Mitochondrial dysfunction in the offspring of obese mothers and it's transmission through damaged oocyte mitochondria: Integration of mechanisms.

In vivo and in vitro studies demonstrate that mitochondria in the oocyte, are susceptible to damage by suboptimal pre/pregnancy conditions, such as obesity. These suboptimal conditions have been shown to induce mitochondrial dysfunction (MD) in multiple tissues of the offspring, suggesting that mitochondria of oocytes that pass from mother to offspring, can carry information that can programme mitochondrial and metabolic dysfunction of the next generation. They also suggest that transmission of MD could increase the risk of obesity and other metabolic diseases in the population inter- and trans-generationally. In this review, we examined whether MD observed in offspring tissues of high energetic demand, is the result of the transmission of damaged mitochondria from the oocytes of obese mothers to the offspring. The contribution of genome-independent mechanisms (namely mitophagy) in this transmission were also explored. Finally, potential interventions aimed at improving oocyte/embryo health were investigated, to see if they may provide an opportunity to halter the generational effects of MD.

A Dynamic Ankle Orthosis Reduces Tibial Compressive Force and Increases Ankle Motion Compared With a Walking Boot.

PURPOSE: Tibial bone stress injuries are a common overuse injury among runners and military cadets. Current treatment involves wearing an orthopedic walking boot for 3 to 12 wk, which limits ankle motion and leads to lower limb muscle atrophy. A dynamic ankle orthosis (DAO) was designed to provide a distractive force that offloads in-shoe vertical force and retains sagittal ankle motion during walking. It remains unclear how tibial compressive force is altered by the DAO. This study compared tibial compressive force and ankle motion during walking between the DAO and an orthopedic walking boot. METHODS: Twenty young adults walked on an instrumented treadmill at 1.0 m·s -1 in two brace conditions: DAO and walking boot. Three-dimensional kinematic, ground reaction forces, and in-shoe vertical force data were collected to calculate peak tibial compressive force. Paired t -tests and Cohen's d effect sizes were used to assess mean differences between conditions. RESULTS: Peak tibial compressive force ( P = 0.023; d = 0.5) and Achilles tendon force ( P = 0.017; d = 0.5) were moderately lower in the DAO compared with the walking boot. Sagittal ankle excursion was 54.9% greater in the DAO compared with the walking boot ( P = 0.05; d = 3.1). CONCLUSIONS: The findings from this study indicated that the DAO moderately reduced tibial compressive force and Achilles tendon force and allowed more sagittal ankle excursion during treadmill walking compared with an orthopedic walking boot.

Impact of primary care usual provider type and provider interdependence on outcomes for patients with diabetes: a cohort study.

BACKGROUND: Interprofessional primary care (PC) teams are key to the provision of high-quality care. PC providers often 'share' patients (eg, a patient may see multiple providers in the same clinic), resulting in between-visit interdependence between providers. However, concern remains that PC provider interdependence will reduce quality of care, causing some organisations to hesitate in creating multiple provider teams. If PC provider teams are formalised, the PC usual provider of care (UPC) type (physician, nurse practitioner (NP) or physician assistant/associate (PA)) should be determined for patients with varying levels of medical complexity. OBJECTIVE: To evaluate the impact of PC provider interdependence, UPC type and patient complexity on diabetes-specific outcomes for adult patients with diabetes. DESIGN: Cohort study using electronic health record data from 26 PC practices in central North Carolina, USA. PARTICIPANTS: Adult patients with diabetes (N=10 498) who received PC in 2016 and 2017. OUTCOME: Testing for diabetes control, testing for lipid levels, mean glycated haemoglobin (HbA1c) values and mean low-density lipoprotein (LDL) values in 2017. RESULTS: Receipt of guideline recommended testing was high (72% for HbA1c and 66% for LDL testing), HbA1c values were 7.5% and LDL values were 88.5 mg/dL. When controlling for a range of patient and panel level variables, increases in PC provider interdependence were not significantly associated with diabetes-specific outcomes. Similarly, there were no significant differences in the diabetes outcomes for patients with NP/PA UPCs when compared with physicians. The number and type of a patient's chronic conditions did impact the receipt of testing, but not average values for HbA1c and LDL. CONCLUSIONS: A range of UPC types on PC multiple provider teams can deliver guideline-recommended diabetes care. However, the number and type of a patient's chronic conditions alone impacted the receipt of testing, but not average values for HbA1c and LDL.

