Sonodynamic Therapy: Advances and Challenges in Clinical Translation

Sonodynamic therapy (SDT) consists of the synergetic interaction between ultrasound and a chemical agent. In SDT, the cytotoxicity is triggered by ultrasonic stimuli, notably through cavitation. The unique features of SDT are relevant in the clinical context more than ever: the need for efficacy, accuracy, and safety while being noninvasive and preserving the patient's quality of life. However, despite the promising results of this technique, only a few clinical reports describe the use of SDT. The objective of this article is to provide an extensive overview of the clinical and preclinical research conducted in vivo on SDT, to identify the limitations, and to detail the developed strategies to overcome them.     

The Protective Role of Glutathione, Cysteine and Vitamin C against Oxidative DNA Damage Induced in Rat Kidney by Potassium Bromate

The roles of glutathione (GSH), cysteine, vitamin C., liposome-encapsulated superoxide dismutase (L-SOD) and vitamin E in preventing oxidative DNA damage and cytotoxicity in the rat kidney after administration of potassium bromate (KBrO₃) to male F344 rats were investigated by measuring 8-hydroxydeoxyguanosine (8-OH-dG), an oxidative DNA product, lipid peroxidation (LPO) levels and relative kidney weight (RKW). Combined pre- and posttreatment of animals with 2 × 800 mg/kg GSH i.p. inhibited the increase of 8-OH-dG, LPO levels and RKW caused by 80 mg/kg KBrO₃ i.p. administration. In contrast, pretreatment with 0.3 ml/kg diethylmaleate (DEM) i.p., a depletor of tissue GSH, was associated with elevation of 8-OH-dG, LPO levels and RKW after a 20 mg/kg KBrO₃ i.p. treatment, which itself caused no change. Administration of KBrO₃ itself reduced renal non-protein thiol levels, but this was inhibited by the two doses of exogenous GSH. Combined treatment with DEM and KBrO₃ lowered the non-protein thiol level in the kidney more than did DEM treatment alone. Protective effects against the oxidative damage caused by KBrO₃ were also observed for pre- and posttreatment with 400 mg/kg cysteine i.p., another sulfhydryl compound, and daily i.g. application of 200 mg/kg vitamin C for 5 days. However, no influence was evident after pre- and posttreatment with 18,000 U/kg L-SOD i.p. or daily i.g. 100 mg/kg of vitamin E for 5 days. The results suggest that intracellular GSH plays an essential protective role against renal oxidative DNA damage and nephrotoxicity caused by KBrO₃.     

Synthesis of 1-N-(D-threo- and racemic erythro-3-amino-2-hydroxybutanoyl)-2',3'-dideoxykanamycin A

1-N-(D-Threo-3-amino-2-hydroxybutanoyl)-2',3'-dideoxykanamycin+ ++ A has been prepared by coupling of 3,6'-bis(N-benzyloxycarbonyl)-2',3'-dideoxy-3"-N-(trifluoroacetyl)kanamy cin A with D-threo-3-azido-2-hydroxybutanoic acid. A diastereomeric mixture of the erythro analog has also been prepared by use of racemic erythro-3-azido-2-hydroxybutanoic acid. Synthesis of the D-threo- and racemic erythro-3-amino-2-hydroxybutanoic acids has been described.     

Pathogenesis of pancreatic atrophy by avian influenza a virus infection

Specific-pathogen-free (SPF), 2-day-old chicks were inoculated with type A influenza virus (A/whistling swan/Shimane/499/83/(H5N3)) into their caudal thoracic air sac. The original isolate of the virus was of low virulence (ICPI 0. 20 to 0.40), and was passaged 10 times through the respiratory organs of SPF chicks. Most of the chicks inoculated with the passaged virus (strain 499) showed respiratory and alimentary signs. Three of 30 chicks died on days 2, 6 and 7 post-inoculation (p.i.). Almost half of the infected chicks showed poor growth, and the variation of body size in the flock became prominent from day 10 p.i. Infected chicks consistently had pathological changes in the pancreas, liver, kidneys and respiratory tracts, and occasionally in the brain, duodenum and bone marrow. Positive immunoreaction to avian influenza virus (AIV) antigen and recovery of the virus persisted for longer period in the pancreas than in other organs. The pancreatic lesions were caused by a direct, lytic virus infection of the acinar cells and contributed to poor growth of the chicks.     

