Selective prevention of combat-related post-traumatic stress disorder using attention bias modification training: a randomized controlled trial.

BACKGROUND: Efficacy of pre-trauma prevention for post-traumatic stress disorder (PTSD) has not yet been established in a randomized controlled trial. Attention bias modification training (ABMT), a computerized intervention, is thought to mitigate stress-related symptoms by targeting disruptions in threat monitoring. We examined the efficacy of ABMT delivered before combat in mitigating risk for PTSD following combat. METHOD: We conducted a double-blind, four-arm randomized controlled trial of 719 infantry soldiers to compare the efficacy of eight sessions of ABMT (n = 179), four sessions of ABMT (n = 184), four sessions of attention control training (ACT; n = 180), or no-training control (n = 176). Outcome symptoms were measured at baseline, 6-month follow-up, 10 days following combat exposure, and 4 months following combat. Primary outcome was PTSD prevalence 4 months post-combat determined in a clinical interview using the Clinician-Administered PTSD Scale. Secondary outcomes were self-reported PTSD and depression symptoms, collected at all four assessments. RESULTS: PTSD prevalence 4 months post-combat was 7.8% in the no-training control group, 6.7% with eight-session ABMT, 2.6% with four-session ABMT, and 5% with ACT. Four sessions of ABMT reduced risk for PTSD relative to the no-training condition (odds ratio 3.13, 95% confidence interval 1.01-9.22, p < 0.05, number needed to treat = 19.2). No other between-group differences were found. The results were consistent across a variety of analytic techniques and data imputation approaches. CONCLUSIONS: Four sessions of ABMT, delivered prior to combat deployment, mitigated PTSD risk following combat exposure. Given its low cost and high scalability potential, and observed number needed to treat, research into larger-scale applications is warranted. The ClinicalTrials.gov identifier is NCT01723215.

Repeated low-dose exposures to sarin, soman, or VX affect acoustic startle in guinea pigs.

Chemical warfare nerve agents (CWNAs) are known to cause behavioral abnormalities in cases of human exposures and in animal models. The behavioral consequences of single exposures to CWNAs that cause observable toxic signs are particularly well characterized in animals; however, less is known regarding repeated smaller exposures that may or may not cause observable toxic signs. In the current study, guinea pigs were exposed to fractions (0.1, 0.2, or 0.4) of a medial lethal dose (LD50) of sarin, soman, or VX for two weeks. On each exposure day, and for a post-exposure period, acoustic startle response (ASR) was measured in each animal. Although relatively few studies use guinea pigs to measure behavior, this species is ideal for CWNA-related experiments because their levels of carboxylesterases closely mimic those of humans, unlike rats or mice. Results showed that the 0.4 LD50 doses of soman and VX transiently increased peak startle amplitude by the second week of injections, with amplitude returning to baseline by the second week post-exposure. Sarin also increased peak startle amplitude independent of week. Latencies to peak startle and PPI were affected by agent exposure but not consistently among the three agents. Most of the changes in startle responses returned to baseline following the cessation of exposures. These data suggest that doses of CWNAs not known to produce observable toxic signs in guinea pigs can affect behavior in the ASR paradigm. Further, these deficits are transient and usually return to baseline shortly after the end of a two-week exposure period.

Hemimandibulectomy and therapeutic neck dissection with radiotherapy in the treatment of oral squamous cell carcinoma involving mandible: a critical review of treatment protocol in the years 1994-2004.

This retrospective non-randomized 10-year follow-up study compared 147 patients with squamous cell carcinoma (SCC) of the oral cavity requiring hemimandibulectomy, treated by surgical resection, therapeutic neck dissection and radiotherapy. The 5-year survival rates were compared related to localization, size of the tumour, infiltration of locoregional lymph nodes, distant metastases, histopathological grading, radicality of surgery, and invasion of tumour into the mandible. Occurrence of tumour relapse and its localization was studied. The mean 5-year survival rate was 26%. Patients with SCC of the mandibular alveolar process had higher rates; the lowest rates occurred in SCC of the buccal mucosa. Survival rate was significantly lower with insufficient resection of the tumour (85% relapse). An important number of patients with radical resection died within 3 months of surgery. In almost 55% of the mandibles tumour was not present. In 5% of infiltrated mandibles, dissemination into inferior alveolar nerve was proven. Decreasing survival rate was seen with increasing size of tumour and higher histological grade. Therapeutic neck dissection significantly reduces survival rate and increases the percentage of lymph node relapse. Elective neck dissection should be performed in SCC requiring hemimandibulectomy. Primary reconstruction should reverse the high percentage of postoperative complication arising from increased radicality.

