Experimental investigation of geologically produced antineutrinos with KamLAND.

The detection of electron antineutrinos produced by natural radioactivity in the Earth could yield important geophysical information. The Kamioka liquid scintillator antineutrino detector (KamLAND) has the sensitivity to detect electron antineutrinos produced by the decay of 238U and 232Th within the Earth. Earth composition models suggest that the radiogenic power from these isotope decays is 16 TW, approximately half of the total measured heat dissipation rate from the Earth. Here we present results from a search for geoneutrinos with KamLAND. Assuming a Th/U mass concentration ratio of 3.9, the 90 per cent confidence interval for the total number of geoneutrinos detected is 4.5 to 54.2. This result is consistent with the central value of 19 predicted by geophysical models. Although our present data have limited statistical power, they nevertheless provide by direct means an upper limit (60 TW) for the radiogenic power of U and Th in the Earth, a quantity that is currently poorly constrained.

Beta-arrestin-dependent formation of beta2 adrenergic receptor-Src protein kinase complexes.

The Ras-dependent activation of mitogen-activated protein (MAP) kinase pathways by many receptors coupled to heterotrimeric guanine nucleotide binding proteins (G proteins) requires the activation of Src family tyrosine kinases. Stimulation of beta2 adrenergic receptors resulted in the assembly of a protein complex containing activated c-Src and the receptor. Src recruitment was mediated by beta-arrestin, which functions as an adapter protein, binding both c-Src and the agonist-occupied receptor. beta-Arrestin 1 mutants, impaired either in c-Src binding or in the ability to target receptors to clathrin-coated pits, acted as dominant negative inhibitors of beta2 adrenergic receptor-mediated activation of the MAP kinases Erk1 and Erk2. These data suggest that beta-arrestin binding, which terminates receptor-G protein coupling, also initiates a second wave of signal transduction in which the "desensitized" receptor functions as a critical structural component of a mitogenic signaling complex.

Initial functional status predicts infections during steroid therapy for renal diseases.

BACKGROUND AND AIM: Corticosteroid therapy is an effective way of treatment for many renal diseases, however, it is sometimes associated with infections. Our aim is to identify useful predictive markers of infection during steroid therapy. METHODS: We examined 121 patients (M/F = 71/50, mean age 43.8, range 15 - 82 years) who were treated with corticosteroids (IgA nephropathy in 51, minimal-change disease in 17, membranous nephropathy in 16 rapidly progressive glomerulonephritis (RPGN) in 13, lupus nephritis in 12 and other disorders in 12). Karnofsky's performance score (KPS) was employed to assess the physical functional status at the time of diagnosis. Infections were defined as conditions that required more than 1-week care, and those that caused the patient's death. RESULTS: Nineteen patients (15.7%) had infections during treatment. A logistic multivariate analysis showed significant correlations between infection and the use of immunosuppressive agents (relative risk RR = 7.7, p = 0.0265), ages of 52.9 years or more (RR = 13.5, p = 0.0026), initial number of lymphocytes (Lym) less than 1.250/microl (RR = 14.2, p = 0.0011), and KPS less than 77.4 (RR = 12.1, p = 0.0020). All correlations with infection were independent of all the other variables listed above. CONCLUSION: KPS, along with age, Lym and the use of immunosuppressive agents, are useful for the prediction of infectious complications during steroid therapy.

Involvement of PYK2 in angiotensin II signaling of vascular smooth muscle cells.

