Surgery versus conservative care for Rathke's cleft cyst.

BACKGROUND: Rathke's cleft cysts are benign cystic lesions of the sellar region, which may cause headache, pituitary deficiencies and visual disturbances from mass effect. Their management is not standardized yet. This study is about establishing a consensus for medical care of RCC. MATERIAL AND METHODS: We performed a retrospective observational study of all patients that were diagnosed or followed for RCC between 2008 and 2018 (11 years), in the neurosurgical and the adult endocrine departments of our institution. The study's average time length of follow-up is 72.9 months (from 2 to 385 months). RESULTS: The 57 included patients were divided into 2 groups: group A, which included 39 patients that were conservatively managed and group B, which included 18 surgically treated patients. Group A showed either an improvement or a spontaneous resolution of headaches in 56.1% of the cases (P<0.01); a resolution of hyperprolactinemia in 70% of the cases (P=0.21); and of hypogonadism, ACTH deficiency, growth hormone deficiency in 100% of the cases. There was no spontaneous improvement of visual disturbances (P<0.01) or diabetes insipidus (P=0.29) during follow-up. Regarding group B, surgery allowed improvement or complete resolution of headaches in 60% of the cases; visual troubles in 100% of the cases (P<0.01); and hyperprolactinemia in 100% of the cases. Pituitary deficiencies were not improved by surgery. CONCLUSIONS: This study offers guidance in decision-making regarding the management of RCC patients. Surgery is particularly suitable for treating visual disturbances caused by RCC. Regular follow-up is more appropriate than surgery concerning headaches, hyperprolactinemia, endocrine disruptions and diabetes insipidus.

Osteoarthritis year in review 2020: rehabilitation and outcomes.

OBJECTIVE: Systematically review and synthesize guidelines, systematic reviews, or randomized controlled trials (RCTs) published between April 1, 2019 and April 30, 2020 which evaluated or made recommendations for rehabilitation of persons with osteoarthritis. DESIGN: Five electronic databases (Medline, EMBASE, Cochrane CENTRAL, CINHAL, Web of Science) were searched with a comprehensive search strategy. Guidelines for rehabilitation of persons with osteoarthritis, and systematic reviews and RCTs evaluating osteoarthritis rehabilitation that included at least one patient-reported outcome measure and/or clinical test of function were included. Two authors independently screened records and assessed methodological quality using the AGREE-II (guidelines), AMSTAR-2 (systematic reviews) or PEDro scale (RCTs). Data were extracted to summarize included records and a narrative synthesis of findings related to core recommended osteoarthritis rehabilitation treatments performed. RESULTS: Of 2,479 potential records, 253 records were reviewed. Two guidelines, 18 systematic reviews and 38 RCTs were included. 84% (n = 49) of included records related to knee osteoarthritis, 13% (n = 8) to hip, 10% (n = 6) to hand, 3% (n = 2) to mixed, and 1% (n = 1) to foot osteoarthritis. Exercise-therapy, methods to deliver exercise-therapy remotely, and approaches to facilitate exercise-therapy behaviour change were the most commonly evaluated interventions (n = 27). 94% of systematic reviews and 63% of RCTs rated high-quality. CONCLUSIONS: Osteoarthritis rehabilitation research continues to focus on knee osteoarthritis and exercise-based interventions. Emerging topics include rehabilitation of comorbid populations, exercise behaviour change and technology supports. A better understanding of rehabilitation of osteoarthritis in joints other than the knee, and methods to determine and promote ideal exercise-therapy prescription are needed.

Tetrahydroxanthone-chromanone heterodimers from lichen Usnea aciculifera and their cytotoxic activity against human cancer cell lines.

Four new tetrahydroxanthone-chromanone heterodimers, usneaxanthones E-H (1-4) together with eleven known compounds (5-15) were isolated from lichen Usnea aciculifera Vain (Parmeliaceae). Their structures and absolute configurations, particularly the central and axial chiralities, were unambiguously demonstrated by a combination of spectroscopic data (1D, 2D NMR, HRESIMS), electronic circular dichroism (ECD) experiments, and single-crystal X-ray crystallographic analyses. The cytotoxicity of new compounds was evaluated on four human cancer cell lines including HCT116 colorectal cancer, MCF-7 breast cancer, A549 lung cancer, and OVCAR-3 ovarian cancer. Compounds 1-4 exhibited good cytotoxicity against all tested cancer cell lines, except ovarian cancer, with the best IC50 value of 3.37 µM. All compounds showed potent cytotoxicity against HCT116 colon cancer with IC50 value from 3.37 to 4.53 µM.

