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PubMed2003

Meiotic recombination and spermatogenic impairment in Mus musculus domesticus carrying multiple simple Robertsonian translocations.

We quantitatively analyzed the spermatogenic process, including evaluation of seminiferous tubules with defective cycles, rates of germ cell death and sperm morphology, in adult male mice with standard telocentric chromosomes (2n = 40, CD1 strain), homozygous (2n = 24, Mil II population) and heterozygous (2n = 24 x 40) for Robertsonian (Rb) rearrangements. The animals were analyzed at three different ages: three, five and seven months after birth. The number and position of crossover events were also determined by chiasmata counting and immunostaining with an antibody against mouse MLH1 protein. Our analysis of spermatogenesis confirms the impairment of the spermatogenic process in multiple simple heterozygotes due to both germ cell and abnormal sperm morphology. The detrimental effects exerted by Rb heterozygosities were found to be at least partially buffered with time: the frequency of defective tubules was lower and germ cell survival and sperm morphology better in 7-month-old animals than in the 3- and 5-month-old mice. While there are previously published data on germ cell death in multiple simple heterozygotes, this is the first report of a partial rescue of spermatogenesis with time. The mean frequency of MLH1 foci was lower in Rb homozygous and heterozygous mice than in mice carrying all telocentric chromosomes. The lower number of foci in Rb mice can be ascribed to a decrease in the number of multiple chiasmata and the maintenance of single chiasmata preferentially located in the terminal region of both the telocentric and metacentric chromosomes.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Use of vagal nerve stimulation as a treatment for refractory epilepsy in dogs.

OBJECTIVE: To evaluate safety and efficacy of vagal nerve stimulation in dogs with refractory epilepsy. DESIGN: Placebo-controlled, double-masked, crossover study. ANIMALS: 10 dogs with poorly controlled seizures. PROCEDURE: A programmable pacemaker-like device designed to deliver intermittent stimulation to the left cervical trunk of the vagus was surgically implanted in each dog. Dogs were assigned randomly to two 13-week test periods, 1 with nerve stimulation and 1 without nerve stimulation. Owners recorded data on seizure frequency, duration, and intensity, as well as adverse effects. RESULTS: No significant difference in seizure frequency, duration, or severity was detected between overall 13-week treatment and control periods. During the final 4 weeks of the treatment period, a significant decrease in mean seizure frequency (34.4%) was detected, compared with the control period. Complications included transient bradycardia, asystole, and apnea during intraoperative device testing, and seroma formation, subcutaneous migration of the generator, and transient Horner's syndrome during the 14-day period between surgery and suture removal. No adverse effects of stimulation were detected, and most owners were satisfied with the treatment. CONCLUSIONS AND CLINICAL RELEVANCE: Vagal nerve stimulation is a potentially safe approach to seizure control that appears to be efficacious in certain dogs and should be considered a possible treatment option when antiepileptic medications are ineffective.

Animals↗
PubMed1975

A double blind trial of lithium carbonate and haloperidol in Huntington's chorea.

Six patients with a family history of Huntington's chorea (HC) participated in a double blind crossover trial involving four treatments--lithium carbonate, haloperidol, lithium carbonate and haloperidol, and placebo. Each treatment was administered for three weeks and, at the end of each treatment period, assessments were made of chorea and a number of psychological variables. None of the treatments significantly affected chorea measurements. With regard to the psychological variables, the levels of irritability, the frequency of angry outbursts and depression did appear to be affected in some patients by the treatment. Three patients improved on a combination of lithium carbonate and haloperidol while the remaining three did not. Haloperidol alone significantly raised depression ratings above levels for other treatments including placebo. It is suggested that lithium carbonate and haloperidol together should be seriously considered in the treatment of HC when patients are excessively irritable and impulsive.

Anger↗
PubMed1996

Assessment of pharmacokinetic and pharmacodynamic drug interactions between nefazodone and digoxin in healthy male volunteers.