Vespa velutina nigrithorax venom allergy: inhibition studies approach for the choice of specific immunotherapy.

Summary: Vespa velutina nigrithorax (VVN), commonly known as Asian wasp because endemic in Asia, represents an alien species in Europe. VVN can induce allergic reactions similar to those caused by other Hymenoptera and death after VVN stings, presumably due to fatal allergic reactions, has been reported. In the treatment of Hymenoptera venom hypersensitivity, specific immunotherapy (VIT) is highly effective. Currently, there is no specific available VIT for VVN, so it is relevant to assess if patients stung by VVN and showing allergic reactions could be treated with the Hymenoptera commercially available extracts Vespa crabro (VC) and Vespula spp (Vspp) or if they need the specific VIT with VVN venom extract. Methods. Four patients with a clinical history of systemic reactions after VVN sting were evaluated. Serum specific IgE were assayed quantitatively with an automated fluoro-enzyme immunoassay ImmunoCAP™ Specific IgE by Phadia™ 1000 System (Thermo Fisher Scientific, Uppsala, Sweden) for VC, Vspp and VVN. Cap inhibition assays were performed incubating serum samples with 200 µl of each venom at increasing concentrations and subsequently specific IgE against each of the venoms were determined in the samples by Phadia™ 250 System (Thermo Fisher Scientific, Uppsala, Sweden). Results. Our results suggested that both Vspp and VC venoms were able to inhibit the specific IgE for VVN, although the VC compared to the Vspp venom showed a higher inhibition. Conclusions. Our inhibition studies suggested that VIT with VC venom, nowadays when there is not specific available VIT for VVN, may be more effective than Vspp VIT in patients with VVN sting reactions.

When is caring sharing? Primary care provider interdependence and continuity of care.

ABSTRACT: Efforts to improve access to high-quality, efficient primary care have highlighted the need for team-based care. Most primary care teams are designed to maintain continuity of care between patients and primary care providers (PCPs), because continuity of care can improve some patient outcomes. However, PCPs are interdependent because they care for, or share, patients. PCP interdependence, and its association with continuity of care, is not well described. This study describes a measure of PCP interdependence. We also evaluate the association between patient and panel characteristics, including PCP interdependence. Our results found that the extent of interdependence between PCPs in the same clinic varies widely. A range of patient and panel characteristics affect continuity of care, including patient complexity and PCP interdependence. These results suggest that continuity of care for complex patients is sensitive to panel characteristics, including PCP interdependence and panel size. This information can be used by primary care organizations for evidence-based team design.

New insights into the comorbid conditions of Turner syndrome: results from a long-term monocentric cohort study.

PURPOSE: Many questions concerning Turner syndrome (TS) remain unresolved, such as the long-term complications and, therefore, the optimal care setting for adults. The primary aim of this long-term cohort study was to estimate the incidence of comorbid conditions along the life course. METHODS: A total of 160 Italian patients with TS diagnosed from 1967 to 2010 were regularly and structurally monitored from the diagnosis to December 2019 at the University Hospital of Bologna using a structured multidisciplinary monitoring protocol. RESULTS: The study cohort was followed up for a median of 27 years (IQR 12-42). Autoimmune diseases were the comorbid condition with the highest incidence (61.2%), followed by osteoporosis and hypertension (23.8%), type 2 diabetes (16.2%) and tumours (15.1%). Median age of onset ranged from 22 years for autoimmune diseases to 39 years for type 2 diabetes. Malignant tumours were the most prominent type of neoplasm, with a cumulative incidence of 11.9%. Papillary thyroid carcinoma was the most common form of cancer, followed by skin cancer and cancer of the central nervous system. Only one major cardiovascular event (acute aortic dissection) was observed during follow-up. No cases of ischaemic heart disease, heart failure, stroke or death were recorded. CONCLUSIONS: This cohort study confirms the need for continuous, structured and multidisciplinary lifelong monitoring of TS, thus ensuring the early diagnosis of important comorbid conditions, including cancer, and their appropriate and timely treatment. In addition, these data highlight the need for the increased surveillance of specific types of cancer in TS, including thyroid carcinoma.

