Metabolic inflexibility in youth with obesity: Is it a feature of obesity or distinctive of youth who are metabolically unhealthy?

Individuals with obesity have metabolic inflexibility with diminished fasting fat oxidation and blunted increase in respiratory quotient (RQ) in insulin-stimulated states. However, it is unclear if metabolic inflexibility is a characteristic of obesity per se or is unique to youth who have metabolically unhealthy obesity (MUO) compared with metabolically healthy obesity (MHO). We investigated metabolic flexibility in youth with MUO, MHO and normal weight (NW) and compared their metabolic characteristics. Youth (n = 188) were divided, based on cut-off points for in vivo insulin sensitivity (IS) of adolescents with NW, into 137 with MUO and 51 with MHO. Fasting hepatic IS (HIS) from hepatic glucose production by [6,6-2 H2 ]glucose, adipose tissue IS (ATIS) from whole-body lipolysis by [2 H5 ]glycerol, RQ (indirect calorimetry) during fasting and a hyperinsulinemic (80 mU/m2 /min)-euglycemic clamp were measured. Youth with MUO versus MHO had blunted ΔRQ (p = .035) and lower HIS and ATIS (both p < .0001), while ΔRQ, HIS and ATIS were not different between youth with MHO and NW. In a pair-matched sub-analyses of 30 MUO and 30 MHO the results were similar to the total cohort. Metabolic inflexibility, does not appear to be a feature of obesity per se rather distinctive of youth with MUO, who also have worse HIS and ATIS compared with youth with MHO.

Silybum marianum total extract, silymarin and silibinin abate hepatocarcinogenesis and hepatocellular carcinoma growth via modulation of the HGF/c-Met, Wnt/ß-catenin, and PI3K/Akt/mTOR signaling pathways.

Hepatocellular carcinoma (HCC) has been identified as one of the most deadly malignancies with limited therapeutic efficacy worldwide. However, understanding the molecular mechanisms of crosstalk between signaling pathways in HCC and predicting cancer cell responses to targeted therapeutic interventions remain to be challenge. Thus, in this study, we aimed to evaluate the anticancerous efficacy of Silybum marianum total extract (STE), silymarin (Sm), and silibinin (Sb) against experimentally-induced HCC in rats. In vitro investigations were also performed and the anticancer effects against HCC cell lines (HepG2 and Huh7) were confirmed. Wistar rats were given diethylnitrosamine (DEN)/2-acetylaminofluorene (AAF)/carbon tetrachloride (CCl4) and were orally treated with STE (200 mg/kg body weight (bw)), Sm (150 mg/kg bw), and Sb (5 mg/kg bw) every other day from the 1st or 16th week to the 25th week of DEN/AAF/CCl4 injection. Treatment with STE, Sm, and Sb inhibited the growth of cancerous lesions in DEN/AAF/CCl4-treated rats. This inhibition was associated with inhibition of Ki-67 expression and repression of HGF/cMet, Wnt/ß-catenin, and PI3K/Akt/mTOR signaling pathways. STE, Sm, and Sb improved liver function biomarkers and tumor markers (AFP, CEA, and CA19.9) and increased total protein and albumin levels in serum. STE, Sm, and Sb treatment was also noted to reduce the hepatic production of lipid peroxides, increase hepatic glutathione content, and induce the activities of hepatic antioxidant enzymes in DEN/AAF/CCl4-treated rats. These results indicate that STE, Sm, and Sb exert anti-HCC effects through multiple pathways, including suppression of Ki-67 expression and HGF/cMet, Wnt/ß-catenin, and PI3K/Akt/mTOR pathways and enhancement of antioxidant defense mechanisms.

Tackling of Renal Carcinogenesis in Wistar Rats by Silybum marianum Total Extract, Silymarin, and Silibinin via Modulation of Oxidative Stress, Apoptosis, Nrf2, PPARγ, NF-κB, and PI3K/Akt Signaling Pathways.

