membrane protein with 11 transmembrane domains, a long extracellular N terminus with multiple binding domains, and a short cytoplasmic C terminus that interacts with multiple proteins, including the protein product of PKD2, polycystin-2 (PC-2).⁶ PC-2 is a significantly smaller 110-kD protein with six transmembrane domains. PC-1 and PC-2 are located in the plasma membrane and cilia of renal epithelia.^6–8To enable the analyses of AQP11 in mice at the protein level in vivo, we generated AQP11 BAC transgenic mice (Tg^AQP11) that express AQP11 tagged with 3×hemagglutinin (HA) sequence at its N terminus and showed that AQP11 localizes to the endoplasmic reticulum (ER) of proximal tubule cells in vivo. Moreover, to investigate the mechanisms of cystogenesis in AQP11(−/−) mouse kidneys, we focused on PC-1 and PC-2. Impaired glycosylation processing and membrane trafficking of PC-1 in AQP11(−/−) mouse kidneys were found, which could represent a key mechanism of cyst formation in AQP11(−/−) mice.     

Dietary l-Lysine Prevents Arterial Calcification in Adenine-Induced Uremic Rats

Vascular calcification (VC) is a life-threatening complication of CKD. Severe protein restriction causes a shortage of essential amino acids, and exacerbates VC in rats. Therefore, we investigated the effects of dietary l-lysine, the first-limiting amino acid of cereal grains, on VC. Male Sprague-Dawley rats at age 13 weeks were divided randomly into four groups: low-protein (LP) diet (group LP), LP diet+adenine (group Ade), LP diet+adenine+glycine (group Gly) as a control amino acid group, and LP diet+adenine+l-lysine·HCl (group Lys). At age 18 weeks, group LP had no VC, whereas groups Ade and Gly had comparable levels of severe VC. l-Lysine supplementation almost completely ameliorated VC. Physical parameters and serum creatinine, urea nitrogen, and phosphate did not differ among groups Ade, Gly, and Lys. Notably, serum calcium in group Lys was slightly but significantly higher than in groups Ade and Gly. Dietary l-lysine strongly suppressed plasma intact parathyroid hormone in adenine rats and supported a proper bone-vascular axis. The conserved orientation of the femoral apatite in group Lys also evidenced the bone-protective effects of l-lysine. Dietary l-lysine elevated plasma alanine, proline, arginine, and homoarginine but not lysine. Analyses in vitro demonstrated that alanine and proline inhibit apoptosis of cultured vascular smooth muscle cells, and that arginine and homoarginine attenuate mineral precipitations in a supersaturated calcium/phosphate solution. In conclusion, dietary supplementation of l-lysine ameliorated VC by modifying key pathways that exacerbate VC.Medial vascular calcification is common in aging, diabetes, and CKD.^1–4 Because the presence of vascular calcification is strongly associated with increased cardiovascular morbidity and mortality, several studies in both animals and humans have sought ways to reduce the extent of vascular calcification.^5–10 However, satisfactory therapies have not yet been established.¹¹Adenine-induced renal failure is one of the commonly used animal models for studying the development of vascular calcification, but the prevalence of vascular calcification in this model is not very high. Indeed, Price et al. reported that vascular calcification was detected in only 30% of rats with adenine-induced chronic renal failure (adenine rats) fed a normal-protein diet.⁵ These authors speculated that consistent vascular calcification might require a longer period of adenine feeding. On the basis of this idea, they designed a low-protein (LP) diet in an attempt to reduce the nitrogen load and thus enable the rats to thrive on the adenine diet for longer periods. As a result of this attempt, Price et al. unexpectedly found that adenine rats fed a LP diet had extensive vascular calcification without a longer feeding period.⁵ All 13 adenine rats fed the LP diet had uniform alizarin red staining of the aorta, whereas only 3 of the 11 adenine rats fed a normal-protein diet had partial calcification.⁵ These findings indicated that dietary protein deficiency correlates with the extent of vascular calcification.Proteins are usually made from 20 kinds of amino acids. On the basis of nutritional requirements, these amino acids can be divided into two groups: essential amino acids (EAAs) and non-EAAs. Because restriction of dietary protein results in a shortage of EAAs, the level of dietary EAAs may be relevant to the extent of vascular calcification. Among nine EAAs, this study focused on l-lysine (l-Lys) based on the following three reasons. First, l-Lys is the first-limiting amino acid in most cereal grains.¹² Second, the safety of l-Lys supplementation has been verified in the area of animal husbandry. l-Lys has long been added to feed grains in order to improve the utility of feed proteins.¹³ Third, several studies have demonstrated that dietary supplementation with l-Lys protects bones from osteoporosis, a pathologic condition that often coexists with vascular calcification.^14,15 These points prompted us to hypothesize that supplementation with l-Lys would ameliorate vascular calcification. Therefore, in this study, we tested this hypothesis using adenine rats.     