Teaming up in primary care: Membership boundaries, interdependence, and coordination.

OBJECTIVE: Increased demand for quality primary care and value-based payment has prompted interest in implementing primary care teams. Evidence-based recommendations for implementing teams will be critical to successful PA participation. This study sought to describe how primary care providers (PCPs) define team membership boundaries and coordinate tasks. METHODS: This mixed-methods study included 28 PCPs from a primary care network. We analyzed survey data using descriptive statistics and interview data using content analysis. RESULTS: Ninety-six percent of PCPs reported team membership. Team models fell into one of five categories. The predominant coordination mechanism differed by whether coordination was required in a visit or between visits. CONCLUSIONS: Team-based primary care is a strategy for improving access to quality primary care. Most PCPs define team membership based on within-visit task interdependencies. Our findings suggest that team-based interventions can focus on clarifying team membership, increasing interaction between clinicians, and enhancing the electronic health record to facilitate between-visit coordination.

Retrieval practice via corrective feedback: is learning better for targets in an expected or surprising sense?

Adult participants learned homographic cue words and weakly associated targets. Each target was in the dominant (expected) sense of the cue (e.g., habit - daily) or the subordinate (surprising) sense (e.g., habit - nun). Attempting to guess the target before reading it produced better target retention than did simply reading the cue and target without guessing. Replicating recent studies, recall accuracy was also higher for expected than surprising targets, whether the cue + target reading time was fixed (Experiment 1) or under participants' control (Experiment 2). A new result was that this advantage was larger in the guess than the read condition. In Experiment 3, all targets were in the dominant sense of the cue, and prime phrases activated the dominant or subordinate sense before the target was either guessed or presented. Experiment 3 thus disentangled guess-target congruence from target sense. When the analysis was restricted to trials with a guess consistent with the prime, subordinate primes (incongruent with the targets) produced substantially lower target recall accuracy. This result suggests that guess-target congruence aids learning, and that the results of Experiment 1 and 2 were not due to pre-existing differences in the characteristics of dominant and subordinate targets.

Effects of Maternal Obesity On Placental Phenotype.

The incidence of obesity is rising rapidly worldwide with the consequence that more women are entering pregnancy overweight or obese. This leads to an increased incidence of clinical complications during pregnancy and of poor obstetric outcomes. The offspring of obese pregnancies are often macrosomic at birth although there is also a subset of the progeny that are growth-restricted at term. Maternal obesity during pregnancy is also associated with cardiovascular, metabolic and endocrine dysfunction in the offspring later in life. As the interface between the mother and fetus, the placenta has a central role in programming intrauterine development and is known to adapt its phenotype in response to environmental conditions such as maternal undernutrition and hypoxia. However, less is known about placental function in the abnormal metabolic and endocrine environment associated with maternal obesity during pregnancy. This review discusses the placental consequences of maternal obesity induced either naturally or experimentally by increasing maternal nutritional intake and/or changing the dietary composition. It takes a comparative, multi-species approach and focusses on placental size, morphology, nutrient transport, metabolism and endocrine function during the later stages of obese pregnancy. It also examines the interventions that have been made during pregnancy in an attempt to alleviate the more adverse impacts of maternal obesity on placental phenotype. The review highlights the potential role of adaptations in placental phenotype as a contributory factor to the pregnancy complications and changes in fetal growth and development that are associated with maternal obesity.

Utilization and Costs by Primary Care Provider Type: Are There Differences Among Diabetic Patients of Physicians, Nurse Practitioners, and Physician Assistants?