The present work was designed to assess the efficacy of Silybum marianum total extract (STE), silymarin (Sm), and silibinin (Sb) against experimentally induced renal carcinogenesis in male Wistar rats and their roles in regulating oxidative stress, inflammation, apoptosis, and carcinogenesis. The diethylnitrosamine (DEN)/2-acetylaminofluorene (AAF)/carbon tetrachloride (CCl4)-administered rats were orally treated with STE (200 mg/kg b.w.), Sm (150 mg/kg b.w.), and Sb (5 mg/kg b.w.) every other day either from the 1st week or from the 16th week of carcinogen administration to the end of 25th week. The treatments with STE, Sm, and Sb attenuated markers of toxicity in serum, decreased kidney lipid peroxidation (LPO), and significantly reinforced the renal antioxidant armory. The biochemical results were further confirmed by the histopathological alterations. The treatments also led to suppression of proinflammatory mediators such as NF-κß, p65, Iκßα, and IL-6 in association with inhibition of the PI3K/Akt pathway. Furthermore, they activated the expressions of PPARs, Nrf2, and IL-4 in addition to downregulation of apoptotic proteins p53 and caspase-3 and upregulation of antiapoptotic mediator Bcl-2. The obtained data supply potent proof for the efficacy of STE, Sm, and Sb to counteract renal carcinogenesis via alteration of varied molecular pathways.

Two Patients with Atypical Choroidal Detachment.

Serous choroidal detachment that is caused by rhegmatogenous retinal detachment (RRD) may present a significant diagnostic challenge as delayed recognition and repair of the underlying RRD can severely impact the final anatomical and visual outcome. We report 2 consecutive patients with atypical choroidal detachments who were later found to have underlying RRDs. A 71-year-old female presented with a 1-week history of painful vision loss and floaters in the left eye. Examination revealed choroidal detachments in the nasal and temporal periphery and an overlying retinal detachment with shifting subretinal fluid. However, no retinal breaks were identified. An extensive laboratory workup and imaging of the orbits were unrevealing. She was treated with 80 mg oral prednisone daily for 2 weeks with subsequent resolution of the choroidals but persistence of the retinal detachment. Similarly, a 52-year-old male presented with a 3-week history of flashes and floaters followed by painful vision loss in the left eye 1 day prior to presentation. He had hand motion vision OS and the intraocular pressure was undetectable by hand-held tonometry OS. Dense brunescent cataract prevented adequate viewing of the posterior pole. B-scan ultrasonography revealed a funnel retinal detachment, with homogenous choroidal echogenicities suggestive of hemorrhagic choroidal detachment. Extensive laboratory workup was unrevealing. The patient was started on 60 mg oral prednisone and re-evaluated every 2 days, but ultrasonography revealed persistence of the choroidal detachment after 1 week. The diagnosis of RRD with an associated choroidal detachment should be considered, even in the absence of an identifiable causative retinal break.

Combined radiotherapy and concurrent tumor treating fields (TTFields) for glioblastoma: Dosimetric consequences on non-coplanar IMRT as initial results from a phase I trial.

