Left ventricular dysfunction and intra-ventricular dyssynchrony in idiopathic pulmonary arterial hypertension.

BACKGROUND: Left ventricular (LV) filling pressures are normal in idiopathic pulmonary arterial hypertension (IPAH). However, direct and indirect interactions between the RV and LV can affect LV performance. We explored LV strain and LV intra-ventricular dyssynchrony in IPAH using feature tracking CMR (CMR-FT). METHODS: Seventy IPAH patients and 40 healthy volunteers were included. Patients underwent CMR and right heart catheterisation. The 4-chamber cine was used to calculate LV longitudinal strain (EllLV). LV circumferential (EccLV) and radial strain (ErrLV) were derived from a short axis cine. LV longitudinal, circumferential and radial intra-ventricular dyssynchrony indices were calculated. RESULTS: There were no differences between the IPAH and healthy volunteer group in LV ejection fraction (66.1% vs 64.2% p = 0.6672). EccLV (-29.1 vs -32.1 p = 0.0323) and EllLV (-16.6 vs -23.7 p < 0.0001) were lower in IPAH. In patients with more severe disease, there was greater impairment of ErrLV compared to mild disease (50.9 vs 87.5 P < 0.0001). LV synchrony was impaired in all directions in IPAH. ErrLV was associated with RV ejection fraction (r = 0.66), RV end-systolic volume index (r = -0.59), pulmonary vascular resistance (PVR)(r = 0.51) and stroke volume index (SVI)(r = 0.44). In a multivariate model with age, SVI and PVR, ErrLV (HR 0.970 p = 002) and radial dyssynchrony (HR 3.759 p < 0.0001) independently predicted survival. CONCLUSION: In IPAH, LV is dyssynchronous with impaired function. Measures of LV strain and intraventricular synchrony were associated with known markers of disease severity. These LV variables which are likely to be related to ventricular interaction, may add incremental value to known prognostic variables in IPAH.

Folate hydrolase-1 (FOLH1) is a novel target for antibody-based brachytherapy in Merkel cell carcinoma.

BACKGROUNDS: Folate Hydrolase-1 (FOLH1; PSMA) is a type II transmembrane protein, luminally expressed by solid tumour neo-vasculature. Monoclonal antibody (mAb), J591, is a vehicle for mAb-based brachytherapy in FOLH1+ cancers. Brachytherapy is a form of radiotherapy that involves placing a radioactive material a short distance from the target tissue (e.g., on the skin or internally); brachytherapy is commonly accomplished with the use of catheters, needles, metal seeds and antibody or small peptide conjugates. Herein, FOLH1 expression in primary (p) and metastatic (m) Merkel cell carcinoma (MCC) is characterized to determine its targeting potential for J591-brachytherapy. MATERIALS & METHODS: Paraffin sections from pMCC and mMCC were evaluated by immunohistochemistry for FOLH1. Monte Carlo simulation was performed using the physical properties of conjugated radioisotope lutetium-177. Kaplan-Meier survival curves were calculated based on patient outcome data and FOLH1 expression. RESULTS: Eighty-one MCC tumours were evaluated. 67% (54/81) of all cases, 77% (24/31) pMCC and 60% (30/50) mMCC tumours were FOLH1+. Monte Carlo simulation showed highly localized ionizing tracks of electrons emitted from the targeted neo-vessel. 42% (34/81) of patients with FOLH1+/- MCC had available survival data f or analysis. No significant differences in our limited data set were detected based on FOLH1 status (p = 0.4718; p = 0.6470), staining intensity score (p = 0.6966; p = 0.9841) or by grouping staining intensity scores (- and + vs. ++, +++, +++) (p = 0.8022; p = 0.8496) for MCC-specific survival or recurrence free survival, respectively. CONCLUSIONS: We report the first evidence of prevalent FOLH1 expression within MCC-associated neo-vessels, in 60-77% of patients in a large MCC cohort. Given this data, and the need for alternatives to immune therapies it is appropriate to explore the safety and efficacy o f FOLH1-targeted brachytherapy for MCC.