-PYK2, a recently identified Ca2+-sensitive tyrosine kinase, has been implicated in extracellular signal-regulated kinase (ERK) activation via several G protein-coupled receptors. We have reported that angiotensin II (Ang II) induces Ca2+-dependent transactivation of the epidermal growth factor receptor (EGFR) which serves as a scaffold for preactivated c-Src and downstream adaptors (Shc/Grb2), leading to ERK activation in cultured rat vascular smooth muscle cells (VSMC). Herein we demonstrate the involvement of PYK2 in this cascade. Ang II rapidly induced tyrosine phosphorylation of PYK2, whose effect was completely inhibited by an AT1 receptor antagonist and an intracellular Ca2+ chelator. A Ca2+ ionophore also induced PYK2 tyrosine phosphorylation to a level comparable with that by Ang II, whereas phorbol ester-induced phosphorylation was less than that by Ang II. Moreover, PYK2 formed a complex coprecipitable with catalytically active c-Src after Ang II stimulation. Although a selective EGFR kinase inhibitor completely abolished Ang II-induced recruitment of Grb2 to EGFR and markedly attenuated Ang II-induced ERK activation, it had no effect on Ang II-induced PYK2 tyrosine phosphorylation or its association with c-Src and Grb2. These data suggest that the AT1 receptor uses Ca2+-dependent PYK2 to activate c-Src, thereby leading to EGFR transactivation, which preponderantly recruits Grb2 in rat VSMC.

Cytoplasmic and nuclear polyglutamine aggregates in SCA6 Purkinje cells.

Aggregations of the alpha1A-calcium channel protein have been previously demonstrated in spinocerebellar ataxia type 6 (SCA6). Here the authors show that small aggregates, labeled by a monoclonal antibody 1C2 that preferentially detects expanded polyglutamine larger than that in SCA6 mutation, are present mainly in the cytoplasm but also in the nucleus of Purkinje cells. Although the length of expansion is small in SCA6, the current finding might indicate that SCA6 conforms to the pathogenic mechanism(s) in other polyglutamine diseases.

Effect of glycemic control on vitamin B12 metabolism in diabetes mellitus.

To determine the effect of glycemic control on vitamin B12 (B12) metabolism in diabetes mellitus, we studied B12 metabolism in 19 diabetic patients with poor glycemic control and 15 normal individuals. The diabetic patients had significantly higher total B12 binding capacity (3303 +/- 963 pg/ml), higher serum B12 levels (1173 +/- 503 pg/ml) and unsaturated B12 binding capacity (2131 +/- 902 pg/ml) when compared with the normal controls, but there was no difference in R-binder levels and the B12 binding ratio between the two groups. During a 2-week admission to establish glycemic control, the fructosamine levels in the diabetic patients decreased from 556 to 428 mumol/l and the total B12 binding capacity as well as unsaturated B12 binding capacity were significantly improved to the normal range (P < 0.01), but serum B12 levels, R-binder levels and the B12 binding ratio were not changed. There was a significant association between serum fructosamine levels and the total B12 binding capacity in poorly controlled diabetic patients and the decrease of fructosamine was correlated significantly with the change of total B12 binding capacity and serum B12 levels in diabetic patients. These results indicate the effects of glycemic control on B12 metabolism in diabetes mellitus.

Etiological evaluation of dural arteriovenous malformations of the lateral and sigmoid sinuses based on histopathological examinations.

Controversy persists concerning the pathogenesis of dural arteriovenous malformations (AVM's) and whether they are congenital or acquired. Furthermore, it remains undetermined whether the lesion is located in the sinus itself or within the sinus wall. In order to elucidate the pathogenesis of dural AVM's of the lateral and sigmoid sinuses, histopathological profiles of this disease were studied in serial sections of completely resected lesions from three patients. The essential lesion was histologically confirmed to be a dural arteriovenous fistula within the wall of the venous sinuses. The etiology process of this disease and its progression were evaluated.

Long-term follow-up study of unruptured vertebral artery dissection: clinical outcomes and serial angiographic findings.