The effect of nefazodone on pharmacokinetic and pharmacodynamic parameters of digoxin were evaluated in an open, randomized, multiple-dose, three-way crossover study of 18 healthy male volunteers. The volunteers received nefazodone alone (200 mg twice daily), digoxin alone (0.2 mg daily), or nefazodone combined with digoxin during three 8-day treatment periods, with a single dose on the ninth day. There was a 10-day washout period between treatment periods. Coadministration of nefazodone with digoxin had no effect on the frequency and severity of adverse events compared with those observed with either drug alone. Steady-state area under the concentration-time curve (AUC) and peak (Cmax) and trough (Cmin) concentrations of digoxin were significantly higher (15%, 29%, and 27%, respectively) after coadministration of nefazodone/digoxin than after administration of digoxin. Despite these increases, no clinically significant changes in vital signs, heart rate, or PR, QRS, and QT intervals on the electrocardiogram occurred after coadministration from those measured after digoxin monotherapy. Coadministration did not affect the pharmacokinetics of nefazodone or its metabolites (hydroxynefazodone, m-chlorophenylpiperazine, triazole dione). Because digoxin has a narrow therapeutic index, monitoring of plasma digoxin levels and appropriate adjustment of dosage are recommended when nefazodone and digoxin are administered concurrently.

Adult↗
PubMed1985

Safety and efficacy of a twice-daily dosing regimen for moricizine (ethmozine).

Moricizine (ethmozine), a phenothiazine-related new antiarrhythmic agent previously used thrice daily, was studied to determine whether a twice daily regimen could be used with the same degree of efficacy and safety. Ten patients entered a single-blind, 35-day, placebo-controlled, outpatient longitudinal, crossover comparison using 10 to 12 mg/kg/day of moricizine. There were five 7-day phases in which the first, third, and fifth were placebo dosing and the second and fourth were randomized as to moricizine dosage regimen (every 8 hours vs every 12 hours). There were no statistically significant differences between the three placebo periods in ventricular premature complex (VPC) frequency. There was no statistically significant difference between the two dosing regimens for ventricular arrhythmia control with the first day of moricizine dosing; however, when averaging the sixth and seventh days on drug, there was a significantly greater reduction in frequency on the every 12 hour regimen compared to the every 8 hour regimen (p = 0.004). No relationship was found between the percent arrhythmia suppression and dose or plasma concentration. Six patients had transient side effects on the every 12 hour regimen vs four patients with side effects on the every 8 hour regimen. This study demonstrates that moricizine may be used every 12 hours with excellent efficacy and tolerance.

Anti-Arrhythmia Agents↗
PubMed1987

Multiple recombination sites at the 5'-end of murine coronavirus RNA.

Mouse hepatitis virus (MHV), a murine coronavirus, contains a nonsegmented RNA genome. We have previously shown that MHV could undergo RNA-RNA recombination in crosses between temperature-sensitive mutants and wild-type viruses at a very high frequency (S. Makino, J.G. Keck, S.A. Stohlman, and M.M.C. Lai (1986) J. Virol. 57, 729-737). To better define the mechanism of RNA recombination, we have performed additional crosses involving different sets of MHV strains. Three or possibly four classes of recombinants were isolated. Recombinants in the first class, which are similar to the ones previously reported, contain a single crossover in either gene A or B, which are the 5'-most genes. The second class of recombinants contain double crossovers in gene A. The third class of recombinants have crossovers within the leader sequence located at the 5'-end of the genome. The crossover sites of the third class have been located between 35 and 60 nucleotides from the 5'-end of the leader RNA. One of these recombinants has double crossovers within the short region comprising the leader sequences. Finally, we describe one recombinant which may contain a triple crossover. The presence of so many recombination sites within the 5'-end of the genome of murine coronaviruses confirms that RNA recombination is a frequent event during MHV replication and is consistent with our proposed model of "copy-choice" recombination in which RNA replication occurs in a discontinuous and nonprocessive manner.

Murine hepatitis virus↗
PubMed1995

Alpha sympathomimetic treatment of autonomic insufficiency with orthostatic hypotension.