In vitro characterization of the effects of chronic insulin stimulation in mouse 3T3-L1 and human SGBS adipocytes.

Hyperinsulinemia is the hallmark of the development of insulin resistance and precedes the diagnosis of type 2 diabetes. Here we evaluated the effects of prolonged exposure (≥4 days) to high insulin doses (150 nM) in vitro in two adipose cell types, mouse 3T3-L1 and human SGBS. Chronic insulin treatment significantly decreased lipid droplet size, insulin signalling and insulin-stimulated glucose uptake. 3T3-L1 displayed an increased basal glucose internalization following chronic insulin treatment, which was associated with increased GLUT1 expression. In addition, both cells showed increased basal lipolysis. In conclusion, we report the effects of prolonged hyperinsulinemia in 3T3-L1 and SGBS, highlighting similarities and discrepancies between the cell types, to be considered when using these cells to model insulin-induced insulin resistance.

Acquired cancer resistance to combination immunotherapy from transcriptional loss of class I HLA.

Understanding mechanisms of late/acquired cancer immunotherapy resistance is critical to improve outcomes; cellular immunotherapy trials offer a means to probe complex tumor-immune interfaces through defined T cell/antigen interactions. We treated two patients with metastatic Merkel cell carcinoma with autologous Merkel cell polyomavirus specific CD8+ T cells and immune-checkpoint inhibitors. In both cases, dramatic remissions were associated with dense infiltration of activated CD8+s into the regressing tumors. However, late relapses developed at 22 and 18 months, respectively. Here we report single cell RNA sequencing identified dynamic transcriptional suppression of the specific HLA genes presenting the targeted viral epitope in the resistant tumor as a consequence of intense CD8-mediated immunologic pressure; this is distinguished from genetic HLA-loss by its reversibility with drugs. Transcriptional suppression of Class I loci may underlie resistance to other immunotherapies, including checkpoint inhibitors, and have implications for the design of improved immunotherapy treatments.

Patient-reported mobility function and engagement in young adults with cerebral palsy: a cross-sectional sample.

PURPOSE: To describe self-reported life satisfaction and motor function of young adults with cerebral palsy (CP). METHODS: A total of 57 young adults with spastic CP classified as levels I (seven), II (25), III (16), IV (nine) by the Gross Motor Function Classification System, followed from childhood by our CP clinic, returned at a mean age of 27 years two months (SD 3 years 4 months). Self-reported life satisfaction and mobility status were measured by the Pediatric Outcomes Data Collection Instrument (PODCI), Patient-Reported Outcomes Measurement Information System (PROMIS), Functional Mobility Scale (FMS) and a project questionnaire. Surgical history and childhood mobility were confirmed from medical records. RESULTS: The Functional Mobility Scale demonstrated limited but stable mobility function from childhood to adulthood. The PROMIS and PODCI revealed limited motor function compared with a non-disabled normative reference (p < 0.05). Descriptive results showed high dependence on transportation, housing and income; although PROMIS subscales revealed satisfaction with social activities. Self-recall of childhood mobility function using the FMS correlated highly (r = 0.8; p < 0.0001) with historical records. CONCLUSION: Although functional mobility is limited and community independence is not fully achieved in young adults with CP, these participants maintained childhood levels of mobility function into young adulthood, were satisfied with social roles and had minimal reports of pain.

Flexed-knee gait in children with cerebral palsy: a long-term follow-up study.

