Dissolution of three insensitive munitions formulations.

The US military fires live munitions during training. To save soldiers lives both during training and war, the military is developing insensitive munitions (IM) that minimize unintentional detonations. Some of the compounds in the IM formulation are, however, very soluble in water, raising environmental concerns about their fate and transport. We measured the dissolution of three of these IM formulations, IMX101, IMX104 and PAX21 using laboratory drip tests and studied the accompanying changes in particle structure using micro computed tomography. Our laboratory drip tests mimic conditions on training ranges, where spatially isolated particles of explosives scattered by partial detonations are dissolved by rainfall. We found that the constituents of these IM formulations dissolve sequentially and in the order predicted by their aqueous solubility. The order of magnitude differences in solubility among their constituents produce water solutions whose compositions and concentrations vary with time. For IMX101 and IMX104, that contain 3-nitro-1,2,4-triazol-5-one (NTO), the solutions also vary in pH. The good mass balances measured for the drip tests indicate that the formulations are not being photo-or bio-transformed under laboratory conditions.

Severe Breast Pain Resolved with Pectoral Muscle Massage.

Many mothers stop breastfeeding because of breast and/or nipple pain, despite recommendations by the World Health Organization to exclusively breastfeed for the first 6 months. Most commonly, such pain is thought to be caused by fungal or bacterial infection; however, many women do not respond to usual treatments for such diagnoses. Furthermore, there is much dispute in the literature about these diagnoses and treatments. We submit a series of 3 cases of mothers who presented with severe mastalgia (breast pain) and who did not respond to conventional treatments. After treating the patients with pectoral muscle massage and stretching, they each had complete resolution of their pain. We suggest that each of these mothers experienced constriction of the upper thoracic muscles on their mammary neurovasculature.

Modulation of genioglossus muscle activity across sleep-wake states by histamine at the hypoglossal motor pool.

STUDY OBJECTIVES: Histamine neurons comprise a major component of the aminergic arousal system and significantly influence sleep-wake states, with antihistamines widely used as sedative hypnotics. Unlike the serotonergic and noradrenergic components of this arousal system, however, the role of histamine in the central control of respiratory motor activity has not been determined. The aims of this study were to characterize the effects of histamine receptor agonists and antagonists at the hypoglossal motor pool on genioglossus muscle activity across sleep and awake states, and also determine if histamine contributes an endogenous excitatory drive to modulate hypoglossal motor outflow to genioglossus muscle. DESIGN, PARTICIPANTS, AND INTERVENTIONS: Thirty-three rats were implanted with electroencephalogram and neck electrodes to record sleep-wake states, and genioglossus and diaphragm electrodes for respiratory muscle recordings. Microdialysis probes were inserted into the hypoglossal motor nucleus. MEASUREMENTS AND RESULTS: Histamine at the hypoglossal motor nucleus significantly increased tonic genioglossus muscle activity in wakefulness, non-REM sleep and REM sleep. The activating effects of histamine on genioglossus muscle activity also occurred with a histamine type-1 (H1) but not H2 receptor agonist. However, H1 receptor antagonism at the hypoglossal motor nucleus did not decrease genioglossus muscle activity in wakefulness or sleep. CONCLUSIONS: The results suggest that histamine at the hypoglossal motor pool increases genioglossus muscle activity in freely behaving rats in wakefulness, non-REM, and REM sleep via an H1 receptor mechanism.

Three-dimensional volumetric analysis of irradiated lung with adjuvant breast irradiation.