PURPOSE: In this double-blind study, the authors compared the safety and efficacy of the investigational oral agent midodrine, a specific alpha 1-sympathomimetic agent, with ephedrine, a nonspecific alpha- and beta-adrenergic receptor agonist. Eight patients (4 men and 4 women) with refractory orthostatic hypotension resulting from autonomic failure were studied. This study was based on the notion that neurogenic orthostatic hypotension results from attenuation of adrenergic nerve traffic and not from alpha-adrenergic receptor dysfunction. Although arteriolar vasoconstrictors seem to be appropriate therapeutic agents, their success has been limited, and the search for an ideal drug is ongoing. METHODS: The authors employed a blocked, double-blind, randomized crossover design. The single-blind placebo run-in period was 2 days. The double-blind titration period with either midodrine or ephedrine was 3 to 5 days; the titration end point was to increase standing systolic blood pressure to > or = 80 mm Hg and to maintain a supine pressure below 180/100 mm Hg. The maintenance period was 3 to 5 days. A 4-day placebo washout period was interposed at the crossover point. RESULTS: The ability to stand improved in patients treated with midodrine but not with ephedrine. Midodrine significantly increased both systolic (P < 0.001) and diastolic (P < 0.001) standing blood pressure over placebo (P < 0.001) and ephedrine (P < 0.05). In contrast, ephedrine-induced changes in standing pressures did not significantly differ from placebo (P > 0.05). Midodrine treatment improved the frequency of the ability to stand as compared with ephedrine, and was associated with a significantly higher incidence of standing systolic pressures > 80 mm Hg than was placebo (P < 0.001). Both midodrine and ephedrine significantly increased supine systolic and diastolic blood pressures over placebo (P < 0.001, P < 0.01, P < 0.01, P < 0.01, respectively), but were not significantly different from each other. Ephedrine significantly increased (P < 0.05) the pulse rate as compared with placebo and midodrine, whereas midodrine produced a statistically significant (P < 0.05) but clinically minimal decrease in pulse rate compared with placebo. Neither drug affected clinical laboratory variables. CONCLUSIONS: Midodrine safely and effectively improved orthostatic hypotension caused by autonomic failure. Our data suggest that the ability to stand is improved better by midodrine than by ephedrine.

Adrenergic alpha-Agonists↗
PubMed1994

The antiprogestin RU486 delays the midcycle gonadotropin surge and ovulation in gonadotropin-releasing hormone-induced cycles.

OBJECTIVE: To investigate whether the antiprogestin RU486 acts primarily on the hypothalamus to delay the midcycle gonadotropin surge and thus gain insight into the site(s) of action of P in the control of ovulation. DESIGN: Prospective, crossover, single-blinded clinical study. SETTING: Outpatient clinic in an academic research environment. PATIENTS: Women with hypothalamic amenorrhea. INTERVENTIONS: RU486 or a placebo was given orally at a low dose of 1 mg/d for 5 days, starting when the dominant follicle reached 14 to 16 mm, to women with hypothalamic amenorrhea undergoing ovulation induction with GnRH pulses of unvarying frequency and dose. Blood samples and ovarian ultrasounds were obtained daily in the late follicular phase and every 3 to 4 days in the remainder of the cycle. MAIN OUTCOME MEASURES: Follicular diameter and plasma levels of LH, FSH, E2, and P. RESULTS: RU486 consistently delayed the timing of the midcycle gonadotropin surge and ovulation. Gonadotropin and steroid levels were suppressed during RU486 treatment, but follicular growth progressed normally in most patients. CONCLUSIONS: RU486 does not act primarily on the hypothalamus to delay ovulation. Rather, this compound appears to antagonize P at the pituitary level to suppress gonadotropin and steroid hormone secretion. P may thus act on the pituitary, independent of any hypothalamic effects, to regulate the timing of the midcycle gonadotropin surge and ovulation.

Adult↗
PubMedDate not supplied

Selective alterations of the first NREM sleep cycle in humans by a dopamine D1 receptor antagonist (NNC-687).

