The vascular disrupting agent combretastatin-A4-phosphate (CA4P) demonstrated antitumour activity in preclinical studies when combined with radiation.
Patients with non-small-cell lung cancer ...(NSCLC), prostate adenocarcinoma, and squamous cell carcinoma of the head and neck (SCCHN) received 27 Gy in 6 fractions treating twice weekly over 3 weeks, 55 Gy in 20 fractions over 4 weeks, and 66 Gy in 33 fractions over 6 weeks respectively. CA4P was escalated from 50 mg/m2 to 63 mg/m2. CA4P exposure was further increased from one to three to six doses. Patients with SCCHN received cetuximab in addition.
Thirty-nine patients received 121 doses of CA4P. Dose-limiting toxic effects (DLTs) of reversible ataxia and oculomotor nerve palsy occurred in two patients with prostate cancer receiving weekly CA4P at 63 mg/m2. DLT of cardiac ischaemia occurred in two patients with SCCHN at a weekly dose of 50 mg/m2 in combination with cetuximab. Three patients developed grade 3 hypertension. Responses were seen in 7 of 18 patients with NSCLC. At 3 years, 3 of 18 patients with prostate cancer had prostate-specific antigen relapse.
Radiotherapy with CA4P appears well tolerated in most patients. The combination of CA4P, cetuximab, and radiotherapy needs further scrutiny before it can be recommended for clinical studies.
Estrogen replacement increases both the number of dendritic spines and the density of axospinous synapses in the hippocampal CA1 region in young rats, yet this is attenuated in aged rats. The ...estrogen receptor-alpha (ER-alpha) is localized within select spines of CA1 pyramidal cells in young animals and thus may be involved locally in this process. The present study investigated the effects of estrogen on the ultrastructural distribution of ER-alpha in the CA1 of young (3-4 months) and aged (22-23 months) Sprague Dawley rats using postembedding immunogold electron microscopy. Within dendritic spines, most ER-alpha immunoreactivity (IR) was seen in plasmalemmal and cytoplasmic regions of spine heads, with a smaller proportion within 60 nm of the postsynaptic density. In presynaptic terminals, ER-alpha-IR was clustered and often associated with synaptic vesicles. Significant effects of both aging and estrogen were observed. Quantitative analysis revealed that nonsynaptic pools of ER-alpha-IR within the presynaptic and postsynaptic compartments were decreased (35 and 27%, respectively) in the young estrogen-replaced animals compared with those that received vehicle. Such localized regulation of ER-alpha in response to circulating estrogen levels might directly affect synaptic signaling in CA1 pyramidal cells. No estrogen treatment-related differences were observed in the aged animals. However, 50% fewer spines contained ER-alpha in the aged compared with young hippocampus. These data suggest that the decreased responsiveness of hippocampal synapses to estrogen in aged animals may result from age-related decrements in ER-alpha levels and its subcellular localization vis-à-vis the synapse. Such a role for spinous ER-alpha has important implications for age-related attenuation of estrogen-induced hippocampal plasticity.
Here, we map a quantitative trait locus (QTL) with a large effect on predisposition to barbiturate (pentobarbital) withdrawal to a 0.44 Mb interval of mouse chromosome 1 syntenic with human 1q23.2. ...We report a detailed analysis of the genes within this interval and show that it contains 15 known and predicted genes, 12 of which demonstrate validated genotype-dependent transcript expression and/or nonsynonymous coding sequence variation that may underlie the influence of the QTL on withdrawal. These candidates are involved in diverse cellular functions including intracellular trafficking, potassium conductance and spatial buffering, and multimolecular complex dynamics, and indicate both established and novel aspects of neurobiological response to sedative-hypnotics. This work represents a substantial advancement toward identification of the gene(s) that underlie the phenotypic effects of the QTL. We identify Kcnj9 as a particularly promising candidate and report the development of a Kcnj9-null mutant model that exhibits significantly less severe withdrawal from pentobarbital as well as other sedative-hypnotics (zolpidem and ethanol) versus wild-type littermates. Reduced expression of Kcnj9, which encodes GIRK3 (Kir3.3), is associated with less severe sedative-hypnotic withdrawal. A multitude of QTLs for a variety of complex traits, including diverse responses to sedative-hypnotics, have been detected on distal chromosome 1 in mice, and as many as four QTLs on human chromosome 1q have been implicated in human studies of alcohol dependence. Thus, our results will be primary to additional efforts to identify genes involved in a wide variety of behavioral responses to sedative-hypnotics and may directly facilitate progress in human genetics.
