Spin and orbital quantization of electronic states as origins of second harmonic generation in semiconductors.

Basically different mechanisms of optical second harmonic generation (SHG) in semiconductors, induced by an external magnetic field H, have been identified experimentally by studying the diluted magnetic semiconductor (Cd,Mn)Te. For paramagnetic (Cd,Mn)Te the SHG response is governed by spin quantization of electronic states, in contrast with diamagnetic CdTe with its dominating orbital quantization. The mechanisms can be identified by the distinct magnetic field dependence of the SHG intensity which scales with the spin splitting in the paramagnetic case as compared to the H2 dependence observed for the diamagnetic case.

Magnetic-field-induced second-harmonic generation in semiconductor GaAs.

We show that application of a magnetic field induces optical second-harmonic generation (SHG) in GaAs. This phenomenon arises from field-induced symmetry breaking causing new optical nonlinearities. A series of narrow SHG lines is observed in the spectral range from 1.52 to 1.77 eV that we attribute to Landau-level quantization of the band energy spectrum. The rotational anisotropy of the SHG signal distinctly differs from that of the electric-dipole approximation. Model calculations reveal that nonlinear magneto-optical spatial dispersion that comes together with the electric-dipole term is the dominant mechanism for this nonlinearity.

Magnetic-field induced second harmonic generation in CuB2O4.

Three types of optical magnetic-field induced second harmonic (MFISH) generation are observed in CuB2O4. Unusually sharp and intense electronic transitions in MFISH and linear absorption spectra provide selective access to the two nonequivalent Cu2+ sublattices. The magnetic phase diagram for both sublattices is determined by MFISH. Magnetic structure is dominated by antiferromagnetic order at the 4b site. Sublattice interactions transfer it to the 8d site where it coexists with a discoupled paramagnetic component.

Antifilarial activities of benzazole derivatives. 3. Effects of benzothiazoles on third stage larvae and preadult worms of Acanthocheilonema viteae, Brugia malayi and B. pahangi in Mastomys natalensis.

Ten structurally defined benzothiazoles (5-methyl and the analogous 5-methoxy derivatives) with known macrofilaricidal and microfilaricidal activities were tested for efficacy against third stage larvae and preadult worms in Acanthocheilonema viteae, Brugia malayi, and B. pahangi infected Mastomys natalensis. Drugs were administered in single oral doses of maximally 100 mg/kg. The benzothiazoles were active against the two stages of the three species. Generally the 5-methoxy derivatives displayed slightly higher activity than the 5-methyl compounds. 6-Isothiocyanates (CGP 21306, CGP 20308) and 6-dithiocarbamic-S-(2-carboxyethyl)esters (CGP 21835, CGP 20376) were more active than thiocarbonylamides (CGP 21833, CGP 20309, CGP 26702, CGP 24589). 6-Dithiocarbamic-S-(sulfomethylsodium)esters (CGP 26701, CGP 24588) showed intermediate efficacy. A. viteae was usually slightly more resistant than the Brugia spp. Minimum curative doses (greater than 95% reduction of worms) against the two stages of the various species were either identical or preadult worms were slightly more resistant than third stage larvae. When these curative doses were compared with curative adulticidal doses or effective doses against microfilariae the various doses were very similar and never differed from each other by more than the factor 2.

Altered immune response (humoral and delayed-type hypersensitivity reactions) to sheep red blood cells in the course of experimental filarial infections (Litomosoides carinii, Brugia malayi, Acanthocheilonema viteae) of Mastomys natalensis.

