Refining the Definitions of Biochemical and Clinical Cure for Primary Aldosteronism Using the Primary Aldosteronism Surgical Outcome (PASO) Classification System.

INTRODUCTION: Determination of outcomes after adrenalectomy for primary aldosteronism (PA) is limited by the lack of standardized definitions of cure. The Primary Aldosteronism Surgical Outcomes (PASO) group recently established new consensus definitions for biochemical and clinical cure of PA. We hypothesize that utilization of PASO definitions will better stratify patient outcomes after surgery compared to original and current criteria utilized to document cure. MATERIALS AND METHODS: Patients undergoing adrenalectomy for PA from 1996 to 2016 were studied. Clinical data were reviewed. Three different sets of criteria (original, current, and PASO) were evaluated for differences in documentation of cure. Demographic data were reported as median (range). Comparisons were made using the Mann-Whitney U test; p < 0.05 is significant. RESULTS: A total of 314 patients with PA were identified. Ninety patients (60 males) elected to proceed with surgery. In Group 1 (35 patients), 30 patients had clinical follow-up and 29 (97%) were cured using original criteria. In Group 2 (55 patients), cure was recorded in 98% when original criteria for cure were applied, 89% cured applying current criteria, and 6% had complete biochemical and clinical cure by PASO criteria. Aldosterone rose 3.6 ng/dL (0.1-34.8) in five patients during extended follow-up, with two patients changing from complete to partial or missing biochemical success. CONCLUSION: Significant heterogeneity exists in outcomes criteria utilized to document cure or clinical improvement after adrenalectomy for primary aldosteronism. Aldosterone levels change over time after adrenalectomy. PASO definitions of cure appear to allow for improved stratification of short- and long-term outcomes.

Novel C-Terminal Heat Shock Protein 90 Inhibitors (KU711 and Ku757) Are Effective in Targeting Head and Neck Squamous Cell Carcinoma Cancer Stem cells.

Advanced head and neck squamous cell carcinoma (HNSCC) remains a therapeutic challenge due to the development of therapy resistance. Several studies have implicated the development of cancer stem cells as a possible mechanism for therapy resistance in HNSCC. Heat shock protein 90's (Hsp90's) molecular chaperone function is implicated in pathways of resistance in HNSCC. Therefore, in the present study, we investigated the efficacy of novel C-terminal Hsp90 inhibitors (KU711 and KU757) in targeting HNSCC cancer stem cells (CSCs). Treatment of HNSCC human cell lines MDA1986, UMSCC 22B, and UMSCC 22B cisplatin-resistant cells with the KU compounds indicated complete blockage of self-renewal for the resistant and parent cell lines starting from 20 µM KU711 and 1 µM KU757. Dose-dependent decrease in the cancer stem cell markers CD44, ALDH, and CD44/ALDH double-positive cells was observed for all cell lines after treatment with KU711 and KU757. When cells were treated with either drug, migration and invasion were downregulated greater than 90% even at the lowest concentrations of 20 µM KU711 and 1 µM KU757. Western blot showed >90% reduction in client protein "stemness" marker BMI-1 and mesenchymal marker vimentin, as well as increase in epithelial marker E-cadherin for both cell lines, indicating epithelial to mesenchymal transition quiescence. Several CSC-mediated miRNAs that play a critical role in HNSCC therapy resistance were also downregulated with KU treatment. In vivo, KU compounds were effective in decreasing tumor growth with no observed toxicity. Taken together, these results indicate that KU compounds are effective therapeutics for targeting HNSCC CSCs.

Clinical outcomes of proximal row carpectomy versus four-corner arthrodesis for post-traumatic wrist arthropathy: a systematic review.