PURPOSE: To retrospectively evaluate the dose-volume histogram data of irradiated lung in adjuvant breast radiotherapy (ABR) using a three-dimensional computed tomography (3D-CT)-guided planning technique; and to investigate the relationship between lung dose-volume data and traditionally used two-dimensional (2D) parameters, as well as their correlation with the incidence of steroid-requiring radiation pneumonitis (SRRP). METHODS AND MATERIALS: Patients beginning ABR between January 2005 and February 2006 were retrospectively reviewed. Patients included were women aged >or=18 years with ductal carcinoma in situ or Stage I-III invasive carcinoma, who received radiotherapy using a 3D-CT technique to the breast or chest wall (two-field radiotherapy [2FRT]) with or without supraclavicular irradiation (three-field radiotherapy [3FRT]), to 50 Gy in 25 fractions. A 10-Gy tumor-bed boost was allowed. Lung dose-volume histogram parameters (V(10), V(20), V(30), V(40)), 2D parameters (central lung depth [CLD], maximum lung depth [MLD], and lung length [LL]), and incidence of SRRP were reported. RESULTS: A total of 89 patients met the inclusion criteria: 51 had 2FRT, and 38 had 3FRT. With 2FRT, mean ipsilateral V(10), V(20), V(30), V(40) and CLD, MLD, LL were 20%, 14%, 11%, and 8% and 2.0 cm, 2.1 cm, and 14.6 cm, respectively, with strong correlation between CLD and ipsilateral V(10-V40) (R(2) = 0.73-0.83, p < 0.0005). With 3FRT, mean ipsilateral V(10), V(20), V(30), and V(40) were 30%, 22%, 17%, and 11%, but its correlation with 2D parameters was poor. With a median follow-up of 14.5 months, 1 case of SRRP was identified. CONCLUSIONS: With only 1 case of SRRP observed, our study is limited in its ability to provide definitive guidance, but it does provide a starting point for acceptable lung irradiation during ABR. Further prospective studies are warranted.

Temporal changes in IMRT contouring of organs at risk for nasopharyngeal carcinoma - the learning curve blues and a tool that could help.

With improved target conformality, the transition to IMRT for nasopharyngeal cancer (NPC) has moved contouring accuracy and consistency to the forefront. At NUH, IMRT for NPC was implemented in 2005, with more than 70 patients treated since then. The objective was to measure the accuracy and variability of contouring organs at risk (OAR) over time. The first 10 patients, 5 from each of the two head and neck (H&N) Radiation Oncologists, treated by IMRT in 2005 formed cohort A. Ten patients, matched by stage, treated by IMRT in 2007 formed cohort B. The RTOG 0225 protocol was followed. These 20 plans were retrieved from archive. A H&N Radiologist, who is a member of the UICC Expert Panel for the TNM Staging of NPC, reviewed the original OAR contours and developed a standardized OAR contouring template. Using the template, the OAR volumes were then re-contoured in all 20 cases, representing the gold standard against which the original volume was compared. For each patient, comparisons were made between the original and standardized contours using volumetric and spatial parameters. Cohort A was then compared with cohort B to determine whether accuracy and variability changed over time. Evaluated OAR volumes included the temporal lobes, brainstem, optic nerves, optic chiasm, pituitary, temporo-mandibular joint (TMJ), parotid glands, inner ears, eyes, and thyroid. While the original temporal lobe contours were significantly larger in cohort B (60.2 vs. 106.8 mL, p=0.02), the absolute difference between the original and standardized volumes was reduced by 53% (p=0.02) and there was no difference in the centroid coordinates and the overlapping fraction. While the inner ear was consistently contoured between cohort A and B, there was systematic exclusion of the cochlea in the contours. The original optic nerve contours decreased from cohort A to B (p=0.008), with an improvement in overlap fraction (p=0.06). The TMJ original volumes were smaller for cohort B than A, with a correspondingly significant improvement in overlapping fraction (p=0.02) with the standardized volumes. No difference was seen in the remaining OAR.

Systemic vs. central administration of common hypnotics reveals opposing effects on genioglossus muscle activity in rats.

STUDY OBJECTIVES: To determine if systemic administration of selected sedative-hypnotics that modulate the function of the y-amino-butyric acid-A (GABAA) receptor can: (i) delay arousal thereby allowing genioglossus (GG) activity to increase more in response to respiratory stimulation during sleep, (ii) also cause the robust increase in GG activity during undisturbed sleep recently observed with barbiturates. We also determined effects on GG activity with local application to the hypoglossal motor nucleus (HMN). DESIGN, PARTICIPANTS, AND INTERVENTIONS: Sleep-wake states, GG and diaphragm activities were recorded in freely-behaving rats after systemic administration of lorazepam (0.5 mg/kg and 1 mg/kg, n = 9 and 5 mg/kg, n = 7), zolpidem (5 mg/kg and 10 mg/kg, n = 6) and the antihistamine diphenhydramine (20 mg/kg, n = 9). Rats were also exposed to ramp increases in inspired CO2 in NREM sleep. The effects of lorazepam and zolpidem applied directly to the HMN were also determined in 37 anesthetized rats. MEASUREMENTS AND RESULTS: Lorazepam, zolpidem and diphenhydramine all increased arousal threshold, consistent with their sedative action. GG activity before arousal in response to hypercapnia was increased with lorazepam and zolpidem only, an effect mainly due to increased baseline activity before CO2 stimulation. Lorazepam and zolpidem applied directly to the HMN, however, decreased GG activity. CONCLUSIONS: Lorazepam and zolpidem have an inhibitory effect on GG activity via local effects at the HMN. Following systemic administration, however, this inhibitory effect can be outweighed both by a delay in arousal (allowing greater CO2-mediated respiratory stimulation in sleep) and excitatory influences on baseline GG activity via mechanisms operating outside the HMN.

