Yukishige Yanagawa

β2-Adrenoceptor Activation Attenuates Endotoxin-Induced Acute Renal Failure

ABSTRACT. Abnormalities in the β 2 -adrenergic control of organ function have been implicated in the pathogenesis of several disease states, such as septic shock. The objectives of the present study were to define the contribution of β 2 -adrenoceptors (β 2 -AR) to normal renal physiology and to investigate whether overexpression of renal β 2 -AR might be potentially beneficial in preventing progressive renal damage associated with endotoxemia. Adenoviral transgenes containing the human β 2 -AR (Adeno-β 2 -AR) were constructed and delivered into the rat kidney by means of intraparenchymal injections. Administration of 10 9 total viral particles of Adeno-β 2 -AR induced an approximately threefold increase in β 2 -AR density in the renal tissue, which 2 wk after delivery, enhanced GFR and sodium reabsorption compared with control rats. The enhanced GFR was abolished by the addition of the β 2 -AR antagonist, ICI 118,551. Administration of lipopolysaccharide (LPS) caused a reduction in GFR, β 2 -AR density, and cAMP together with enhanced TNF-α mRNA in the kidney. In rats overexpressing β 2 -AR, the reduction in baseline GFR and elevation of TNF-α mRNA and leukocyte infiltration into the kidney associated with the endotoxin were blocked. These findings suggested the possibility that a renal-specific overexpression of β 2 -AR preserves basal renal function in response to a ligand-independent β 2 -AR activation and that the delivery of Adeno-β 2 -AR gene is a potential novel therapeutic strategy for treatment of acute renal failure associated with sepsis.

Effective prophylactic therapy for cyclic vomiting syndrome in children using valproate.

This trial sought to evaluate our experience using the antimigraine prophylactic drug, use of valproate for the prophylactic management of cyclic vomiting syndrome (CVS) in children. Thirteen children diagnosed with severe CVS were enrolled. Prophylactic therapy consisted of valproate administered at a dose of 10-40 mg/kg/day. Upon enrollment in the study, all patients underwent diagnostic tests to rule out organic causes of their symptoms. Vomiting was severe enough in all patients to cause dehydration requiring hospitalization for intravenous rehydration. Nine of 13 patients did not respond to numerous previous medical therapies like propranolol, amitriptyline, cyproheptadine, phenobarbital, phenytoin, and carbamazepine. Three of 13 patients required combination therapy with valproate and phenobarbital. Of the 13 patients, two showed complete resolution of their symptoms, nine had marked improvement in their symptoms, as evidenced by infrequent attacks of reduced severity, and two failed to respond to valproate therapy. Four patients experienced relapse with a decreased dosage of valproate. Side effects associated with long-term valproate administration were not observed. Valproate appears to be effective for the prophylactic management of severe CVS, with 85% of all patients achieving at least a reduction in the frequency of attacks.

Girl with accelerated growth, hearing loss, inner ear anomalies, delayed myelination of the brain, and del(22)(q13.1q13.2).

We report on an 18-month-old Japanese girl with 46,XX,del(22)(q13.1q13.2). To our knowledge, this is the first report of a case of interstitial deletion of a 22q13.1-q13.2 segment. Clinical features included hearing loss accompanied by inner ear anomalies, hypotonia and minor anomalies, such as a long philtrum, full eyelids, epicanthus, left transverse palmar crease and psychomotor developmental delay. Despite the chromosomal deletion, her physical growth was accelerated: her height was between the 75th and 90th percentiles for her age. Her brain MRI showed signs of delayed myelination. The three-dimensional MRI of the inner ear showed abnormalities of the cochlea and vestibule in both ears. Clinical features of the patient are similar to those of a patient with a del(22)(q13.1q13.33) karyotype previously reported by Romain et al.

