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Neutrophil gelatinase-associated lipocalin (Ngal, 24p3, SIP24, lipocalin 2, or siderocalin) was originally purified from neutrophils, but with unknown function. Recently, it was identified that Ngal activates nephron formation in the embryonic kidney, is rapidly and massively induced in renal failure and possesses kidney-protective activity. We would like to propose that blood, urine, and kidney Ngal levels are the real-time indicators of active kidney damage, rather than one of many markers of functional nephron number (as Forest Fire Theory). Ngal is a novel iron-carrier protein exerting pleiotropic actions including the upregulation of epithelial marker E-cadherin expression, opening an exciting field in cell biology.

Urinary neutrophil gelatinase-associated lipocalin (Ngal or lipocalin 2) is a very early and sensitive biomarker of kidney injury. Here we determined the origin and time course of Ngal appearance in several experimental and clinically relevant renal diseases. Urinary Ngal levels were found to be markedly increased in lipoatrophic- and streptozotocin-induced mouse models of diabetic nephropathy. In the latter mice, the angiotensin receptor blocker candesartan dramatically decreased urinary Ngal excretion. The reabsorption of Ngal by the proximal tubule was severely reduced in streptozotocin-induced diabetic mice, but upregulation of its mRNA and protein in the kidney was negligible, compared to those of control mice, suggesting that increased urinary Ngal was mainly due to impaired renal reabsorption. In the mouse model of unilateral ureteral obstruction, Ngal protein synthesis was dramatically increased in the dilated thick ascending limb of Henle and N was found in the urine present in the swollen pelvis of the ligated kidney. Five patients with nephrotic syndrome or interstitial nephritis had markedly elevated urinary Ngal levels at presentation, but these decreased in response to treatment. Our study shows that the urinary Ngal level may be useful for monitoring the status and treatment of diverse renal diseases reflecting defects in glomerular filtration barrier, proximal tubule reabsorption, and distal nephrons.

To assess whether biomarkers of systemic inflammation are associated with HIV acquisition or with the timing of ART initiation (“immediate”, at diagnosis, versus “deferred”, at 24 weeks post-diagnosis) in men-who-have-sex-with-men (MSM) and transgender women, we conducted a retrospective study comparing inflammatory biomarkers in participants’ specimens collected before infection and after ≥2 years of effective ART. We measured biomarkers in four longitudinally collected plasma, including two specimens collected from each participant before and two after HIV acquisition and confirmed ART-suppression. Biomarkers were quantified by enzyme-linked immuno-assay or Meso Scale Discovery. When evaluating systematic variation in these markers over time, we found that multiple biomarkers consistently varied across participants’ two pre-infection or two post-ART-suppression specimens. Additionally, we compared changes in biomarkers after vs before HIV acquisition. Across 47 participants, the levels of C-reactive protein (CRP), monocyte chemo-attractant protein-1, tumor necrosis factor-α and interferon gamma-induced protein-10 significantly increased while leptin and lipopolysaccharide binding protein (LBP) significantly decreased following HIV infection. Randomization to deferred-ART initiation was associated with greater increases in CRP and no decrease in LBP. Acquisition of HIV appeared to induce systemic inflammation, with elevation of biomarkers previously associated with infections and cardiovascular disease. Initiation of ART during the early weeks of infection tempered the increase in pro-inflammatory biomarkers compared to delaying ART for ~24 weeks after HIV diagnosis. These findings provide insight into potential mediators by which immediate-ART initiation improves health outcomes, perhaps because immediate-ART limits the size of the HIV reservoir or limits immune dysregulation that in turn trigger systemic inflammation.

