Abnormal calcium homeostasis in astrocytes from the trisomy 16 mouse

BACKGROUND: The laparoscopic application of LAP-BAND is gaining widespread acceptance as a gastric restrictive procedure. At the same time the reported morbidities (i.e., gastric perforation, stomach and/or band slippage) are cause for some concern. METHODS: From September 1993 until May 1997, 260 patients underwent LAP-BAND at the Department of Surgery at the University of Padova, Italy. RESULTS: The mortality rate was zero and the morbidity rate requiring reoperation was 3.4% (stomach slippage, gastric perforation, erosion). In order to avoid complications the key points of the technique are reviewed: (1) reference points for dissection (equator of the balloon, left crus); (2) retrogastric tunnel within the layers of the phrenogastric ligament; (3) embedment of the band; (4) proper outlet calibration; and (5) retention sutures. CONCLUSIONS: Attention to technical details is of paramount importance for a safe, standardized and effective operation.     

Status epilepticus related to alcohol abuse

We reviewed the case records of 249 adult patients with generalized convulsive status epilepticus (SE) examined in San Francisco General Hospital between 1977 and 1989 and identified 27 patients (10.8%) in whom alcohol abuse was the only identifiable precipitating cause of SE. In 12 patients (44% of the study group), SE was the first presentation of alcohol-related seizures. Seizures with focal features were observed in 11 patients (40.1%), but there was little correlation with localized computed tomography (CT) or EEG abnormalities. SE was controlled with phenytoin (PHT), with or without a benzodiazepine (BZD), in 18 patients (66.7%). Twenty-two patients (81.5%) were discharged with no new neurologic deficits, but time to recovery of baseline mental status was prolonged (> 12 h) in 24 patients. With regard to alcohol abuse history, study patients did not differ from a comparison group with isolated alcohol withdrawal seizures. The results indicate that alcohol abuse is a common cause of SE and that SE may be the first presentation of alcohol-related seizures. Furthermore, the outcome of patients with alcohol-related SE compares favorably with that of patients with SE due to other causes, but recovery of these patients may be complicated by a prolonged postictal state.     

Superolateral dislocation of an intact mandibular condyle into the temporal fossa: a case report

An unusual case of superolateral dislocation of an intact mandibular condyle into the temporal fossa is reported. The different methods of treatment and the difficulties that may arise in the treatment of such cases are discussed briefly, and the literature is reviewed.     

Long-lasting complete inhibition of human solid tumors in SCID mice by targeting endothelial cells of tumor vasculature with antihuman endoglin immunotoxin

In the present study, we developed an antitumor immunoconjugate that appears to be promising as a novel curative antitumor agent against a variety of human solid tumors. We generated a new antihuman endoglin (EDG) monoclonal antibody (mAb) K4-2C10 (or termed SN6f) that cross-reacts with mouse endothelial cells. Such cross-reactive anti-EDG mAbs have not been reported previously. This mAb was used to target tumor-associated vasculature in SCID mice inoculated with human tumors. No anti-EDG mAb or its immunoconjugates have previously been successfully used for targeting vasculature in vivo. In this study, MCF-7 human breast cancer cells were inoculated s.c. into SCID mice. K4-2C10 did not react with the MCF-7 cells but showed a weak reactivity with mouse endothelial cells. The mAb reacted with the proliferating endothelial cells more strongly than with the quiescent endothelial cells. The mAb exhibited much stronger reactivity (>10-fold) with human endothelial cells than with mouse endothelial cells and reacted strongly with vascular endothelium of tumor-associated blood vessels in a variety of human malignant tissues. Conjugates of K4-2C10 with ricin A chain (RA) and deglycosylated ricin A chain (dgRA) showed a weak but specific cytotoxic activity against murine endothelial cells in vitro; the 50% inhibitory dose of the RA and dgRA conjugates was 54 nm and 29 nm, respectively. Remarkable antitumor efficacy was observed when a small amount (a total of 60 microgram corresponding to 24% of the LD50 dose) of the dgRA conjugate was administered i.v. into SCID mice that had been inoculated s.c. with MCF-7. Unconjugated mAb K4-2C10 was not significantly effective in the inhibition of the tumor growth. The immunotoxin (IT) completely inhibited growth of the tumor in all of the treated mice (n = 8). Furthermore, similar antitumor efficacy was observed when the IT was administered i.v. into the tumor-inoculated SCID mice that had been pretreated with unconjugated K4-2C10 to block the potentially available weak binding sites of normal tissues. The strong therapeutic effects of the IT were reproduced in another set of therapeutic experiments. No significant side effects were observed in the mice. The differences in the tumor growth between the control group and the IT-treated groups were statistically significant. The IT showed antiangiogenic activity in the dorsal air sac method. The results indicate that K4-2C10 IT effectively treated the tumor-bearing mice by selectively inhibiting the tumor-associated blood vessels and by disrupting tumor-associated angiogenesis. The strong antitumor efficacy of the K4-2C10 IT is remarkable in view of the fact that K4-2C10 and its IT showed only a weak reactivity with mouse endothelial cells, and a relatively small amount of the IT was administered i.v. to treat s.c. tumors. We anticipate that the K4-2C10 IT will show much stronger antitumor efficacy and antiangiogenic activity in patients with solid tumors and other angiogenesis-associated diseases. The present results demonstrate for the first time that an anti-EDG mAb or its immunoconjugate can effectively target tumor-associated vasculature in vivo.     

Effect of disposition of mannich antimalarial agents on their pharmacology and toxicology

The use of the antimalarial agent amodiaquine has been curtailed due to drug-induced idiosyncratic reactions. These have been attributed to the formation of a protein-reactive quinoneimine species via oxidation of the 4-aminophenol group. Therefore, the effects of chemical modifications on the disposition of amodiaquine in relation to its metabolism, distribution, and pharmacological activity have been investigated. The inclusion of a group at the C-5' position of amodiaquine reduced or eliminated bioactivation, as determined by glutathione conjugate formation in vivo. This can be seen in two series of C-5'-substituted compounds: the bis-Mannich antimalarial agents, including cycloquine and pyronaridine, and mono-Mannich antimalarial agents containing a 5'-chlorophenyl group (tebuquine and 5'-ClPAQ). Chemical substitution at the C-5' position also resulted in compounds which underwent slower elimination (<5% of the dose excreted into bile and urine, compared with 50% for amodiaquine) and increased levels of accumulation in tissue (10% of the dose in the liver at 48 h compared with 1% with amodiaquine). This may be due to an increase in either the lipophilicity or the basicity of the analogs and may reflect the lack of metabolic clearance for these compounds. The alteration in the disposition following the introduction of the C-5' substituent resulted in an increased duration of antimalarial activity in the mouse compared with that for amodiaquine. While this is desirable in the treatment of malaria, repeated administration for prophylaxis may induce toxicity through accumulation. Therefore, by simple chemical modification it is possible to block the bioactivation of amodiaquine while maintaining and in some cases extending the duration of antimalarial activity.