OBJECT: Although the spontaneous occurrence of an unruptured vertebral artery (VA) dissection has increasingly been recognized as a relatively common cause of stroke, and the clinical aspects of this lesion have gradually been determined, its natural course remains obscure. The main goal of this study was to clarify the management protocol for this condition by examining serial angiographic changes in patients with unruptured VA dissections. METHODS: Seventeen patients with unruptured VA dissections, including 13 men and four women, were clinically and angiographically examined between 1993 and 1998. All patients were observed using serial angiography studies. The initial angiography examinations most frequently revealed stenotic lesions (appearance of a pearl-and-string sign or string sign) in eight (47.1%) of 17 cases. In 15 cases (88.2%), changes in the lesions were evident on follow-up angiography studies. Stenotic lesions resulted in occlusion in four cases, normalization in three, and subsequent formation of an aneurysm in one case, which was treated successfully by proximal occlusion of the affected vessel performed using a detachable balloon. Occluded lesions, which were initially observed in three patients, recanalized in two patients and remained unchanged in one patient. Fusiform dilation alone was demonstrated in three patients during the initial angiography session; these lesions became normalized or were unchanged on follow-up studies. Saccular aneurysms were observed in two patients. In one of these cases, proximal ligation of the parent artery was successfully performed because of subsequent aneurysm enlargement. A double lumen, which appeared in one patient with an extradural VA dissection, became occluded. Magnetic resonance T2-weighted imaging studies revealed infarction corresponding to the posterior circulation in seven cases. During long-term observation in this series, good or excellent recovery was obtained in 14 (87.5%) of 16 patients, and moderate or severe disability in two (12.5%); one patient was lost to follow up after the second angiography study. CONCLUSIONS: A follow-up angiography study must be performed during the early stage (within approximately 3 weeks after onset of symptoms) to confirm the formation or enlargement of an aneurysm, because such conditions may be amenable to surgical treatment. Unruptured VA dissection could otherwise be treated and followed conservatively. Although the majority of dissected lesions seem likely to stabilize within a few months, as evidenced on angiography, in some cases a longer observation period is required.

Prostacyclin analogue, beraprost, sustains recanalization duration after thrombolytic therapy in acute myocardial infarction model.

Platelets play an important role in acute reocclusion after thrombolysis in acute myocardial infarction. We tested a new antiplatelet agent, the stable prostacyclin analogue, beraprost, in the prevention of reocclusion of reperfused vessels with a combination of recombinant tissue-type plasminogen activator (rt-PA) in a canine preparation of coronary artery thrombosis superimposed on high-grade stenosis. Intravenous infusion of rt-PA (17 micrograms/kg/min for 30 min) was combined with beraprost (100, 200 or 300 ng/kg/min for 60 min) or aspirin (35 mg/kg bolus i.v. before rt-PA infusion). The reperfusion time did not differ among the 4 groups. The time from reperfusion to reocclusion (one cycle) in the rt-PA plus beraprost 200 ng/kg/min group was significantly longer than the rt-PA alone group (40 +/- 8 min vs. 9 +/- 2 min, P < 0.05) and the recanalization duration calculated as the mean time from reperfusion to reocclusion in each cycle was prolonged in the rt-PA plus beraprost 200 ng/kg/min group compared with the rt-PA alone group (48 +/- 6 min vs 18 +/- 5 min, P < 0.05) and the reocclusion time and recanalisation duration tended to be elongated in the rt-PA plus beraprost 300 ng/kg/min group, whereas those were not altered by aspirin and 100 ng/kg/min of beraprost. Bleeding time was slightly prolonged and ex vivo platelet aggregation was slightly depressed by beraprost and aspirin. Systemic blood pressure was lowered with higher doses of beraprost. Beraprost sustained coronary reperfusion time and recanalization duration at the higher doses with an optimal level, but could not eliminate reocclusion completely.(ABSTRACT TRUNCATED AT 250 WORDS)

A case of secondary hyperparathyroidism whose high turnover bone improved after the direct injection of acetic acid into the parathyroid glands.