This study aims to assess in residual periodontal pockets the clinical, microbiological, and local biological effects of antimicrobial photodynamic therapy (PDT), delivered after ultrasonic instrumentation either once or twice in a 1-week interval. A single center, three-arm randomized longitudinal study was carried out for 6 months. Twenty-eight systemically healthy patients on periodontal maintenance with residual pockets (pocket depth (PD) ≥5 mm, clinical attachment loss ≥2 mm, and bleeding upon probing (BOP+)) were included. Residual pockets on three teeth, separated from each other by at least two other teeth, served as study sites. After ultrasonic debridement, they were randomly assigned to either PDT delivered twice within 1 week (group A), PDT delivered only once (group B), or sham treatment without activating the laser (group C). Methylene blue was applied with a blunt irrigator tip into the pockets. Sites were irradiated with laser light at a wavelength of 670 nm using a light-diffusing tip introduced into the pocket. Initial PD was 5.9 ± 0.9, 6.3 ± 1.3, and 6.3 ± 1.5 mm in groups A, B, and C, respectively, differences being nonsignificant. PD was significantly reduced in all groups. At month 3, PD was significantly lower in groups A (2.9 ± 1.1 mm; p  = 0.04) and B (2.8 ± 1.1 mm; p  = 0.03) compared to group C (3.5 ± 1.2 mm). At month 6, none of the sites in group A had persisting pockets PD >4 mm and BOP+, whereas two sites in group B and four sites in group C stayed in this category. Detection frequencies of the studied microorganisms at >1,000 and >100.000 cells/ml did not change significantly from baseline to months 3 or 6 in any group. A significant overall decrease was observed from baseline to month 6 for C-reactive protein, serum amyloid A, fibrinogen, procalcitonin, and α-2 macroglobulin. When looking at the groups separately, C-reactive protein was significantly lower only if the laser had been activated twice ( p  < 0.05). Other differences between groups were not significant. A single or double episodes of PDT had some additional benefit over ultrasonic instrumentation alone.

To explore a potential link between resistance exercise and the gut‐brain axis, this study examined the impact of resistance exercise on intestinal permeability, as indicated by lipopolysaccharide binding protein (LBP), and mood state in healthy adults. Sedentary participants (n = 20; 39.5 ± 12.1 y; 27.4 ± 5.3 kg/m2) were randomly assigned to the resistance exercise (REX) or wait‐listed control (CON) groups. REX participants strength trained 3× weekly (advancing from 45%–55% to 70%–80% 1RM for 3–4 sets over 8 weeks). Strength testing, evaluation of mood states, and collection of fasting blood occurred at baseline and weeks 4 and 8. At baseline, LBP concentrations were inversely correlated to all strength measures (r range: −0.48 to −0.57; p < 0.05). The gain in total strength [(split squat left + right)/2 + bench press] was 45% higher for REX versus CON participants (p = 0.019), and serum LBP concentrations fell 16% for REX participants and rose 9% in CON participants (p = 0.014). Mood was significantly improved by resistance training versus control (but this improvement was not related to changes in LBP; r = −0.001). These findings support a role for resistance exercise in improving mood state and intestinal barrier function, but more research is warranted to further explore the effects of resistance training on the gut‐brain axis.

This study aimed to determine whether published pharmacokinetic (PK) models can adequately predict the PK profile of imatinib in a new indication, such as coronavirus disease 2019 (COVID‐19). Total (bound + unbound) and unbound imatinib plasma concentrations obtained from 134 patients with COVID‐19 participating in the CounterCovid study and from an historical dataset of 20 patients with gastrointestinal stromal tumor (GIST) and 85 patients with chronic myeloid leukemia (CML) were compared. Total imatinib area under the concentration time curve (AUC), maximum concentration (Cmax) and trough concentration (Ctrough) were 2.32‐fold (95% confidence interval [CI] 1.34–3.29), 2.31‐fold (95% CI 1.33–3.29), and 2.32‐fold (95% CI 1.11–3.53) lower, respectively, for patients with CML/GIST compared with patients with COVID‐19, whereas unbound concentrations were comparable among groups. Inclusion of alpha1‐acid glycoprotein (AAG) concentrations measured in patients with COVID‐19 into a previously published model developed to predict free imatinib concentrations in patients with GIST using total imatinib and plasma AAG concentration measurements (AAG‐PK‐Model) gave an estimated mean (SD) prediction error (PE) of −20% (31%) for total and −7.0% (56%) for unbound concentrations. Further covariate modeling with this combined dataset showed that in addition to AAG; age, bodyweight, albumin, CRP, and intensive care unit admission were predictive of total imatinib oral clearance. In conclusion, high total and unaltered unbound concentrations of imatinib in COVID‐19 compared to CML/GIST were a result of variability in acute phase proteins. This is a textbook example of how failure to take into account differences in plasma protein binding and the unbound fraction when interpreting PK of highly protein bound drugs, such as imatinib, could lead to selection of a dose with suboptimal efficacy in patients with COVID‐19.

