Efficacy and safety of dolutegravir/lamivudine in virologically suppressed female participants: week 48 data from the pooled TANGO and SALSA studies.

OBJECTIVES: Women represent >50% of people with HIV globally but have historically been underrepresented in clinical trials. We evaluated the efficacy and safety of switching to dolutegravir/lamivudine (DTG/3TC) vs continuing their current antiretroviral regimen (CAR) by sex assigned at birth (female and male) in virologically suppressed adults with HIV-1 without prior virological failure in a pooled analysis of two randomized controlled trials. METHODS: This analysis included 48-week data from the phase 3 TANGO and SALSA studies. Primary and key secondary endpoints included proportions of participants with HIV-1 RNA ≥50 and <50 copies/mL at week 48, respectively. Safety was also assessed. RESULTS: Of 1234 participants, 250 (DTG/3TC, n = 133; CAR, n = 117) were female at birth. Week 48 proportions of participants with Snapshot HIV-1 RNA ≥50 copies/mL were similar regardless of sex at birth (DTG/3TC vs CAR: female, <1% [1/133] vs 2% [2/117]; male, <1% [1/482] vs <1% [3/502]). Proportions with HIV-1 RNA <50 copies/mL were high across sexes and treatment groups (DTG/3TC vs CAR: female, 91% [121/133] vs 89% [104/117]; male, 94% [455/482] vs 94% [471/502]). Immunological response with DTG/3TC was slightly higher in female participants. Incidences of adverse events leading to withdrawal and serious adverse events were low and comparable between treatment groups and across sexes. Weight gain was higher with DTG/3TC than with CAR among female participants aged ≥50 years (treatment difference 2.08 kg [95% confidence interval 0.40-3.75]). CONCLUSIONS: Results confirm the robustness of DTG/3TC as a switch option in virologically suppressed females with HIV-1, with outcomes similar to those in males.

Leukocyte counts in cerebrospinal fluid and blood following firategrast treatment in subjects with relapsing forms of multiple sclerosis.

BACKGROUND AND PURPOSE: Firategrast is an orally bioavailable alpha4 beta1/alpha4 beta7 integrin antagonist designed to reduce trafficking of lymphocytes into the central nervous system (CNS). This could decrease multiple sclerosis (MS) activity, but may compromise CNS immune surveillance. We aimed to quantitate the effect of firategrast treatment on cerebrospinal fluid (CSF) lymphocyte count and the extent/speed of recovery after its discontinuation. METHODS: Forty-six subjects with relapsing forms of MS were treated for up to 24 weeks with open-label firategrast, 900 (females) or 1200 (males) mg twice daily. CSF and blood cell counts, and lymphocyte composition were determined using flow cytometry. RESULTS: Median (n, range) CSF lymphocyte counts (cells/µl) at weeks 0, 24, 28 and 36 were: 5.3 (44, 0.3-70.2), 3.3 (31, 0.0-99.0), 3.0 (32, 0.0-58.2) and 3.5 (29, 0.0-274.8). CD4+, CD8+ T- and CD19+ B-lymphocyte counts followed a similar pattern. Minimal changes were observed for CD3-CD16+CD56+ natural killer cells. Median CD4 : CD8 ratios were: 2.9 (41, 1.1-10.9), 2.2 (29, 0.6-5.9), 3.8 (28, 1.6-9.0) and 3.8 (21, 2.1-9.4). Blood lymphocyte counts were elevated at weeks 4 and 24, consistent with the mechanism of firategrast, and returned to baseline when firategrast was discontinued. There were minimal changes in CD4 : CD8 ratios. CONCLUSIONS: Firategrast treatment was associated with modest decreases in median CSF total, CD4, CD8 and CD19 lymphocyte counts. The generally small magnitude of decreases suggests that sufficient numbers of lymphocytes can access the subarachnoid space, preserving CNS immune surveillance.

Esophageal tumors: The keys to diagnosis by pneumo-computed tomography.

OBJECTIVE: To review and describe the most characteristic radiological findings of the most frequent esophageal tumor lesions, with emphasis on the esophago-gastric distention technique pneumo-computed tomography performed in our institution. To know the main advantage of this distension technique. CONCLUSION: Malignant tumor lesions (predominantly squamous cell carcinoma in the mid esophagus and adenocarcinoma in the distal esophagus) present as asymmetric wall thickening, mucosal irregularity, or mass extending into adjacent organs with lymph node involvement. Benign tumors (mainly leiomyoma being the most frequent and others such as lipoma) present as endoluminal growth, with defined borders and homogeneous attenuation. Post-contrast enhancement is scarce or moderate. The technique of computed tomography pneumotomography technique achieves an additional distension of the esophageal lumen in all cases. It allows delimiting the superior and inferior borders of the lesions, helping the surgeon to define the therapeutic strategy.

