CD44 ligation induces apoptosis via caspase- and serine protease-dependent pathways in acute promyelocytic leukemia cells.

We have recently reported that ligation of the CD44 cell surface antigen with A3D8 monoclonal antibody (mAb) triggers incomplete differentiation and apoptosis of the acute promyelocytic leukemia (APL)-derived NB4 cells. The present study characterizes the mechanisms underlying the apoptotic effect of A3D8 in NB4 cells. We show that A3D8 induces activation of both initiator caspase-8 and -9 and effector caspase-3 and -7 but only inhibition of caspase-3/7 and caspase-8 reduces A3D8-induced apoptosis. Moreover, A3D8 induces mitochondrial alterations (decrease in mitochondrial membrane potential DeltaPsi m and cytochrome c release), which are reduced by caspase-8 inhibitor, suggesting that caspase-8 is primarily involved in A3D8-induced apoptosis of NB4 cells. However, the apoptotic process is independent of TNF-family death receptor signalling. Interestingly, the general serine protease inhibitor 4-(2-aminoethyl)-benzenesulfonyl fluoride (AEBSF) decreases A3D8-induced apoptosis and when combined with general caspase inhibitor displays an additive effect resulting in complete prevention of apoptosis. These results suggest that both caspase-dependent and serine protease-dependent pathways contribute to A3D8-induced apoptosis. Finally, A3D8 induces apoptosis in all-trans-retinoic acid-resistant NB4-derived cells and in APL primary blasts, characterizing the A3D8 anti-CD44 mAb as a novel class of apoptosis-inducing agent in APL.     

Synthesis and the Antiinflammatory Activity of New N-Acyl-5-Bromanthranilamides

Nineteen N-acyl-5-bromanthranilic acid amides were synthesized via acylation of 5-bromanthranilamide with suitable anhydrides. The antimicrobial activity of the synthesized compounds with respect to Staphylococcus aureus and Escherichia coli was evaluated. Compounds with diphenyl, furoyl, and tetrachlorophthalyl moieties in the acyl part of the molecule showed significant inhibition of microbial growth. The minimum inhibiting concentrations of this compounds were 15.6 μg/ml against S. aureus and 15.6 – 31 μg/ml against E. coli. Other tested amides were considerably less active.__________Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 39, No. 1, pp. 17 – 18, January, 2005.     

Neuroleptic drugs in the management of behavioral symptoms of Alzheimer's disease.

Physicians have long been wary of chronically administering neuroleptic drugs to the demented elderly for fear of significant side effects. In this article, the authors present evidence to support these fears. A discussion of the early and late emerging side effects of neuroleptic drugs is presented.     

Ganglioside or sialic acid attenuates ethanol-induced decrements in locomotion, nose-poke exploration, and anxiety, but not body temperature.

1. This laboratory has previously reported that pretreatment with ganglioside, or even with its constituent, sialic acid (SA), can attenuate certain intoxicating effects of ethanol. It was important to see if these findings could be replicated, particularly by using other measures of ethanol effects. Herein we report that pretreatment with either gangliosides or SA attenuated ethanol-induced decrements in locomotion, nose-poke exploration, and anxiety, but not body temperature. 2. An ethanol dose of 4 gm/kg caused a temperature drop of about 3 degrees C, which was unaffected by any pretreatment. The onset to sleep, however, was delayed an average of 18 or 36 secs in mice pretreated with ganglioside or SA, respectively. Ethanol-only (4 gm/kg) depressed mean cumulative locomotor activity to 31% of normal, whereas the depression was 83% of normal with beef brain ganglioside pretreatment. At 2 gm/kg ethanol alone decreased nose poking in a hole-board test to 29% of normal, but the depression was only 55-63% of normal with SA or ganglioside pretreatment. In a staircase climbing anxiety test, this dose of ethanol had no effect by itself, but both ganglioside and SA pre-treatment increased climbing by 22%. Ethanol did depress rearing to only 11% of normal, whereas rearing was 51 and 99% of normal with SA and ganglioside pretreatment, respectively. In a dark-preference test, ethanol-only caused mice to spend 64% of the time in the light, compared to 31% for controls. Time in the light was only 39 and 46% with ganglioside and SA pretreatment, respectively. 3. Blood levels of ethanol were not significantly affected by pretreatment. 4. When given alone, gangliosides significantly stimulated locomotion and staircase climbing. SA significantly decreased rearing in the staircase test. Both gangliosides and SA tended to increase nose poking, number of crossings in the dark-preference test, and time in a lighted compartment. Thus, it is possible that some of the attenuation of intoxication is attributable to non-specific stimulant properties of gangliosides and SA.     