DNA fragmentation in leukocytes following subacute low-dose nerve agent exposure.

The objective of the present study was to determine levels of DNA fragmentation in blood leukocytes from guinea pigs by single-cell gel electrophoresis (comet assay) after exposure to the chemical warfare nerve agent (CWNA), soman, at doses ranging from 0.1 LD50 to 0.4 LD50, once per day for either 5 or 10 days. Post-exposure recovery periods ranged from 0 to 17 days. Leukocytes were imaged from each animal, and the images analyzed by computer. Data obtained for exposure to soman demonstrated significant increases in DNA fragmentation in circulating leukocytes in CWNA-treated guinea pigs compared with saline-injected control animals at all doses and time points examined. Notably, significantly increased DNA fragmentation was observed in leukocytes 17 days after cessation of soman exposure. Our findings demonstrate that leukocyte DNA fragmentation assays may provide a sensitive biomarker for low-dose CWNA exposure.

[Increased fetal risk of primary venous thrombosis presenting at a young age]. / A fiatalkori primer vénás thrombosis fokozott magzati kockázata.

Based on the hypothesis that the predisposition to thrombosis in women suffering from deep venous thrombosis at young age can disturb also the uteroplacental circulation, the authors retrospectively analyzed the fetal outcome of 333 pregnancies in 101 women with thromboembolic event before 40 years of age and compared it to the fetal outcome of 2943 pregnancies in 1000 randomly selected obstetrical patients without thrombosis. The relative risks of adverse fetal outcomes in thromboembolic women were as follows: 1.85 (95% C.I.: 1.35-2.55) for the spontaneous miscarriage, 3.9 (95% C.I.: 2.20-6.93) for the second-trimester miscarriage, 1.74 (95% C.I.: 1.15-2.64) for the low birth weight, 2.82 (95% C.I.: 1.28-6.30) for the perinatal loss and 7.17 (95% C.I.: 2.64-19.47) for the abruption of placentae. Data obtained suggest that women with deep venous thrombosis at young age should encounter a higher risk of the uteroplacental thrombosis which results in increasing fetal morbidity and mortality during the second and third trimesters of gestation.

Effects of selected anticholinergics on acoustic startle response in rats.

The present study compared the effects of the anticholinergics aprophen hydrochloride, atropine sulfate, azaprophen hydrochloride, benactyzine hydrochloride, biperiden hydrochloride, diazepam, procyclidine hydrochloride, scopolamine hydrobromide and trihexyphenidyl hydrochloride on acoustic startle response in rats. Peak startle amplitude, latency to peak startle amplitude and prepulse inhibition following 100- and 120-dB tones were recorded 15 min following drug administration in food-restricted rats. Aprophen, atropine, azaprophen, benactyzine, biperiden and scopolamine significantly increased peak startle amplitude and decreased latency to peak startle amplitude following 100-dB pulses. In contrast, only biperiden increased peak startle amplitude following 120-dB pulses, whereas atropine and trihexyphenidyl decreased latency to peak startle amplitude following 120-dB pulses. Benactyzine decreased prepulse inhibition following both 100- and 120-dB pulses, whereas both biperiden and scopolamine decreased prepulse inhibition following 120-dB pulses. Acoustic startle response measures were effective in differentiating the effects of anticholinergic compounds. The comparison of drug effects on the acoustic startle response may be useful in selecting efficacious anticholinergic drug therapies with a minimal range of side-effects. In addition, these data may be useful in down-selecting the number of anticholinergic drugs that need to be tested in comparison studies involving more complex behavioral tests.

Behavioral effects Of 8-OH-DPAT in chronically stressed male and female rats.

The present study tested the hypothesis that chronic stress desensitizes serotonergic 5-HT(1A) receptors and alters behavioral changes following 5-HT(1A) agonist administration. Eating, acoustic startle response (ASR), and locomotor activity were measured in stressed and nonstressed male and female rats after 8-OH-DPAT administration. Stressed rats were paired and stressed by around-the-clock intermittent foot shock. Controllable stress (CS) rats could avoid/terminate shock for themselves and their yoked partners by pulling a ceiling chain, whereas their partners, the uncontrollable stress (UCS) rats, could not. Rats earned their entire daily ration of food by pressing a lever. In previous experiments, this paradigm was stressful, but not debilitating and rats continued to eat, groom, sleep, and avoid/escape greater than 99% of shock trials. Locomotor activity and ASR were measured in the present study after saline and 8-OH-DPAT administration (0.25 mg/kg, IP) before, 24 h, and 72 h after shock onset. 8-OH-DPAT only decreased food intake significantly in male and female rats after the first administration. Stress decreased food intake in both the CS and UCS rats, with UCS rats eating the least. However, the effects of stress and 8-OH-DPAT were not additive. 8-OH-DPAT significantly increased peak startle amplitude at 100 and 120 dB, and decreased latency to peak startle amplitude at 100 dB in male and female rats. In contrast, 8-OH-DPAT did not alter percent prepulse inhibition (%PPI) at 100 dB, but significantly decreased %PPI in males but not females at 120 dB. Stress did not have a consistent effect on ASR, but reduced %PPI in males, but not females. Neither stress nor 8-OH-DPAT significantly altered locomotor activity. Although the results do not show an increased sensitivity to 8-OH-DPAT in stressed rats, the unexpectedly weak effects of 8-OH-DPAT alone on the behavioral measures chosen limits the conclusions that can be drawn.

