Functional connectivity between pre-supplementary motor area and inferior parietal lobule associated with impaired motor response inhibition in first-degree relatives of patients with obsessive-compulsive disorder.

Previous studies have suggested that specific fronto-striatal circuits are associated with impaired motor response inhibition in patients with obsessive-compulsive disorder (OCD) and their relatives. However, no study has investigated the underlying resting-state network associated with motor response inhibition in the unaffected first-degree relatives of patients with OCD. We measured motor response inhibition using stop-signal task, and obtained resting-state fMRI in 23 first-degree relatives and 52 healthy control participants. We explored the group differences in the functional network from seed regions-of-interest (ROIs) associated with motor response inhibition abilities. We used the inferior frontal gyrus (IFG) and pre-supplementary motor area (pre-SMA) as seed-ROIs. A significant group difference was observed in functional connectivity between the pre-SMA and inferior parietal lobule. In the relative group, reduced functional connectivity between these areas was associated with a longer stop-signal reaction time. Additionally, relatives showed significantly greater functional connectivity between the IFG and SMA, precentral, and postcentral areas. Our results could provide new insights into the resting-state neural activity of the pre-SMA underlying impaired motor response inhibition of unaffected first-degree relatives. In addition, our results suggested that relatives have an altered connectivity of the sensorimotor region, similar to that of patients with OCD shown in previous literature.

Increased functional connectivity between presupplementary motor area and inferior frontal gyrus associated with the ability of motor response inhibition in obsessive-compulsive disorder.

Recent evidence suggests that presupplementary motor area (pre-SMA) and inferior frontal gyrus (IFG) play an important role in response inhibition. However, no study has investigated the relationship between these brain networks at resting-state and response inhibition in obsessive-compulsive disorder (OCD). We performed resting-state functional magnetic resonance imaging scans and then measured the response inhibition of 41 medication-free OCD patients and 49 healthy control (HC) participants by using the stop-signal task outside the scanner. We explored the differences between OCD and HC groups in the functional connectivity of pre-SMA and IFG associated with the ability of motor response inhibition. OCD patients showed a longer stop-signal reaction time (SSRT). Compared to HC, OCD patients exhibit different associations between the ability of motor response inhibition and the functional connectivity between pre-SMA and IFG, inferior parietal lobule, dorsal anterior cingulate cortex, insula, and anterior prefrontal cortex. Additional analysis to investigate the functional connectivity difference from the seed ROIs to the whole brain voxels revealed that, compared to HC, OCD exhibited greater functional connectivity between pre-SMA and IFG. Also, this functional connectivity was positively correlated with the SSRT score. These results provide additional insight into the characteristics of the resting-state functional connectivity of the regions belonging to the cortico-striato-thalamo-cortical circuit and the cingulo-opercular salience network, underlying the impaired motor response inhibition of OCD. In particular, we emphasize the importance of altered functional connectivity between pre-SMA and IFG for the pathophysiology of motor response inhibition in OCD.

A pilot study exploring the association of morphological changes with 5-HTTLPR polymorphism in OCD patients.

BACKGROUND: Clinical and pharmacological studies of obsessive-compulsive disorder (OCD) have suggested that the serotonergic systems are involved in the pathogenesis, while structural imaging studies have found some neuroanatomical abnormalities in OCD patients. In the etiopathogenesis of OCD, few studies have performed concurrent assessment of genetic and neuroanatomical variables. METHODS: We carried out a two-way ANOVA between a variable number of tandem repeat polymorphisms (5-HTTLPR) in the serotonin transporter gene and gray matter (GM) volumes in 40 OCD patients and 40 healthy controls (HCs). RESULTS: We found that relative to the HCs, the OCD patients showed significant decreased GM volume in the right hippocampus, and increased GM volume in the left precentral gyrus. 5-HTTLPR polymorphism in OCD patients had a statistical tendency of stronger effects on the right frontal pole than those in HCs. CONCLUSIONS: Our results showed that the neuroanatomical changes of specific GM regions could be endophenotypes of 5-HTTLPR polymorphism in OCD.

Biological heterogeneity of obsessive-compulsive disorder: A voxel-based morphometric study based on dimensional assessment.