OBJECTIVE: The objective of this study was to compare health care utilization and costs among diabetes patients with physician, nurse practitioner (NP), or physician assistant (PA) primary care providers (PCPs). RESEARCH DESIGN AND METHODS: Cohort study using Veterans Affairs (VA) electronic health record data to examine the relationship between PCP type and utilization and costs over 1 year in 368,481 adult, diabetes patients. Relationship between PCP type and utilization and costs in 2013 was examined with extensive adjustment for patient and facility characteristics. Emergency department and outpatient analyses used negative binomial models; hospitalizations used logistic regression. Costs were analyzed using generalized linear models. RESULTS: PCPs were physicians, NPs, and PAs for 74.9% (n=276,009), 18.2% (n=67,120), and 6.9% (n=25,352) of patients respectively. Patients of NPs and PAs have lower odds of inpatient admission [odds ratio for NP vs. physician 0.90, 95% confidence interval (CI)=0.87-0.93; PA vs. physician 0.92, 95% CI=0.87-0.97], and lower emergency department use (0.67 visits on average for physicians, 95% CI=0.65-0.68; 0.60 for NPs, 95% CI=0.58-0.63; 0.59 for PAs, 95% CI=0.56-0.63). This translates into NPs and PAs having ~$500-$700 less health care costs per patient per year (P<0.0001). CONCLUSIONS: Expanded use of NPs and PAs in the PCP role for some patients may be associated with notable cost savings. In our cohort, substituting care patterns and creating similar clinical situations in which they practice, NPs and PAs may have reduced costs of care by up to 150-190 million dollars in 2013.

Hyperspectral imaging with a TWINS birefringent interferometer.

We introduce a high-performance hyperspectral camera based on the Fourier-transform approach, where the two delayed images are generated by the Translating-Wedge-Based Identical Pulses eNcoding System (TWINS) [Opt. Lett. 37, 3027 (2012)], a common-path birefringent interferometer that combines compactness, intrinsic interferometric delay precision, long-term stability and insensitivity to vibrations. In our imaging system, TWINS is employed as a time-scanning interferometer and generates high-contrast interferograms at the single-pixel level. The camera exhibits high throughput and provides hyperspectral images with spectral background level of -30dB and resolution of 3 THz in the visible spectral range. We show high-quality spectral measurements of absolute reflectance, fluorescence and transmission of artistic objects with various lateral sizes.

Impact Of Physicians, Nurse Practitioners, And Physician Assistants On Utilization And Costs For Complex Patients.

Because of workforce needs and demographic and chronic disease trends, nurse practitioners (NPs) and physician assistants (PAs) are taking a larger role in the primary care of medically complex patients with chronic conditions. Research shows good quality outcomes, but concerns persist that NPs' and PAs' care of vulnerable populations could increase care costs compared to the traditional physician-dominated system. We used 2012-13 Veterans Affairs data on a cohort of medically complex patients with diabetes to compare health services use and costs depending on whether the primary care provider was a physician, NP, or PA. Case-mix-adjusted total care costs were 6-7 percent lower for NP and PA patients than for physician patients, driven by more use of emergency and inpatient services by the latter. We found that use of NPs and PAs as primary care providers for complex patients with diabetes was associated with less use of acute care services and lower total costs.

Intermediate Diabetes Outcomes in Patients Managed by Physicians, Nurse Practitioners, or Physician Assistants: A Cohort Study.

Background: Primary care provided by nurse practitioners (NPs) and physician assistants (PAs) has been proposed as a solution to expected workforce shortages. Objective: To examine potential differences in intermediate diabetes outcomes among patients of physician, NP, and PA primary care providers (PCPs). Design: Cohort study using data from the U.S. Department of Veterans Affairs (VA) electronic health record. Setting: 568 VA primary care facilities. Patients: 368 481 adult patients with diabetes treated pharmaceutically. Measurements: The relationship between the profession of the PCP (the provider the patient visited most often in 2012) and both continuous and dichotomous control of hemoglobin A1c (HbA1c), systolic blood pressure (SBP), and low-density lipoprotein cholesterol (LDL-C) was examined on the basis of the mean of measurements in 2013. Inverse probability of PCP type was used to balance cohort characteristics. Hierarchical linear mixed models and logistic regression models were used to analyze continuous and dichotomous outcomes, respectively. Results: The PCPs were physicians (n = 3487), NPs (n = 1445), and PAs (n = 443) for 74.9%, 18.2%, and 6.9% of patients, respectively. The difference in HbA1c values compared with physicians was -0.05% (95% CI, -0.07% to -0.02%) for NPs and 0.01% (CI, -0.02% to 0.04%) for PAs. For SBP, the difference was -0.08 mm Hg (CI, -0.34 to 0.18 mm Hg) for NPs and 0.02 mm Hg (CI, -0.42 to 0.38 mm Hg) for PAs. For LDL-C, the difference was 0.01 mmol/L (CI, 0.00 to 0.03 mmol/L) (0.57 mg/dL [CI, 0.03 to 1.11 mg/dL]) for NPs and 0.03 mmol/L (CI, 0.01 to 0.05 mmol/L) (1.08 mg/dL [CI, 0.25 to 1.91 mg/dL]) for PAs. None of these differences were clinically significant. Limitation: Most VA patients are men who receive treatment in a staff-model health care system. Conclusion: No clinically significant variation was found among the 3 PCP types with regard to diabetes outcomes, suggesting that similar chronic illness outcomes may be achieved by physicians, NPs, and PAs. Primary Funding Source: VA Health Services Research and Development.

