Paltusotine is a nonpeptide selective somatostatin receptor 2 agonist in development as once-daily oral treatment for acromegaly.
To evaluate the efficacy and safety of paltusotine in the treatment ...of patients with acromegaly previously controlled with injected somatostatin receptor ligands (SRLs).
This phase 3, randomized, double-blind, placebo-controlled trial enrolled adults with acromegaly who had insulin-like growth factor I (IGF-I) ≤1.0 times the upper limit of normal (×ULN) while receiving a stable dose of depot octreotide or lanreotide. Patients were switched from injected SRLs and randomized to receive paltusotine or placebo orally for 36 weeks. The primary endpoint was proportion of patients maintaining IGF-I ≤1.0×ULN. Secondary endpoints were change in IGF-I level, change in Acromegaly Symptom Diary (ASD) score, and maintenance of mean 5-sample growth hormone (GH) <1.0 ng/mL.
The primary endpoint was met: 83.3% (25/30) of patients receiving paltusotine and 3.6% (1/28) receiving placebo maintained IGF-I ≤1.0×ULN (odds ratio: 126.53; 95% CI: 13.73, >999.99; P<.0001). Paltusotine was also superior to placebo for all secondary endpoints: mean (±SE) change in IGF-I of 0.04±0.09×ULN versus 0.83±0.1×ULN (P<.0001); mean (±SE) change in ASD score of -0.6±1.5 versus 4.6±1.6 (P=.02); mean GH maintained at <1.0 ng/mL in 20/23 (87.0%) versus 5/18 (27.8%) patients (odds ratio: 16.61; 95% CI: 2.86, 181.36; P=.0003). The most common adverse events were acromegaly symptoms and gastrointestinal effects characteristic of SRLs.
Replacement of injected SRLs by once-daily oral paltusotine was effective in maintaining both biochemical and symptom control in patients with acromegaly and was well tolerated.
It has been reported that cardiological screening and genetic evaluation in relatives of families with sudden unexplained death syndrome and unexplained cardiac arrest (UCA) may uncover a heritable ...etiology in a significant proportion of families.
To evaluate the yield of a comprehensive evaluation protocol of a large unselected cohort of consecutive families with autopsy-negative sudden unexplained death syndrome (termed sudden arrhythmic death syndrome SADS) and UCA.
We studied (1) 109 consecutive families (411 relatives) referred with 1 or more sudden deaths in the family and (2) 52 consecutive probands with UCA (91 relatives) referred by cardiologists between January 2007 and December 2012. A comprehensive cardiological screening was performed followed by targeted genetic evaluation if a clinical phenotype was proven or suspected. Diagnosis was made by a multidisciplinary team using published clinical criteria.
A diagnosis was made in 19 of 109 families with SADS (yield 18%), with the majority having long QT syndrome (LQTS). Diagnosis varied according to proband age, with LQTS most common in the very young (≤20 years) and Brugada syndrome in the older age probands (≥40 years) (P = .03). In contrast, a diagnosis was made in 32 of 52 families with UCA (yield 62%), the majority of which had LQTS and Brugada syndrome. No clinical or circumstantial factors increased the likelihood of diagnosis in families with either SADS or UCA.
In contrast to previously published series, a comprehensive strategy of cardiological evaluation and targeted genetic testing in more than 100 families with SADS was found to have a lower diagnostic yield (18%). Diagnostic yield in families with UCA was approximately 4 times higher (62%), which is consistent with the published literature.
Hydrogen peroxide (H2O2) and methylhydroperoxide (CH3OOH) are studied with a coupled gas phase and aqueous phase chemical model representing a remote nonprecipitating cloudy boundary layer. Cloud ...interactions may deplete or enhance H2O2 but have a minor effect on CH3OOH. Therefore two primary questions are addressed: (1) do nonprecipitating clouds perturb the ratio of H2O2/CH3OOH, and if so, (2) what is the rate of reestablishment of this ratio to clear‐sky levels following cloud contact. The results show that the rate of recovery of the ratio of H2O2 to Ch3OOH after perturbation by cloud interactions depends on NOx (=NO + NO2) mixing ratios and on the time of day that cloud is encountered. When cloud contact is followed by a significant period of daylight, recovery to precloud values is rapid; however, when cloud contact occurs during the late afternoon or night, recovery can take up to 24 hours under high NOx conditions. Sensitivity tests show that in‐cloud heterogeneous conversion of HNO3 to aerosol has a small but detectable effect (∼10%) on the recovery of the ratio. Neglecting dry deposition of H2O2 and HNO3 increases the predicted ratio H2O2/CH3OOH in clear air prior to cloud contact, and has a small effect on the relative recovery rate of the ratio. In‐cloud consumption of H2O2 by SO2 suppresses the postcloud ratio by ∼40% relative to that in the base case for low levels of SO2 (∼200 ppt), with a more pronounced effect on the ratio and its rate of recovery for SO2 ∼1 ppb. Because of the uncertainties associated with measurement of peroxides, and the dependence of the recovery of the ratio on the time of cloud contact, it is suggested that measurements of the ratio be considered judiciously and that they may not be of broad utility in predicting recent cloud contact.
