Correlation between deletion patterns of SMN and NAIP genes and the clinical features of spinal muscular atrophy in Japanese patients

We conducted molecular analysis of two candidate genes for spinal muscular atrophy (SMA), the survival motor neuron gene (SMN) and the neuronal apoptosis inhibitory protein gene (NAIP), in 16 Japanese patients with SMA and compared the phenotypic features of SMA in these patients with the corresponding genotypes. Exons 7 and/or 8 of SMN were homozygously deleted in 11 SMA type I (Werdnig-Hoffmann disease) patients, two SMA type II patients and one SMA type III patient. Exons 5 and 6 of NAIP were homozygously deleted in six SMA type I patients. No patient had a deletion in NAIP without a deletion in SMN. Mechanical ventilation was required during the first 7 months of life in the SMA type I patients who had a deletion in both SMN and NAIP. Ventilatory support was initiated within 2 years after birth in patients who had a deletion in SMN but not in NAIP. We detected homozygous deletion of exon 5 of NAIP in the unaffected mothers of two SMA type I patients. In these families, the patients exhibited a deletion in both SMN and NAIP. The parents and unaffected siblings of these patients did not have a deletion in SMN. The present findings support the hypothesis that SMN deletion plays an important role in the development of SMA and suggest that combined deletion of both SMN and NAIP may be relevant for determining the disease severity.     

Possible Involvement of Hypothyroidism as a Cause of Lithium-Induced Sinus Node Dysfunction

Although several reports have stated that even therapeutic levels of lithium can induce sinus node dysfunction, the mechanism has not been fully elucidated. We present here two patients with sinus node dysfunction after long-term lithium therapy. Following lithium discontinuation, sinus node function recovered completely. After resuming lithium, however, irreversible sinus node dysfunction recurred and a permanent pacemaker was implanted in one patient. The serum concentration of lithium was within therapeutic levels. Nevertheless, hypothyroidism was associated with the sinus node dysfunction in both patients. Thus, thyroid function may play an important role in sinus node dysfunction induced by lithium. (PACE 1999; 22[Pt. I]-.954-957) lithium, sinus node dysfunction, hypothyroidism, sick sinus syndrome     

Effect of Low Dose Aspirin on Augmented Piasminogen Activator Inhibitor Type 1 Activity in Patients with Permanent Pacemakers

To clarify the activity states of coagulation and fibrinolysis in patients with a permanent pacemaker, we studied 29 patients more than 4 months after operation. They were divided into a single pacemaker lead group (S, n = 14) and a double lead group (D, n = 15). Prothrombin time, activated partial thromboplastin time, fibrinogen, antithrombin III, tissue-type plasminogen activator (tPA) activity, plasminogen activator inhibitor type-1 (PAI-1) activity, and platelet aggregation were measured and compared to those in an age-matched control group (C, n - 7). The effects of low dose aspirin (81 mg/day) in the patients (n = 21) were also studied 2 weeks after administration. PAI-1 activity in groups S and D was significantly higher than that in the group C (53.5 ± 36.5, 86.8 ± 59.2 ng/ mL vs 19.4 ± 7.2 ng/mL; P < 0.01 and P < 0.005). Platelet aggregation induced by collagen was slightly higher in groups S and D than group C. Other parameters were not significantly different. In the patients, low dose aspirin significantly suppressed collagen induced platelet aggregation (71.8 ± 20.3% vs 41.7 ± 28.3%; P < 0.005), but not PAI-1 activity. tPA activity was increased significantly by the low dose aspirin administration (3.94 ± 1.85 ng/mL vs 2.48 ± 1.19 ng/mL; P < 0.005). Thus, PAI-1 activity in patients with a permanent pacemaker is elevated, and the activity is not suppressed by low dose aspirin unlike the platelet aggregation.     

Inhibitory Activity of Camptothecin Derivatives Against Acetylcholinesterase in Dogs and Their Binding Activity to Acetylcholine Receptors in Rats

Abstract— A camptothecin derivative, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11), shows a potent antitumour activity in experimental tumour models and in clinical trials. However, CPT-11 induced early diarrhoea and vomiting at high dose levels in clinical studies and showed an acetylcholine-like action on the guinea-pig ileum and trachea. In the present study, we investigated the activities of camptothecin derivatives in inhibiting acetylcholinesterase (AChE) and in binding to muscarinic acetylcholine receptors (AChR). CPT-11 inhibited AChE and binding of the specific ligand to AChR with respective 50% inhibition concentrations of 0·2 and 5 μm . These inhibitions were induced by camptothecin derivatives having an amino group at the C-10 position (or the C-4 position of hexacyclic derivatives), but were not or were only slightly induced by the others. Early defecation and vomiting in dogs were observed after intravenous injection of DU-6596 and DU-6888, two hexacyclic derivatives having the aminomethyl group at the C-4 position, and of CPT-11. DU-6174, however, which has a hydroxy group at this position, induced no early defecation and little vomiting. Plasma concentrations of CPT-11, DU-6596 and DU-6888 after intravenous treatment at doses causing such early adverse effects were maintained for 1 h or longer at levels sufficient to inhibit AChE. These results suggest that the inhibition of AChE by camptothecin derivatives with an amino group at the C-10 position (or the C-4 position) relates to the early defecation or diarrhoea and vomiting.     