Olive leaf extract counteracts cell proliferation and cyst growth in an in vitro model of autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive enlargement of kidney cysts, leading to chronic kidney disease. Since the available treatment for ADPKD is limited, there is emerging interest for natural compounds as potential therapeutic candidates. The aim of our study was to investigate whether an olive leaf extract may be able to counteract the cyst growth in an in vitro model of ADPKD. We treated WT9-12 cells with an olive leaf extract (OLE). In monolayer culture we evaluated cell viability by the MTT assay, protein expression by western-blot analysis and apoptosis by DNA laddering and TUNEL assays. For functional studies we used transient transfection and ChIP assays. Intracellular calcium measurement was performed with a spectrofluorimeter using a fluorescent probe. 3D-cell-culture was used for cyst growth studies. OLE reduced the WT9-12 cell growth rate and affected intracellular signaling due to high c-AMP levels, as OLE reduced PKA levels, enhanced p-AKT, restored B-Raf-inactivation and down-regulated p-ERK. We elucidated the molecular mechanism by which OLE, via Sp1, transactivates the p21WAF1/Cip1 promoter, whose levels are down-regulated by mutated PKD1. We demonstrated that p-AKT up-regulation also played a crucial role in the OLE-induced anti-apoptotic effect and that OLE ameliorated intracellular calcium levels, the primary cause of ADPKD. Finally, using a 3D-cell-culture model we observed that OLE reduced the cyst size. Therefore, multifaceted OLE may be considered a new therapeutic approach for ADPKD treatment.

Quality assurance of ultrasound systems: current status and review of literature.

Diagnostic ultrasound (US) images can be obtained from a quality device, in optimal working conditions, combined with the capable actions of the operator in tweaking the equipment's characteristics. The quality assurance (QA) is the topic of this review article, and it is addressed in an US practice through proper selection of the equipment when purchasing, and through care and preventive maintenance of the machine for ensuring accurate performance. For optimal US system functioning, QA steps carried out on the basis of a scheduled program are needed in any US practice or department. It is critical to confirm in a semiannual or annual basis that the image quality is maintained according to standards and any subtle change in equipment's functioning is detected and amended at an early stage. The use of test objects (also called US testing phantoms) is required above the basic level of QA testing. The scope of this review article is to inform the US user about necessary QA knowledge and at the same time, present the state of the art of the most suitable test methods for US QA. We referred to relevant publications, selected after performing a systematic literature search of the MEDLINE, EMBASE and COCHRANE databases, and also to the standards established by authoritative international societies.

Rapamycin-induced autophagy protects proximal tubular renal cells against proteinuric damage through the transcriptional activation of the nerve growth factor receptor NGFR.