We conducted a systematic review of studies reporting clinical outcomes after proximal row carpectomy or to four-corner arthrodesis for scaphoid non-union advanced collapse or scapholunate advanced collapse arthritis. Seven studies (Levels I-III; 240 patients, 242 wrists) were evaluated. Significantly different post-operative values were as follows for four-corner arthrodesis versus proximal row carpectomy groups: wrist extension, 39 (SD 11º) versus 43 (SD 11º); wrist flexion, 32 (SD 10º) versus 36 (SD 11º); flexion-extension arc, 62 (SD 14º) versus 75 (SD 10º); radial deviation, 14 (SD 5º) versus 10 (SD 5º); hand grip strength as a percentage of contralateral side, 74% (SD 13) versus 67% (SD 16); overall complication rate, 29% versus 14%. The most common post-operative complications were non-union (grouped incidence, 7%) after four-corner arthrodesis and synovitis and clinically significant oedema (3.1%) after proximal row carpectomy. Radial deviation and post-operative hand grip strength (as a percentage of the contralateral side) were significantly better after four-corner arthrodesis. Four-corner arthrodesis gave significantly greater post-operative radial deviation and grip strength as a percentage of the opposite side. Wrist flexion, extension, and the flexion-extension arc were better after proximal row carpectomy, which also had a lower overall complication rate.

Congenital cholesteatoma in siblings.

INTRODUCTION: The exact aetiology of congenital cholesteatoma, the less common form of this destructive disease, is still under debate. CASE REPORT: A two-year-old boy was referred to paediatric otolaryngology with persistent, bloody, left-sided otorrhoea refractory to oral and ototopical antibiotics. Prior to its onset at age 16 months, all ear examinations on the affected side were normal. Physical examination, imaging with computed tomography and eventual tympanomastoidectomy revealed extensive cholesteatoma. The extent of the disease, age at onset of symptoms and absence of otological disease before initial presentation suggested the diagnosis of congenital cholesteatoma. Review of the family history revealed that the patient's older brother had undergone tympanomastoidectomy for a small, well-encapsulated, mesotympanic congenital cholesteatoma at two years of age. DISCUSSION: This case joins a single, previous report describing congenital cholesteatoma in multiple family members, suggesting that in some cases, hereditary factors may play a role in the formation of the disease.

HIV-1 gp41 envelope IgA is frequently elicited after transmission but has an initial short response half-life.

Prevention of HIV-1 transmission at mucosal surfaces will likely require durable pre-existing mucosal anti-HIV-1 antibodies (Abs). Defining the ontogeny, specificities and potentially protective nature of the initial mucosal virus-specific B-cell response will be critical for understanding how to induce protective Ab responses by vaccination. Genital fluids from patients within the earliest stages of acute HIV-1 infection (Fiebig I-VI) were examined for multiple anti-HIV specificities. Gp41 (but not gp120) Env immunoglobulin (Ig)A Abs were frequently elicited in both plasma and mucosal fluids within the first weeks of transmission. However, shortly after induction, these initial mucosal gp41 Env IgA Abs rapidly declined with a t(½) of ∼2.7 days. B-cell-activating factor belonging to the TNF family (BAFF) was elevated immediately preceding the appearance of gp41 Abs, likely contributing to an initial T-independent Ab response. HIV-1 transmission frequently elicits mucosal HIV-1 envelope-specific IgA responses targeted to gp41 that have a short half-life.

Pulmonary outflow tract obstruction in fetuses with complex congenital heart disease: predicting the need for neonatal intervention.

OBJECTIVE: To identify prenatal echocardiographic markers that could predict the need for neonatal intervention in fetuses with right ventricular outflow tract obstruction. METHODS: This was a retrospective study of 52 fetuses with right ventricular outflow tract obstruction. Echocardiograms were evaluated for fetuses with either two-ventricle anatomy with a large ventricular septal defect or single-ventricle anatomy. Fetuses with pulmonary atresia were excluded. Parameters were compared between groups that did and did not require an intervention at age < 30 days. RESULTS: Fifty-two fetuses were studied; 20 (38%) underwent neonatal intervention and 32 (62%) did not. The most common diagnosis was tetralogy of Fallot (n = 32). Fetuses with two ventricles that required an intervention had lower pulmonary valve diameter Z-score (PV-Z-score) (-4.8 ± 2.1 vs. -2.6 ± 1.1; P = 0.0002) and lower pulmonary valve to aortic valve annular diameter ratio (PV/AoV) (0.53 ± 0.15 vs. 0.66 ± 0.1; P = 0.003). Using a PV/AoV ratio of < 0.6 or a PV-Z-score of < -3 at final echocardiographic examination was highly sensitive (92%) but poorly specific (50%), whereas classifying direction of flow in the ductus arteriosus as either normal (all pulmonary-to-aorta) or abnormal (aorta-to-pulmonary or bidirectional) was both highly sensitive (100%) and specific (95%) for predicting the need for a neonatal intervention. Parameters for the single-ventricle cohort did not reach statistical significance. CONCLUSIONS: Analysis of the pulmonary outflow tract and ductus arteriosus flow in the fetus with complex congenital heart disease can aid in identifying those that will require a neonatal intervention to augment pulmonary blood flow. This has important implications for the planning of delivery strategies.