Can all centers plan intensity-modulated radiotherapy (IMRT) effectively? An external audit of dosimetric comparisons between three-dimensional conformal radiotherapy and IMRT for adjuvant chemoradiation for gastric cancer.

PURPOSE: To compare dosimetric endpoints between three-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT) at our center with limited IMRT experience, and to perform an external audit of the IMRT plans. METHODS AND MATERIALS: Ten patients, who received adjuvant chemoradiation for gastric cancer, formed the study cohort. For standardization, the planning target volume (PTV) and organs at risk were recontoured with the assistance of a study protocol radiologic atlas. The cohort was replanned with CMS Xio to generate coplanar 3D-CRT and IMRT plans. All 10 datasets, including volumes but without the plans (i.e., blinded), were transmitted to an experienced center where IMRT plans were designed using Nomos Corvus (IMRT-C) and ADAC Pinnacle (IMRT-P). All IMRT plans were normalized to D95% receiving 45 Gy. RESULTS: Intensity-modulated radiotherapy yielded higher PTV V45 (volume that receives > or = 45 Gy) (p < 0.001) than 3D-CRT. No difference in V20 was seen in the right (p = 0.9) and left (p = 0.3) kidneys, but the liver mean dose (p < 0.001) was superior with IMRT. For the external audit, IMRT-C (p = 0.002) and IMRT-P (p < 0.001) achieved significantly lower left kidney V20 than IMRT, and IMRT-P (p < 0.001) achieved lower right kidney V20 than IMRT. The IMRT-C (p = 0.003) but not IMRT-P (p = 0.6) had lower liver mean doses than IMRT. CONCLUSIONS: At our institution with early IMRT experience, IMRT improved PTV dose coverage and liver doses but not kidney doses. An external audit of IMRT plans showed that an experienced center can yield superior IMRT plans.

Optimising radiation therapy techniques for tumours of the central nervous system.

INTRODUCTION: This study aims to assess the early tumour outcome and morbidity associated with radiation therapy (RT) in tumours of the central nervous system (CNS). MATERIALS AND METHODS: Patients receiving RT with radical intent were entered on a prospective database. Tumour types were categorised into glioma, base of skull, pituitary, germ cell or primitive neuroectodermal tumour (PNET) and other malignant CNS tumours. Study endpoints were overall survival and progression free survival. Acute and late toxicity endpoints included Common Terminology Criteria version 3.0 (CTC) grade 3 or 4 events, need for admission during RT and change in performance status at 12 months. RESULTS: One hundred and fifty-two patients with CNS tumours were managed with radical intent over the 4-year period. The median age was 49 years and 68.4% were Eastern Co-operative Group (ECOG) 0-1 performance status. The major pathology groups were glioma (59.9%) and base of skull tumours (17.1%). Gross total resection was performed in 28.3% only and RT was delayed after diagnosis until time of progression in 19.7%. For the 91 patients with glioma, the median survival and 2-year survival rate was 19.1 months and 44.1%, respectively. The 2-year survival rates for the subgroups of WHO Grade I or II, III and IV were 100%, 52% and 35%, respectively. For the non-glioma tumour groups, the relapse varied with pathology. Toxicity was minimal with only 3 acute and 3 late CTC grade 3 or 4 events occurring. Overall, 47 or 31% of patients required some inpatient hospitalisation during RT, although this was determined to have some causative relationship to RT in only 12 or 8% of patients. In the 12 months post-RT, performance status was stable or improved in 76.2% of patients, and most deterioration was associated with tumour relapse. CONCLUSIONS: RT for CNS tumours using modern techniques was well-tolerated with good tumour outcome and minimal morbidity.