We reviewed and meta-analyzed 10 studies (N = 492) that examined the association between (risk for) child maltreatment perpetration and basal autonomic activity, and 10 studies (N = 471) that ...examined the association between (risk for) child maltreatment and autonomic stress reactivity. We hypothesized that maltreating parents/at-risk adults would show higher basal levels of heart rate (HR) and skin conductance (SC) and lower levels of HR variability (HRV) and would show greater HR and SC stress reactivity, but blunted HRV reactivity. A narrative review showed that evidence from significance testing within and across studies was mixed. The first set of meta-analyses revealed that (risk for) child maltreatment was associated with higher HR baseline activity (g = 0.24), a possible indication of allostatic load. The second set of meta-analyses yielded no differences in autonomic stress reactivity between maltreating/at-risk participants and nonmaltreating/low-risk comparison groups. Cumulative meta-analyses showed that positive effects for sympathetic stress reactivity as a risk factor for child maltreatment were found in a few early studies, whereas each subsequently aggregated study reduced the combined effect size to a null effect, an indication of the winner’s curse. Most studies were underpowered. Future directions for research are suggested.
Detailed geochemical and field data for the volcanic sequence and intrusions of the Etendeka Igneous Province are used to construct a stratigraphic framework for petrogenetic interpretation of the ...evolution of the Etendeka-Parana continental flood volcanic event. Geochemical and petrographic characterization of over 1,000 analyzed samples allows 8 mafic and 17 silicic magma types to be recognized. Both silicic and mafic types can be grouped into high-Ti and low-Ti suites on the basis of elevated Ti relative to other elements. The mafic magmas are: Khumib (high-Ti), Tafelberg, Kuidas, Horingbaai, Huab, Tafelkop, Albin, and Esmeralda (all low-Ti). Amongst the silicic types, the Goboboseb, Springbok, Wereldsend, Grootberg, and Beacon low-Ti quartz latites, and the Nil Desperandum high-Ti latite have been described previously. In addition, the Hoas (low-Ti), Nadas, Sechomib, and Hoarusib, (all high-Ti) latites and the Fria (low-Ti), Sarusas, Ventura, Khoraseb, Naude, and Elliott (all high-Ti) quartz latites are described for the first time here. There is a marked provinciality in the distribution of the high- and low-Ti suites, with the former concentrated in the Northern Etendeka region and the latter dominant in the Southern Etendeka. Stratigraphic distribution of magma types allows two new formations to be defined in the Northern Etendeka - the Khumib Formation of basaltic flows and the Skeleton Coast Formation dominated by silicic sheets. The geochemical provinciality hampers precise correlations between Northern and Southern Etendeka. Available evidence suggests that the lower part of the Awahab Formation in the Southern Etendeka is coeval with the lower part of the Khumib Formation and that the silicic units in the upper part of the Tafelberg Formation probably correlate with the Skeleton Coast Formation. The paucity of Khumib dykes in relation to Tafelberg dykes and their field relationships with regard to the volcanic sequence in the Northern Etendeka suggests that the main Khumib eruptive centers lay further north, consistent with southward thinning of the Khumib basalts. In the Southern Etendeka, the Doros complex is the eruptive center of the plume-derived Tafelkop basalts, which probably built a shield volcano within the regional flood lava field. This work indicates that the Etendeka has a greater variety of both silicic and low-Ti mafic magma types than are known from the SE Parana. Detailed comparisons reveal that all the important silicic types in the Parana have geochemical equivalents in the Etendeka. New correlations are Santa Maria=Fria, Ourinhos=Khoraseb, Guarapuava=Sarusas, thus extending the previously recognized correlations between Southern Etendeka quartz latites and the Caixas do Sul and Anita Garibaldi "rhyolites." These correlations emphasize that very large volume silicic systems develop with pronounced lithospheric rifting in continental flood basalt provinces.
Stereotactic radiosurgery (SRS) is a procedure that delivers a single large radiation dose to a well‐defined target. Here, we describe a frameless SRS technique suitable for intracranial targets in ...canines. Medical records of dogs diagnosed with a primary intracranial tumour by imaging or histopathology that underwent SRS were retrospectively reviewed. Frameless SRS was used successfully to treat tumours in 51 dogs with a variety of head sizes and shapes. Tumours diagnosed included 38 meningiomas, 4 pituitary tumours, 4 trigeminal nerve tumours, 3 gliomas, 1 histiocytic sarcoma and 1 choroid plexus tumour. Median survival time was 399 days for all tumours and for dogs with meningiomas; cause‐specific survival was 493 days for both cohorts. Acute grade III central nervous system toxicity (altered mentation) occurred in two dogs. Frameless SRS resulted in survival times comparable to conventional radiation therapy, but with fewer acute adverse effects and only a single anaesthetic episode required for therapy.