AIM: Although many neuroimaging studies of obsessive-compulsive disorder (OCD) have reported broad abnormalities in gray matter (GM), their results remain inconsistent. One reason for this inconsistency could be the heterogeneity of OCD. In the present study, we aimed to classify alterations in brain anatomy by OCD subtype. METHODS: Magnetic resonance imaging examinations of 37 OCD patients and 37 matched healthy controls were conducted using a 3.0-Tesla scanner. In the voxel-based morphometric procedure, preprocessed GM structural images were used to compare the two groups, and multiple regression analysis was used to investigate the correlation between regional GM volume in OCD patients and the OCD symptom dimension type assessed by using the Dimensional Yale-Brown Obsessive-Compulsive Scale. RESULTS: We found significant reductions in GM volume in broad areas of the left prefrontal, right orbitofrontal, right parietal, right temporal, and right posterior cingulate cortex in the OCD patients compared to healthy controls. In addition, we found specific negative correlations between symptomatic dimension scores and regional GM volumes, mainly as decreased right cerebellum in 'aggression/checking' and decreased right insula in 'contamination/washing'. CONCLUSION: The pathophysiology of OCD may involve widely distributed neural systems. Moreover, there are distinct correlations among symptomatic dimensions and structural abnormalities.

[A case of thrombotic microangiopathy with glomerular subendothelial IgA deposition due to bevacizumab].

Bevacizumab, an inhibitor of vascular endothelial growth factor, is approved for the treatment of various cancers, but the incidence of proteinuria as a side effect has been reported to be 2-64%. We report a case of renal impairment due to thrombotic microangiopathy (TMA) accompanied with glomerular subendothelial deposition of IgA resulting from bevacizumab administration. A 57-year-old female with advanced breast cancer, to whom bevacizumab had been administered from October 2012, developed proteinuria and epithelial casts in her urine about a month later. Serum creatinine remained at 0.7-0.8 mg/dL until June 2013, but gradually increased to 1.3 mg/dL in September. She was referred to our hospital because her renal function had not improved despite termination of bevacizumab, and a renal biopsy was performed in October. At that time, the levels of proteinuria, serum creatinine and serum IgA were high at 1.3 g/g x Cr, 1.6 mg/dL and 430 mg/dL, respectively. Histological examinations showed prominent IgA deposits in the subendothelial area and glomerular infiltration of CD68 positive cells in addition to features of TMA, such as narrowed glomerular capillary lumina and double contours of the basement membranes. In consideration of her clinical history, a diagnosis of bevacizumab-induced TMA was made. Through follow-up care without readministration of bevacizumab, epithelial casts in her urine disappeared, and proteinuria decreased to 0.62 g/g x Cr in November. Serum creatinine remains high at around 1.3 mg/dL, but has not elevated further. Serum IgA gradually decreased and reached 289 mg/dL in April 2014. TMA due to bevacizumab described in several other reports was also accompanied by glomerular IgA deposition, thus a differential diagnosis of IgA nephropathy is required. TMA was recently added to a section of "significant adverse effects" in the package insert of bevacizumab. Nephrologists should be fully aware of this drug-induced nephropathy.

Renal tamponade in a patient with hydronephrosis-related Page kidney.

A 48-year-old woman presented with hyperreninemic hypertension and renal dysfunction and was diagnosed with hydronephrosis-related Page kidney. The pathophysiology was "renal tamponade", in which the kidney was compressed by the renal pelvis and Gerota's fascia, resulting in intrarenal microvascular ischemia. Ureteral stent placement promptly improved the hyperreninemic hypertension and renal dysfunction, and additional perirenal fluid drainage gradually improved these conditions. These observations indicated the following three points. First, renal compression-induced renin-angiotensin-aldosterone system upregulation plays an important role in the pathogenesis of Page kidney. Second, physicians should consider perirenal fluid drainage as a therapeutic option in addition to ureteral stenting in patients with hydronephrosis-related Page kidney. Third, bilateral perirenal subcapsular hematomas in this case could be caused by hydronephrosis. Hydronephrosis-induced intrarenal pressure elevation possibly caused chronic perirenal subcapsular hemorrhage at the vulnerable sites of the renal cortex and peeling of the renal capsule from the cortex, resulting in the bilateral massive subcapsular hematomas and Page kidney.

Posterior cingulate cortex spontaneous activity associated with motor response inhibition in patients with obsessive-compulsive disorder: A resting-state fMRI study.