This paper details the first study of the effects of dopamine D1 receptor antagonism on the regulation of human sleep EEG (electroencephalogram). The investigational drug NNC-687 (NNC 01-0687/CEE 03-310) was administered to 20 healthy young men in doses of 5, 10, and 15 mg in a double blinded, placebo controlled, crossover design. In rats, dopamine D1 receptor antagonism can produce large increases in the amounts of both rapid eye-movement (REM) and non-rapid eye-movement (NREM) sleep. In this study, drug effects were most prominent in the first NREM period. D1 antagonism markedly reduced the peak-amplitude of delta EEG waves but increased their instantaneous frequency as well as enhancing the total number, incidence, and burst-duration of sleep spindles. The length of the first NREM period was increased up to 47% over baseline. Despite these large increases in NREM sleep time, the amount of delta EEG power accumulated over the first NREM period was conserved at baseline levels. We note that the sleep-EEG profile of D1 antagonism is very similar to that of GABAA (gamma-aminobutyric acid) receptor modulators and suggest that D1 antagonism may alter the properties of the neuronal networks which generate delta and spindle, and K-complex EEG waveforms through the upstream modulation of GABAA receptor activity.

Adult↗
PubMed2001

Perception of pitch and roughness in vocal signals with subharmonics.

Pitch and roughness were rated according to the extent of amplitude modulation (AM) and frequency modulation (FM) of a subharmonic [fundamental frequency (F0)/2]. The objective was to determine the identification boundaries for pitch and roughness and to discover how both kinds of modulation affect these boundaries. Another objective was to judge the reliability between subjects when identifying subharmonic-related pitch and roughness. Three procedures were used: ABX comparisons, method of adjustment, and rating of roughness. Results indicated that the crossover point to the lower pitch (associated with the subharmonic) occurred between 10% and 30% modulation, depending on modulation type and F0. Subjects demonstrated highly variable perceptions of pitch and roughness, with poor intersubject reliability.

Adult↗
PubMed1994

Sex-linkage of two enzyme loci in Oncorhyncus mykiss (rainbow trout)

We report the first sex-linked loci in Oncorhynchus mykiss (rainbow trout). Previous cytological and breeding experiments have demonstrated an XX/XY sex determining system in this and other salmonid species. Joint segregation data from fathers indicated an average of 8.1 per cent recombination between HEX-2 and the sex determining locus (SEX). The average recombination between HEX-2 and sSOD-1 in fathers was 26.8 per cent. No evidence of non-random segregation of HEX-2 and sSOD-1 was found in mothers; this difference in recombination rates between males and females is concordant with previous studies with rainbow trout and other salmonid species. These results also suggest the possibility that proper chromosomal pairing and segregation in salmonid males does not require a crossover event. Unlike the extreme XX/XY heteromorphy in mammals, functional alleles for HEX-2 and sSOD-1 occur on both the X and Y chromosomes. Significant non-random associations (i.e. gametic disequilibrium) occur between genotypes at HEX-2 and SEX in the hatchery population used for the inheritance study. This gametic disequilibrium has resulted in large changes in allele frequency at HEX-2 from one generation to the next and an excess of heterozygotes in comparison to expected binomial (i.e. Hardy-Weinberg) proportions.

Animals↗
PubMed1997

Mouse mast cell protease 9, a novel member of the chromosome 14 family of serine proteases that is selectively expressed in uterine mast cells.

Mouse mast cell protease (mMCP) 1, mMCP-2, mMCP-4, and mMCP-5 are members of a family of related serine proteases whose genes reside within an approximately 850 kilobase (kb) complex on chromosome 14 that does not readily undergo crossover events. While mapping the mMCP-1 gene, we isolated a novel gene that encodes a homologous serine protease designated mMCP-9. The mMCP-9 and mMCP-1 genes are only approximately 7 kb apart on the chromosome and are oriented back to back. The proximity of the mMCP-1 and mMCP-9 genes now suggests that the low recombination frequency of the complex is due to the closeness of some of its genes. The mMCP-9 transcript and protein were observed in the jejunal submucosa of Trichinella spiralis-infected BALB/c mice. However, in normal BALB/c mice, mMCP-9 transcript and protein were found only in those mast cells that reside in the uterus. Thus, the expression of mMCP-9 differs from that of all other chymases. The observation that BALB/c mouse bone marrow-derived mast cells developed with interleukin (IL) 10 and c-kit ligand contain mMCP-9 transcript, whereas those developed with IL-3 do not, indicates that the expression of this particular chymase is regulated by the cytokine microenvironment. Comparative protein structure modeling revealed that mMCP-9 is the only known granule protease with three positively charged regions on its surface. This property may allow mMCP-9 to form multimeric complexes with serglycin proteoglycans and other negatively charged proteins inside the granule. Although mMCP-9 exhibits a >50% overall amino acid sequence identity with its homologous chymases, it has a unique substrate-binding cleft. This finding suggests that each member of the chromosome 14 family of serine proteases evolved to degrade a distinct group of proteins.