Dimeric tetrahydroxanthones from the lichen Usnea aciculifera.

Four unusual heterodimeric tetrahydroxanthones, usneaxanthones A-D (1-4) were isolated from lichen Usnea aciculifera Vain (Parmeliaceae). Their structures and absolute configurations, particularly the central and axial chiralities, were unambiguously demonstrated by a combination of spectroscopic data (1D, 2D NMR, HRESIMS), electronic circular dichroism (ECD) experiments, and single-crystal X-ray crystallographic analyses. Cytotoxic effects of isolated compounds (1, 2 and 4) were evaluated on HT-29 human colorectal cancer cells. Compound 4 showed potent cytotoxicity against HT-29 with IC50 values of 2.41 µM.

Persistence of detectable insecticidal proteins from Bacillus thuringiensis (Cry) and toxicity after adsorption on contrasting soils.

Insecticidal Cry, or Bt, proteins are produced by the soil-endemic bacterium, Bacillus thuringiensis and some genetically modified crops. Their environmental fate depends on interactions with soil. Little is known about the toxicity of adsorbed proteins and the change in toxicity over time. We incubated Cry1Ac and Cry2A in contrasting soils subjected to different treatments to inhibit microbial activity. The toxin was chemically extracted and immunoassayed. Manduca sexta was the target insect for biotests. Extractable toxin decreased during incubation for up to four weeks. Toxicity of Cry1Ac was maintained in the adsorbed state, but lost after 2 weeks incubation at 25 °C. The decline in extractable protein and toxicity were much slower at 4 °C with no significant effect of soil sterilization. The major driving force for decline may be time-dependent fixation of adsorbed protein, leading to a decrease in the extraction yield in vitro, paralleled by decreasing solubilisation in the larval gut.

Melittin disruption of raft and non-raft-forming biomimetic membranes: a study by quartz crystal microbalance with dissipation monitoring.

In this work we examine the role of lateral phase separation in cholesterol-containing biomimetic membranes on the disrupting action of melittin using a label-free surface-sensitive technique, quartz crystal microbalance with dissipation monitoring (QCM-D). Melittin disruption mechanisms depend strongly on the geometry of the lipid layer; however, despite the interplay between layer geometry/thickness and melittin activity, results indicate that the presence of lipid heterogeneity and lateral phase separation greatly influences the disrupting efficiency of melittin. In homogeneous non-raft forming membranes with high cholesterol content, melittin spontaneous activity is strongly delayed compared to heterogeneous raft-forming systems with the same amount of cholesterol. These results confirm the importance of lateral phase separation as a determinant factor in peptide activity. The information provided can be used for the design of more efficient antimicrobial peptides and the possibility of using a label-free approach for tailored-membranes and interactions with other types of peptides, such as amyloid peptides.

Lactate dehydrogenase as an indicator of severe illness in neonatal intensive care patients: a longitudinal cohort study.

AIM: Lactate dehydrogenase (LDH) increases in several critical conditions that cause cell damage and could potentially be used for early detection of serious illness in the newborn. Our aim was to investigate the relationship between the early clinical course of NICU infants and LDH in plasma at admission. METHODS: LDH was measured in a cohort of patients consecutively admitted to a major NICU in Hanoi. The infants were classified as 'obviously needing intensive care during the first week' (n = 83) or 'not receiving intensive care measures during the first week' (n = 260) by a senior neonatologist blinded to the LDH and lactate activity. RESULTS: LDH differed significantly between the groups in infants born after 32 gestational weeks. LDH differed with the vitality of the patient (F = 26.25, p < 0.0001) at admittance and correlated with lactate (R = 0.496, p < 0.0001). Also, the predictive value for obvious need of intensive care was higher for LDH than for lactate assessed by area under the curve calculated with ROC-curves [0.82 (0.77-0.88) vs. 0.67 (0.60-0.75)]. CONCLUSION: There is a strong relationship between bad clinical condition of infants during first week of life and elevated plasma LDH. The results suggest that LDH might be a valuable support in decision making in the neonatal period.