Recent evidence suggests that broad brain regions, not limited to the fronto-striato-thalamo-cortical circuit, play an important role in motor response inhibition. However, it is still unclear which specific key brain region is responsible for impaired motor response inhibition observed in obsessive-compulsive disorder (OCD). We calculated the fractional amplitude of low-frequency fluctuations (fALFF) and measured response inhibition ability using the stop-signal task in 41 medication-free patients with OCD and 49 healthy control (HC) participants. We explored the brain region that shows different association between the fALFF and the ability of motor response inhibition. Significant differences in fALFF associated with the ability of motor response inhibition were identified in dorsal posterior cingulate cortex (PCC). There was a positive correlation between increased fALFF in the dorsal PCC and impaired motor response inhibition in OCD. In the HC group, there was a negative correlation between the two variables. Our results suggest that the magnitude of resting-state blood oxygen level-dependent oscillation of the dorsal PCC is a key brain region for the underlying mechanisms of impaired motor response inhibition in OCD. Future studies should examine whether this characteristic of dorsal PCC affects other large-scale networks responsible for motor response inhibition of OCD.

Seroma as a Rare Complication of Autologous Arteriovenous Fistula Creation in the Forearm of a Hemodialysis Patient: A Case Report.

Aim of the study: Seromas are rarely reported as complications of autologous arteriovenous fistula creation. Case description: An 89-year-old woman was hospitalized for hemodialysis and underwent an autologous arteriovenous fistula creation in the forearm. During cephalic vein expansion using a heparinized saline solution, leakage occurred. A suture was placed to control the leakage, and a Penrose drain was inserted. Serosanguineous drainage ceased on postoperative day two; however, a seroma occurred approximately two weeks after the surgery. Follow-up ultrasonography revealed no growth tendency; therefore, excision and aspiration were unnecessary. Conclusion: This seroma was associated with postoperative dead space, surgical technique, and patient clinical status. Sufficient preoperative ultrasonographic vascular mapping is required to avoid inappropriate handling of veins and prevent seroma formation. Postoperative ultrasonographic follow-up is recommended due to the future risk of fistula dysfunction and infection associated with seroma enlargement, which may necessitate surgical seroma excision.

Vancomycin Intoxication and Cefepime-induced Encephalopathy Treated by Abdominal Drainage of Massive Ascites in Addition to Online Hemodiafiltration.

A patient with recurrent plasmacytoma with massive ascites exhibited vancomycin intoxication and cefepime-induced encephalopathy due to renal dysfunction. The ascitic accumulation of these drugs was suspected because of the refractory intoxicated state. To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was performed in addition to online hemodiafiltration. If patients with renal dysfunction and massive ascites develop vancomycin intoxication and cefepime-induced encephalopathy that cannot be improved by drug discontinuation, physicians should suspect ascitic accumulation and evaluate the ascitic concentration. Furthermore, if a high accumulation in massive ascites occurs, physicians should perform abdominal drainage along with blood purification.

Acute Brachial Arterial Embolic Occlusion Following Anticoagulant Discontinuation in a Renal Biopsy of a Nephrotic Syndrome Patient.

A 73-year-old woman with atrial fibrillation treated with rivaroxaban was hospitalized for nephrotic syndrome. After discontinuation of rivaroxaban to lower the risk of hemorrhagic events, a renal biopsy was performed. Rivaroxaban was scheduled to resume a week after the biopsy to prevent renal hemorrhaging. However, she developed acute brachial arterial embolic occlusion and mural thrombosis in the abdominal aorta before resuming rivaroxaban. If immune-mediated renal diseases are suspected in anticoagulated patients at a risk of thrombotic events, physicians should consider initiating glucocorticoid therapy without a renal biopsy in order to avoid hemorrhagic and thrombotic events.

Duration effect of obsessive-compulsive disorder on cognitive function: a functional MRI study.

BACKGROUND: The inconsistency of previous reports examining cognitive function in obsessive-compulsive disorder (OCD) suggests its heterogeneity. In this study, we examined the effect of illness duration on cognitive function in OCD. METHODS: We examined the cognitive function of 32 OCD patients and 16 healthy volunteers by neuropsychological tests and functional magnetic resonance imaging while they performed the Stroop and N-back tasks to assess attention and nonverbal memory. The patients were divided into two groups by illness duration: a short-term group (n=17, 5.5+/-3.1 years) and a long-term group (n=15, 20.3+/-6.1 years). Statistical analysis was performed to determine the differences between these two groups and the normal control group (n=16). RESULTS: The long-term group showed attention deficit and nonverbal memory dysfunction on the neuropsychological tests. In contrast, on functional magnetic resonance imaging, the short-term group showed weaker activation of the right caudate during the Stroop task and stronger activation of the right dorso-lateral prefrontal cortex during the N-back task than the long-term and normal control groups. CONCLUSIONS: The results suggested that abnormal brain activation occurs in the early phase of OCD and that the long-term persistence of OCD might involve a decline in cognitive function.