Pentobarbital sedation increases genioglossus respiratory activity in sleeping rats.

OBJECTIVE: To determine whether certain sedatives may, by increasing arousal threshold, allow pharyngeal dilator muscle activity to increase more in response to chemical stimuli before arousal occurs. DESIGN, PARTICIPANTS AND INTERVENTIONS: Thirteen chronically instrumented rats were studied during sleep following injections of placebo or sedating doses of pentobarbital (10 mg/kg). Intermittently, inspired CO2 was increased gradually until arousal occurred. MEASUREMENTS AND RESULTS: Maximum genioglossus activity reached before arousal was higher with pentobarbital than placebo (34.5 +/- 24.3 vs 3.7 +/- 2.9mV; P < 0.001) for 2 reasons. First, genioglossus activity was greater during undisturbed sleep before CO2 was applied (23.3 +/- 15.3 vs 2.5 +/- 1.5 mV, P < 0.001). When sleep periods were long, a ramp-like increase in genioglossus activity (GG-Ramp) began and progressed until arousal. GG-Ramps developed with both placebo and pentobarbital but reached higher levels with pentobarbital due to longer sleep periods and faster increase in genioglossus activity during the ramp. GG-Ramps began when diaphragm activity was lowest and progressed despite unchanged diaphragm activity. Second, as hypothesized, the increase in genioglossus activity with CO2 before arousal was greater than with placebo (11.2 +/- 2.5 vs 1.2 +/- 2.5mV; P < 0.05) due to increased arousal threshold. In 27 of 126 CO2 challenges delivered while GG-Ramps were in progress, genioglossus activity paradoxically decreased despite increased diaphragmatic activity. These negative responses occurred randomly in 7 of 13 rats. CONCLUSIONS: In rats: 1) Sedatives may allow genioglossus activity to reach higher levels during sleep. 2) A time-dependent increase in genioglossus activity occurs during undisturbed sleep that is unrelated to chemical drive. 3) Transient hypercapnia may elicit inhibition of genioglossus activity under currently unidentified circumstances.

Role of inhibitory amino acids in control of hypoglossal motor outflow to genioglossus muscle in naturally sleeping rats.

The hypoglossal motor nucleus innervates the genioglossus (GG) muscle of the tongue, a muscle that helps maintain an open airway for effective breathing. Rapid-eye-movement (REM) sleep, however, recruits powerful neural mechanisms that can abolish GG activity even during strong reflex stimulation such as by hypercapnia, effects that can predispose to sleep-related breathing problems in humans. We have developed an animal model to chronically manipulate neurotransmission at the hypoglossal motor nucleus using in vivo microdialysis in freely behaving rats. This study tests the hypothesis that glycine receptor antagonism at the hypoglossal motor nucleus, either alone or in combination with GABAA receptor antagonism, will prevent suppression of GG activity in natural REM sleep during room air and CO2-stimulated breathing. Rats were implanted with electroencephalogram and neck muscle electrodes to record sleep-wake states, and GG and diaphragm electrodes for respiratory muscle recording. Microdialysis probes were implanted into the hypoglossal motor nucleus for perfusion of artificial cerebrospinal fluid (ACSF) and strychnine (glycine receptor antagonist, 0.1 mM) either alone or combined with bicuculline (GABAA antagonist, 0.1 mM) during room air and CO2-stimulated breathing. Compared to ACSF controls, glycine receptor antagonism at the hypoglossal motor nucleus increased respiratory-related GG activity in room air (P = 0.010) but not hypercapnia (P = 0.221). This stimulating effect of strychnine in room air did not depend on the prevailing sleep-wake state (P = 0.625) indicating removal of a non-specific background inhibitory glycinergic tone. Nevertheless, GG activity remained minimal in those REM sleep periods without phasic twitches in GG muscle, with GG suppression from non-REM (NREM) sleep being > 85 % whether ACSF or strychnine was at the hypoglossal motor nucleus or the inspired gas was room air or 7 % CO2. While GG activity was minimal in these REM sleep periods, there was a small but measurable increase in GG activity after strychnine (P < 0.05). GG activity was also minimal, and effectively abolished, in the REM sleep periods without GG twitches with combined glycine and GABAA receptor antagonism at the hypoglossal motor nucleus. We conclude that these data in freely behaving rats confirm that inhibitory glycine and GABAA receptor mechanisms are present at the hypoglossal motor nucleus and are tonically active, but that such inhibitory mechanisms make only a small contribution to the marked suppression of GG activity and reflex responses observed in periods of natural REM sleep.