Experimental evidence demonstrated that macroautophagy/autophagy exerts a crucial role in maintain renal cellular homeostasis and represents a protective mechanism against renal injuries. Interestingly, it has been demonstrated that in the human proximal tubular renal cell line, HK-2, the MTOR inhibitor rapamycin enhanced autophagy and mitigated the apoptosis damage induced by urinary protein overload. However, the underlying molecular mechanism has not yet been elucidated. In our study we demonstrated, for the first time, that in HK-2 cells, the exposure to low doses of rapamycin transactivated the NGFR promoter, leading to autophagic activation. Indeed, we observed that in HK-2 cells silenced for the NGFR gene, the rapamycin-induced autophagic process was prevented, as the upregulation of the proautophagic markers, BECN1, as well as LC3-II, and the autophagic vacuoles evaluated by transmission electron microscopy, were not found. Concomitantly, using a series of deletion constructs of the NGFR promoter we found that the EGR1 transcription factor was responsible for the rapamycin-mediated transactivation of the NGFR promoter. Finally, our results provided evidence that the cotreatment with rapamycin plus albumin further enhanced autophagy via NGFR activation, reducing the proapoptotic events promoted by albumin alone. This effect was prevented in HK-2 cells silenced for the NGFR gene or pretreated with the MTOR activator, MHY1485. Taken together, our results describe a novel molecular mechanism by which rapamycin-induced autophagy, mitigates the tubular renal damage caused by proteinuria, suggesting that the use of low doses of rapamycin could represent a new therapeutic strategy to counteract the tubule-interstitial injury observed in patients affected by proteinuric nephropathies, avoiding the side effects of high doses of rapamycin.

Active compounds extracted from extra virgin olive oil counteract mesothelial-to-mesenchymal transition of peritoneal mesothelium cells exposed to conventional peritoneal dialysate: in vitro and in vivo evidences.

During peritoneal dialysis (PD), peritoneal mesothelial cells undergo a transition from an epithelial phenotype to a mesenchymal phenotype that, together with the inflammatory process, promotes tissue fibrosis and a failure of peritoneal membrane function. To date, there is no definitive treatment for the progressive thickening and angiogenesis of the peritoneal membrane associated with PD. In this study we tested, in vitro and in vivo, the ability of active compounds extracted from extra virgin olive oil (AC-EVOO) to counteract the mesothelial-to-mesenchymal transition process (MMT) observed in mesothelial cells chronically exposed to the conventional peritoneal dialysate (DL). In particular, we used a cultivar from southern Italy known to have a high polyphenol content. Our results showed that, in mesothelial cells exposed to DL, the combined treatment with AC-EVOO prevented the genic and protein upregulation of key mesenchymal and inflammatory markers, as well as the MCs' migratory capacity. Concomitantly, we tested the antifibrotic efficacy of AC-EVOO in mesothelial cells obtained from effluents of patients undergoing PD, whose "fibroblast-like" phenotype was defined by flow-cytometry assay. We observed that in these cells AC-EVOO significantly mitigated, but did not reverse, the MMT process. In conclusion, our preliminary results suggest that AC-EVOO can interfere with critical factors in the process of differentiation, preventing myofibroblast formation, but once fibrosis has already progressed it is unable to promote the redifferentiation to the epithelial phenotype. Further studies are needed to establish whether AC-EVOO could represent a new therapeutic target to prevent peritoneal fibrosis.

High doses of hydroxytyrosol induce apoptosis in papillary and follicular thyroid cancer cells.

PURPOSE: Recent evidences indicates that hydroxytyrosol, one of the main olive oil phenols, possess antitumor effects because of its pro-oxidant properties and the capacity to inhibit proliferation and to promote apoptosis in several tumor cell lines, although most of the results were obtained for breast and digestive systems cancers. METHODS: In this study, we evaluated the activities of hydroxytyrosol against papillary (TPC-1, FB-2) and follicular (WRO) thyroid cancer cell lines. RESULTS: Cellular viability revealed that high doses of hydroxytyrosol reduced cancer cells viability concomitantly with a reduction of cyclin D1 expression and an up-regulation of cell cycle key modulator p21 levels. In the same experimental conditions, Annexin V-PI staining and DNA laddering revealed that hydroxytyrosol exerts proapoptotic effects on papillary and follicular cancer cells. Furthermore, by Western blot analysis, we observed that hydroxytyrosol treatment reduced thyroid cancer cells viability by promoting apoptotic cell death via intrinsic pathway. CONCLUSIONS: Collectively, our results demonstrated for the first time that in thyroid cancer cells hydroxytyrosol promoted apoptosis at higher doses with respect to other cancer cells lines. Therefore, further studies will reveal the mechanisms by which thyroid cancer cells are more resistant to the proapoptotic effect exerted by hydroxytyrosol as well as the potential application as novel target therapeutic in thyroid cancer.