Social stress effects on territorial marking and ultrasonic vocalizations in mice.

Acute social defeat (SD) leads to transient and persistent physiological and behavioral changes. We examined the effects of acute SD on territorial urine marking and ultrasonic courtship vocalizations in DBA/2 male mice. Both behaviors are considered androgen dependent and are influenced by social status, with dominant mice displaying more of both behaviors. In Experiment 1, male mice that received SD displayed prolonged inhibition of territorial urine marking, relative to nondefeated control mice (NOSD). In addition, territorial marking increased with repeated tests. In Experiment 2, male mice that received 3 successive days of SD displayed fewer ultrasonic courtship vocalizations at 30 min. post-SD1 and 30 min. post-SD2, relative to NOSD mice. In Experiment 2, we also observed decreased territorial marking 4 weeks post-SD. In sum, SD induced prolonged inhibition of territorial marking, but had only transient effects on ultrasonic courtship vocalizations, suggesting that different mechanisms may mediate the maintenance of these behaviors.

Dose-response curves and time-course effects of selected anticholinergics on locomotor activity in rats.

RATIONALE: In order to facilitate direct comparisons of anticholinergic drug effects on activity, nine drugs were tested in one laboratory using a standardized procedure. OBJECTIVE: The present study compared the effects of aprophen hydrochloride, atropine sulfate, azaprophen hydrochloride, benactyzine hydrochloride, biperiden hydrochloride, diazepam, procyclidine hydrochloride, scopolamine hydrobromide, and trihexyphenidyl hydrochloride on activity levels in rats. METHODS: Both fine motor activity (reflecting smaller movements) and ambulatory activity (reflecting larger movements) were recorded for 23 h following drug administration in food-restricted rats. All drugs were administered during the light period of the photocycle. RESULTS: Atropine, azaprophen, biperiden, scopolamine, and trihexyphenidyl increased both ambulations and fine motor activity significantly during the first hour post-injection, but the increased activity levels returned to vehicle control levels within 2-6 h post-injection. Benactyzine and procyclidine only increased fine motor activity significantly above vehicle control levels and activity levels returned to vehicle control levels within 2-3 h. Finally, aprophen and diazepam generally did not increase measures of activity significantly above vehicle controls at the dose ranges examined. CONCLUSIONS: Based on potencies relative to scopolamine, the potency of the drugs could be ranked as follows: scopolamine > trihexyphenidyl > biperiden > azaprophen > procyclidine > benactyzine > atropine > aprophen. The comparison of drug effects on activity may be useful in selecting anticholinergic drug therapies with a minimal range of side effects. In addition, these data may reduce the number of anticholinergic drugs that need to be tested in comparison studies involving more complex behavioral tests.

Intracranial androgenic activation of male-typical behaviours in house mice: concurrent stimulation of the medial preoptic area and medial nucleus of the amygdala.

This experiment examined whether testosterone proprionate (T) action in the medial preoptic area (MPO) would synergize with T action in the medial nucleus of the amygdala (AME) for the expression of androgen-dependent behaviors in house mice. Cannulae containing T were bilaterally implanted into the MPO, the AME, or both areas concurrently (MPO/AME) of castrated males. In addition, other castrates were implanted subcutaneously with empty Silastic capsules (BSIL) or Silastic capsules containing T (TSIL). All subjects were examined for the following androgen-dependent, male-typical behaviors: mounting, urinary scent marking, preference for female urine over male urine, preference for female over male conspecifics and ultrasonic mating vocalizations. MPO implants restored ultrasonic vocalizations and preference for females, but had little or no effect upon urine marking, mounting or preference for female urine. In contrast, AME implants were ineffective at restoring any of these male-typical behaviors. The combined MPO/AME implants were not more effective in restoring male-typical behaviors than MPO implants alone, thus providing no evidence for synergy in hormone action between these two brain areas. In general, castration (BSIL) resulted in low levels of all behaviors whereas systemic T replacement (TSIL) resulted in high levels of behavior, verifying the androgen-dependence of these behaviors. Group differences in male-typical behavior could not be accounted for by differences in general activity levels. Moreover, none of the brain-implanted groups had larger seminal vesicles than those of the BSIL. Thus, when the brain implants affected behavior, they most probably did so through their effects within the brain. Although the AME is a target for steroid hormones and is an important area for the expression of male-typical behaviors, intracranial T implants into the AME did not demonstrate a role for androgen in the AME in restoring male-typical behaviors in castrated mice.