We report a case of a rare cystic renal tumor previously termed cystic hamartoma of the renal pelvis. A 53-year-old woman presented to her gynecologist with menometorrhagia. She subsequently had a ...computed tomographic scan that demonstrated an incidental cystic mass in the lower pole of the left kidney. Histologically, the tumor was composed of a mixture of benign mesenchymal and epithelial components. The stroma consisted of spindle cells with monomorphic nuclei and abundant eosinophilic cytoplasm that resembled smooth muscle and that reacted positively with antibodies to alpha-smooth muscle actin, desmin, and vimentin. The epithelial component was composed mostly of cysts lined by cuboidal-to-columnar epithelium. Focal dilated cysts were lined by epithelium with oncocytic features. We think that this entity is distinct from other renal tumors, including mesoblastic nephroma, cystic nephroma, or a cystic, partially differentiated nephroblastoma, and that it is best classified as a cystic hamartoma of the renal pelvis.
In this collection, researchers examine areas in which biosocial health can be better understood through a syndemic framework by looking at how social and biological interactions are driven by stigma.
The geoduck clam, Panope abrupta, is a valuable economic resource in Washington State. Prior to the mid 1970s, the levels of paralytic shellfish poisoning (PSP) toxins in Washington State geoducks ...were not considered by the Washington State Department of Health (WDOH) to be a risk to public health because the viscera were presumed to be discarded. Recent monitoring information indicates that geoducks accumulate high levels of toxins, primarily in the viscera. The purposes of this study were to determine: (1) the seasonal concentration of paralytic shellfish toxins in geoduck clams at two sites and at two depths within each site; (2) the variability of PSP toxin levels among individual clams within each site; (3) the anatomical distribution of toxins: and (4) the correlation between two methods for estimating PSP toxins. From the summer of 1997 through the winter of 1998, 12-24 geoducks were collected biweekly from a shallow (7 m) and a deep (17 m) location in each of two tracts in Puget Sound, Washington: Quartermaster Harbor (QH) and Agate Pass (AP). Geoducks, dissected into siphon, mantle, and visceral portions, were assayed separately using the mouse bioassay (MBA), while only the visceral portions were assayed using the receptor-binding assay (RBA). Results indicated that toxin variability between individual clams was high in the shallow areas, with coefficients of variation (CVs) ranging from 20-98%, and lower in the deep areas (CV = 18-62%). In QH, only geoducks from the shallow water had toxin levels greater than the regulatory level of 80 mu g saxitoxinequivalents (STX eq) times 100 g shellfish tissue super(-1), while all geoducks from AP contained toxin above the regulatory level, with clams from shallow water considerably more toxic than those from deep water. Anatomically, the highest concentrations of PSP toxins were localized in the viscera of geoducks. There was a significant positive correlation between toxin levels measured by the MBA compared to values obtained using the RBA (r super(2) = 0.83). The large differences in toxicity between geoducks sampled at different depths and harvest tracts indicate that careful management plans must be designed in order to ensure public health.
The echinocandins are a well-known class of lipopeptides characterized by their potent antifungal activity against Candida species. The mechanism of action of the echinocandins is generally thought ...to be the inhibition of beta-1,3-glucan synthesis, an important structural component in the cell wall of Candida species. Extensive structure-activity studies on the fatty acid side chain of echinocandin B (1) led to the preparation of the clinical candidate cilofungin (4). However, little is known about the cyclic peptide. We now report the preparation, by solid-phase synthesis, of a series of simplified analogs of cilofungin in which the unusual amino acids found in the echinocandins were replaced with more readily accessible natural amino acids. The solid-phase approach to the total synthesis of these analogs allowed us to conveniently explore structural modifications that could not be accomplished by chemical modification of the natural product. The simplest analog 5 showed no biological activity. Structural complexity was then returned to the system in a systematic fashion so as to reapproach the original cilofungin structure. Antifungal activity and the inhibition of beta-1,3-glucan synthesis were monitored at each step of the process, thereby revealing the basic structure-activity relationships of the amino acids and the minimal structural requirements for biological activity in the echinocandin ring system. The results suggests that the 3-hydroxy-4-methylproline residue enhances activity but the L-homotyrosine residue is crucial for both antifungal activity and the inhibition of beta-1,3-glucan synthesis.
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