Litomosoides carinii-, Acanthocheilonema viteae- or Brugia malayi-infected Mastomys natalensis were sensitised against sheep red blood cells (SRBC) on various occasions after infection to determine the effect of filarial infections on the immune response to a non-filarial antigen. The phagocytic activity of the reticuloendothelial system (RES) was controlled in vivo by the elimination of 51Cr-labelled SRBC. Antibody titres against SRBC (agglutinating and lytic antibodies) were similar to those of uninfected controls in L. carinii- or B. malayi-infected Mastomys sensitised during prepatency or early patency up to 90 days post infection (p.i.) but were reduced in animals sensitised during patency. A significant inverse correlation existed between anti-SRBC antibody titres and microfilaraemia levels. In contrast, A. viteae-infected Mastomys showed reduced humoral anti-SRBC responses at the end of prepatency, whereas the response tended towards normal with increasing parasitaemia. Delayed-type hypersensitivity (DTH) against SRBC was measured as footpad swelling after sensitisation by the s.c. or i.v. route and intraplantar challenge. DTH reactions were reduced during prepatency in all infections after s.c. sensitisation. During patency, 24-h reactions were similar to those of age-matched controls but the swelling persisted 24 or 48 h longer than in the latter. In A. viteae infections, even enhanced 24-h reactions were found during patency. Histological investigations did not reveal differences in the type of cell infiltrations between infected and control animals. After i.v. sensitisation with SRBC, L. carinii- and A. viteae-infected animals showed weaker DTH reactions than the controls, independent of the period after infection. In the case of B. malayi infections, DTH reactions were similar to those of controls during early prepatency, whereas reduced DTH responses were observed later than 50 days p.i. As shown in L. carinii-infected animals, depressed DTH reactions after i.v. sensitisation did not depend on an altered expression phase but rather on an altered regulation during the inductive phase of the response: increases in the sensitising SRBC doses that caused decreasing DTH reactions in uninfected animals led to enhanced reactions in infected animals. Phagocytosis of i.v. injected 51Cr-labelled SRBC was enhanced during prepatency in L. carinii infection and during patency in all infections.

Antifilarial activities of benzazole derivatives. 2. Microfilaricidal effects against Litomosoides carinii, Acanthocheilonema. vitae, Brugia malayi and B. pahangi in Mastomys natalensis.

The spectrum of antimicrofilarial activities of eighteen 2-tertbutylbenzazole derivatives was evaluated comparatively in Mastomys natalensis infected with Litomosoides carinii, Acanthocheilonema viteae, Brugia malayi or B. pahangi. The minimal effective dose (DEM) against microfilariae (greater than 95% reduction of microfilariae counts in the peripheral blood) was determined on day 3 (DEM-3), on day 7, 14, 21, 28 and 42 (DEM-7, DEM-14, DEM-21, DEM-28 and DEM-42) after the first treatment. All compounds were effective against the microfilariae of all 4 species. The benzoxazole derivatives were invariably less potent than the corresponding benzothiazole analogues. Upon repeated oral treatment (once daily [o.d.] for five days) the DEM-7 of the benzoxazoles varied depending on the species and on the chemical structure between 25 mg/kg o.d. x 5 and greater than 100mg/kg o.d. x 5 days. Within the benzothiazole series the DEM-7 varied between 6.25 mg/kg o.d. x 5 and 100 mg/kg x 5. In all but 5 of the 40 parasite-compound combinations of the benzothiazoles the 5-methoxy-derivates were more effective than the 5-methyl analogues. Similar differences were found with the eight benz-oxazoles tested. The lowest DEM-7 was observed with compound CGP 20308 which is 2-tert-butyl-5-methoxy-6-isothio-cyanatobenzothiazole and with compound CGP 20376 which is 3-(2-tert-butyl-5-methoxy-benzothiazol-6-yl] amino-thiocabo-nylthio) propionic acid.(ABSTRACT TRUNCATED AT 250 WORDS)

Antifilarial activities of benzazole derivatives. 1. Macrofilaricidal effects against Litomosoides carinii, Dipetalonema viteae, Brugia malayi, and B. pahangi in Mastomys natalensis.