Traumatic ulnar translocation of the carpus: early recognition and treatment.

This study evaluated the clinical outcomes and radiographic features of surgically treated traumatic ulnocarpal translocation in nine patients (ten cases). All ligament and fracture repairs were completed within 2 months of injury. Seven cases were examined at a mean of 6.5 years, and information in three cases was obtained from medical records at a mean of 13 months after injury. At final evaluation, the mean disabilities of the arm, shoulder, and hand score was 6 (range, 0-16), and the mean Mayo modified wrist score was 76 (range, 40-100). Ulnocarpal translocation was evident in nine of the injured wrists, six of which showed arthritis, and in four of the uninjured wrists. Ulnar variance measured negative in nine cases and neutral in one case. Pre-existing medial alignment of the carpus and ulnar minus variance may predispose to traumatic ulnocarpal translocation. Early injury repair does not assure restoration of radiocarpal alignment or prevent joint deterioration; however, these changes do not always portend a suboptimal result.

An implantable RF solenoid for magnetic resonance microscopy and microspectroscopy.

Miniature solenoids routinely enhance small volume nuclear magnetic resonance imaging and spectroscopy; however, no such techniques exist for patients. We present an implantable microcoil for diverse clinical applications, with a microliter coil volume. The design is loosely based on implantable depth electrodes, in which a flexible tube serves as the substrate, and a metal stylet is inserted into the tube during implantation. The goal is to provide enhanced signal-to-noise ratio (SNR) of structures that are not easily accessed by surface coils. The first-generation prototype was designed for implantation up to 2 cm, and provided initial proof-of-concept for microscopy. Subsequently, we optimized the design to minimize the influence of lead inductances, and to thereby double the length of the implantable depth (4 cm). The second-generation design represents an estimated SNR improvement of over 30% as compared to the original design when extended to 4 cm. Impedance measurements indicate that the device is stable for up to 24 h in body temperature saline. We evaluated the SNR and MR-related heating of the device at 3T. The implantable microcoil can differentiate fat and water peaks, and resolve submillimeter features.

Interaction of 5-HT2A and 5-HT2C receptors in R(-)-2,5-dimethoxy-4-iodoamphetamine-elicited head twitch behavior in mice.

Drug-elicited head-twitch behavior is a useful model for studying hallucinogen activity at 5-HT(2A) receptors in the mouse. Chemically diverse compounds active in this assay yield biphasic dose-effect curves, but there is no compelling explanation for the "descending" portion of these functions. A set of experiments was designed to test the hypothesis that the induction of head-twitch behavior is mediated by agonist actions at 5-HT(2A) receptors, whereas the inhibition of head-twitch behavior observed at higher doses results from competing agonist activity at 5-HT(2C) receptors. The effects of the phenethylamine hallucinogen R(-)-2,5-dimethoxy-4-iodoamphetamine (DOI) on head-twitch behavior were studied over a range of doses in the mouse, generating a characteristic biphasic dose-response curve. Pretreatment with the selective 5-HT(2A) antagonist (+)-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol (M100907) shifted only the ascending limb of the DOI dose-effect function, whereas pretreatment with the nonselective 5-HT(2A/2C) antagonist 3-{2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl}quinazoline-2,4(1H,3H)-dione (ketanserin) produced a parallel shift to the right in the DOI dose-response curve. Administration of the 5-HT(2C) agonist S-2-(chloro-5-fluoro-indol-l-yl)-1-methylethylamine (Ro 60-0175) noncompetitively inhibited DOI-elicited head-twitch behavior across the entire dose-effect function. Finally, pretreatment with the selective 5-HT(2C) antagonists 6-chloro-5-methyl-1-[(2-[2-methylpyrid-3-yloxy]pyrid-5yl)carbamoyl]indoline (SB242084) or 8-[5-(2,4-dimethoxy-5-(4-trifluoromethylphenylsulfonamido)phenyl-5-oxopentyl]-1,3,8-triazaspiro[4,5]decane-2,4-dione hydrochloride (RS 102221) did not alter DOI-elicited head-twitch behavior on the ascending limb of the dose-response curve but shifted the descending limb of the DOI dose-response function to the right. The results of these experiments provide strong evidence that DOI-elicited head-twitch behavior is a 5-HT(2A) agonist-mediated effect, with subsequent inhibition of head-twitch behavior being driven by competing 5-HT(2C) agonist activity.