Functional MRI study of brain activation alterations in patients with obsessive-compulsive disorder after symptom improvement.

Dysfunction of the frontal-subcortical circuits has been the most common finding in the pathophysiology of obsessive-compulsive disorder (OCD), and recent neuropsychological studies have shown cognitive impairments in OCD. To clarify the pathophysiology of OCD without the confounding effects of medication, we investigated the alterations of brain function in OCD patients and changes after clinical improvement due solely to behavior therapy. The participants were 11 outpatients with OCD and 19 normal controls. The patients received 12 weeks of behavior therapy. We investigated the differences in the behavioral performance and functional magnetic resonance imaging results during the Stroop test in the patients and normal controls, and their changes after treatment in the patients. The patients showed less activation in the anterior cingulate gyrus and cerebellum than control subjects. Following significant improvement in OC symptoms, the cerebellum and parietal lobe showed increased activation, and the orbitofrontal cortex, middle frontal gyrus, and temporal regions showed decreased activation during the Stroop task, and performance of the task itself improved. Our findings suggest that dysfunction of the posterior brain regions, especially the cerebellum, is involved in the pathogenesis of OCD, and that normalization in function can occur with improvement of OC symptoms.

Evaluation of markers to estimate volume status in hemodialysis patients: atrial natriuretic peptide, inferior vena cava diameter, blood volume changes and filtration coefficients of microvasculature.

Relationships among five markers of volume status - cardio-thoracic ratio (CTR), atrial natriuretic peptide (ANP), inferior vena cava diameter at quiet expiration (IVCe), blood volume change (Delta BV/TUF) during ultrafiltration and filtration coefficients of microvasculature (Lpst) - were investigated. Fifty stable hemodialysis patients were enrolled. The CTR was measured before hemodialysis (HD), and ultrasonic measurement of IVCe and sample collection for ANP were performed shortly after HD. Lpst and Delta BV/TUF were calculated using a CRIT-LINE monitor. Overhydrated patients determined by each marker (OVERctr, OVERivc, OVERanp, OVERlp and OVERbv) were compared. The agreement of volume status determined by each marker was assessed by kappa value, and the sensitivity and specificity of each marker to distinguish overhydrated patients were analyzed by a receiver-operating characteristic (ROC) curve. IVCe, ANP, Delta BV/TUF and Lpst, significantly correlated with each other. The correlation coefficients of Lpst with IVCe, ANP and Delta BV/TUF were higher than the others. The kappa value between ANP and Lpst was the highest. OVERanp was the highest, then OVERlp, OVERivc and OVERbv, in this order. The OVERlp and OVERivc patients were completely included in OVERanp. All patients, except one OVERbv patient, were included in OVERlp. The relatively high distinguishing ability of Lpst was demonstrated by ROC analysis. These results suggest that the determination of overhydration solely by ANP was an overestimation and by Delta BV/TUF was an underestimation. The relatively high correlation coefficients of Lpst with other markers, as well as its distinguishing ability, suggest that Lpst fluctuates in close relation to other markers.

[Duration effect on neuropsychological function and treatment response of OCD].

Because of inconsistency among previous reports that examined neuropsychological function and treatment response of OCD patients, we here consider the heterogeneity of OCD; for example: symptom-based clusters, degree of insight, age of onset, and comorbid diagnoses. In this study, we examined neuropsychological function and the treatment response of OCD patients. Thirty-two OCD patients participated in this study. We examined their clinical symptoms by Y-BOCS, MOCI and other scales, and examined their cognitive function with several neuropsychological tests including: WAIS-R, Stroop test, WCST, WMS-R and R-OCFT. We then randomly assigned them to three treatment packages including: behavior therapy, pharmacotherapy by fluvoxamine, and controlled therapy. The patients were divided into two groups by duration of illness: short to middle range group (Group S, n=17, 5.5+/-3.1 years), and long range group (Group L, n=15, 20.3+/-6.1 years). The mean age of Group L was higher than that of Group S (Group S: 30.6+/-9.7 years old, Group L: 36.1+/-6.2 years old). There was no significant group difference in sex ratio or number of years of education. The mean age of onset of Group L was significantly lower than that of Group S (Group S; 25.5+/-10.2 years old, Group L; 15.3+/-7.1 years old). The total Y-BOCS mean score and MOCI score showed no group differences. These two groups showed similar clinical characteristics such as the severity of OC symptom, OC subtypes, and comorbid depression. Group S, however, demonstrated significantly more obsession with the need for correction. Group L had significantly higher levels of anxiety and compulsion. There were also no group differences in the mean HDRS or STAI scores. As a result, compared to Group S, Group L showed significant attention deficit in the Stroop test and the WMS-R though other neuropsychological dysfunctions such as intellectual level, executive function, verbal memory, and nonverbal memory were found in this group. Concerning treatment response, Group L showed little improvement by pharmacotherapy. Behavior therapy brought significant improvement to all patients of both groups. Long duration of the illness might cause attention deficit and a lowered pharmaceutical response in OCD patients.

