A comparison of the estrogenic potencies of estradiol,ethynylestradiol, diethylstilbestrol,nonylphenol and methoxychlor in vivo and in vitro

Five natural, pharmaceutical, or xenobiotic chemicals [17beta-estradiol (E2), ethynylestradiol (EE2), diethystilbestrol (DES), methoxychlor (MXC), nonylphenol (NP)] were tested in two in vitro assays [yeast estrogen screen (YES), MCF-7 breast tumor cell proliferation (E-Screen)], and compared with previously reported results from two in vivo male sheepshead minnow vitellogenin (VTG) production studies. The purpose of this investigation was to determine how accurately the two in vitro assays predicted responses observed in live animals. EC50 values for all five chemicals were approximately one order of magnitude less sensitive in the YES assay than in the MCF-7 assay. Based on the EC50 values, DES was 1.1 (YES) to 2.5 (MCF-7) times more potent in these receptor binding assays than was E2, while EE2 was slightly less potent than E2 in the YES assay (0.7) and nearly twice as potent (1.9) as E2 in the MCF-7 assay. EE2 and DES were of approximately equal potency in the 13-day sheepshead minnow VTG production bioassay. Both MXC and NP were 10(7) times less potent than E2 in the YES assay, MXC was 10(5) times less estrogenic than E2 in the MCF-7 assay, while both were approximately 100 times less potent than E2 in the live animal bioassay. The in vitro tests were substantially less sensitive (at least 1000 times) than the sheepshead minnow VTG assay for estimating estrogenic potency of the two xenobiotic chemicals, which suggests that in vitro-based, large-scale screening programs could potentially result in many false negative evaluations.     

Percutaneous nephrolithotripsy under assisted local anaesthesia for high risk patients: Is it effective?

ObjectivesThe aim of the present study is to evaluate the feasibility and safety of performing PNL under local anesthesia in a selected group of patients who are at high risk for general anesthesia.Patients and methodsForty seven patients underwent PNL under local anesthesia. There were 38 males and 9 females with a mean age of 62 years. All patients were at medical high-risk for general anesthesia, with an American Society of Anesthesiologists (ASA) score of 3. The indications for local anesthesia in this study were obstructed single functioning kidney with azotemia in 29 patients, hepatic insufficiency in 8 patients, cardiac problems in 7 patients and 3 patients had hepatocellular carcinoma. The mean stone size was 2.7 cm (range 2–3.1 cm). Local infiltration with 10–20 cc of 2% lidocaine at the site of puncture was used in all cases. Narcotics were given 30 min prior to the procedure and medazolam was given intraoperatively upon demand. Utrasound guided puncture was performed in all cases and tract dilatation was then done under fluoroscopy using high pressure balloon catheter in 35 and Alken's metal dilators in 12 cases. Stones were then retrieved after disintegration in the same cession in 33 patients, while the other 14 patients underwent staged PNL, where a 12 Fr. nephrostomy tube was placed in the first stage, followed by tract dilatation and stone retrieval one week later.ResultsOut of 47 patients included, 44 had successful PNL either one stage (30 patients) or two stages (14 patients). Only 3 patients could not tolerate pain and the procedure was terminated after placement of nephrostomy tube and stone retrieval was completed later under general anesthesia.ConclusionOur results demonstrated that PNL under local anesthesia with narcotics and sedatives seems to be a satisfying solution for the treatment of a selected group of patients with renal pelvic stones and who have high anesthetic risk. However, additional studies with different groups of patients are required to validate our results.     

Further delineation of the KBG syndrome caused by ANKRD11 aberrations

Loss-of-function variants in ANKRD11 were identified as the cause of KBG syndrome, an autosomal dominant syndrome with specific dental, neurobehavioural, craniofacial and skeletal anomalies. We present the largest cohort of KBG syndrome cases confirmed by ANKRD11 variants reported so far, consisting of 20 patients from 13 families. Sixteen patients were molecularly diagnosed by Sanger sequencing of ANKRD11, one familial case and three sporadic patients were diagnosed through whole-exome sequencing and one patient was identified through genomewide array analysis. All patients were evaluated by a clinical geneticist. Detailed orofacial phenotyping, including orthodontic evaluation, intra-oral photographs and orthopantomograms, was performed in 10 patients and revealed besides the hallmark feature of macrodontia of central upper incisors, several additional dental anomalies as oligodontia, talon cusps and macrodontia of other teeth. Three-dimensional (3D) stereophotogrammetry was performed in 14 patients and 3D analysis of patients compared with controls showed consistent facial dysmorphisms comprising a bulbous nasal tip, upturned nose with a broad base and a round or triangular face. Many patients exhibited neurobehavioural problems, such as autism spectrum disorder or hyperactivity. One-third of patients presented with (conductive) hearing loss. Congenital heart defects, velopharyngeal insufficiency and hip anomalies were less frequent. On the basis of our observations, we recommend cardiac assessment in children and regular hearing tests in all individuals with a molecular diagnosis of KBG syndrome. As ANKRD11 is a relatively common gene in which sequence variants have been identified in individuals with neurodevelopmental disorders, it seems an important contributor to the aetiology of both sporadic and familial cases.     