A 48-year-old male was admitted to our hospital because of increasing knee pain and thigh muscle weakness. He had been undergoing hemodialysis for 15 years. His serum intact PTH value was 1,600 pg/ml with elevated ALP (387 IU/l) and osteocalcin (400 ng/ml). Ultrasound (US) examination disclosed 2 enlarged parathyroid glands. Because of poor cardiac function, an US-guided acetic acid injection into the enlarged parathyroids (percutaneous acetic acid injection therapy; PAIT) was performed. Soon after the PAIT, his arthralgia disappeared. Serum PTH fell to 220 pg/ml with the regression of bone marker 1 year following the PAIT. The size of his parathyroid glands dramatically regressed and 1 of the enlarged glands finally disappeared. Repeated bone biopsies following double tetracycline labeling showed a significant improvement from osteitis fibrosa to the mild lesion. This is the first known case report of severe secondary hyperparathyroidism whose PTH and high turnover bone was successfully managed by the direct injection of acetic acid into the parathyroid glands. As long as we pay attention to avoiding recurrent nerve palsy induced by acetic acid, US-guided PAIT may be an alternative to percutaneous ethanol injection therapy (PEIT) or surgical parathyroidectomy (PTx).

Midkine inhibits apoptosis via extracellular signal regulated kinase (ERK) activation in PC12 cells.

Midkine (MK) is a new member of the family of heparin-binding neurotrophic factors. MK has several important biological effects and plays an important role in the development and survival of neurons. The mechanism by which MK exerts its neurotrophic actions, however has not been sufficiently clarified. To understand the intracellular pathway activated by MK, we established an apoptosis-induction system with the neuronal cell line PC12 and studied the involvement of the mitogen-activated protein kinase (MAPK) cascade in neuroprotective actions of MK. We demonstrate here that MK rescued PC12 cells from apoptosis induced by serum deprivation in a dose-dependent manner. MK also activated extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2), which are well known as signal transducer acting downstream several receptors. PD98059, an inhibitor of MAPK kinase (MAPKK), inhibited ERK activation and also prevented the trophic effect of MK. These results indicate that MK exerts its neuroprotective actions mainly via ERK activation.

Acute subdural hematoma in patients who underwent aneurysm clipping--four case reports.

Four patients presented with intracranial hemorrhage mainly consisting of acute subdural hematoma (ASDH), who had all undergone aneurysm clipping 2-20 years earlier. Whether the clips had slipped or new trauma had caused the bleeding was difficult to determine, since the initial computed tomography showed that the subarachnoid hemorrhage or the intracerebral hematoma developed near the clips. Angiography in three patients showed that the clips had not slipped off. Three of four ASDHs appeared in the same side as the craniotomy used for the previous aneurysm surgery. Anti-platelet agents and ventriculoperitoneal shunting had been previously used in two patients with no causal signs of trauma. The outcomes were poor in three patients and one patient died. Weakening of the extra- or intracranial structure after aneurysm surgery might have been involved together with the postoperative anti-platelet agent and shunt treatment in the etiology of the present ASDH.

[Case of polycystic kidney associated with non-ruptured cerebral aneurysm].

Polycystic kidney is a familial disorder known to be complicated often by liver cyst, pancreas cyst and cerebral aneurysm. While numerous reports have been made on the concurrence polycystic kidney and cerebral aneurysm in foreign countries, there are only several autopsy cases documented so far in Japan. This paper describes a surgically treated case of proven non-ruptured aneurysms of bilateral middle cerebral arteries associated with polycystic kidney, and discusses the epidermology of cerebral aneurysm accompanying polycystic kidney in Japan. According to the Annual Report of Pathological Autopsy Cases in Japan, 1981, 8.4% of the cases of polycystic kidney were associated with cerebral aneurysms. The patients with polycystic kidney should be investigated for cerebral aneurysms.

[Giant basilar aneurysm--a case report (author's transl)].