GABAA receptor antagonism at the hypoglossal motor nucleus increases genioglossus muscle activity in NREM but not REM sleep.

The pharyngeal muscles, such as the genioglossus (GG) muscle of the tongue, are important for effective lung ventilation since they maintain an open airspace. Rapid-eye-movement (REM) sleep, however, recruits powerful neural mechanisms that can abolish GG activity, even during strong reflex respiratory stimulation by elevated CO2. In vitro studies have demonstrated the presence of GABAA receptors on hypoglossal motoneurons, and these and other data have led to the speculation that GABAA mechanisms may contribute to the suppression of hypoglossal motor outflow to the GG muscle in REM sleep. We have developed an animal model that allows us to chronically manipulate neurotransmission at the hypoglossal motor nucleus using microdialysis across natural sleep-wake states in rats. The present study tests the hypothesis that microdialysis perfusion of the GABAA receptor antagonist bicuculline into the hypoglossal motor nucleus will prevent the suppression of GG muscle activity in REM sleep during both room-air and CO2-stimulated breathing. Ten rats were implanted with electroencephalogram and neck muscle electrodes to record sleep-wake states, and GG and diaphragm electrodes for respiratory muscle recording. Microdialysis probes were implanted into the hypoglossal motor nucleus for perfusion of artificial cerebrospinal fluid (ACSF) or 100 microM bicuculline during room-air and CO2-stimulated breathing (7 % inspired CO2). GABAA receptor antagonism at the hypoglossal motor nucleus increased respiratory-related GG activity during both room-air (P = 0.01) and CO2-stimulated breathing (P = 0.007), indicating a background inhibitory GABA tone. However, the effects of bicuculline on GG activity depended on the prevailing sleep-wake state (P < 0.005), with bicuculline increasing GG activity in non-REM (NREM) sleep and wakefulness both in room air and hypercapnia (P < 0.01), but GG activity was effectively abolished in those REM periods without phasic twitches in the GG muscle. This abolition of GG activity in REM sleep occurred regardless of ACSF or bicuculline at the hypoglossal motor nucleus, or room-air or CO2-stimulated breathing (P > 0.63). We conclude that these data in freely behaving rats confirm previous in vitro studies that GABAA receptor mechanisms are present at the hypoglossal motor nucleus and are tonically active, but the data also show that GABAA receptor antagonism at the hypoglossal motor nucleus does not increase GG muscle activity in natural REM sleep.

Glycine at hypoglossal motor nucleus: genioglossus activity, CO(2) responses, and the additive effects of GABA.

There is evidence for glycine and GABA(A)-receptor-mediated inhibition of hypoglossal motoneurons in vitro. However, comparable studies have not been performed in vivo, and the interactions of such mechanisms with integrative reflex respiratory control have also not been determined. This study tests the hypotheses that glycine at the hypoglossal motor nucleus (HMN) will suppress genioglossus (GG) muscle activity, even in the presence of hypercapnic respiratory stimulation, and the effects of glycine will be blocked by strychnine. We also determined whether coapplication of glycine and muscimol (GABA(A)- receptor agonist) to the HMN is additive in suppressing GG activity. Twenty-four urethane-anesthetized, tracheotomized, and vagotomized rats were studied. Diaphragm and GG activities, the electroencephalogram, and blood pressure were recorded. Microdialysis probes were implanted into the HMN for delivery of artificial cerebrospinal fluid (control), glycine (0.0001-10 mM), or muscimol (0.1 microM). Increasing glycine at the HMN produced graded suppression of GG activity (P < 0.001), although the GG still responded to stimulation with 7% inspired CO(2) (P = 0.002). Strychnine (0.1 mM) reversed the glycine-mediated suppression of GG activity, whereas combined glycine and muscimol were additive in GG muscle suppression. It remains to be determined whether the recruitment of such glycine and GABA mechanisms explains the periods of major GG suppression in behaviors such as rapid eye movement sleep.