[Severe genital mycoplasma infection following cesarean section]. / Genitális mycoplasmák által okozott súlyos fertözés sectio caesareát követöen.

Authors report a serious case of post-caesarean delivery endometritis caused, probably exclusively, by genital mycoplasmas: Ureaplasma urealyticum and Mycoplasma hominis. The initial treatment of the patient with various penicillins, ceftriaxone, gentamicin, metronidazole and nystatine proved ineffective. Subsequently, as microbiological tests turned out positive for genital mycoplasmas, a therapy of doxycyclin was introduced and a full recovery could be attained. Authors' experience is consistent with the observation of American scientists that U. urealyticum is an important pathogen in post-caesarean delivery endometritis. Since the carriage of U. urealyticum in women is frequent in Hungary, it is suggested that microbiological investigations related to sectio caesarea always include tests for genital mycoplasmas.

Characterization of calcified deposits on contraceptive intrauterine devices.

The formation of calcified deposits on > 200 contraceptive intrauterine devices (IUD) was quantitated as a function of time in healthy women, pregnant women, and women with a pathologic lesion. The incrustment formation was significantly enhanced when inflammation occurred, but change could not be observed in cases of pregnancy. The incrustments were analyzed by x-ray diffraction, infrared spectroscopy, x-ray microprobe, and ultramicrochemical stone analysis techniques. Major components and their average w/w percent quantities in the incrustments are as follows: calcium carbonate 75%, apatite 5%, and organic matrix 20%. Earlier hypotheses on the chemical processes of deposit formation are discussed, and a new, ionic mechanism of calcification on IUD surfaces is suggested.

PIP: Calcium incrustation on the surface of an IUD significantly increases the likelihood of side effects such as bacterial and fungoid infections. The time-dependence of calcification on IUDs and the chemical composition of calcified deposits were investigated in devices removed from more than 200 healthy women with lower abdominal complaints or a planned or accidental pregnancy. A linear relationship was found between the amount of incrustation on plastic IUDs and the duration of IUD use. Incrustment formation was faster when inflammation occurred, presumably as a result of enhanced excretion of incrustment-forming compounds, but pregnancy had no effect on this rate. Deposit formation on copper IUDs was less uniform and proceeded at a slower rate. The incrustments were characterized by x-ray diffraction, infrared spectroscopy, x-ray microprobe, and ultramicrochemical stone analysis techniques. On average, incrustments were composed of calcium carbonate (75%), organic matrix (20%), and apatite (5%). The rate of incrustation depended not only on the size and quality of the IUD, but also on the individual capability of the uterus to produce calcium ions. The growth of incrustments on IUDs can be monitored by noninvasive ultrasonography.

Concurrent androgenic stimulation of the ventral tegmental area and medial preoptic area: synergistic effects on male-typical reproductive behaviors in house mice.

Cannulae containing testosterone proprionate (T) were bilaterally implanted into the medial preoptic area (MPO), the ventral tegmental area (VTA), or both areas concurrently (MPO/VTA) of castrated male house mice. A fourth group of castrates in which the intracranial implants missed their targets (MIMP) served as controls. In addition, other castrates were implanted subcutaneously with empty silastic capsules (BSIL) or silastic capsules containing T (TSIL). All subjects were examined for the following male-typical behaviors: mounting, attraction to female urine, ultrasonic mating vocalizations and urinary scent marking. In addition, the males were tested for activity levels to insure that they were not motorically impaired. In general, TSIL implants restored all male-typical behaviors to normal levels, whereas BSIL and MIMP implants were generally ineffective. Similar to previous findings, MPO implants alone completely restored ultrasonic vocalizations, partially restored urine marking, and had little or no effect upon mounting or urine preference. In contrast, VTA implants alone were ineffective at restoring any of these male-typical behaviors. However, the combined MPO/VTA implants were the most effective in restoring male-typical behaviors. In fact, a synergism between concurrent hormone action in the MPO and VTA was seen for mounting and urine preference. We interpret these data to indicate that androgen may act simultaneously in the MPO and VTA for more complete expression of some male-typical reproductive behaviors.