BACKGROUND: Glioblastoma is a rapidly proliferating tumor. Patients bear an inferior prognosis with a median survival time of 14-16 months. Proliferation and repopulation are a major resistance promoting factor for conventionally fractionated radiotherapy. Tumor-Treating-Fields (TTFields) are an antimitotic modality applying low-intensity (1-3 V/cm), intermediate-frequency (100-300 kHz) alternating electric-fields. More recently interference of TTFields with DNA-damage-repair and synergistic effects with radiotherapy were reported in the preclinical setting. This study aims at examining the dosimetric consequences of TTFields applied during the course of radiochemotherapy. METHODS: Cone-beam-computed-tomography (CBCT)-data from the first seven patients of the PriCoTTF-phase-I-trial were used in a predefined way for dosimetric verification and dose-accumulation of the non-coplanar-intensity-modulated-radiotherapy (IMRT)-treatment-plans as well as geometric analysis of the transducer-arrays by which TTFields are applied throughout the course of treatment. Transducer-array-position and contours were obtained from the low-dose CBCT's routinely made for image-guidance. Material-composition of the electrodes was determined and a respective Hounsfield-unit was assigned to the electrodes. After 6D-fusion with the planning-CT, the dose-distribution was recalculated using a Boltzmann-equation-solver (Acuros XB) and a Monte-Carlo-dose-calculation-engine. RESULTS: Overdosage in the scalp in comparison to the treatment plan without electrodes stayed below 8.5% of the prescribed dose in the first 2 mm below and also in deeper layers outside 1cm2 at highest dose as obtained from dose-volume-histogram comparisons. In the clinical target volume (CTV), underdosage was limited to 2.0% due to dose attenuation by the electrodes in terms of D95 and the effective-uniform-dose. Principal-component-analysis (PCA) showed that the first principal-position-component of the variation of repeated array-placement in the direction of the largest variations and the perpendicular second-component spanning a tangential plane on the skull had a standard deviation of 1.06 cm, 1.23 cm, 0.96 cm, and 1.11 cm for the frontal, occipital, left and right arrays for the first and 0.70 cm, 0.71 cm, 0.79 cm, and 0.68 cm, respectively for the second-principal-component. The variations did not differ from patient-to-patient (p > 0.8, Kruskal-Wallis-tests). This motion led to a diminution of the dosimetric effects of the electrodes. CONCLUSION: From a dosimetric point of view, dose deviations in the CTV due to transducer-arrays were not clinically significant in the first 7 patients and confirmed feasibility of combined adjuvant radiochemotherapy and concurrent TTFields. PriCoTTF Trial: A phase I/II trial of TTFields prior and concomitant to radiotherapy in newly diagnosed glioblastoma. DRKS-ID: DRKS00016667. Date of Registration in DRKS: 2019/02/26. Investigator Sponsored/Initiated Trial (IST/IIT): yes. Ethics Approval/Approval of the Ethics Committee: Approved. (leading) Ethics Committee Nr.: 18-8316-MF, Ethik-Kommission der Medizinischen. Fakultät der Universität Duisburg-Essen. EUDAMED-No. (for studies acc. to Medical Devices act): CIV-18-08-025247.

HIV-1 elite controllers: an immunovirological review and clinical perspectives.

HIV type 1 (HIV-1) elite controllers (ECs) represent a rare group of individuals with an ability to maintain an undetectable HIV-1 viral load overtime in the absence of previous antiretroviral therapy. The mechanisms associated with this paradigm remain not clearly defined. However, loss of virological control, morbidity and mortality persist in these individuals, such as progress to AIDS-defining conditions together with persistent high rate of immune activation. Further insight into potential therapeutic options is therefore warranted. In this review, we discuss recent data on the type of immune responses understood to be associated with chronic virological control, the potential for disease progression and therapeutic options in ECs.

Delayed sleep phase syndrome and bipolar disorder: Pathogenesis and available common biomarkers.

Circadian rhythm disturbances are common in bipolar affective disorder (BD). Delayed sleep-wake phase syndrome (DSWPD) is the most prevalent circadian rhythm sleep-wake disorder (CRSWDs) and is frequently observed in BD. It is unclear whether DSWPD in BD is an independent process or is a consequence of BD. In this hypothetical review, we discuss the overlap between BD and DSWPD and potential common biomarkers for DSWPD and BD. The review will include a discussion of the genetics of DSWPD and BD. Biomarkers elucidating the pathophysiological processes occurring in these two disorders may offer insight into the etiology and prognosis of both conditions.

Prevalence of prediabetes and its association with obesity among college students in Kuwait: A cross-sectional study.

This cross-sectional study sought to estimate the prevalence of prediabetes and assess its association with obesity among young adults in Kuwait; a country with a high prevalence of obesity and diabetes. The estimated prevalence of prediabetes was 6.3% (95% CI: 4.8-8.1) and obesity was associated with elevated prediabetes prevalence.

Neuroproteomics and microRNAs studies in multiple sclerosis: transforming research and clinical knowledge in biomarker research.