Eighteen 2-tert-butyl-benzazole derivatives were evaluated comparatively as macrofilaricidal agents against L. carinii (L.c.), D. viteae (D.v.), B. malayi (B.m.) and B. pahangi (B.p.). Upon repeated treatment (once daily) for five consecutive days the eight benzoxazole derivatives were invariably less potent than the corresponding benzothiazole derivatives. The minimal curative dose (DCM) of the benzoxazoles varied depending on the species and on the chemical structure between 25 and 100 mg/kg p.o. once daily for five days. In the benzothiazole series the lowest DCMs were observed with compound CGP 20376 which is the 5-methoxy-6-dithiocarbamic-S-(2-carboxy-ethyl)ester derivative. This compound eliminated all macrofilariae of L.c., B.m. and Bp. at 6.25 mg/kg p.o. once a day for five days, whereas 12.5 mg/kg x 5 days were needed against D.v. For all other benzothiazole derivatives the DCMs varied between 6.25 mg/kg p.o. x 5 to 100 mg/kg x 5. Six of the most potent benzothiazoles were tested by single oral treatment. In general doses had to be increased 2-4 times to reach minimum curative effects. CGP 20376 was fully effective against B.m. and B.p. at 12.5 mg/kg p.o., against L.c. at 25 mg/kg p.o. and against D.v. at 50 mg/kg p.o.. This compound has been selected from this series of novel benzazoles as a first candidate for trials against human bancroftian filariasis.

Effect of ivermectin in Dipetalonema viteae and Litomosoides carinii infections of Mastomys natalensis.

In D. viteae infected M. natalensis oral or subcutaneous (s.c.) treatment with ivermectin on 5 consecutive days with at least 0.05 mg/kg and single dose treatment with 0.1 mg/kg caused a 100% reduction of microfilaraemia throughout the investigation period of 42 days. Using lower doses (lowest dose used 5 X 0.003 mg/kg) animals were free from circulating microfilariae at least until day 7. The drug was active against adult worms. Treatment with doses of 5 X 0.2 mg/kg and above resulted in 81-93% and 38-83% reductions of male and female worms, respectively. Lower doses caused inconsistent macrofilaricidal effects but mainly male worms were affected. After treatment with 5 X 3.25 mg/kg and above increased rates of pathologically altered intrauterine stages were found in surviving female worms. After treatment of L. carinii infected Mastomys with doses of at least 5 X 1.5 mg/kg animals remained amicrofilaraemic until autopsy on day 42 and in case of lower doses (lowest dose used 5 X 0.006 mg/kg) at least until day 7. After single dose treatment (s.c.) with 0.2 mg/kg and above animals were free from microfilariae in the blood throughout the observation period. Single dose treatment with 0.05 and 0.0125 mg/kg removed all microfilariae from the blood until 8 and 48 hours, respectively but microfilariae occurred in the blood again after 14 days. Ivermectin did not affect the numbers of adult L. carinii but female worms isolated 42 days after treatment with 5 X 0.78 mg/kg and above were free from motile, normally shaped microfilariae and contained increased rates of pathologically altered embryonic stages.(ABSTRACT TRUNCATED AT 250 WORDS)

Reaginic and homocytotropic IgG antibody response of Mastomys natalensis in experimental infections of filarial parasites (Litomosoides carinii, Dipetalonema viteae, Brugia malayi, B. pahangi).

Reaginic and homocytotropic IgG antibodies in sera using passive cutaneous anaphylaxis (PCA) test and antigen from Litomosoides carinii were followed in Mastomys natalensis, infected with L. carinii, Dipetalonema viteae, Brugia malayi or B. pahangi. Groups of animals with infections of various ages so as to cover a total infection period of up to 300 to 420 days post-infection (p.i.), depending on the species of parasites, were bled at 1- to 3-week intervals over periods of 50-112 days. In addition, intradermal tests were performed on animals infected with L. carinii to detect immediate type hypersensitivity. Reaginic antibodies were usually first detected in the 3rd week after infection. Thereafter, a marked increase of PCA titres was observed in the 4th week p.i. leading to maximum titres 4 weeks after infection with D. viteae and B. pahangi and 6 weeks after B. malayi infection. Mean maximum titres were between 1:40 and 1:160. Following the peak response, titres decreased markedly until the beginning of patency in infections with D. viteae, B. malayi and B. pahangi whereas a constant course was observed at this time in animals infected with L. carinii. A further rise in PCA titres occurred in all infections around the beginning of patency, resulting in maximum reagin levels in L. carinii infections (mean titre 1:80) and moderate titres in the other infections. During early patency there was an inverse relationship between microfilaraemia density and levels of reaginic antibodies. However, in the phase of decreasing parasitaemia in L. carinii infected animals, microfilariae counts and PCA titres were directly correlated. Homocytotropic IgG antibodies showed relatively constant PCA titres of about 1:20 in L. carinii infected Mastomys throughout the observation period. In D. viteae infections they were demonstrated at 30 days p.i., reaching titres of about 1:40. B. malayi infected animals showed a maximum titre of 1:40 40 days p.i.. Thereafter, titres decreased continuously and homocytotropic IgG antibodies were absent at 110 days p.i.. High titres were observed at day 150 but thereafter sera were negative. B. pahangi infected animals showed moderate titres (1:5) 35 days p.i.. Thereafter, antibodies were found at low titres until 115 days p.i.. Intradermal reactions in L. carinii infected animals generally increased in size from 30-60 but decreased when microfilariae appeared in the blood.(ABSTRACT TRUNCATED AT 400 WORDS)