Prenatal diagnosis of Menkes disease by genetic analysis and copper measurement

Carrier detection for 12 women and prenatal diagnosis for six fetuses in Japanese families with a patient with Menkes disease (MNK) were performed by gene analysis and/or measurement of the copper concentration in cultured cells. Six out of eight mothers of MNK patients were carriers while two (25%) were not carriers. Two unrelated patients showed the same mutation (R986X): one patients mother was a carrier while the other was not. One male and three female fetuses did not have the same mutant allele as the respective MNK proband and have been healthy since birth. One female fetus had the same mutant allele as her affected brother. Gene analysis is very useful and reliable, although such examination is only indicated in families in which a mutation has been identified. In one family in which a mutation in ATP7A was not found, cultured amniocytes from a male fetus had a high copper concentration. Thus after his birth, the biochemical findings confirmed the presence of MNK and early treatment was started. As his early treatment with parenteral copper-histidine prevented the neurological disorders effectively, prenatal diagnosis is very important.

Regional cerebral blood flow abnormalities in patients with kawasaki disease.

Purpose: Kawasaki disease (KD) is an acute febrile disorder of unknown etiology. Brain single-photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI) help in detecting regional cerebral blood flow abnormalities and brain damage. The usefulness of SPECT and MRI in patients with KD was evaluated. Materials and Methods: All 22 patients with KD underwent brain SPECT using Tc-99m-hexamethyl propylene amine oxime from 6 days to 3 years after onset, and 8 patients underwent brain MRI. Of the 22 patients, 4 had neurologic symptoms. Case 1 showed prolonged apnea; case 2, prolonged disturbance of consciousness; and cases 3 and 4 generalized tonic-clonic seizures. Initial brain SPECT showed localized hypoperfusion in 4 and 13 patients with and without neurologic symptoms, respectively. Results: All patients with neurologic symptoms underwent follow-up SPECT; localized hypoperfusion was detected between 1- and 6-month follow-up in 3 of these patients. Six patients without neurologic symptoms underwent follow-up SPECT. Localized hypoperfusion was detected at approximately 1- to 11-month follow-up in 4 of these patients. Diffusion-weighted imaging revealed abnormal high-intensity areas in the corpus callosum in case 1. Case 2 showed a bilateral chronic subdural hematoma with decreased size and ischemic changes, and case 3 showed bilateral hippocampal atrophy and left hippocampal sclerosis. Conclusions: Because the occurrence of localized hypoperfusion is possibly not restricted to only the acute phase in KD, brain SPECT and MRI should also be performed in KD patients with neurologic symptoms.

Protection from sepsis-induced acute renal failure by adenoviral-mediated gene transfer of β2-adrenoceptor

BACKGROUND Sepsis is a common cause of acute renal failure (ARF) and results in a high mortality rate. The objective of the present study was to evaluate adenoviral transgenes containing the human beta(2)-adrenoceptor (adeno-beta(2)-AR) as a possible therapy for subjects at high risk for developing sepsis-induced ARF. METHODS An endotoxaemic rat model of ARF was induced by renal artery occlusion plus subcutaneous injections of Escherichia coli in 4-week-old Wistar rats. A subset of rats was given intraperitoneal injection of the adeno-beta(2)-AR gene. RESULTS Sepsis produced a depression in glomerular filtration rate and in the renal beta(2)-AR signalling system, which were both reversed by delivery of the beta(2)-AR gene. While delivery of the adeno-beta(2)-AR gene had no effect on recovery of cytokines and C-reactive protein in the systemic circulation, it did significantly depress (P < 0.01) the expression of the renal cannabinoid-1 (CB-1) receptor, CD14, toll-like receptor 4 (TLR4) and tumour necrosis factor (TNF)-alpha protein. Gene delivery also increased nitric oxide (NO) and decreased angiotensin II (Ang II). Finally, transfer of the beta(2)-AR gene also improved the survival of the rats exposed to sepsis-induced ARF. CONCLUSIONS A renal-specific over-expression of beta(2)-AR, resulting from gene delivery, appeared to modulate renal dysfunction and inflammation following sepsis by altering cAMP-PKA, CB-1 and CD14-TLR4-TNF-alpha pathways. In addition, gene delivery and activation of beta(2)-AR produced modulation of systemic NO and Ang II, which further protected against renal dysfunction. Administration of the Adeno-beta(2)-AR gene has potential as a therapeutic agent against ARF following the onset of sepsis.