A case of a giant aneurysm arising from the basilar artery is presented. The patient a 41--year-old female, had recent memory disturbance, miscalculations and hemiparesis on admission. Vertebral angiograms displayed a giant aneurysm measuring approximately 66 mm in diameter arising from the basilar artery, a tortuous vertebral artery, an extremely dilated basilar artery and an agenesis of the left carotid artery. Due to the enormous size of the aneurysm and its location in the deep intracranial portion, radical surgery was abandoned. Six months following her discharge, she died. At autopsy, the giant aneurysm arising from the top of the basilar artery was found, existing just beneath the third ventricle and extending to the left basal ganglia. The lateral ventricle, the third ventricle and the Sylvian fissure were filled by hematoma resulting from the rupture of the aneurysm. It is possible that this giant aneurysm could be considered a vascular anomaly, and hence be distinguished from saccular aneurysms.

[Usefulness of myocardial imaging by 123I-MIBG in assessment of diabetic neuropathy].

In diabetic patients with autonomic neuropathy, it is suggested that there is a reduced uptake of 123I-MIBG in the heart. We compared the difference of myocardial 123I-MIBG accumulation between 4 diabetic patients with triopathy and 6 patients without it. In all 10 patients, coronary angiography and 201Tl imaging (rest and 4 hours later) were performed. 123I-MIBG (111 MBq) was administered intravenously and its imaging was recorded on 15 minutes and 4 hours after injection. In all 4 cases with triopathy, 123I-MIBG imaging showed defect in apical and inferior region. In 2 out of 6 cases without triopathy, rapid clearance was noticed in apical and inferior region. There was no significant stenosis in right coronary artery and no defect in initial and delayed 201Tl images in all cases. We concluded that diabetic autonomic neuropathy in the heart was prominent in apical and inferior region and 123I-MIBG imaging might be useful for the evaluation of degrees in diabetic neuropathy.

[Autosomal dominant spinocerebellar degeneration with pigmentary retinopathy in a Japanese family].

We report a pedigree of autosomal dominant spinocerebellar degeneration associated with pigmental retinopathy. The proband is a 75-year-old man. He noticed night blindness at the age of 10 years and a diagnosis of bilateral pigmentary retinopathy was made at age 63. At the age of 65 years, he developed dysarthria and difficulty in walking. At age 69, neurological examination revealed cerebellar signs, and brain CT scans showed mild atrophy of the brain stem and cerebellum. Repeated brain CT scans revealed slight progression of the brain stem and cerebellar atrophy. Molecular genetic studies showed the absence of any mitochondrial DNA mutation at 8993. The father of the proband exhibited cerebellar signs and pigmentary retinopathy. One older brother had cerebellar signs and another had pigmentary retinopathy. To our knowledge, hereditary spinocerebellar degeneration with retinal degeneration is rare in Japan. This study is the first full report on hereditary spinocerebellar degeneration with pigmentary retinopathy in Japan, although an abstract was published by Konishi et al. We also discuss the neuropathological discordance on hereditary olivoponto-cerebellar atrophy with retinal degeneration.

[Pick's disease in senescence].

We report two patients with Pick's disease in senescence. Patient 1 is a 78-year-old woman. She developed abnormal behavior at the age of 76 years. Neurological examination at age 76 revealed poor rapport, easy angriness, "Denkfaulheit", oral tendency, and slight dementia [WAIS (Wechsler Adult intelligence Scale) total IQ 62]. Cranial CT scan and MRI showed bilateral atrophy of the frontal and temporal lobe, especially of the temporal lobe. Patient 2 is a 73-year-old man. He developped sexual abnormal behavior and "triebhafte Hemmungslossigkeit" at the age of 71 years. Neurological examination at age 72 revealed poor rapport, lack of spontaneity, easy angriness, "Denkfaulheit", and slight dementia [WAIS total IQ 91]. Transient "stehende Redensarten" was noticed. Cranial CT scan and MRI showed bilateral atrophy of the frontal and temporal lobe, especially of the frontal lobe. To our knowledge, Pick's disease with an onset in the senescence is very rare. Pick's disease should be included in the differential diagnosis of abnormal behavior in the senescence.

[Estimation of I-123 metaiodobenzylguanidine (MIBG) myocardial washout].