Amino Acid Sequence↗
PubMed1999

Effect of losartan on heart rate and blood pressure variability during tilt test and trinitroglycerine vasodilation.

OBJECTIVE: To define the changes in variability of heart rate and of blood pressure during vasodilation in a group of hypertensive patients treated with an angiotensin II type I (AT1) receptor inhibitor. DESIGN: Losartan (50 mg/day at 0800 h) or placebo were administered for 3 weeks according to a single blind, crossover, randomized protocol, to 18 hypertensive patients (16 men and two women, mean age 42 + 3.6 years). Continuous ECG recording and beat-to-beat blood pressure monitoring were carried out with subjects in the supine position and during a head-up tilt test, as well as after sublingual administration of trinitroglycerine. The elaboration of ECG traces in the frequency domain, was carried out using an autoregressive method and measured using the autoregressive moving average technique. RESULTS: Orthostatic stimulus, both during treatment with losartan and with placebo, caused a significant decrease in the heart rate high frequency power; on the other hand, the low frequency power appeared unchanged after placebo and was significantly reduced with losartan. Five minutes after the administration of trinitroglycerine, the low frequency power with placebo showed a significant increase (817 -+ 221 versus 465 + 101 ms2, P < 0.03). No change was recorded in total power nor in low frequency or high frequency power during losartan therapy. The ratio of low frequency to high frequency powers showed a sympathetic prevalence during vasodilation only during placebo treatment, whereas a mainly unchanged balance was maintained during losartan treatment Blood pressure variability showed a sympathetic prevalence after upright and trinitroglycerine stimulation only in placebo-treated subjects. CONCLUSIONS: Our study demonstrated that vasodilation is not able to evoke an unbalancing of the autonomic modulation in hypertensive patients treated with an AT1 receptor inhibitor, but permits the maintenance of a significant vagal component, thus highlighting the favorable profile of this drug in the autonomic control of circulation.

Adult↗
PubMed1999

Wave transport in random media: the ballistic to diffusive transition.

The character of wave transport through a strongly scattering medium, excited by a pulsed plane-wave source, is investigated as a function of sample thickness over the range from about one to 13 mean free paths. To examine the behavior theoretically, we perform a first-principles calculation of both the frequency correlation function of the transmitted field and the time-domain profile of the transmitted intensity. These quantities are investigated experimentally using an ultrasonic technique, which allows us to separate the ballistic and scattered components of the total transmitted field, and hence to measure the scattered component unambiguously in thin samples. For sample thicknesses greater than about four mean free paths, we find good agreement between our theory, the diffusion approximation, and our experimental data for both the frequency correlation function and the intensity time profile. In thinner samples, there are systematic differences between theory and experiment. To characterize the transition from ballistic to diffusive behavior in thin samples, we focus on the arrival time of the peak in the scattered component of the transmitted intensity; unexpectedly we find that the scattered peak arrival time exhibits an abrupt crossover between ballistic and diffusive behavior when the ratio of sample thickness to mean free path, L/l, is approximately equal to 3. Excellent agreement is obtained between our theory and experiment for this crossover behavior over the entire range of sample thicknesses investigated.

Journal Article↗
PubMed1986

A comparison of the gastric and central nervous system effects of two substituted benzamides in normal volunteers.