The Treatment of Acute Pain in the Emergency Department: A White Paper Position Statement Prepared for the American Academy of Emergency Medicine

Background

Pain is one of the most common reasons patients present to the emergency department (ED). Emergency physicians should be aware of the numerous opioid and nonopioid alternatives available for the treatment of pain.

Questions to and answers from the International AIDS Society-USA Resistance Testing Guidelines Panel

In 1996 the International AIDS Society-USA convened an international panel of experts in HIV drug resistance and clinical management to develop guidelines for the clinical use and limitations of resistance testing. Since then the International AIDS Society-USA Resistance Testing Guidelines Panel has developed and regularly published its recommendations. The latest panel recommendations appear in the July 1 issue of Clinical Infectious Diseases. We periodically pose questions to the panel relating to clinical elements of resistance testing that have been collected from HIV practitioners across the nation. We are happy to feature the latest edition in this issue of Topics in HIV Medicine. It is our hope that addressing these issues will help guide your treatment strategy decisions regarding resistance testing.     

Thiocarbohydrazide-crosslinked chitosan as a bioinspired corrosion inhibitor for protection of stainless steel in 3.5% NaCl

A facile single-step synthesis was performed to cross-link chitosan with thiocarbohydrazide to yield thiocarbohydrazide-chitosan (TC-Cht) which was for the first time evaluated as an inhibitor for corrosion of stainless steel in 3.5% NaCl solution. A comprehensive electrochemical analysis employing electrochemical impedance spectroscopy (EIS), potentiodynamic polarization (PDP), and cyclic voltammetry (CV) was undertaken and showed that the TC-Cht acts by adsorption on the steel surface and exhibits mixed type behavior with predominantly cathodic nature. The adsorption of TC-Cht molecules on the surface of stainless steel followed the Langmuir isotherm. The TC-Cht showed a high inhibition efficiency of >94% at 500 mg L^?1 concentration. Surface investigation using SEM and EDX supported the inhibitor adsorption on the steel surface.     

Ontogenesis of insulin processing in fetal rat hepatocytes

Summary We studied insulin processing and hepatic glycogenesis in cultured hepatocytes isolated from rat fetuses of 17, 19, and 21 days of gestation. Steady-state insulin binding increased by 250% between days 17 and 19, from 145±8 to 361±52 fmol/mg protein, and by an additional 40% (405±69 fmol/mg protein) by 21 days of gestation. At 37°C, ¹²⁵I-insulin was rapidly (t_1/2<5 min) internalized by hepatocytes at all three ages, reaching maximal levels (63–76% of the total cell-associated radioactivity) by 15 min. ¹²⁵I-labelled degradation products appeared rapidly (t_1/2<15 min) within the cells. Yet, the majority (68–77%) of the intracellular radioactivity consisted of intact ¹²⁵I-insulin, even after 4 h at 37°C. Hepatocytes pre-loaded with ¹²⁵I-insulin and then acid-stripped of surface-bound radioactivity, rapidly released both intact ¹²⁵I-insulin (retroendocytosis) and its radiolabelled degradation products. While intact insulin was initially released more rapidly (t_1/2<6 min), and reached a plateau after 15–30 min, the degradation products continued to accumulate in the medium for at least 4 h. Methylamine inhibited intracellular ¹²⁵I-insulin degradation at all three gestational ages and also blocked insulin-stimulated glycogenesis in 19- and 21-day hepatocytes, without altering basal glycogen synthesis. Insulin-stimulated glycogenesis was not induced in 17-day fetal rat hepatocytes in control or methylamine-treated cultures. We conclude that both degradative and retroendocytotic pathways for processing insulin are present in fetal rat hepatocytes by 17 days of gestation. Further, insulin-receptor processing was functionally related to the glycogenic action of insulin in responsive 19- and 21-day fetal rat hepatocytes     

Residual human immunodeficiency virus (HIV) Type 1 RNA and DNA in lymph nodes and HIV RNA in genital secretions and in cerebrospinal fluid after suppression of viremia for 2 years

Residual viral replication persists in a significant proportion of human immunodeficiency virus (HIV)-infected patients receiving potent antiretroviral therapy. To determine the source of this virus, levels of HIV RNA and DNA from lymphoid tissues and levels of viral RNA in serum, cerebrospinal fluid (CSF), and genital secretions in 28 patients treated for < or =2.5 years with indinavir, zidovudine, and lamivudine were examined. Both HIV RNA and DNA remained detectable in all lymph nodes. In contrast, HIV RNA was not detected in 20 of 23 genital secretions or in any of 13 CSF samples after 2 years of treatment. HIV envelope sequence data from plasma and lymph nodes from 4 patients demonstrated sequence divergence, which suggests varying degrees of residual viral replication in 3 and absence in 1 patient. In patients receiving potent antiretroviral therapy, the greatest virus burden may continue to be in lymphoid tissues rather than in central nervous system or genitourinary compartments.