A crosstalk from I-123 to Tl-201 (Tl) window was 35 +/- 30% (mean +/- SD) and 30 +/- 10% in a myocardial phantom and the images of 6 patients respectively. However, the crosstalk from Tl to I-123 was approximately 1% in each. I-123 MIBG (MIBG) and Tl myocardial SPECT images were recorded in 3 normal volunteers (N), 10 patients with myocardial infarction (MI), and 4 with dilated cardiomyopathy (DCM). The MIBG and Tl imagings were performed on the other day to avoid the crosstalk. Myocardial washout rates (WR) of Tl and MIBG were derived from 15 min and 4 hour images. WR of Tl was approximately 36% in each group. On the other hand, WR of MIBG in DCM (52 +/- 7%) and MI (41 +/- 14%) groups were statistically higher than in N (24 +/- 7%) group. Thus WR of MIBG would be useful to detect abnormalities in adrenergic nervous system.

[Assessment of myocardial viability by resting 201Tl SPECT image].

The aim of this study was to assess whether resting 201Tl scintigraphy is superior in detecting viable myocardium than previous conventional methods. We performed not only stress 201Tl SPECT but also resting 201Tl SPECT within one month in 65 patients with coronary artery disease. Resting 201Tl images were quantitatively compared with 4 hour late images of stress study using a polar map. In stress study, redistribution was recognized on 83% (25/30) of non-MI SEGs with perfusion defect in the stress 201Tl image, and on 39% (18/46) of infarcted SEGs. The agreement of resting 201Tl study with 4 hour late images of stress study was shown on 93% (28/30) of non-MI SEGs and on 52% (24/46) of MI SEGs. The increased uptake of 201Tl in resting study, however, was found on 13 (46%) of 28 MI SEGs showing fixed defects in stress study. In stress delayed image with fixed defect, the %Tl uptake of improved SEGs was higher than that of unchanged SEGs (59 +/- 10% vs 48 +/- 11%; p greater than 0.05). There was no viable myocardium which had %Tl uptake less than 40% at stress delayed image. In conclusion, the resting 201Tl imaging will give an important information as for the myocardial viability showing fixed defects, if more than 40% Tl uptake is observed.

[A case of interstitial nephritis induced by a super antigen produced by methicillin-resistant Staphylococcus aureus (MRSA) presenting as acute renal failure].

We report the case of a 21-year-old man who had been developing acute renal failure with Methicillin-resistant Staphylococcus aureus (MRSA) colitis and sepsis. He was admitted for consciousness disturbance, nausea, vomiting, and diarrhea. Oliguria was also observed and his serum creatinine level was elevated to 10 mg/dl. Urinary protein was positive and an abundance of hyaline cast were seen in urinary sedimentation. Diarrhea and pyrexia were prolonged and serum C-reactive proteins were elevated, but lymphocyte and leukocyte counts temporarily decreased from the 3rd to the 6th hospital day and remained low until normalizing after the 14th day. His clinical symptoms improved with hemodialysis (HD) and effective antibiotic therapies. An MRSA strain producing toxic shock syndrome toxin-1 (TSST-1), a super antigen which specifically stimulates human V beta 2-positive T cells, was separated from his feces and blood. To ascertain the cause of his renal dysfunction, a renal biopsy was performed on the 8th day. His renal histology revealed acute interstitial nephritis with severe inflammatory cell infiltration around the medullary areas without glomerular changes. Most of the infiltrated cells were small monocytes, and lymphoid cells were rich in the interstitium. With immunohistochemical staining, over 70% of T-cells were V beta 2-positive. TSST-1-producing MRSA was detected in his blood specimen. Furthermore, V beta 2-positive T cells were accumulated in the renal intersititium, and transient lymphocytopenia was observed. These data suggested the following possible pathogenesis for interstitial nephritis: TSST-1 acts as a super antigen in the renal interstitium where major histocompatibility complex (MHC) is class-2-positive, thereby resulting in interstitial nephritis with T cell migration.