Differential neural network of checking versus washing symptoms in obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is clinically heterogeneous. The aim of this study was to investigate differential neural responses to a symptom provocation task in drug-free patients who have predominantly aggression/checking symptoms (Checkers) and patients with contamination/washing symptoms (Washers). We compared the Checkers (n=10) and the Washers (n=12) separately to normal controls during the symptom provocation tasks using fMRI (functional magnetic resonance imaging). Moreover, we performed correlative analysis in each OCD group between brain activation and symptom severity. The Checkers showed hypoactivation in the left caudate and left anterior cingulate cortex (ACC) compared to the normal controls and a positive correlation between activated brain areas and symptom severity in the left ACC. The Washers showed hyperactivation in several bilateral cortico-cerebellar regions and a positive correlation between symptom severity and the bilateral fronto-temporal gyrus. We suggest that the caudate and ACC are associated with checking rituals and that large cortical brain regions are related to washing rituals.

Bmp7 maintains undifferentiated kidney progenitor population and determines nephron numbers at birth.

The number of nephrons, the functional units of the kidney, varies among individuals. A low nephron number at birth is associated with a risk of hypertension and the progression of renal insufficiency. The molecular mechanisms determining nephron number during embryogenesis have not yet been clarified. Germline knockout of bone morphogenetic protein 7 (Bmp7) results in massive apoptosis of the kidney progenitor cells and defects in early stages of nephrogenesis. This phenotype has precluded analysis of Bmp7 function in the later stage of nephrogenesis. In this study, utilization of conditional null allele of Bmp7 in combination with systemic inducible Cre deleter mice enabled us to analyze Bmp7 function at desired time points during kidney development, and to discover the novel function of Bmp7 to inhibit the precocious differentiation of the progenitor cells to nephron. Systemic knockout of Bmp7 in vivo after the initiation of kidney development results in the precocious differentiation of the kidney progenitor cells to nephron, in addition to the prominent apoptosis of progenitor cells. We also confirmed that in vitro knockout of Bmp7 in kidney explant culture results in the accelerated differentiation of progenitor population. Finally we utilized colony-forming assays and demonstrated that Bmp7 inhibits epithelialization and differentiation of the kidney progenitor cells. These results indicate that the function of Bmp7 to inhibit the precocious differentiation of the progenitor cells together with its anti-apoptotic effect on progenitor cells coordinately maintains renal progenitor pool in undifferentiated status, and determines the nephron number at birth.

fMRI of patients with social anxiety disorder during a social situation task.

Previous functional neuroimaging studies found that the amygdala and other limbic regions may play a substantial role in social anxiety disorder (SAD). However, more widely distributed large-scale brain systems may be involved in cognitive processing in SAD patients when confronted with social situations. We employed functional MRI (fMRI) to investigate local brain activation of patients with SAD (n=6) and healthy controls (HC, n=9) during cognitive work. During fMRI scanning, subjects performed a social situation task using a block design paradigm in which the task and control trials were performed by turn. The patients with SAD showed higher anxiety levels during scanning in all social situations. The HC group showed greater common activation in the posterior cingulate cortex (PCC), cuneus, occipital gyrus, and cerebellum. Although the patients with SAD showed activation patterns similar to that of the HC group, they showed comparatively significant decreased activation in the left cerebellum, left precuneus, and bilateral PCC. The present study demonstrates that SAD may involve dysfunction of a broad neuronal network including the limbic system, parieto-posterior cortex and cerebellum. The findings contribute to previous findings that revealed abnormal activities of emotion-related regions including the amygdala and insular cortex during facial perception in SAD.