Fine-needle aspiration diagnosis of metastatic urothelial carcinoma: a review.

Urothelial carcinoma (UC) is the most common malignant neoplasm of the urinary tract. Metastases of UC are most common in the regional lymph nodes, lungs, liver, bone, and adrenal glands. Fine-needle aspiration cytology diagnosis of such metastases can be difficult, particularly in the setting of incomplete clinical history or when multiple primary neoplasms may be present. This review focuses on the cytologic features helpful in differentiating UC from its potential mimics, as well as ancillary studies that may be helpful in the distinction.

Long isoform of ErbB3 binding protein, p48, mediates protein kinase B/Akt-dependent HDM2 stabilization and nuclear localization.

p48 is a long isoform of the ErbB3 binding protein that has oncogenic functions including promotion of carcinogenesis and induction of malignant transformation through negative regulation of tumor suppressor p53. Here, we show that high level of p48 protein expression leads to enhance HDM2 phosphorylation by Akt and inhibits the self-ubiquitination of HDM2 by up-regulation of Akt activity, thereby promoting its protein stability. Moreover, p48 expression leads to accumulated nuclear localization of HDM2, whereas p48 depletion disturbs its nuclear localization. Hence, higher expression of p48 in cancer cells reduces p53 levels through modulation of HDM2 nuclear localization and protein stability via regulation of its Akt-mediated phosphorylation.

Akt2 and nucleophosmin/B23 function as an oncogenic unit in human lung cancer cells.

The signaling network of protein kinase B(PKB)/Akt has been implicated in survival of lung cancer cells. However, understanding the relative contribution of the different isoform of Akt network is nontrival. Here, we report that Akt2 is highly expressed in human lung adenocarcinoma cell line A549 cells. Suppression of Akt2 expression in A549 cells results in notable inhibition of cell poliferation, soft agar growth, and invasion, accompanying by a decrease of nucleophosmin/B23 protein. Overexpression of Akt1 restores cancerous growth of A549 cells in B23-knockdown (KD) cells while Akt2 overexpression did not restore proliferating potential in cells with downregulated B23, thus suggesting Akt2 requires B23 to drive proliferation of lung cancer cell. Loss of functional Akt2 and B23 has similar defects on cell proliferation, apoptotic resistance and cell cycle regulation, while loss of Akt1 has less defects on cell proliferation, survival and cell cycle progression in A549 cells. Moreover, overexpression of B23 rescues the proliferative block induced as a consequence of loss of Akt2. Thus our data suggest that Akt2/B23 functions as an oncogenic unit to drive tumorigenesis of A549 lung cancer cells.

Negative regulation of p53 by the long isoform of ErbB3 binding protein Ebp1 in brain tumors.

The ErbB3 binding protein Ebp1 has been implicated in a number of human cancers. Ebp1 includes 2 isoforms, p48 and p42, that exhibit different cellular activities. Here we show that the larger p48 isoform is transforming and that it promotes cell growth, clonogenicity, and invasion in human glioblastoma (GBM). P48 overexpression in GBM cells facilitated tumorigenesis and enhanced tumor growth in mouse xenograft models. Human GBM tissues displayed elevated levels of p48 compared with surrounding normal tissues or low-grade tumors. Notably, p48 levels were inversely correlated with poor prognosis in GBM patients. We determined that p48 binds to the p53 E3 ligase HDM2, enhancing HDM2-p53 association and thereby promoting p53 polyubiquitination and degradation to reduce steady-state p53 levels and activity. Together, our findings suggest that p48 functions as an oncogene by promoting glioma tumorigenicity via interactions with HDM2 that contribute to p53 downregulation.

Neuroprotection signaling pathway of nerve growth factor and brain-derived neurotrophic factor against staurosporine induced apoptosis in hippocampal H19-7/IGF-IR [corrected].