Aims: The purpose of this study was to evaluate the long-term outcome of adolescents with cerebral palsy who have undergone single-event multilevel surgery for a flexed-knee gait, followed into young adulthood using 3D motion analysis. Patients and Methods: A total of 59 young adults with spastic cerebral palsy, with a mean age of 26 years (sd 3), were enrolled into the study in which their gait was compared with an evaluation that had taken place a mean of 12 years (sd 2) previously. At their visits during adolescence, the children walked with excessive flexion of the knee at initial contact and surgical or therapeutic interventions were not controlled between visits. Results: Based on the change in flexed-knee gait over approximately ten years, improvements were seen in increased Gait Deviation Index (p < 0.001) and decreased flexion of the knee at initial contact (p < 0.001). Greater popliteal angle (p < 0.001), reduced Gross Motor Function Measure section D (p = 0.006), and reduced speed of gait (p = 0.007) suggested a mild decline in function. Quality-of-life measures showed that these patients fell within normal limits compared with typical young adults in areas other than physical function. Conclusion: While some small significant changes were noted, little clinically significant change was seen in function and gait, with gross motor function maintained between adolescence and young adulthood. Cite this article: Bone Joint J 2018;100-B:549-56.

Longitudinal change in foot posture in children with cerebral palsy.

PURPOSE: Foot deformities are common in children with cerebral palsy (CP), yet the evolution of such deformities is not well documented. We aimed to observe and analyse changes in foot posture during growth in children with CP. Methods We followed 51 children (16 unilateral, 35 bilateral; 37 Gross Motor Function Classification Scale (GMFCS) I/II, 14 III/IV) aged two to 12 years in this level II, IRB-approved prospective longitudinal study. Data after bony foot corrections were excluded. Outcome measures included coronal plane pressure index (CPPI) and pressure impulses from the heel, medial midfoot and medial forefoot. Data were LOESS smoothed and resulting models were compared for significant differences across time using a derived FANOVA method. RESULTS: The GMFCS I/II group had more foot valgus than typically developing (TD) children until seven years which normalised thereafter. From two to 12 years, GMFCS III/IV children had more foot valgus than TD children. Heel impulse was significantly reduced in both GMFCS groups compared with TD children, and the III/IV group had less heel contact than the I/II group. CONCLUSIONS: Due to early variability and the tendency for resolving valgus foot posture in children with CP, conservative management of coronal plane foot deformity is suggested in early childhood, especially for children classified as GMFCS I and II.

Hyperconnectivity in juvenile myoclonic epilepsy: a network analysis.

OBJECTIVE: Juvenile myoclonic epilepsy (JME) is a common idiopathic (genetic) generalized epilepsy (IGE) syndrome characterized by impairments in executive and cognitive control, affecting independent living and psychosocial functioning. There is a growing consensus that JME is associated with abnormal function of diffuse brain networks, typically affecting frontal and fronto-thalamic areas. METHODS: Using diffusion MRI and a graph theoretical analysis, we examined bivariate (network-based statistic) and multivariate (global and local) properties of structural brain networks in patients with JME (N = 34) and matched controls. Neuropsychological assessment was performed in a subgroup of 14 patients. RESULTS: Neuropsychometry revealed impaired visual memory and naming in JME patients despite a normal full scale IQ (mean = 98.6). Both JME patients and controls exhibited a small world topology in their white matter networks, with no significant differences in the global multivariate network properties between the groups. The network-based statistic approach identified one subnetwork of hyperconnectivity in the JME group, involving primary motor, parietal and subcortical regions. Finally, there was a significant positive correlation in structural connectivity with cognitive task performance. CONCLUSIONS: Our findings suggest that structural changes in JME patients are distributed at a network level, beyond the frontal lobes. The identified subnetwork includes key structures in spike wave generation, along with primary motor areas, which may contribute to myoclonic jerks. We conclude that analyzing the affected subnetworks may provide new insights into understanding seizure generation, as well as the cognitive deficits observed in JME patients.

Serum estrogenicity and biological responses in African catfish raised in wastewater ponds in Ghana.