Multiple sclerosis (MS) is a complex disease characterized by extensive phenotypic variability. Biomarkers to capture the different aspects of MS heterogeneity, and to help make a diagnosis and monitor disease progression, while providing insights into etiopathogenesis and response to treatment, are urgently needed. Omics technologies and research efforts with microRNAs have provide unparalleled opportunities for exploring altered protein profiles associated with molecular mechanisms of disease, substantially expanding the list of candidate biomarkers for MS. This review presents evidence from proteomic studies that have focused on identification of biomarkers released in biofluids as a result of the different pathophysiological processes of MS. Also discussed is the emerging role of miRNAs as complementary biomarkers related to cellular processes occurring in MS patients. Also provided is an overview of candidate biomarkers that have been proposed for elucidating pathophysiological processes and disease activity and for guiding clinical diagnosis and/or therapeutic interventions in MS.

Does laryngopharyngeal reflux affect healing and recovery after tonsillectomy?

INTRODUCTION: Laryngopharyngeal reflux is increasingly being implicated in several otolaryngological disorders. AIMS: To study a potential correlation between pre-operative laryngopharyngeal reflux and wound healing and recovery after tonsillectomy, based on subjective and objective findings. MATERIALS AND METHODS: A prospective, blinded study was undertaken, including 60 patients scheduled for tonsillectomy, divided into two equal groups: a study group (group A) with pre-operative laryngopharyngeal reflux documented using ambulatory 24-hour pH monitoring; and a control group (group B) without laryngopharyngeal reflux. RESULTS: Group A had significantly higher pain scores on the seventh and 14th post-operative days (p = 0.022 and p = 0.000, respectively) and took a significantly longer time to return to normal eating (p = 0.013), compared with group B. Group A also showed significantly slower healing on the seventh and 14th post-operative days, as estimated by assessing the grade of post-operative slough formation (p = 0.016 and p = 0.029, respectively). A significant correlation between the number of pharyngeal reflux episodes and the degree of post-operative slough was also found. CONCLUSIONS: Laryngopharyngeal reflux can significantly decrease wound healing following tonsillectomy. Therefore, pre-operative recognition and management of this condition is desirable in order to eliminate its negative post-operative effect.

Endoscopic radical antrectomy: a permanent replacement for the Caldwell-Luc operation.

INTRODUCTION: Chronic inflammation of sinus mucosa is a multifactorial condition which sometimes results in irreversible pathological mucosal changes. AIMS: To evaluate the efficacy of endoscopic radical antrectomy in treating chronic, hyperplastic, eosinophilic sinusitis, and to compare this procedure with classical endoscopic middle meatal antrostomy. MATERIALS AND METHODS: A randomised, controlled trial with parallel design was conducted between July 2000 and December 2004, including 119 patients who fulfilled the clinical, radiological and histopathological criteria for chronic, hyperplastic, eosinophilic sinusitis. Patients were randomly allocated to two treatment groups: classical endoscopic middle meatal antrostomy and endoscopic radical antrectomy. The main outcome measures were recorded in each subgroup at the time of the patient's last clinic visit. In each subgroup, these included subjective improvement and evaluation of the endoscopic appearance of the maxillary sinus. RESULTS: Thirty-two per cent of patients in the endoscopic middle meatal antrostomy group were considered surgical failures, compared with 14.5 per cent of the endoscopic radical antrectomy group. This was statistically significant (p = 0.023). Unhealthy maxillary sinuses were significantly more prevalent in the endoscopic middle meatal antrostomy group (p = 0.029). CONCLUSIONS: In those patients fulfilling the criteria suggestive of chronic, irreversible sinonasal pathology, primary endoscopic radical antrectomy was significantly better than endoscopic middle meatal antrostomy, based on subjective and objective findings.

Helicobacter pylori infection and chronic, persistent cough: is there an association?