Correlation between pneumo-computed tomography and pathology findings for subepithelial gastric lesions.

OBJECTIVE: This article aims to show the usefulness of the pneumo-computed tomography gastric distention technique in the detection and morphological characterization of subepithelial gastric lesions. We correlate the pneumo-computed tomography and pathology findings in lesions studied at our institution and review the relevant literature. CONCLUSION: Pneumo-computed tomography, combined with multiplanar reconstructions, three-dimensional reconstructions, and virtual endoscopy, is useful for delineating the morphological details of subepithelial gastric lesions, thanks to the additional gastric distention. This technique better delimits and characterizes the upper and lower margins of the lesions. Pneumo-computed tomography can be considered a useful noninvasive imaging techniques for characterizing these lesions.

Mesenchymal hamartoma and undifferentiated embryonal sarcoma: diagnostic keys that radiologists need to know. / Hamartoma mesenquimatoso y sarcoma embrionario indiferenciado: claves diagnósticas que el radiólogo debe conocer.

OBJECTIVE: Hepatic tumors are uncommon in pediatric patients. Among the most common of these uncommon tumors are mesenchymal hamartoma and undifferentiated embryonal sarcoma, which have different origins but similar appearance on imaging studies. This paper reviews the characteristic findings and differential diagnosis of these entities. Ultrasonography is the first-line imaging test to study these tumors. Magnetic resonance imaging and computed tomography are useful for further characterizing the tumors and planning surgery. CONCLUSION: Radiologists need to be familiar with the imaging findings of the different disease entities and to evaluate them together with the patient's age, personal history, and bloodwork.

Sclerosing encapsulating peritonitis: imaging findings in an uncommon entity. / Peritonitis esclerosante encapsulante: hallazgos en imágenes de una entidad poco frecuente.

OBJECTIVES: To describe the most characteristic imaging findings for sclerosing encapsulating peritonitis, with an emphasis on the computed tomography findings. CONCLUSION: The incidence of sclerosing encapsulating peritonitis is low. The pathophysiology of this condition is unclear. Two types are recognized: idiopathic and secondary; the secondary type is generally a complication of peritoneal dialysis. Its nonspecific clinical presentation and the absence of blood markers mean that sclerosing encapsulating peritonitis is usually diagnosed late. Thus, it is important to know the imaging signs; these include thickening and calcification of the peritoneum and dilation of bowel loops with thickening and calcification of bowel walls, whether in isolation or in association with loculated ascites. Although ultrasonography allows the complexity of the collections to be evaluated, computed tomography is the most useful technique for the general assessment of the signs mentioned above.

Osprey distribution, abundance, reproductive success and contaminant burdens along lower Columbia River, 1997/1998 versus 2004.

The osprey (Pandion haliaetus) population nesting along the lower portion of the Columbia River (river mile 29 to 286) increased from 94 in 1997 to 103 occupied nests in 1998 (9.6% annual rate of increase) to 225 occupied nests in 2004 (13.9% annual rate of increase). The more recent rate of population increase was associated with higher reproductive rates than in 1997/1998, and significantly lower egg concentrations of most organochlorine (OC) pesticides, polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs). A comparison of observed egg residue concentrations in 2004 with effect-level information for ospreys indicated that reproduction at few, if any, nests was adversely affected. As recent as 1997/1998, dichlorodiphenyldichloroethylene (DDE) was still adversely affecting reproductive success for a portion of this population. Mercury was the only contaminant evaluated in both 1997/1998 and 2004 that showed a significant increase in eggs over time, but concentrations in 2004 (0.09 microg g(-1) ww) remained below established effect levels for birds (generally reported at 0.50 microg g(-1) ww or higher). The significant increase in mercury justifies the need for future monitoring. All contaminants mentioned that biomagnify up food chains can be effectively monitored in osprey eggs. The osprey has been shown to be an excellent sentinel species for long-term monitoring with their many useful traits described.

Hormonal regulation of insulin-like growth factor II and insulin-like growth factor binding protein expression by breast cancer cells in vivo: evidence for stromal epithelial interactions.