Reuse of wastewater for aquaculture improves the efficient use of water and promotes sustainability but the potential effects of endocrine disrupting compounds including estrogens in wastewater are an emerging challenge that needs to be addressed. We examined the biological effects of wastewater-borne estrogens on African catfish (Clarias gariepinus) raised in a wastewater stabilization pond (WSP) of a functioning municipal wastewater treatment plant, a wastewater polishing pond (WWP) of a dysfunctional treatment plant, and a reference pond (RP) unimpacted by wastewater, located in Ghana. Measurements of estrogen concentrations in pond water by liquid chromatography/tandem mass spectrometry showed that mean 17 ß-estradiol concentrations were higher in the wastewater ponds (WWP, 6.6 ng/L±2.7 ng/L; WSP, 4.9 ng/L±1.0) than the reference (RP, 3.4±1.1 ng/L). Estrone concentrations were found to be highest in the WSP (7.8 ng/L±1.7) and lowest in the WWP (2.2 ng/L±2.4) with the RP intermediate (4.7±5.0). Fish serum estrogenicity assayed by E-SCREEN was significantly higher in female vs. male catfish in the RP and WSP but not in the WWP (p≤0.05). Histological examination of liver and gonad tissue showed no apparent signs of intersex or pathology in any ponds. The similarities in various measures of body indices between fish of this study and African catfish from freshwater systems suggest that aquaculture may be a suitable reuse option for treated municipal wastewater.

Herd management factors that affect duration and variation of adherence of an external teat sealant.

During 1998 and 1999, a purposive sample of Ontario dairy herds was enrolled in a study to examine management factors associated with adherence of an external teat sealant. A total of 74 herds were recruited that had previously complied with a provincial Sentinel Herd mastitis study. All herds were sent a management survey and a commercially available external teat sealant product. The sealant was applied to all cows in first lactation or greater that were scheduled to go dry. Adherence of the teat sealant was scored on a scale of 1 to 5 (1 = sealant completely removed) for the first 12 d following dry off. Complete data were analyzed from 806 cows in 48 herds (mean of 17 cows/herd). Mean duration of adherence of the teat sealant was 4 d (range 1 to 7 d). Of the management factors recorded, only changing the feed to reduce milk production prior to drying off was significantly associated with 0.78-d prolonged adherence. No factors related to dry cow housing, bedding material, or floor surface were associated with the duration of adherence. The variance around the duration of adherence was examined. The median variance of adherence was 3.0 d(2), which was equivalent to a standard deviation of 2.6 d. Herds in which dry cows were housed in tie-stall barns, and the herds that used a penicillin and novobiocin combination dry cow antibiotic had the greatest variation. We concluded that modifying the ration to reduce milk production enhanced adherence of an external teat sealant. Teat-end preparation prior to application of the teat sealant is an important factor to consider when choosing to adopt this dry period mastitis prevention strategy. This study demonstrates that beyond cow- and quarter-level factors, herd management factors can influence the duration and variation of sealant adherence experienced among different herds.

Diabetic ketoacidosis associated with aripiprazole.

BACKGROUND: Atypical antipsychotics have become the mainstay of management of schizophrenia and other psychotic disorders due to low risk of extrapyramidal symptoms. However, postmarketing data has reported atypical antipsychotic agents being associated with hyperglycaemia and diabetic ketoacidosis (DKA). We believe this to be the first published report of hyperglycaemia and DKA with the newest atypical antipsychotic agent, aripiprazole. CASE REPORT: A 34-year-old African-American female with schizophrenia presented to the emergency department with nausea, vomiting, and malaise for 3-4 days shortly after initiation of aripiprazole therapy. Initial laboratory results revealed significant hyperglycaemia with metabolic acidosis. The patient received treatment for DKA with an intravenous insulin infusion and fluid replacement. Isophane insulin suspension (NPH insulin) was begun immediately following the insulin drip and continued upon discharge from the hospital. Outpatient follow-up information was not available. CONCLUSION: To our knowledge, this is the first case report of aripiprazole associated with hyperglycaemia and DKA. This case is striking in that DKA occurred 4 days following initiation of aripiprazole and the patient had rapid resolution of symptoms and normalization of laboratory values upon discontinuation of aripiprazole. It is important that health-care providers monitor for hyperglycaemia when prescribing atypical antipsychotics including aripiprazole.

"Stable" inertial cavitation.

