Chronotherapy with a Renin-angiotensin System Inhibitor Ameliorates Renal Damage by Suppressing Intrarenal Renin-angiotensin System Activation.

Objective The intrarenal renin-angiotensin system (RAS) is activated in chronic kidney disease (CKD) patients and is not suppressed at night in CKD patients showing nocturnal hypertension, contributing to renal damage. Furthermore, changes in RAS inhibitor administration from morning to evening, namely chronotherapy, ameliorates renal damage at night. We attempted to clarify whether or not chronotherapy ameliorates renal damage by suppressing the intrarenal RAS activity. Methods We recruited 34 CKD patients with RAS inhibitors in the morning. We conducted ambulatory blood pressure (BP) monitoring and urine collection and evaluated urinary albumin (Alb) and angiotensinogen (AGT), which are surrogate markers for intrarenal RAS activity during the day and at night, respectively. The same experiments were conducted after changing the administration time. The ratio of values associated with morning versus evening dosing was defined as the morning to evening (M/E) ratio. Results The M/E ratio of urinary Alb had a significant and positive relationship with that of urinary AGT during the day and at night in all CKD patients. However, no significant relationships were found between the M/E ratios of urinary Alb and AGT using multiple linear regression analyses. Conversely, there was a significant and positive relationship between the M/E ratios of urinary Alb and AGT at night but not during the day in CKD patients whose estimated glomerular filtration rate was <45 mL/min/1.73 m2 and whose night-to-day ratio of systolic BP was >0.90, even after adjustment. Conclusion This study indicated that chronotherapy with RAS inhibitors improved the renal damage via intrarenal RAS suppression, especially in CKD patients with an impaired renal function and nocturnal hypertension.

[A case of human adjuvant disease with clinical features of Guillain-Barré syndrome].

A 69-year-old female developed subacute diplopia, right peripheral facial nerve palsy, bilateral upper and lower extremities dysesthesia and weakness 50 years after silicone injection for breast augmentation. Motor conduction study revealed prolonged distal latency and reduced amplitude in the median, ulnar, and peroneal nerves. Sensory conduction velocities were reduced in the median and ulnar nerves, and sensory potential in the sural nerve could not be recorded. While intravenous immunoglobulin therapy was ineffective, explantation of silicone breast implants improved her neurological symptoms. Histopathological study of axillary lymph node revealed foreign body granulomas and macrophages phagocyting silicone. The patient was diagnosed with human adjuvant disease presenting clinical features of Guillain-Barré syndrome. Human adjuvant disease should be considered in the patients with implants like silicone and neurological symptoms.

Melatonin ameliorates intrarenal renin-angiotensin system in a 5/6 nephrectomy rat model.

BACKGROUND: Activation of the intrarenal renin-angiotensin system (RAS) plays a critical role in the pathophysiology of chronic kidney disease (CKD) and hypertension. It has been reported that reactive oxygen species (ROS) are important components of intrarenal RAS activation. Melatonin is recognized as a powerful antioxidant, and we recently reported that impaired nighttime melatonin secretion correlates negatively with urinary angiotensinogen excretion, the surrogate marker of intrarenal RAS activity in patients with CKD. However, whether melatonin supplementation ameliorates the augmentation of intrarenal RAS in CKD has remained unknown. We aimed to clarify whether exogenous melatonin ameliorates intrarenal RAS activation via the reduction of ROS production. METHODS: 5/6 Nephrectomized (Nx) rats were used as a chronic progressive CKD model and compared with sham-operated control rats. The Nx rats were divided into untreated Nx rats and melatonin-treated Nx rats. The levels of intrarenal RAS, ROS components, and renal injury were evaluated after 4 weeks of treatment. RESULTS: Compared with the control rats, the untreated Nx rats exhibited significant increases in intrarenal angiotensinogen, angiotensin II (AngII) type 1 receptors, and AngII, accompanied by elevated blood pressure, higher oxidative stress (8-hydroxy-2'-deoxyguanosine), lower antioxidant (superoxide dismutase) activity, and increased markers of interstitial fibrosis (α-smooth muscle actin, Snail, and type I collagen) in the remnant kidneys. Treatment with melatonin significantly reversed these abnormalities. CONCLUSION: Antioxidant treatment with melatonin was shown to ameliorate intrarenal RAS activation and renal injury in a 5/6 Nx rat model.

Copper Accumulates in Hemosiderins in Livers of Patients with Iron Overload Syndromes.