Time courses of antibody levels in Mastomys natalensis after infections with Litomosoides carinii, Dipetalonema viteae, Brugia malayi or B. pahangi, Determined by ELISA.

Using a Litomosoides carinii adult antigen, time courses of antibody levels were followed by an ELISA in L. carinii, Dipetalonema viteae, Brugia malayi and B. pahangi infected Mastomys natalensis. Using various groups of infected animals, periods up to 400 days after infection were covered. In L. carinii infected Mastomys, antibodies were first detected 11 days p.i. and levels increased rapidly until day 40. Temporarily reduced levels about the beginning of patency were followed by increasing values until about 100 days p.i. Then the antibody content of the sera remained more or less constant until about 250 days p.i. although maximum levels were found at day 170. Thereafter, the antibody concentration in the sera declined slowly but high levels were still observed 390 days p.i. The antibody content was usually higher in animals with high microfilariae densities than in those with low microfilariae counts but relations could not be proven statistically. In D. viteae infected Mastomys, maximum antibody values were reached within the beginning of patency. Levels were not altered markedly until about 110 days p.i. Thereafter they decreased slightly but then remained constant until the end of the investigation period 350 days p.i. B. malayi infected animals showed a rapid increase of the antibody content in the sera; a maximum was reached by 20 days after the infection. Thereafter, somewhat constant levels were found for 4--5 months. After 300 days p.i. the antibody levels declined progressively, accompanied with increasing parasitaemia densities; after 380 days the levels reached about 2/3 of the maximum. However, despite this, no relation was found between the levels of parasitaemia and antibody in individual animals. In B. pahangi infections the main prepatent antibody increase occurred during week 5 p.i., when maximum values were observed. The beginning of patency and the early patency were accompanied with slightly declining antibody levels. From 150 days p.i. until the end of the investigation 400 days p.i., the antibody content of the sera was fairly constant.

Filarial infections of Mastomys natalensis and their relevance for experimental chemotherapy.

Experimental filarial infections of Mastomys natalensis, strain GRA Giessen, with Litomosoides carinii, Dipetalonema viteae, Brugia malayi (subperiodic), and Brugia pahangi were compared. Mean prepatent periods of 52, 57, 107, and 73 days p.i. were observed after subcutaneous inoculation of 40, 50, 85, and 70 infective larvae of L. carinii, D. viteae, B. malayi, and B. pahangi, respectively, in the neck region. All of the L. Carinii, D. viteae, and B. pahangi infected Mastomys showed a regularly detectable microfilaraemia. In B. malayi infections 95.5% of the animals developed parasitaemias, when the larvae had been inoculated in the neck region, whereas after groin infections only in 66.7% of the animals became patient. For both Brugia species, infections in the groin resulted in considerably lower microfilarial levels. Maximum microfilariae densities could be detected at day 120 (L. carinii) and at day 1980 (D. viteae) p.i. In the case of Brugia neck infections, the microfilarial levels increased usually until the end of the observation period, 300-350 days p.i. Worm recovery rates were 63% (L. carinii), 20.6% (D. viteae), 21.1% (B. malayi), and 31.4% (B. pahangi) of the inoculated larvae. When third stage larvae of Brugia species were inoculated in the neck region, adults of B. malayi and B. pahangi were isolated predominantly from the heart of lungs (84.4 and 78.5%, respectively). Only 12.3% of B. pahangi parasites were found in the testes; 3.4% and 18.1% were localized in the lymphatics. After inoculation of infective larvae in the groin more worms could be recovered in the testes and lymphatics, i.e. 23.4% and 14.9% (B. malayi) or 19.1% and 45.2% (B.pahangi), respectively. The results are discussed under the aspect of chemotherapeutic investigations for the evaluation of microfilaricidal, macrofilaricidal or chemoprophylactic compounds. It is concluded, that Mastomys natalensis, an animal with a broad spectrum of susceptibility for filarial infections, can be used as an alternative experimental model system, similar to that of the jird.