This note compares theoretical predictions of pressure waves scattered by free gas bubbles with recent acoustical determinations of cavitation thresholds for individual microbubbles of the surfactant-stabilized contrast agent Sonazoid(R). The results indicate that surfactant-coated microbubbles undergo "stable" (i.e., repetitive) inertial cavitation above a threshold of 0.3 to 0.4 MPa at 2.5 MHz, and that irreversible postcollapse bubble fragmentation usually requires much higher pressures (approximately 1.5 MPa). Adverse bioeffects can be expected in vivo far below these fragmentation pressures when contrast agents are present. With diagnostically relevant exposures, the threshold for the generation of petechiae in skeletal muscle is approximately 0.6 MPa at 2.5 MHz.

Prussian blue for treatment of radiocesium poisoning.

Prussian blue is a crystal lattice that exchanges potassium for cesium at the surface of the crystal. When given orally, it binds cesium that is secreted in the gut before it can be reabsorbed. Data suggest that in humans, Prussian blue can reduce cesium's half-life by approximately 43% and reduce total body burdens. Prussian blue is well tolerated at a dosage of 3 g/day with appropriate monitoring of serum potassium levels and observing for signs of constipation. Clinical data on the efficacy of Prussian blue in the management of radiocesium poisoning were evaluated. Articles published in English describing distribution and elimination of cesium in both humans and animals were reviewed, along with articles describing administration of Prussian blue in clinical toxicology.

Structure and function of Pet100p, a molecular chaperone required for the assembly of cytochrome c oxidase in Saccharomyces cerevisiae.

The assembly of cytochrome c oxidase in the inner mitochondrial membranes of eukaryotic cells requires the protein products of a large number of nuclear genes. In yeast, some of these act globally and affect the assembly of several respiratory-chain protein complexes, whereas others act in a cytochrome c oxidase-specific fashion. Many of these yeast proteins have human counterparts, which when mutated lead to energy-related diseases. One of these proteins, Pet100p, is a novel molecular chaperone that functions to incorporate a subcomplex containing cytochrome c oxidase subunits VII, VIIa and VIII into holo-(cytochrome c oxidase). Here we report the topological disposition of Pet100p in the inner mitochondrial membrane and show that its C-terminal domain is essential for its function as a cytochrome c oxidase-specific 'assembly facilitator'.

Effects of common topical otic preparations on the morphology of isolated cochlear outer hair cells.

Otic drops are commonly used not only for otitis externa but also for otorrhea in the presence of tympanostomy tube or tympanic membrane perforation. Many studies have demonstrated the ototoxicity of common otic preparations such as Cortisporin otic drops. Recent studies have suggested the use of fluoroquinolone antibiotic drops as an alternative owing to their excellent antimicrobial coverage and no ototoxic effect. The purpose of this study was to assess the relative ototoxicity of four common otic preparations by direct exposure to isolated cochlear outer hair cells (OHCs). OHCs from adult chinchilla cochlea were exposed to standard bathing solution (control), Cortisporin, Cipro HC, Ciloxan, and Floxin. The cells were observed using an inverted microscope, and the images recorded in digital still-frame and video, and analyzed on the Image Pro-Plus 3.0 program. As measured by time to cell death and change in morphology of OHCs, Cortisporin was most toxic to OHCs. Among the fluoroquinolone drops, Floxin was more toxic than Ciloxan or Cipro HC.

Interferon-alpha2a and 13-cis-retinoic acid with radiation treatment for high-grade glioma.