A case of a 2-year-old boy with tuberous sclerosis complicated with descending aortic aneurysm

Tuberous sclerosis (TS) is an autosomal dominant disorder associated with the development of multiple systemic hamartomas. Its classic triad includes seizure, mental retardation, and facial angiofibroma, and it is also known to be accompanied by various other complications. However, there are few reports on patients with TS who have developed an aortic aneurysm. We report a 2-year-old boy with TS who developed asymptomatic descending aortic aneurysm.

Renal Effects of β2-Adrenoceptor Agonist and the Clinical Analysis in Children

The objectives of the present study were to define the contribution of β2-adrenoceptors(β2-ARs) agonists to renal physiology and to investigate whether over-expression of renal β2-ARs might be implicated in the pathogenesis of renal dysfunction in children as an adverse effect of β2-AR activation. The renal functional responses to the systemic injection of the β2-AR agonist terbutaline in Wistar rats over-expressing renal β2-AR were compared with those of nontreated rats. Furthermore, we evaluated intrarenal β2-AR expression in 34 children (age 2–15 y) and the changes in serum creatinine levels of 99 children (age 1–15 y) who received β2-AR agonists. The animal study showed that the suppression of glomerular function by terbutaline was associated with a reduction in systemic blood pressure and over-expression of renal β2-ARs. Moreover, in rats over-expressing renal β2-ARs, administration of terbutaline resulted in a high mortality rate after a lipopolysaccharide challenge. The clinical study showed that renal β2-AR expression gradually increased with age and was up-regulated by steroid therapy. These findings indicate that the renal dysfunction caused by β2-AR agonists can be explained, at least partly, by enhanced β2-AR expression in the kidney. This may have important implications for the use of β2-AR agonists in the treatment of sick children with, for example, steroid therapy or endotoxemia.

Adenoviral delivery of the β2-adrenoceptor gene in sepsis: a subcutaneous approach in rat for kidney protection

Successful gene therapy requires gene delivery that is efficient, has an optimal route of administration and has biosafety. The aims of the present study were to evaluate the safety and applicability of the subcutaneous delivery route for adenoviral transgenes containing the human beta(2)-adrenoceptor (adeno-beta(2)-AR) and to investigate whether this approach prevented renal dysfunction in a rat model of endotoxaemic shock induced by LPS (lipopolysaccharide). Subcutaneous administration of adeno-beta(2)-AR (a total of 10(10) viral particles) significantly increased beta-AR density in the kidney, lung and liver, but was without effect on physiological and plasma biochemical parameters. Moreover, this dose of virus did not cause any of the potential toxic responses of viral administration, such as inflammation and tissue TNF (tumour necrosis factor)-alpha expression. Although the LPS challenge caused a decrease in glomerular filtration rate, fractional excretion of sodium and renal beta-AR density in all groups, the reduction in renal function was significantly less in the rats given adeno-beta(2)-AR compared with non-treated rats. Thus, although further evaluation will be required, this initial study demonstrated that the subcutaneous injection of adeno-beta(2)-AR was efficient, comparatively non-pathogenic and potentially therapeutic to deal with acute renal failure associated with sepsis.

Circadian rhythm of the autonomic nervous system in long QT syndrome

The circadian changes in the activity of the autonomic nervous system in a group showing long QT duration in electrocardiogram (ECG) were studied in order to differentiate symptomatic congenital long QT syndrome from asymptomatic. The asymptomatic group presented only long QT duration (QTc > 0.46). Seven girls and two boys, including two subjects experiencing syncope of non‐neurological origins, were examined by using heart rate (HR) power spectrum analysis. In three subjects, the peak of the high frequency band, indicating the parasympathetic activity, disappeared during night‐time (sleep), which means the possibility of a high risk of sudden cardiac death. In two of three subjects, moreover, the averaged sympathetic activity during daytime was significantly increased compared to that during night‐time, in addition to the abrupt increase of sympathetic activity in the morning. These two subjects, in which one boy had a family history of Romano‐Ward syndrome, were the same people experiencing the syncope attack. We succeeded in objectively elucidating that congenital long QT syndrome is adrenergic‐dependent, and suggest that HR power spectrum analysis may be of value in distinguishing symptomatic congenital long QT syndrome from asymptomatic showing only long QT duration.