Critical illness polyneuromyopathy after artificial respiration.

Up to now, 71 critically ill patients have been reported with neuromuscular complications after artificial respiration. The authors review the literature and present data of a personal series of 22 patients all suffering from severe flaccid tetraparesis and muscle atrophy, which developed after an average of two weeks artificial respiration. The prognosis was relatively good in those surviving the primary disease. The multiconditional causes are discussed with emphasis on the combination of polyneuropathy and myopathy. Tumor necrosis factor (TNF), a key mediator of sepsis, which also has an influence on muscle and nerves, is mentioned as a possible cause of this illness.     

Temporal summation of repetitive click stimuli

Monaural loudness balances were performed by eight normal-hearing subjects to determine the effect of click repetition rate on loudness sensation. Click trains of 500 msec duration were matched in loudness to a standard 500 msec 1000 Hz tone burst presented at three reference loudness levels (70, 80, and 90 phons). Click trains were presented at repetition rates of 11, 31, 51, and 91 clicks per sec. It was found that click trains at faster repetition rates required lower intensities for judgments of equal loudness sensation. This finding was attributed to the process of temporal loudness summation. The magnitude and nature of the temporal summation process as well as the influence of the reference loudness level are discussed.     

Quality of life and mechanical heart valve sound

Most currently used mechanical heart valve prostheses generate a distinct metallic sound at closure. Since this sound is often well audible to many patients it can significantly affect their quality of life after heart valve replacement. In this study of surviving patients after heart valve replacement with three types of Bj?rk-Shiley valves (Shiley Inc., Irvine, Ca) one third of the patients claimed that they were in certain situations disturbed by the sound. Several factors were found to be of importance for the perception of mechanical heart valve noise, including age, sex, location of valve, configuration of the thorax, hearing ability and environmental background noise. Preoperative patient information can be of vital importance to avoid postoperative adverse patient reactions.     

Occupation and bladder cancer in Spain: a multi-centre case-control study

A case-control study on bladder cancer was carried out in four regions of Spain. The study included 497 cases (438 males and 59 females), 583 hospital controls and 530 population controls matched by sex, age and residence. The present paper reports the results of the analyses on occupational history. Among men, an increased risk of bladder cancer was found for textile workers (OR = 1.97, 95% CL 1.2-3.3), mechanics and maintenance workers (OR = 1.86, 95% CL 1.2-2.8), workers in the printing industry (OR = 2.06, 95% CL 1.0-4.3) and for managers (OR = 2.03, 95% CL 1.2-3.5). The risk was highest among those first employed in the textile industry before the age of 25 and prior to 1960. Among mechanics the risk was highest for those who started after the age of 25 and later than 1960. The OR for smokers who had also been employed in one of the high risk occupations was 7.82 (95% CL 4.4-14.0) which is compatible with a multiplicative effect of joint exposure to tobacco and occupational hazards.     

Epidemiology of acute diarrhea in children living in Sicily

A longitudinal survey (February 1984 - January 1985) on the incidence of acute diarrhea episodes in a sample of 8,164 children (aged 0–12 years) living in southeastern Sicily was carried out by means of weekly telephone interviews with doctors practising in the territory. The incidence rate was 0.479 (0.472–0.485 95% C.I.) per child per year and the frequency of episodes was significantly higher (p < 0.001) in children aged 0–4 years (0.86). Diarrhea was more frequent in industrial areas than in rural ones, and almost half (45.1%) of the total episodes had a mild course. No death from diarrhea occurred and admission to hospital was reported for 8.4% of all cases.Corresponding author.