Specificity of co-promoting effects of caffeine on thyroid carcinogenesis in rats pretreated with N-bis(2-hydroxypropyl)nitrosamine

The specificity of copromotion effects of caffeine with known goitrogenic factors on thyroid carcinogenesis was examined in rats pretreated with N-bis(2-hydroxypropyl)nitrosamine (DHPN). Male F344 rats were divided into 8 groups, each consisting of 10 animals, and received a single sc injection of 2,800 mg/kg DHPN. From one week after the DHPN initiation, they were given basal diet, iodine deficiency (ID) diet, 500 ppm phenobarbital (PB) solution or 1,000 ppm sulfadimethoxine (SDM) solution with or without 1,500 ppm caffeine feeding for 12 weeks. The caffeine, PB, SDM, and ID treatments significantly (p < 0.05 or 0.01) increased the relative thyroid weights, and the increases with PB or ID were further (p < 0.05 or 0.01) enhanced in combination with caffeine. SDM drastically promoted thyroid carcinogenesis in association with increased serum TSH levels regardless of the caffeine treatment. Thyroid follicular carcinomas and adenomas were more frequently observed in the additional caffeine groups than in the ID alone groups. The incidence and multiplicity of focal thyroid follicular hyperplasias in the ID-treated groups were significantly (p < 0.05 and 0.01) elevated in the case of combination with caffeine. Increases in serum TSH levels with PB or ID were also further enhanced in combination with caffeine. Serum thyroid hormone levels were significantly (p < 0.01) decreased by SDM but significantly (p < 0.05 or 0.01) increased by caffeine, PB or ID. Our results clearly indicate that dietary caffeine at a high dose of 1,500 ppm interacts with ID, but neither SDM nor PB, to promote rat thyroid carcinogenesis although the combined caffeine + PB treatment somewhat affected thyroid weights as well as thyroid hormone levels.     

Canine ganglioneuroblastoma in the oral mucosa

A ganglioneuroblastoma of the oral cavity in a dog was examined histologically and immunohistochemically. This rare neoplasm was considered to be derived from ectopic neural crest cells. This is the first report of a canine ectopic ganglioneuroblastoma located in the oral mucosa.     

Ultrastructure of cryptosporidial life cycle in chicken host cells

Ultrastructural studies were conducted on cryptosporidia in various stages of the life cycle, attached to the epithelial cell surface of the bursa of Fabricius, caecum and trachea in six 5 and 6-week-old chickens fed faeces containing cryptosporidial oocysts. The stages observed were sporozoites or merozoites penetrating the host cells, trophozoites, schizonts, macrogametocytes, microgametocytes and oocysts. The cryptosporidia in the chickens were morphologically and developmen-tally similar to those reported previously in other animals and humans. All the life cycle stages were recognised in each organ examined and sporulating oocysts were found adherent to the host cells. Trophozoites, schizonts and macrogametocytes were common in each organ examined, while oocysts were found only occasionally and microgametocytes and sporozoites or merozoites were uncommon.     

Association of essential hypertension in elderly Japanese with I/D polymorphism of the angiotensin-converting enzyme (ACE) gene

Recent evidence suggests that an insertion/deletion (I/D) polymorphism of the gene encoding angiotensin-converting enzyme (ACE) is associated with myocardial infarction and related cardiovascular diseases. We investigated a possible association of the ACE polymorphism with essential hypertension in a total of 263 cases/controls from among the elderly (age, over 70 years) and middle-aged (age between 30 and 60 years) Japanese population. The frequency of the I/I homozygote was significantly higher in hypertensive subjects than in controls in the elderly age group (33/57 vs 16/46; P = 0.02), but no association was observed in the middle-aged group (25/75 vs 26/85; P = 0.71). Similarly, having at least one insertion allele was associated with essential hypertension in the elderly age group (83/114 vs 46/92 in controls; P = 0.001), but not in the middle-aged group (78/150 vs 94/170; P = 0.524). These data suggest that genetic variation at the ACE locus may be associated with some determinants for blood pressure in elderly persons, and imply the involvement of the ACE insertion/deletion polymorphism in the etiology of age-related essential hypertension in the Japanese population. Received: April 18, 2000 / Accepted: July 25, 2000