Neurotrophins protect neurons against excitotoxicity; however the signaling mechanisms for this protection remain to be fully elucidated. Here we report that activation of the phosphatidyl inositol 3 kinase (PI3K)/Akt pathway is critical for protection of hippocampal cells from staurosporine (STS) induced apoptosis, characterized by nuclear condensation and activation of the caspase cascade. Both nerve growth factor (NGF) and brain-derived growth factor (BDNF) prevent STS-induced apoptotic morphology and caspase-3 activity by upregulating phosphorylation of the tropomyosin receptor kinase (Trk) receptor. Inhibition of Trk receptor by K252a altered the neuroprotective effect of both NGF and BDNF whereas inhibition of the p75 neurotrophin receptor (p75NTR) had no effect. Impairment of the PI3K/Akt pathway or overexpression of dominant negative (DN)-Akt abolished the protective effect of both neurotrophins, while active Akt prevented cell death. Moreover, knockdown of Akt by si-RNA was able to block the survival effect of both NGF and BDNF. Thus, the survival action of NGF and BDNF against STS-induced neurotoxicity was mediated by the activation of PI3K/Akt signaling through the Trk receptor.

True vasculitis in lupus nephritis.

Vascular lesions are encountered frequently in renal biopsy specimens of patients with systemic lupus erythematosus (SLE) and can present in a variety of morphologic forms. True renal lupus vasculitis (TRLV) is one of the rare vascular lesions associated with lupus nephritis that has been infrequently reported in the medical literature. The primary focus on glomerular pathology and collective classification of the vascular lesions under lupus vasculopathy is one of the reasons why this form of inflammatory vasculitis has been under-recognized as a separate disease entity. Here we have comprehensively reviewed the literature on renal vascular involvement in SLE for a better understanding of the epidemiology, morphologic features, pathogenesis, clinical course and treatment of TRLV. It can be morphologically differentiated from other forms of renal vascular lesions in lupus nephritis, i.e. arteriosclerosis, uncomplicated vascular immune deposits, non-inflammatory necrotizing vasculopathy, and thrombotic microangiopathy. Despite close similarities with antineutrophil cytoplasmic autoantibody associated vasculitis (AASV), there are certain morphological differences that warrant a thorough investigation of the possible pauci-immune mechanism of pathogenesis. The vasculitis follows a severe clinical course in general with rapid progression to renal failure, although favorable outcomes have been reported in certain cases. The standard use of steroids and cytotoxic drugs has yielded variable results in the treatment of TRLV. Current treatment modalities being used in lupus nephritis and AASV have been compared in this article with focus on drugs acting on the inflammatory cells implicated in TRLV pathogenesis.

Critical molecular regulators, histomorphometric indices and their correlations in the trabecular bone in primary hip osteoarthritis.

OBJECTIVE: This study examined differential gene expression, histomorphometric indices and relationships between these, in femoral trabecular bone from osteoarthritis (OA) patients and control (CTL) subjects, with the aim of identifying potential molecular drivers consistent with changes in structural and remodelling indices in the OA pathology. MATERIALS AND METHODS: Bone samples from the intertrochanteric (IT) region were obtained from age and sex-matched cohorts of 23 primary hip OA patients and 21 CTL subjects. Real-time polymerase chain reaction (PCR) and histomorphometric analysis were performed on each sample and correlations between gene expression and histomorphometric variables determined. RESULTS: Alterations in gene expression, structural indices and correlations between these were found in OA bone compared to CTL. In OA bone, expression of critical regulators of osteoblast differentiation (TWIST1) and function (PTEN, TIMP4) were decreased, while genes associated with inflammation (SMAD3, CD14) were increased. Bone structural and formation indices (BV/TV, Tb.N, OS/BS) were increased, whereas resorption indices (ES/BS, ES/BV) were decreased. Importantly, significant correlations in CTL bone between CTNNB1 expression and formation indices (OS/BS, OS/BV, OV/BV) were absent in OA bone, indicating altered WNT/ß-catenin signalling. TWIST1 expression and BV/TV were correlated in CTL bone, but not in OA bone, consistent with altered osteoblastogenesis in OA. Matrix metalloproteinase 25 (MMP25) expression and remodelling indices (ES/BS, ES/BV, ES/TV) were correlated only in OA pointing to aberrant bone remodelling in this pathology. CONCLUSIONS: These findings indicate an altered state of osteoblast differentiation and function in OA driven by several key molecular regulators. In association with this differential gene expression, an altered state of both trabecular bone remodelling and resulting microarchitecture were also observed, further characterising the pathogenesis of primary hip OA.