CONTEXT Relapses of acute asthma following emergency
department (ED) discharge can be reduced with systemic corticosteroid
treatment. However, whether inhaled corticosteroids (ICSs) provide
...additional benefit is not known. OBJECTIVE To determine whether the addition of ICSs to oral
corticosteroid treatment would reduce relapses in patients with acute
asthma discharged from the ED. DESIGN AND SETTING Placebo-controlled, double-blind, randomized
clinical trial conducted in a community teaching hospital ED in Canada
between November 1995 and September 1997, with a 21-day follow-up. PARTICIPANTS A total of 1006 consecutive patients aged 16 to 60
years presented to the ED with acute asthma; after excluding those
using oral and/or inhaled corticosteroids as well as those meeting
other exclusion criteria, 188 were included in the study. INTERVENTIONS Patients were discharged with a nontapering course
of oral prednisone (50 mg/d) for 7 days. In a double-blind fashion,
patients were randomly assigned to 1600 µg/d of inhaled budesonide
(n=94) or identical placebo (n=94) for
21 days. MAIN OUTCOME MEASURES Incidence of relapse, defined as an
unscheduled visit for worsening asthma symptoms, in budesonide vs
placebo groups. Secondary outcomes included response to the Asthma
Quality of Life Questionnaire, β2-agonist use, symptom
score, global asthma improvement assessment, and pulmonary function. RESULTS Five patients in the budesonide group and 3 in the placebo
group either dropped out or were lost to follow-up but were included in
primary analyses. After 21 days, 12 (12.8%) of 94 patients in the
budesonide group experienced a relapse compared with 23 (24.5%) of 94
in the placebo group, a 48% relapse reduction
(P=.049). Asthma Quality of Life Questionnaire
scores were higher (better quality) in the budesonide group
(P=.001), as well as for all domain scores
(P=.001 to .01). Fewer
β2-agonist activations were used at the end of the trial
by patients receiving budesonide (2.4/d vs 4.2/d;
P=.01). Symptom scores
(P=.001 to .004) and self-assessed asthma
improvement scores (based on a 7-point Likert scale) (6.2 vs 5.2;
P<.001) were higher (indicating fewer symptoms) for
budesonide vs placebo. There were no differences in pulmonary function
between the groups (peak expiratory flow rate: budesonide, 437 vs
placebo, 453 L/min; P=.39) at 21 days. Using
this approach, as few as 9 patients would require budesonide to prevent
1 relapse. CONCLUSIONS Patients discharged from the ED following treatment
for acute asthma benefit from added treatment with high-dose inhaled
budesonide for 21 days compared with oral corticosteroids
alone.
: We describe a woman with relapsed acute myelogenous leukemia after allogeneic stem cell transplantation who developed disseminated Geotrichum candidum infection during chemotherapy‐induced ...neutropenia. The isolate was susceptible to voriconazole, amphotericin B, and micafungin in vitro. We review the literature regarding invasive infections with G. candidum, which predominantly affect immunocompromised hosts, and discuss potential therapies for this rare pathogen.
Minimally invasive neurological surgeries are increasingly being sought after for treatment in neurological pathologies and oncology. A critical limitation in these minimally invasive procedures is ...lack of specialized tools that allow for space-time controlled delivery of sufficient energy for coagulation and cutting of tissue. Advent of fiber-lasers provide high average power with improved beam quality (lower M
), biocompatible silica fiber delivery, reduced cost of manufacturing, and radiant output stability over long operating periods. Despite these advancements, no fiber-laser based surgical tools are currently available for tissue resection
. Here we demonstrate a first to our knowledge, fiber-laser platform for performing precise brain surgery in a murine brain model. In this study, our primary aims were to first demonstrate efficacy of fiber-lasers in performing precise blood-less surgery in a murine brain with limited non-specific thermal damage. Second, fiber-lasers' ability to deliver radiant energy through biocompatible silica fibers was explored in a murine brain model for blood less resection. A bench-top optical coherence tomography (OCT) guided fiber-laser platform was constructed with a stereotactic stage for performing precision brain surgery. A pulsed quasi-continuous wave ytterbium (Yb) fiber-laser (1.07 µm) was used to perform vascular specific coagulation while a pulsed nanosecond thulium fiber-laser (1.94 µm) was used to conduct bloodless cutting, all under the guidance of a swept-source OCT system centered at 1310 +/- 70 nm. Specialty linear and circular cuts were made in an
murine brain for bloodless brain tissue resection. The two fiber-lasers were combined into a single biocompatible silica fiber to conduct brain surgery resection under the bench-top OCT system's imaging microscope. Vascular specific coagulation was demonstrated in all five mice studied. Bloodless linear cuts and point cuts were demonstrated
. Histologically, thermal injury was measured to be less than 100 µm while a removal rate of close to 5 mm
/s was achieved with an average Tm fiber-laser power of 15 W. To the authors' knowledge, this is the first demonstration of a fiber-laser platform for conducting
bloodless brain tissue resection with a pulsed thulium (Tm) fiber-laser and a quasi-continuous wave (QCW) Yb fiber-laser. The demonstrated fiber-laser platform, if successfully configured for use in the operating room (OR), can provide surgeons a tool for rapid removal of tissue while making surgical resections of brain regions more precise, and can be basis for a flexible cutting tool capable of reaching hard-to-operate regions.
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