Drug delivery to the lymphatic system: importance in future cancer diagnosis and therapies.

Cancer is the second leading cause of death in the US. Currently, protocols for cancer treatment include surgery to remove diseased and suspect tissues, focused radiation, systemic chemotherapy, immunotherapy and their combinations. With conventional chemotherapy, it is almost impossible to deliver anticancer drugs specifically to the tumor cells without damaging healthy organs or tissues. Over the past several decades, efforts have been made to improve drug delivery technologies that target anticancer drugs specifically to tumor cells. It has been known for over four decades that the lymphatics are the first site of metastasis for most solid cancers; however, few efforts have been made to localize chemotherapies to lymphatic tissues. Trials of several systemic targeted drug delivery systems based on nanoparticles containing chemotherapeutic agents (e.g., liposomal doxorubicin) have shown similar antitumor activity but better patient tolerance compared with conventional formulations. Animal studies have demonstrated that nanoparticles made of natural or synthetic polymers and liposomal carriers have higher accumulation in the lymph nodes and surrounding lymphatics compared to conventional intravenous therapies. This combination has the potential to both reduce nonspecific organ toxicities and increase the chemotherapeutic dose to the most likely sites of locoregional cancer metastasis.

Quantitating the multiplicity of infection with human immunodeficiency virus type 1 subtype C reveals a non-poisson distribution of transmitted variants.

Identifying the specific genetic characteristics of successfully transmitted variants may prove central to the development of effective vaccine and microbicide interventions. Although human immunodeficiency virus transmission is associated with a population bottleneck, the extent to which different factors influence the diversity of transmitted viruses is unclear. We estimate here the number of transmitted variants in 69 heterosexual men and women with primary subtype C infections. From 1,505 env sequences obtained using a single genome amplification approach we show that 78% of infections involved single variant transmission and 22% involved multiple variant transmissions (median of 3). We found evidence for mutations selected for cytotoxic-T-lymphocyte or antibody escape and a high prevalence of recombination in individuals infected with multiple variants representing another potential escape pathway in these individuals. In a combined analysis of 171 subtype B and C transmission events, we found that infection with more than one variant does not follow a Poisson distribution, indicating that transmission of individual virions cannot be seen as independent events, each occurring with low probability. While most transmissions resulted from a single infectious unit, multiple variant transmissions represent a significant fraction of transmission events, suggesting that there may be important mechanistic differences between these groups that are not yet understood.

Rapamycin induces transactivation of the EGFR and increases cell survival.

The mammalian target of rapamycin (mTOR) signaling network regulates cell growth, proliferation and cell survival. Deregulated activation of this pathway is a common event in diverse human diseases such as cancers, cardiac hypertrophy, vascular restenosis and nephrotic hypertrophy. Although mTOR inhibitor, rapamycin, has been widely used to inhibit the aberrant signaling due to mTOR activation that plays a major role in hyperproliferative diseases, in some cases rapamycin does not attenuate the cell proliferation and survival. Thus, we studied the mechanism(s) by which cells may confer resistance to rapamycin. Our data show that in a variety of cell types the mTOR inhibitor rapamycin activates extracellularly regulated kinases (Erk1/2) signaling. Rapamycin-mediated activation of the Erk1/2 signaling requires (a) the epidermal growth factor receptor (EGFR), (b) its tyrosine kinase activity and (c) intact autophosphorylation sites on the receptor. Rapamycin treatment increases tyrosine phosphorylation of EGFR without the addition of growth factor and this transactivation of receptor involves activation of c-Src. We also show that rapamycin treatment triggers activation of cell survival signaling pathway by activating the prosurvival kinases Erk1/2 and p90RSK. These studies provide a novel paradigm by which cells escape the apoptotic actions of rapamycin and its derivatives that inhibit the mTOR pathway.