In biology, redox reactions are essential and sometimes harmful, and therefore, iron metabolism is tightly regulated by cuproproteins. Since the state of copper in iron overload syndromes remains unclear, we investigated whether copper metabolism is altered in these syndromes. Eleven patients with iron overload syndromes participated in this study. The clinical diagnoses were aceruloplasminemia (n=2), hemochromatosis (n=5), ferroportin disease (n=2), and receiving excess intravenous iron supplementation (n=2). Liver specimens were analyzed using a light microscope and transmission electron microscope equipped with an X-ray analyzer. In addition to a large amount of iron associated with oxygen and phosphorus, the iron-rich hemosiderins of hepatocytes and Kupffer cells contained small amounts of copper and sulfur, regardless of disease etiology. Two-dimensional imaging clearly showed that cuproproteins were distributed homogenously with iron complexes within hemosiderins. Copper stasis was unlikely in noncirrhotic patients. The enhanced induction of cuproproteins by excess iron may contribute to copper accumulation in hemosiderins. In conclusion, we have demonstrated that copper accumulates in hemosiderins in iron overload conditions, perhaps due to alterations in copper metabolism.

The Possible Link between GABAergic Dysfunction and Cognitive Decline in a Patient with Idiopathic Hypoparathyroidism.

Idiopathic hypoparathyroidism (IHP) is accompanied by cognitive impairment. We report the case of a 70-year-old IHP patient with cognitive disturbance. Brain computed tomography showed bilateral calcification in basal ganglia, thalamus, and cerebellum. Neuropsychological assessment revealed low scores for intelligence, memory, and perseverative errors. Brain positron emission tomography showed a significant reduction in [(18)F]-Fludeoxyglucose (FDG) uptake in bilateral frontal, left temporal and parietal cortices, along with a marked reduction in [(11)C]-flumazenil binding in left frontal, temporal, parietal, and bilateral cerebellum. These findings suggest cognitive impairment in IHP may be ascribed to GABAergic dysfunction, thus leading to, or coexisting with, cerebral hypometabolism.

Induction of murine TNBS colitis is strictly controlled by a modified method using continuous inhalation anesthesia with sevoflurane.

BACKGROUND: Trinitrobenzenesulfonic acid (TNBS)-induced colitis is one of the most widely used experimental colitis models. However, there is no standard procedure for inducing colitis by TNBS because it is difficult to achieve a uniform distribution of colitis. We have developed a modified method of murine TNBS-induced colitis that involves inhalation anesthesia with sevoflurane combined with both single and repeated TNBS administrations. AIMS: To compare the usefulness of our newly developed method for inducing murine TNBS-induced colitis with that of conventional intraperitoneal anesthesia. METHODS: TNBS in ethanol was administered to C57BL/6J mice held in an inverted vertical position either under continuous inhalation anesthesia with sevoflurane, in accordance with our newly developed method, or by intraperitoneal injection with 2.5 % avertin, in accordance with the conventional procedure. Body weight change, cytokine profile, and histological findings were examined during the course of colitis. RESULTS: The dispersion of anesthesia time, TNBS retention time, and nadir weight during the course of colitis was decreased using the newly developed method compared with the conventional procedure. Optimization of the modified TNBS-induced colitis, as evidenced by the predominant expression of Th1 and Th17 cytokines on day 7, was attained by the injection of 2.25 mg TNBS in 55 % ethanol. Regulation of the TNBS retention time using inhalation anesthesia with sevoflurane allowed strict control of the disease severity of TNBS-induced colitis. Using the modified method we were also able to develop a chronic TNBS-induced colitis model by repeated TNBS administration without excessive mortality of the mice. CONCLUSIONS: Our modified method for murine TNBS-induced colitis using continuous inhalation anesthesia with sevoflurane provides a better experimental colitis model following both single and repeated TNBS administrations.

[Familial Wernicke's-like encephalopathy].

Wernicke's encephalopathy is a syndrome characterized by ataxia, ophthalmoplegia, and confusion with thiamine deficiency. We reported on two Japanese brothers with a newly discovered recessively inherited syndrome similar to Wernicke's encephalopathy that developed in the second decade of life; this syndrome was manifested clinically as thiamine-responsive diplopia, ataxia and confusion without serum thiamine deficiency. The patients had complex partial seizure. The administration of high-dose thiamine improved these symptoms. MRI of the brain showed high-intensity signals in the bilateral medial thalamus and periaqueductal region on fluid-attenuated inversion recovery images; these signals were characteristic of findings in Wernicke's encephalopathy. There was no history of chronic alcoholism. The clinical and images features resembling Wernicke's encephalopathy in these patients suggested that the syndrome was caused by a genetic disorder of thiamine metabolism. Genomic analysis of SLC10A3 encoding human thiamine transporter 2 revealed that the patients were compound heterozygotes for the K44E and E320Q mutations. Gene-expression analyses of mammalian culture cells showed that intracellular thiamine uptake activities were decreased significantly. High expression of SLC19A3 RNA in the thalamus may explain the selective thalamic lesions on MRI. The identification of this syndrome proves insight into the thiamine metabolism associated with Wernicke's encephalopathy in humans.