An ephemeral pheromone of female house mice: perception via the main and accessory olfactory systems.

Two experiments examined the chemosensory modalities by which males detect an ephemeral sex pheromone in the freshly voided urine of female mice. Experiment 1 examined the interaction of deafferenting the accessory olfactory system (vomeronasal organ removal) and subsequent sexual experience upon ultrasonic vocalizations by male mice to freshly voided female urine. In general, sexually experienced males vocalized substantially more than sexually naive males. In addition, males possessing a vomeronasal organ vocalized slightly more than those without. Nonetheless, a functioning vomeronasal organ clearly was not essential for vocalizing to fresh female urine. Experiment 2 examined the effects of deafferenting the main olfactory system (ZnSO4 nasal irrigation) and/or the accessory olfactory system (vomeronasal removal) in sexually experienced males. Males with both olfactory systems functioning vocalized at high levels to fresh urine, while males with only one functioning system vocalized at intermediate levels. Males with neither system functioning did not vocalize at all to fresh urine. In contrast, when female mice themselves served as stimuli, all groups of males vocalized at high levels. We conclude that adult male mice can detect the ephemeral pheromone via either the main olfactory system or the accessory olfactory system. However, vocalizations to the female herself can be mediated by other sensory systems as well.

Intracranial androgenic activation of male-typical behaviors in house mice: motivation versus performance.

Castrated male mice were bilaterally implanted with 27 ga cannulae containing testosterone into either the septum, medial preoptic area (MPO), or corticomedial amygdala. One additional group of castrates received no hormone and another received only systemic testosterone via subcutaneous silastic capsules. All males were subsequently tested for ultrasonic mating vocalizations, urine marking, mounting behavior, aggression and gender preference, all of which are androgen-dependent, male-typical behaviors. In general castrates receiving no hormone performed these behaviors at low levels and animals receiving systemic testosterone performed the behaviors at normal male-typical levels. Ultrasonic vocalizations in response to female urine were activated by MPO implants. Urine marking in response to female urine appeared to be partially activated only with MPO implants. Very little mounting or fighting were seen in the brain implanted groups. Gender preference (for females over males) was restored with MPO implants and appeared to be partially activated with septal implants. The seminal vesicles of the castrates receiving brain implants were not significantly different from those receiving no hormone indicating that little or no implanted hormone was exiting the brain into general circulation. The implications of these findings for the neuroanatomy of sexual motivation and performance are discussed.

An ephemeral sex pheromone of female house mice (Mus domesticus): pheromone fade-out time.

Male mice will emit ultrasounds to at least two chemosignals present in female mouse urine: a) an ephemeral unconditioned stimulus (UCS) present in freshly voided urine and b) a conditioned stimulus (CS) that remains after the UCS has disappeared. In this study, four phases examined the time frame over which the UCS disappeared. Urine that had been aged for either 12, 15, 18, or 24 h was compared for vocalization elicitation with fresh urine (which contains the UCS) and metabolic cage-collected urine ( which does not). Under the conditions utilized, significant pheromone fade-out occurred between 15 and 18 h.

An ephemeral sex pheromone in the urine of female house mice (Mus domesticus).

From previous research, the ultrasonic vocalizations of male mice (Mus domesticus) to female mouse urine were hypothesized to be learned as a result of classical conditioning during adult heterosexual encounters. According to this interpretation, a previously neutral conditioned stimulus in female urine comes to elicit vocalizations as a result of its association with some other unknown unconditioned stimulus associated with adult females. However, the research from which this hypothesis was derived utilized urine collected from females housed in metabolic cages. Three experiments further examined the classical conditioning hypothesis using two types of female urine: (i) metabolic-cage-collected urine and (ii) freshly voided urine. Experiment 1 demonstrated that, in contrast to vocalizations to metabolic-cage-collected urine, adult heterosexual experience was not necessary for males to vocalize to freshly voided female urine. In addition, unlike metabolic-cage-collected urine (Experiment 3), freshly voided urine remained a potent stimulus for eliciting vocalizations during repeated testing (Experiments 2 and 3). Finally, freshly voided urine appeared to cause a previously neutral stimulus (cotton swab) to acquire ultrasound eliciting properties (Experiment 2). We suggest from these findings that two chemosignals that elicit vocalizations from males may exist in female mouse urine: (i) a potent, but volatile or easily degraded, unconditioned stimulus to which males vocalize without sexual experience and (ii) a nonvolatile, chemically stable conditioned stimulus.