Pathological effects of neoadjuvant hormonal therapy help predict progression of prostate cancer after radical prostatectomy

BACKGROUND: It is not clear whether pathological changes following neoadjuvant hormonal therapy (NHT) prior to radical prostatectomy have any value as predictors of progression in prostate cancer. METHODS: We conducted a study of 100 patients with prostate cancer who underwent radical prostatectomy following NHT. We used the Japanese general rule as the criterion to assess the biochemical recurrence rate and pathological changes after NHT. RESULTS: In terms of preoperative risk factors, the probability of recurrence was significantly higher for patients with more than 20 ng/mL of pretreatment serum prostate-specific antigen (PSA) and/or a Gleason score of 7 or higher for biopsy specimens. We defined these pretreatment findings as high-risk factors. Among 65 patients with high-risk factors, patients with a post-NHT pathological effect of grade 3 according to the Japanese general rule showed no recurrence, whereas patients with a grade 0 had a poor prognosis. Patients with a PSA nadir 0.5 ng/mL or less tended to have a better prognosis. CONCLUSION: Despite preoperative high-risk factors, patients showing good pathological effects after NHT tend to have a favorable prognosis after radical prostatectomy. Therefore; assessment of the pathological effects of NHT using the Japanese general rule as the criterion proved to be useful for the prediction of biochemical recurrence.     

Cooperative program for Asian pediatricians

The Cooperative Program for Asian Pediatricians (CPAP) is a non-government organization established in 1989 to promote mutual understanding and friendship among young pediatricians in Asian countries. Unlike other government programs and non-government organizations, CPAP is solely facilitating mutual relationships among young inexperienced pediatricians who would otherwise have no chance to travel overseas. It has been funded by donations from members of the alumni association of the Department of Pediatrics at the University of Tokyo and many private companies and individuals. The Cooperative Program for Asian Pediatricians has so far invited 36 Asian pediatricians from 11 countries. By constructing a human network among Asian pediatricians, it is hoped that CPAP will contribute to making international cooperation in the Asian region easier and smoother.     

Treatment of Malignant Neurocardiogenic Vasovagal Syncope with a Rate Drop Algorithm in Dual Chamber Cardiac Pacing

A 29-year-old man with malignant vasovagal syncope presented with episodes of abrupt loss of consciousness associated with an aura, totaling more than 10 episodes over 3 months. Holter monitoring showed cardiac arrest with a duration of 15 seconds. Oral propranolol and disopyramide therapy failed to prevent the syncope. A dual chamber pacemaker with a rate drop response algorithm successfully prevented the syncope but not the aura. There may be multifactors involved in the mechanism of this syndrome. The patient has returned to a normal active life. This rate drop algorithm is an effective therapy for the prevention of syncope in malignant vasovagal syncope.     

Microdislodgment:

High impedance tined steroid-eluting leads, Medtronic CapSure Z family, incorporating a small surface (1.2 mm²) electrode made of porous platinum material are designed to reduce battery current drain. However, in some prior studies, an increased incidence of microdislodgment with this lead was reported thought to be due to the reduced electrode surface area. This article reports the experience that ventricular pacing failure due to microdislodgment occurred after CapSure Z lead implantation and the previous literature is reviewed. (PACE 2003; 26[Pt. I]:1541–1543)     

Successful Treatment of Severe Orthostatic Hypotension with Erythropoietin

KAWAKAMI, K., et al .: Successful Treatment of Severe Orthostatic Hypotension with Erythropoietin. A 71-year-old man, who was diagnosed with familial amyloidosis type I, was admitted for treatment of severe orthostatic hypotension associated with recurrent syncopal attacks. Head-up tilt testing demonstrated severe orthostatic hypotension (114/72 mmHg in the supine position and 62/34 mmHg in the upright position) with syncope or presyncope. Oral midodorine and fludrocortisone therapies failed to prevent his symptoms. After administration of subcutaneous erythropoietin, his blood pressure drop in the upright position was decreased and symptoms disappeared unassociated with improvement of anemia. Although previous reports have shown that the mechanism by which erythropoietin improves orthostatic hypotension is related to improvement in anemia, other mechanisms may also play a role. (PACE 2003; 26[Pt. I]:105–107)