Behavioural effects of a selective NMDA NR1A/2B receptor antagonist in rats with unilateral 6-OHDA+parafascicular lesions.

Experimental lesions involving the parafascicular (Pf) nucleus and medial forebrain bundle (MFB) may model to some extent the pathological loss of glutamatergic neurons from the centromedian-parafascicular (CM-Pf) complex and nigral dopaminergic cell loss observed clinically at post-mortem in Parkinson's disease (PD) cases. Our study investigated whether there were alterations in symptomatology in such rats with unilateral 6-OHDA+Pf lesions after treatment with either a selective NR1A/NR2B NMDA antagonist and/or l-dopa. Rats were given dual surgery to the MFB with 6-hydroxydopamine (6-OHDA) and Pf with N-methyl-d-aspartate (NMDA). (i) An NR1A/NR2B selective NMDA antagonist (BZAD-01; 10mg/kg), (ii) l-dopa (25mg/kg), (iii) BZAD-01+l-dopa (10mg/kg; 25mg/kg) or (iv) vehicle solution were administered for 6 weeks, during which behavioural testing was performed. BZAD-01 improved postural asymmetry in the first month as well as apomorphine-induced rotation. The latter was also improved by l-dopa in this model. These data support the use of selective NR1/NR2B NMDA antagonists in the therapeutics of PD.

Nuclear Akt interacts with B23/NPM and protects it from proteolytic cleavage, enhancing cell survival.

B23/NPM is a major nucleolar phosphoprotein that has a critical role in cell proliferation and cell death. Here, we show that it forms a complex with Akt on growth factor (GF) stimulation in both the cytoplasm and the nucleus, for which Akt activation is indispensable. The C terminus of B23 (239-294 residues) potently binds pleckstrin homology (PH) domain of Akt. Akt binding to B23 protects it from proteolytic degradation by caspase-3, leading to the up-regulation of cell survival. Interestingly, unsumoylated B23 K263R, but not wild-type B23, strongly interacts with Akt in the nucleoplasm in the absence of GFs. Furthermore, we show that Akt2, but not other isoforms, specifically regulates B23 sumoylation and protein stability. Also, nuclear Akt regulates the cell cycle progression activity of B23. Therefore, our findings support that nuclear Akt binds and stabilizes B23 in the nucleoplasm, and regulates its activities in cell survival and cell cycle.

Developing a preclinical model of Parkinson's disease: a study of behaviour in rats with graded 6-OHDA lesions.

Injection of increasing concentrations of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle (MFB) can be used to establish a graded model of different clinical stages of Parkinson's disease (PD). We investigated the relationship between behavioural alterations and loss of dopaminergic neurons in the substantia nigra pars compacta (SNc). Forty female Sprague-Dawley rats were injected with either (i) 4 microg (ii) 8 microg or (iii) 16 microg 6-hydroxydopamine (6-OHDA) to mimic the preclinical, mild and advanced clinical stages of PD, respectively. Vehicle was injected in a separate control group. Behaviours analysed included postural asymmetry, balance, locomotion, sensorimotor deficits and apomorphine rotation. At post-mortem the degree of tyrosine immunoreactive dopaminergic cell (TH-ir) loss was then estimated. There was a graded and consistent trend in each of the behaviours studied with respect to cell loss between the different sized lesion groups when examined using correlation analysis (all comparisons, r > 0.8, p < 0.001). Rats with large lesions demonstrated more significant behavioural changes over 8 weeks of testing than those with intermediate and smaller lesions (group comparisons p < 0.001). PD symptomatology became overt when cell loss reached 70%, however some significant changes can be observed with as little as 40% dopaminergic cell loss. Thus, injection with increasing concentrations 6-OHDA into the MFB can produce increasing extents of cell loss and behavioural changes, which were well correlated. This graded model can be useful for testing potential neuroprotective compounds for PD.

Predictive value of anti-cell and anti-human immunodeficiency virus (HIV) humoral responses in HIV-1-exposed seronegative cohorts of European and Asian origin.