Interferon-alpha (IFN-alpha) has been safely given concurrently with radiation therapy (RT) in treating gliomas. As single agents, both IFN-alpha and cis-retinoic acid (CRA) have produced objective tumor regressions in patients with recurrent gliomas. In vitro, IFN-alpha2a and CRA enhance radiation therapy effects on glioblastoma cells more than either agent alone. This trial was conducted to determine the clinical effects of IFN-alpha2a and CRA when given concurrently with radiation therapy to patients with high-grade glioma. Newly diagnosed patients with high-grade glioma received IFN-alpha2a at a dosage of 3 to 6 million IU s.c. 4 times a day for 3 days per week and 1 mg/kg CRA by mouth 4 times a day for 5 days per week during the delivery of partial brain radiation therapy at 180 cGy x 33 fractions for 5 days per week for a total of 59.4 Gy during the 7-week period. Use of the antiepileptic phenytoin was prohibited after observing that the combination of IFN-alpha2a, CRA, and phenytoin was associated with a high rate of dermatologic toxicity not seen in a previous study with concurrent IFN-alpha2a and radiation therapy. Forty patients (26 men and 14 women) with a median age of 60 (range, 19 to 81 years) were enrolled between August 1996 and October 1998. Histopathologic diagnoses were glioblastoma multiforme or grade 4 anaplastic astrocytoma in 36 patients, and grade 3 anaplastic astrocytoma in 4 patients. Only 4 patients (10%) underwent a gross total resection of tumor prior to this therapy; 50% were asymptomatic when treatment was initiated. The planned 7-week course of concurrent therapy was completed by 75% of patients; 30% completed the 16-week course of IFN-alpha and CRA alone. At a median follow-up of 36 months, there were 37 deaths, with a median overall survival of 9.3 months and a 1-year survival rate of 42%. There was no improvement in survival compared with a similar group of 19 patients treated with concurrent IFN-alpha2a and radiation therapy in a previous trial. In the high-risk group of patients in the present study, concurrent treatment with IFN-alpha2a, CRA, and RT was feasible, but was not associated with a better outcome compared with a similar patient population treated with radiation therapy and IFN-alpha2a, or compared with radiation therapy alone in other trials.

Determination of ototoxicity of common otic drops using isolated cochlear outer hair cells.

OBJECTIVES: Otic drops are commonly used not only for otitis externa, but also for otorrhea in the presence of tympanostomy tubes or tympanic membrane perforations. Many studies have demonstrated the ototoxicity of common otic preparations such as Cortisporin otic drops (Monarch Pharmaceuticals, Bristol, TN). The purpose of this study was to assess the relative ototoxicity of common otic preparations by direct exposure to isolated cochlear outer hair cells (OHCs). METHODS: OHCs from adult chinchilla cochlea were exposed to standard bathing solution (control), acetic acid, Acetasol HC (Alpharma USPD Inc., Baltimore, MD), Gentacidin (CIBA Vision Ophthalmics, Atlanta, GA), and Tobradex (Alcon, Fort Worth, TX). The cells were observed using an inverted microscope, and the images were recorded in digital still-frame and video, and analyzed on the Image Pro-Plus 3.0 program (Media Cybernetics, Silver Spring, MD). RESULTS AND CONCLUSIONS: As measured by time to cell death and change in morphology of OHCs, acetic acid with or without hydrocortisone was most toxic to OHCs. Cortisporin was more cytotoxic than gentamicin and Tobradex.

Documentation of clinical interventions by pharmacy faculty, residents, and students.

OBJECTIVE: To describe the influence of pharmacy faculty, residents, and students at a community hospital by documenting the number and types of interventions attributable to their involvement in patient-care activities. METHODS: Between September 1, 1997, and May 31, 1999, data were collected using a computerized documentation system to characterize the intervention type, significance, and value of services rendered by an education group composed of pharmacy faculty (n = 2), residents (n = 4), and students (n = 22). RESULTS: The number, nature, and outcome category for all interventions were documented using an existing computerized documentation system. The education group accounted for 13% (n = 2,873) of total clinical activities documented (n = 21,817). The most common activities reported were discharge counseling/education (31%), consultation by physicians and therapeutic recommendations (15%), and route conversion (6%). Interventions documented by the education group were classified as medium or high significance 50% of the time. Sixteen percent ($172,655) of the estimated cost avoidance documented by the pharmacy department was attributed to the education group. CONCLUSIONS: This study demonstrates that educational activities by pharmacy faculty, residents, and students have a positive influence on patient care in a community hospital.