Chemotherapeutic studies on Litomosoides carinii infection of Mastomys natalensis. 8. The action of furazolidone on adult worms and microfilariae.

After oral administration of furazolidone in doses of 5 x 50 mg/kg and 1 x 100 mg/kg body weight to Litomosoides carinii--infected Mastomys natalensis microfilaraemia decreased continuously and was reduced by more than 98% 42 days after start of treatment. After the 5-day treatment all adult female and male worms were found dead and encapsulated within 2 weeks, whereas after the single dose 100% of the female parasites were encapsulated 28 days after treatment. In untreated animals quantiative examinations of the intrauterine stages showed an average number of 500 x 103 embryos per adult female worm. Following the 5-day treatment the number of embryos per female parasite was reduced after 42 days to 12.5 x 103, and after the single treatment to 26.9 x 103. By classification into 5 different stages (2- and 4-cell stages, Morula stage, "Horse-shoe" stage, "Ring" and "Brezel" stages, and intruterine microfilariae) an embryogram showed a continuous increase in pathologically-altered embryos during the whole observation period. The 2- and 4-cell stages suffered the most damaged. By 16 days after the end of the 5-day treatment and by 28 days after the single treatment all embryonic stages in the uteri were found to be pathologically altered. Furazolidone possessess high macrofilaricidal activity together with a considerable adverse effect on embryognesis and some delayed effect on microfilaraemia.

On Dipetalonema viteae infection of Mastomys natalensis.

Experimental infections were carried out with the tissue-dwelling filaria Dipetalonema viteae using the argasid tick Ornithodorus moubata as the intermediate and the multimammate rat Mastomys natalensis (Strain GRA Giessen) as the final host. The optimum infective dose was found to be 50 third-stage larvae, which produced patent infections and the recovery rates of adult parasites were 47.6 and 26.4% of the inoculated larvae 140 and 189 days after infection, respectively. After an average prepatent period of 57 days, the microfilaraemia increased progressively and reached relatively low maximum values about 192 days after infection. These maximum values were followed by rapid decrease of microfilaraemia, but microfilariae were still detectable at 261 days post infection. Following the subcutaneous injection of infected animals with dexamethasone in single doses each of 1, 10 or 20 mg/kg body weight 30 minutes before blood puncture, a dose-dependent increase in the microfilarial counts in the circulating blood was observed, this reaching maximum values between 120 and 160 days after infection. Repeated administration of single doses of 10 mg/kg dexamethasone revealed an uniform but temporary increase in the microfilaraemia but this was not associated with any alterations in the reproductive organs of adult female parasites. No correlation could be found between the number of microfilariae in the circulating blood and the number of adult worms recovered from the subcutaneous connective tissue. At necropsy 300 days after infection living female parasites could not be found any more.

Chemotherapeutic studies on Litomosoides carinii infection of Mastomys natalensis. 7. Filaricidal activity of furazolidone.

Investigations were carried out on the filaricidal activity of furazolidone against Litomosoides carinii infection in Mastomys natalensis. Oral administration of the drug in daily doses of 25, 50, 75, and 150 mg/kg body weight on 5 consecutive days revealed respectively 96,4, 99,3 and, with the two later doses, 100% reduction of macrofilariae in the pleural cavities, and produced a continuing dose-dependant decrease of microfilaraemia in the circulating blood. After oral doses of 5 x 50 mg/kg, all the adult parasites were killed within two weeks of the start of treatment and were found encapsulated in fibrinous masses in the pleural cavities. Deformed and degenerated embryonic stages could be seen in female worms as early as 3 days after the end of treatment. Furazolidone possesses a considerable chemotherapeutic index.