Insulin-like growth factors (IGFs) I and II are potent mitogens for breast cancer cells. Their proliferative activity is likely to be influenced by their binding proteins (IGFBPs), a family of newly identified proteins. We report here on the in vivo hormonal regulation of mRNAs for IGF-II and IGFBPs in the N-nitrosomethylurea-induced rat mammary tumor, a well-established model of hormone-responsive mammary cancer. IGF-II mRNA levels tended to decrease in regressing tumors following ovariectomy, and they markedly increased upon reactivation of tumor growth with hormone repletion. Ovariectomy induced a drastic increase in IG-FBP-6 mRNA which was reversible with hormone repletion. Similar but more modest changes were observed with IGFBP-2 mRNA. In contrast, IGFBP-3 and IGFBP-4 mRNAs tended to decrease with ovariectomy and increase with hormone repletion. These latter effects, however, were modest, variable, and not statistically significant. In situ hybridization analysis revealed that IGF-II, IGFBP-5, and IGFBP-6 mRNAs were localized in the stromal component of the tumor, whereas IGFBP-2 mRNA was expressed by epithelial cells. We conclude that hormonal regulation of IGFBP expression is heterogeneous, thus suggesting divergent biological functions for these peptides. Our data also emphasize the importance of potential stromal-epithelial interactions in the control of breast cancer cell proliferation by IGFs.

Effects of 12-O-tetradecanoylphorbol 13-acetate on glycerolipid metabolism in cultured myoblasts.

We recently reported that treatment of differentiated chick embryo myoblasts in culture with the potent tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA) caused a 2-fold increase in the level of 1,2-diacylglycerol in the plasma membrane fraction within 15-30 min (Grove, R.I. and Schimmel, S.D. (1981) Biochem. Biophys. Res. Commun. 102, 158-164). This system has been characterized further and the metabolic origin and fate of the stimulated diacylglycerol have been investigated. The stimulation of 1,2-diacylglycerol was insensitive to alterations of Ca2+ concentration in the medium and to the presence of inhibitors of Ca2+ flux, protein synthesis and prostaglandin synthesis. The fatty acid composition of the newly formed diacylglycerol was similar to that of phosphatidylcholine. In addition, the glycerol moiety of the diacylglycerol was shown to be derived from a lipid with metabolic turnover similar to that of phosphatidylcholine. The tumor promoter was also found to stimulate rapidly synthesis of phosphatidic acid, phosphatidylinositol and phosphatidylcholine. A possible model is proposed, therefore, in which the tumor promoter stimulates a membrane-associated phospholipase C which generates 1,2-diacylglycerol via the hydrolysis of phosphatidylcholine. The newly formed diacylglycerol is then metabolized back to phosphatidylcholine or to phosphatidic acid and phosphatidylinositol.

Lipopolysaccharide (LPS) alters phosphatidylcholine metabolism in elicited peritoneal macrophages.

We investigated the effects of LPS on mouse peritoneal macrophage phospholipids using radiolabeled precursors. LPS (200 ng/ml) stimulated incorporation of [32P] into all classes of phospholipids within 0.5 hr, and after 2 hr the increase was 60% greater than controls. Separation of the phospholipid classes by thin-layer chromatography revealed a selective increase in incorporation of label into phosphatidylcholine (PC) (90% increase compared to approximately 50% in the other phospholipids). In macrophages labeled with [3H]-choline, LPS stimulated both the incorporation of label into PC and the release of incorporated label into the medium. The time dependencies of stimulated [3H] release and [32P] incorporation were similar. These data are consistent with the hypothesis that LPS activates macrophages via a PC-specific phospholipase-dependent mechanism.

[Cardiac resynchronization therapy (CRT) and anodal stimulation]. / Kardiale Resynchronisationstherapie (CRT) und anodale Stimulation.

We describe a biventricular stimulation mode to pace both ventricles with a single electrical stimulus between the tip of the left ventricular electrode and the tip of the right ventricular electrode: one ventricle is stimulated cathodal the other anodal.

Onset and temporal sequencing of lifetime anxiety, mood and substance use disorders in the general population.