Electricity and Magnetism: Insights into the brain from multimodal imaging.

The windows into brain function given us by the instruments of neuroimaging each are murky and their view is limited. Simultaneous collection of data from multiple modalities offers the potential to overcome the weaknesses of any tool alone. We argue that the combination of electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) offers observations - and hypothesis testing - not possible using either single instrument. Because of their safety profiles and their non-invasive natures, EEG fMRI are among the best available devices for the study of human brain. These methods are complementary. EEG is fast, operating in a time domain comparable to single unit activity, but its localizing power is poor and the field of view is limited. While fMRI has the highest spatial resolution of any noninvasive imaging method and can reveal multiple centers of brain activity implicated in cognitive tasks, it is very slow compared to mental activity and is a poor choice for studying rapidly evolving processes. Here, we address theoretical models of the coupling between EEG and fMRI signals based on cellular physiology and energetics and argue that both tools observe principally synaptic activity. We discuss the technical problems of mutual interference then present several models of brain rhythms for which the joint EEG and fMRI observations provide significant evidence.

Improving strategies for syphilis control in China: selective testing of sexually transmitted disease patients--too little, too late?

SUMMARY: Syphilis testing guidelines in China are usually based on symptomatic criteria, overlooking risk assessment and ultimately opportunities for disease detection and control. We used data from 10,695 sexually transmitted disease (STD) clinic patients in Guangxi, China, to assess the efficacy of a potential screening tool inquiring about behavioural and health risk factors in identifying the STD patients who should not be triaged for syphilis testing under current guidelines, but on the contrary receive such testing. Validity testing of the screening tool was performed and receiver-operating characteristic curves were plotted to determine an optimal total risk score cut-off for testing. About 40.9% of patients with positive toluidine red unheated serum test and Treponema pallidum particle agglutination test did not show hallmark signs of syphilis. The screening tool was more sensitive in detecting infection in non-triaged male versus female patients (highest sensitivity = 90% vs. 55%) and the cut-off score to warrant testing was lower in non-triaged female patients than in non-triaged male patients (cut-off = 1 vs. 2). Most of the cases were missed among female STD patients. In spite of selective testing based on behavioural and health indicators that improve case detection, cases were still missed. Our study supports universal testing for syphilis in the STD population.

Detection of acute HIV infections among sexually transmitted disease clinic patients: a practice in Guangxi Zhuang Autonomous Region, China.

Detection of people with acute HIV infection (AHI) affords an important opportunity for early HIV treatment and prevention. HIV RNA reverse transcriptase-polymerase chain reaction (RT-PCR) testing with two-stage pooling scheme was used to detect the AHI in specimens collected from sexually transmitted disease (STD) clinic patients in Guangxi, China. A total of 246 HIV RNA tests were required to screen 11 395 samples negative for conventional enzyme immunoassay (EIA) and Western blot assays, and five AHI cases (0.04%, 95%CI 0.02% to 0.10%) with a high viral load (median of 265,677 copies per ml) were detected. The total expenditure for RT-PCR testing reflected an added cost of $2.9 per specimen screened and $6575 per additional case of AHI identified among the study population. This study supports the feasibility of pooled RNA testing in addition to detection of HIV infections among patients at STD clinics in China, but the cost effectiveness should be carefully considered.

Intravesical nanocrystalline silver decreases experimental bladder inflammation.