Unconventional immune responses have been demonstrated in individuals who, despite repeated exposure to human immunodeficiency virus (HIV) infection, remain seronegative. As environmental exposure to pathogens and genetic background may modulate immune responses differentially, one Italian and two Asian populations of HIV-1-exposed seronegative individuals were studied. In serum samples from each group, IgG to CCR5, IgG to CD4 and IgA to gp41 were measured, which were previously described as markers of unconventional immunity in HIV-exposed seronegative Caucasians. Given the importance of conformational epitopes in virus-cell interactions, IgG to CD4-gp120 complex was also measured. It was found that markers of HIV exposure were present in all populations studied. HIV-specific humoral responses (IgA to gp41 and IgG to CD4-gp120 complex) were extremely significant predictors of HIV exposure (P<0.0001 in both cases), whereas the predictive values of anti-cell antibodies (anti-CCR5 and anti-CD4) varied between populations. Evidence is provided for the correlation of these differences with route of exposure to HIV and level of natural antibodies to cross-reactive microbial antigens. In conclusion, exposed seronegative individuals of ethnically different origins display similar signs of HIV-dependent unconventional immunity. A specific relevance must be attributed to different innate and acquired factors.

Post anaesthesia care unit discharge: a clinical scoring system versus traditional time-based criteria.

This prospective cohort analysis compared the efficiency of time-based discharge criteria (Group 1) to a modified clinical scoring system (Group 2), incorporating the assessment of pain and temperature, in the post anaesthesia care unit (PACU). Two consecutive series of patients (n = 292) were assessed following general anaesthesia for various surgical procedures. The time taken for patients to satisfy their respective discharge criteria was recorded as PACU length of stay (LOS). Patient group and other factors that may have influenced PACU-LOS were examined using time-to-event analysis. The raw PACU-LOS was not shown to be different between the two groups (log rank test, P = 0.12). Covariate adjusted estimates were used to compare the two discharge criteria and also to identify other factors influencing PACU-LOS. The Cox regression model was poorly specified and a log-logistic accelerated failure time model was found to be the most parsimonious predictive model. Predictors of decreased PACU-LOS were the treatment group (Group 2 versus Group 1) and the covariate recording anaesthetic airway choice (no endotracheal tube (ETT) versus ETT). Surgical time, as a linear function, intra- and postoperative opioid administration, as well as postoperative antiemetic use were predictors of increased PACU-LOS. Patient age, gender, urgency of surgery, and ASA classification were not predictive of PACU-LOS. Using covariate adjusted estimates, the new PACU discharge criteria, based on the Aldrete's scoring system, was associated with a significantly reduced PACU-LOS in comparison with time-based criteria.

New aspects of posttransplant nephrotic syndrome: clinicopathologic correlations with outcomes.

Although posttransplant nephrotic syndrome is frequent, its structural basis and prognosis have not been clearly defined. The biopsy findings of 54 patients with this disorder posttransplant, among 375 total renal transplant recipients engrafted during a 10-year period, were correlated with clinical follow-up data. The mean patient age was 41.7 +/- 12.3 years, female/male ratio 22/32, and cadaveric/living-related donor ratio 37/17. The nephrotic syndrome developed 3 to 91 months posttransplant. At the onset the mean values of serum creatinine was 2.9 +/- 1.8 mg/dL and proteinuria 4.5 +/- 0.8 g/d. The index biopsy findings showed chronic allograft nephropathy (CAN) in 33; de novo glomerulonephritis (GN) in 6, recurrent GN in 9, and undetermined GN in 6 who had an unknown primary renal disease. Among 21 follow-up biopsies during a mean of 44.3 +/- 28 months the CAN progressed but the GN remained the same. The treatment included augmented steroids alone (n = 1) or in combination with cyclophosphamide (n = 2) and with plasmapheresis (n = 1); angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) along (n = 5); calcium channel blockers (CCB) alone (n = 24); or the two types of drugs together (n = 22). Complete or partial remission was achieved in 8 and 5, respectively, but nephrotic syndrome recurred in 3 of these patients at 45.1 +/- 18 months later. Sustained remission was more likely in cases of GN (minimal change disease and IgA nephropathy) and ACEI-ARB treatment (P <.01). Graft failure, which occurred in 35 patients, correlated strongly with serum creatinine at onset, being significantly greater in patients with CAN (P <.005). Both remission of the nephrotic syndrome and graft survival were greater among patients with GN as compared to those with CAN.