INTRODUCTION: Chronic, persistent cough is a common clinical problem, the cause of which sometimes remains unidentifiable. AIMS: To study a potential association between Helicobacter pylori infection and chronic, persistent cough. MATERIALS AND METHODS: A clinical observational study with symptom analysis, including 162 patients whose main presenting complaint was chronic, persistent cough of unidentifiable cause (study group) and 42 patients with chronic, non-specific laryngopharyngeal manifestations not including chronic cough (control group). RESULTS: Active H pylori infection was present in 86.4 per cent (140/162) of patients in the chronic cough group, as opposed to 45.2 per cent (19/42) of the control group, as confirmed by detection of H pylori antigen in stool specimens. This difference was statistically significant (p<0.001). There was a significant improvement of the chronic cough of 75.4 per cent (98/130) of patients after successful H pylori eradication using appropriate medical therapy (p<0.001). CONCLUSIONS: Helicobacter pylori infection may lead to laryngopharyngeal irritation, with several clinical manifestations including chronic, persistent cough. However, the exact mechanism of this requires further research.

Post kala azar dermal leishmaniasis in Sudan.

Post kala azar dermal leishmaniasis (PKDL) is a condition that develops after treatment of kala azar. We report on 42 patients with suspected PKDL, 40% of whom were children. Diagnosis was made though investigation of family history of kala azar, clinical examination and the use of laboratory investigations, such as skin smear, skin biopsy, bone marrow aspiration and the leishmanin skin test. Regarding the lesions, 24 patients (57%) had papular lesions, 10 (24%) had hypopigmented maculopapular lesions and 8 (19%) had nodular lesions. The lesions of PKDL may be confused with other dermatological diseases and therefore it is important that clinicians and pathologists collaborate in diagnosing such cases.

Post kala azar dermal leishmaniasis in Sudan

Post kala azar dermal leishmaniasis [PKDL] is a condition that develops after treatment of kala azar. We report on 42 patients with suspected PKDL, 40% of whom were children. Diagnosis was made though investigation of family history of kala azar, clinical examination and the use of laboratory investigations, such as skin smear, skin biopsy, bone marrow aspiration and the leishmanin skin test. Regarding the lesions, 24 patients [57%] had papular lesions, 10 [24%] had hypopigmented maculopapular lesions and 8 [19%] had nodular lesions. The lesions of PKDL may be confused with other dermatological diseases and therefore it is important that clinicians and pathologists collaborate in diagnosing such cases

Experimental intravenous inoculation of Klebsiella rhinoscleromatis bacilli in albino rats: a histopathological and bacteriological study.

Scleroma, chronic specific granuloma of the nose and upper respiratory tract, is endemic in Egypt and many other countries. The exact pathogenesis of the disease as regards the aetiological role of Klebsiella rhinoscleromatis is contradictory. This work investigated the effect of experimental intravenous injection of K. rhinoscleromatis in albino rats to demonstrate that the micro-organism can fulfil Koch's postulates. Micro-organisms were isolated from biopsy specimens taken from nasal lesions of 10 patients in the granulomatous stage of scleroma. Specimens were subjected to bacteriological and histopathological examinations to confirm the diagnosis. A 100 microl volume of freshly prepared bacterial inoculum containing 10(8) cfu/ml was injected weekly in the tail vein of each of 30 albino rats for 5 consecutive weeks. Biopsy specimens were taken from sacrificed animals and subjected to bacteriological and histopathological examinations. Positive histopathological diagnosis of scleroma was reported in the nose of 66.7% of rats, the larynx of 46.7%, the lungs of 26.7% and liver of 20% of rats. Bacteriological techniques were successful in revealing K. rhinoscleromatis from the nose of 36.7% of rats, the larynx of 30% and the lungs of 20% of rats. Various techniques were carried out to demonstrate the micro-organisms in tissue sections. Two histochemical stains for bacteria were employed: silver and Periodic Acid Schiff (PAS) stains. Immunoperoxidase technique using Klebsiella capsular type 3 antiserum was applied. It gave positive results in 66.7% of the 6 stained liver sections in spite of negative bacteriological cultures. The histiocytic nature of the Mikulicz cells was confirmed using alpha-1 antitrypsin, an immunohistochemical marker of histiocytes, and by studying the ultrastructural features of Mikulicz cells using the transmission electron microscope.