Long-Term Results of Seton Placement for Fistula-in-ano in Infants

Background

The present study aimed to assess the long-term results of seton placement for fistula-in-ano (FIA) in infants.

Methods

Data of patients aged <1 year who presented to our department with perianal abscess (PA) between January 2006 and February 2010 were retrospectively reviewed. Our standard initial treatment for PA was incision and drainage. Patients with systemic diseases and inflammatory bowel diseases were excluded.

Results

Ninety-five patients were treated for PA and/or FIA during the 5-year period, and follow-up data were available for 90 patients. The mean follow-up duration in these patients was 49.8?±?11.4 months, and mean age at presentation was 3.1?±?2.7 months. Of the 90 patients, 36 (40 %) developed FIA (39 lesions) and underwent seton placement. The condition healed in a mean period of 6.3?±?4.0 weeks after the placement of a cutting seton. Healing of the fistula was achieved in 35 (97.2 %) of 36 patients after the initial seton procedure, and one patient who showed recurrence underwent a second seton placement, resulting in successful healing of the FIA after 5 weeks.

Conclusions

The long-term success of seton placement indicates that this procedure should be a treatment option for FIA in infants.     

Beta-blocker stress echocardiography in an aortic stenosis patient with associated left ventricular outflow tract obstruction

An 80-year-old man visited our hospital because of dyspnea on exertion from 6 months ago. Echo Doppler study showed severe calcification in the aortic valve with restricted movement and the sigmoid septum causing obstruction at the LV outflow tract (LVOT). Considering the aortic valve area (AVA) might have been inaccurately estimated, we carried out beta-blocker stress echocardiography. The transaortic pressure gradient and AVA were respectively calculated as 52 mmHg and 0.90 cm² before propranolol administration and as 64 mmHg and 0.86 cm² after propranolol administration. Thus, beta-blocker stress echocardiography may provide an accurate assessment of AS if the LVOT obstruction is concomitant.     

Differences in the Levels of Gastric Cancer Risk Factors Between Nanjing and Minqing Counties,China

Objectives:

In Fujian Province, China, gastric cancer is one of the leading causes of mortality among all malignant tumors. Nanjing county and Minqing county are located in inland Fujian and have similar general demographics. However, the adjusted mortality rate of gastric cancer in Minqing was found to be much higher than that in Nanjing. We sought to explore factors associated with this increased risk of gastric cancer between the two counties.

Methods:

We recruited 231 and 224 residents from Nanjing and Minqing, respectively, and analyzed differences between their dietary habits, Helicobacter pylori infection rates, and concentrations of serum pepsinogen I, pepsinogen II, gastrin-17, and ratio of pepsinogen I:II.

Results:

Subjects in Minqing had more first-degree relatives who had been diagnosed with upper gastrointestinal tumor, more unhealthy dietary habits, a higher Helicobacter pylori positive rate, and greater proportion of abnormal serum gastrin-17 than those in Nanjing did.

Conclusions:

The factors that differed between these two counties might indicate that residents in Minqing have a higher risk for developing gastric cancer than those in Nanjing do.