Aims. To date, very few studies have examined the bi-directional associations between mood disorders (MDs), anxiety disorders (ADs) and substance use disorders (SUDs), simultaneously. The aims of the current study were to determine the rates and patterns of comorbidity of the common MDs, ADs and SUDs and describe the onset and temporal sequencing of these classes of disorder, by sex. Methods. Data came from the 2007 Australian National Survey of Mental Health and Wellbeing, a nationally representative household survey with 8841 (60% response rate) community residents aged 16-85. Results. Pre-existing mental disorders increase the risk of subsequent mental disorders in males and females regardless of the class of disorder. Pre-existing SUDs increase the risk of subsequent MDs and ADs differentially for males and females. Pre-existing MDs increase the risk of subsequent ADs differentially for males and females. Conclusions. Comorbidity remains a significant public health issue and current findings point to the potential need for sex-specific prevention and treatment responses.

Estrogen stimulation of phosphatidylinositol metabolism in mouse uterine tissue.

The effect of estrogens on incorporation of labeled precursor into inositol-containing phospholipids (PI) from ovariectomized mouse uterus was investigated. The results indicate that diethylstilbestrol (DES) a potent mitogen, stimulated incorporation of myo-[3H]inositol into uterine PI in 1-3 h, with maximal incorporation occurring at 6 h. This activity followed a dose-dependent increase, with a maximal effect at 5 micrograms/kg. Incorporation of radiolabeled phosphorous into the polyphosphoinositides was also increased in estrogen-stimulated uterine tissue. Studies using a weak uterotropic DES derivative, Z,Z-dienestrol, produced an early stimulation of the PI response comparable to DES. This activity was increased by Z,Z-dienestrol, with minimal estrogen receptor occupancy, and did not result in stimulation of DNA synthesis. These findings would suggest that uterine PI stimulation may not occur via an estrogen receptor-mediated mechanism related to tissue proliferation induced by estrogens.

Inhibitors of angiotensin converting enzyme decrease early atherosclerosis in hyperlipidemic hamsters. Fosinopril reduces plasma cholesterol and captopril inhibits macrophage-foam cell accumulation independently of blood pressure and plasma lipids.

The effect of two angiotensin converting enzyme (ACE) inhibitors on the development of atherosclerosis was determined in hyperlipidemic hamsters. Preliminary studies indicated that only fosinopril (50 mg/kg) temporarily decreased mean arterial pressure, while after chronic dosing fosinopril and captopril (50 mg/kg) were ineffective. The same dose of fosinopril and captopril inhibited the angiotensin I pressor response, indicating these agents suppressed ACE activity in vivo. In the 3 week atherosclerosis experiment, all hamsters were fed chow supplemented with 0.05% cholesterol and 10% coconut oil. Control hamsters were compared with those receiving either 50 mg/kg per day of fosinopril or 50 mg/kg per day of captopril. After 3 weeks, fosinopril reduced plasma total cholesterol, low density lipoprotein (LDL) plus very low density lipoprotein cholesterol and total triglycerides by 17%, 27% and 45%, respectively. Captopril only reduced high density lipoprotein cholesterol by 20%. Neither fosinopril or captopril altered blood pressure at 3 weeks. Atherosclerosis was quantified from en face preparations of the lesion-prone aortic arch that were stained with oil red O (for cholesteryl ester and triglycerides). In control hamsters, oil red O labeled numerous subendothelial macrophage-foam cells located along the inner curvature of the aortic arch. Compared with controls, fosinopril reduced the number of intimal macrophage-foam cells/mm2, foam cell size and the fatty streak area by 85%, 38% and 90%, respectively. Captopril decreased these parameters by 44%, 16% and 53%. Thus captopril decreased early atherosclerosis without affecting plasma LDL cholesterol or blood pressure, which suggested that inhibiting ACE (or kininase II) directly impeded the accumulation and formation of macrophage-foam cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Proton radiation therapy for medium and large choroidal melanoma: preservation of the eye and its functionality.

PURPOSE: Evaluation of efficacy and safety of proton radiation therapy (PRT) for medium- and large-size choroidal melanoma with focus on preservation of the eye and its function. METHODS: Retrospective review of 78 patients with 60 medium and 18 large-size choroidal melanomas at a median follow-up of 34 months. RESULTS: The 5-year data for local control, metastases-free survival, and disease-specific survival were estimated to be 90.5 +/- 3.7%, 76.2 +/- 6.7%, and 75.6 +/- 7.6%, respectively. Eye preservation was achieved in 75.3% of patients, with useful (better than 20/200) visual acuity (VA) in 49.1% of surviving patients. Both local failure and complications led to enucleation. Prognosticators were tumor close to the optic disc (p = 0.003), large tumors involving the ciliary body (p = 0.041), and local failure (p < 0.001). Prognostic factors for VA following PRT were initial VA (p = 0.001), doses to optic disc (p = 0.001) and fovea (p = 0.022) higher than 35 CGE (Cobalt Gray equivalent), tumor close to the optic disc (p = 0.034), and retinal detachment (p < 0.001). Tumor basis diameter was significantly related to metastases free survival (p = 0.02), overall survival (p = 0.033), and disease specific survival (p = 0.017), but did not impair local tumor control, rate of enucleation, and VA. CONCLUSION: The present data suggest that PRT is an effective and safe treatment for medium and large size choroidal melanoma. PRT can preserve the eye and its function in a reasonable percentage of patients. Further evaluation in controlled clinical trials comparing PRT to plaque radiotherapy and enucleation is required.