Eight healthy male volunteers participated in a single-blind, random allocation, crossover, comparison of intravenous metoclopramide (10 mg), the peripherally acting, gastrointestinal stimulant BRL 20627 (10 mg) and saline. The central nervous system effects were assessed by quantitative electroencephalography (EEG) and by visual analogue scales. Gastric motility and emptying were assessed by epigastric impedance. Metoclopramide increased the EEG amplitude by 10.4% (a statistically significant, P less than 0.05, effect) and increased frequencies above 22 Hz, whereas both BRL 20627 and placebo had only minor effect on the EEG frequencies and slightly decreased the EEG amplitude. Ratings on visual analogue scales showed that metoclopramide caused statistically significant (P less than 0.01 difference from placebo) restlessness and slight but significantly less (P less than 0.05 difference from placebo) feeling of happiness. Epigastic impedance changes indicated that both metoclopramide and BRL 20627 increased gastric contractile activity, but the rate of gastric emptying was not significantly altered by either drug although it tended to be shortened following metoclopramide but not BRL 20627 treatment. It is concluded that since the published animal data show that BRL 20627 has only weak dopamine antagonistic properties this study further implicates dopamine receptor blockade in the akathisia but not in the gastric effect of metoclopramide.

Adult↗
PubMed1982

Intensive conventional and insulin pump therapies in adult type I diabetes. A crossover study.

We examined the relative efficacy of two modes of insulin therapy in five patients with insulin-dependent diabetes. Using a crossover protocol, therapy with multiple insulin injections was compared with the use of continuous subcutaneous insulin infusion (pump therapy); both therapies were regulated by home blood glucose monitoring. Although both therapies were equally effective during 2 to 4 days of inpatient management, pump therapy was clearly superior in the outpatient setting. Mean plasma glucose and hemoglobin A1c concentrations and the frequency of hypoglycemic reactions were significantly less with pump therapy despite apparently equal compliance with both therapies. We conclude that in compliant adult patients with type I diabetes continuous insulin infusion is more effective in achieving normalization of plasma glucose concentration than intensified conventional therapy in the outpatient setting. Although these patients found pump therapy preferable to intensive conventional therapy, the superiority of pump therapy is not explained by this bias. Whether these results are applicable in a more standard treatment setting remains to be established.

Adult↗
PubMed1982

Intergenomic recombination events among pairs of defective cauliflower mosaic virus genomes in plants.

Pairs of defective cauliflower mosaic virus genomes coinoculated in plants are rescued at high frequency by homologous, intergenomic recombination events. Defective genomes may be rescued by one of at least two general types of recombination mechanisms. One mechanism appears to operate on linear DNA molecules with complementary sticky ends. Recombination of this type can be explained by the formation of mixed dimers (or concatamers) which can be resolved into normal genomes by a single crossover event. Another type of recombination takes place among viral DNA molecules which do not have complementary sticky ends. Rescue of this type yields normal viral DNA molecules which can be resolved only by the equivalent of a double crossover or internal gene conversion event between pairs of infecting molecules. Co-infection of plants with pairs of defective genomes derived from different viral isolates results in the formation of hybrid viral genomes. Analysis of these hybrids reveals that recombination can take place at different sites in the viral genome.

DNA↗
PubMed1995

[Effectiveness of and tolerance to intracavernous injection of moxisylyte in patients with erectile dysfunction: effect/dose relationship versus placebo].

The authors investigated the optima dose (efficacy and safety) of moxisylyte, an alpha-blocking agent, in a double-blind placebo-controlled crossover study in 30 patients. The origin of the erectile dysfunction was predominantly psychological in 14 patients and neurological in 16 patients. Each patient received 4 intracavernous injections in a randomized order (placebo, 10, 20, 30 mg of moxisylyte) at 7-day intervals. Regardless of the dose, moxisylyte induced significantly greater penile responses than placebo on all erection criteria. The frequency of responses allowing sexual intercourse appeared to be dose-dependent in the two aetiological groups. The erectile responses most frequently obtained were complete rigidity in the "neurological" group and tumescence in the "psychological" group. The safety was excellent for 95.6% of injections and no case of priapism was observed. One patient (neurological patient) experienced two prolonged erections after the dose of 20 mg and another patient (psychological patient) reported 2 headaches after the dose of 30 mg. No pain was experienced on injection. Moxisylyte is very well tolerated and is able to induce an erectile response from the dose of 10 mg. This dose appears to be sufficient in patients with central neurological erectile dysfunction; a dose of 20 mg tends to improve the quality of response in patients with a predominantly psychological disorder, although the differences observed between the doses were not statistically significant in this number limited of patients.

Adult↗