PURPOSE: Interstitial cystitis is a sterile bladder inflammatory disease characterized by pelvic pain, urinary urgency and frequency. Nanocrystalline silver has anti-inflammatory properties, prompting us to investigate its effect in experimental bladder inflammation. MATERIALS AND METHODS: Nanocrystalline silver (0.01%, 0.05%, 0.1%, 0.5% or 1%) or phosphate buffered saline (Invitrogen) (0.5 ml) was introduced intravesically in Sprague-Dawley female rat (Charles River Laboratories, Wilmington, Massachusetts) bladders for 20 minutes, followed by vehicle or protamine sulfate (10 mg/ml for 30 minutes) and lipopolysaccharide (Sigma) (2 mg/ml for 45 minutes). Urine was collected throughout for histamine assay. The catheter was removed, the rat was returned to its cage and 4 hours later it was sacrificed. The bladder was harvested, minced and cultured overnight. The medium was collected for tumor necrosis factor-alpha assay. RESULTS: Mean +/- SD total urine histamine increased from 270 +/- 190 ng in 4 controls to 842 +/- 239 ng after protamine sulfate/lipopolysaccharide and it decreased to 505 +/- 187 ng in 6 animals after pretreatment with 1% nanocrystalline silver (p = 0.036). Tumor necrosis factor-alpha release in explant medium increased from 0.02 +/- 0.03 pg/mg in 6 controls to 0.28 +/- 0.15 pg/mg in 14 animals after treatment with protamine sulfate/lipopolysaccharide and it decreased to 0.12 +/- 0.11 pg/mg in 10 animals pretreated with nanocrystalline silver (p = 0.009). Nanocrystalline silver was not effective at less than 1% and at 1% alone it released 0.05 +/- 0.07 pg/mg tumor necrosis factor-alpha in 7 rats (vs phosphate buffered saline in 6, p = 0.387). Nanocrystalline silver (1%) significantly decreased bladder inflammation and mast cell activation. These effects were apparent even 4 days later. CONCLUSIONS: Intravesical administration of nanocrystalline silver (1%) decreased urine histamine, bladder tumor necrosis factor-alpha and mast cell activation without any toxic effect. This action may be useful for interstitial cystitis.

Genotypic analysis of the protease and reverse transcriptase of HIV type 1 subtype C isolates from antiretroviral drug-naive adults in Malawi.

The protease (PR) and reverse transcriptase (RT) regions of HIV-1 isolates from 21 antiretroviral (ARV)-naive Malawian adults were sequenced and analyzed to determine the prevalence of drug resistance-associated mutations in this population. Phylogenetic analysis confirmed that all isolates grouped with HIV-1 subtype C, the predominant subtype in Malawi. No major mutations associated with resistance to PR inhibitors (PIs), nucleoside RT inhibitors (NRTIs), or nonnucleoside RT inhibitors (NNRTIs) were found. In contrast, accessory mutations were found in the protease region at positions 10, 20, 36, 63, 77, and 93, and in the RT region at positions 118, 211, and 214. Further studies will be needed to determine the clinical impact of these polymorphisms on viral susceptibility to existing antiretroviral drugs.

Trichomoniasis: clinical manifestations, diagnosis and management.

Trichomonas vaginalis was originally considered a commensal organism until the 1950s when the understanding of its role as a sexually transmitted infection (STI) began to evolve. Trichomoniasis has been associated with vaginitis, cervicitis, urethritis, pelvic inflammatory disease (PID), and adverse birth outcomes. Infection with T vaginalis could have an important role in transmission and acquisition of HIV. T vaginalis is site specific for the genitourinary tract and has been isolated from virtually all genitourinary structures. Asymptomatic disease is common in both men and women, thus screening for disease is important. Various sociodemographic factors have been correlated with presence of T vaginalis, and may be used to predict infection. Diagnosis is usually made from wet mount microscopy and direct visualisation, which are insensitive. DNA amplification techniques perform with good sensitivity, but are not yet approved for diagnostic purposes. In areas where diagnostic methods are limited, management of trichomoniasis is usually as part of a clinical syndrome; vaginal discharge for women and urethral discharge for men. A single dose of metronidazole is effective in the majority of cases. Outside of the United States, other nitroimidazoles may be used and are as effective as metronidazole. Metronidazole resistance is an emerging problem, but its clinical importance is not yet clear. Concomitant treatment of sexual partners is recommended.