Dose response of rat retinal microvessels to proton dose schedules used clinically: a pilot study.

PURPOSE: This preclinical rat pilot study quantifies retinal microvessel, endothelial, and pericyte population changes produced by proton irradiation METHODS AND MATERIALS: The left eyes of rats were irradiated with single doses of 8, 14, 20, and 28 Gy protons; right eyes, with two fractions. Animals were euthanized, and eyes were removed; elastase digests were prepared, and cell populations were counted in sample fields. Results were compared with unirradiated controls. RESULTS: Progressive time- and dose-dependent endothelial cell loss occurred following all schedules. Cell loss was significantly different from control values (p < 0.001) following 28 Gy and following 20 Gy (p < 0.05) in a single dose. Endothelial cell loss was the same for single- and split-dose schedules. Progressive endothelial cell loss produced vessel collapse and acellular vessel strands. Endothelial cells were in the G(0) phase of the mitotic cycle. 28 Gy produced photoreceptor cell loss. CONCLUSION: The retinal digest is an elegant bioassay to quantify the microvessel population response. Single- and split-dose schedules appear to yield similar outcomes, in terms of endothelial cell density.

Quantitative RT-PCR to evaluate in vivo expression of multiple transgenes using a common intron.

An assay measuring RNA expression levels of a gene-encoded therapeutic must distinguish between endogenous mRNA and mRNA transcribed from the transgene. Specificity for the delivered transgene is especially critical when the treatment involves genes that are expressed in the target tissue. To facilitate uniform detection of transgene RNA without interference from endogenous mRNA, we have engineered expression vectors that include a 5' untranslated region (5' UTR) containing a synthetic intron (PGL3). The synthetic intron splice junction was the target sequence for a quantitative reverse transcription (RT)-PCR assay utilizing Taq-Man technology. In this study, we demonstrate that a quantitative RT-PCR assay designed to recognize an engineered intron splice site in the 5'UTR of expression constructs effectively measures the expression level of in vivo-delivered gene therapeutics.

Right-ventricular function as assessed by two radionuclide techniques: concise communication.

The gated semiautomated first pass and non-gated manual first pass methods of right ventricular ejection fraction calculation were compared. It was found that the gated first pass study was the simplest and fastest to process and was overall judged to give at least as much information as the other technique.

Isolation and characterization of human breast cancer cells overexpressing S-adenosylmethionine decarboxylase.

We report the first successful isolation and initial characterization of S-adenosylmethionine decarboxylase (SAMDC)-overexpressing cells using a transfection approach. Stably transfected MCF-7 breast cancer overproducing SAMDC (approximately 5-fold) manifested reduced ornithine decarboxylase while levels of N'-spermidine/spermine acetyltransferase were variably increased. Analysis of cellular polyamine profile showed that spermine was selectively increased (approximately 80%), while spermidine and putrescine levels were reduced (approximately 48% and approximately 15% of control, respectively). Since SAMDC-overexpressing clones exhibited increased clonogenicity in soft agar, our data suggest that spermine may be selectively involved in conferring a more invasive phenotype to breast cancer cells.

Binding of phorbol-12-myristate-13-acetate to cultured myoblasts.

The tumor promoter phorbol 12-myristate 13-acetate (PMA) binds in a rapid (maximal at 30 min), reversible, and non-saturable manner to cultured embryonic chick myoblasts. Serum was not required for binding although it promoted the release of PMA from the cells. This appears to be due to PMA binding to serum proteins. At any concentration tested, approx. 10% of the total PMA was bound at 5 min and 30% was bound at 30 min. It is estimated that a PMA concentration in the cell membrane of only 1 molecule of PMA/5000 molecules of membrane lipid elicits maximal biological responses in these cells.