OBJECTIVE: To assess the additional effect of sudden visceral fat reduction by omentectomy on metabolic syndrome, acute-phase reactants, and inflammatory mediators in patients with grade III obesity (G-III O) undergoing laparoscopic Roux-en-Y gastric bypass (LRYGB). RESEARCH DESIGN AND METHODS: Twenty-two patients were randomized into two groups, LRYGB alone or with omentectomy. Levels of interleukin-6, C-reactive protein, tumor necrosis factor-α, leptin, adiponectin, glucose, total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides, as well as clinical characteristics, were evaluated before surgery and at 1, 3, 6, and 12 months after surgery. Results were compared between groups. RESULTS: Baseline characteristics were comparable in both groups. Mean operative time was significantly higher in the group of patients who underwent omentectomy (P < 0.001). Median weight of the omentum was 795 ± 341 g. In one patient, a duodenal perforation occurred at the time of omentectomy. BMI, blood pressure, glucose, total cholesterol, LDL, and triglycerides significantly improved in both groups at 1, 3, 6, and 12 months of follow-up when compared with basal values. However, there were no consistent statistically significant differences among the groups in terms of metabolic syndrome components, acute-phase reactants, and inflammatory mediators. CONCLUSIONS: Omentectomy does not have an ancillary short-term significant impact on the components of metabolic syndrome and does not induce important changes in the inflammatory mediators in patients undergoing LRYGB. Operative time is more prolonged when omentectomy is performed.

Hypercortisolemia has been suggested as a primary hormonal mediator of whole-body catabolism following severe burn injury. Ketoconazole, an anti-fungal agent, inhibits cortisol synthesis. We, therefore, studied the effect of ketoconazole on post-burn cortisol levels and the hyper-catabolic response in a prospective randomized trial (block randomization 2:1). Fifty-five severely burned pediatric patients with >30% total body surface area (TBSA) burns were enrolled in this trial. Patients were randomized to receive standard care plus either placebo (controls, n = 38) or ketoconazole (n = 23). Demographics, clinical data, serum hormone levels, serum cytokine expression profiles, organ function, hypermetabolism measures, muscle protein synthesis, incidence of wound infection sepsis, and body composition were obtained throughout the acute hospital course. Statistical analysis was performed using Fisher's exact test, Student's t-test, and parametric and non-parametric two-way repeated measures analysis of variance where applicable. Patients were similar in demographics, age, and TBSA burned. Ketoconazole effectively blocked cortisol production, as indicated by normalization of the 8-fold elevation in urine cortisol levels [F(1, 376) = 85.34, p<.001] with the initiation of treatment. However, there were no significant differences in the inflammatory response, acute-phase proteins, body composition, muscle protein breakdown or synthesis, or organ function between groups. Both groups were markedly hypermetabolic and catabolic throughout the acute hospital stay. Normalization of hypercortisolemia with ketoconazole therapy had no effect on whole-body catabolism or the post-burn inflammatory or hypermetabolic response, suggesting that hypercortisolemia does not play a central role in the post-burn hypermetabolic catabolic response. ClinicalTrials.gov NCT00675714; and NCT00673309.

Background Between 2 and 8 weeks before surgery, most bariatric surgery groups establish strict dietary treatments with a total caloric intake of less than 1,000 kcal/day in order to maximize weight loss during this period of time. Methods A prospective randomized clinical trial of all the patients undergoing laparoscopic sleeve gastrectomy (LSG) was performed. Patients were randomly assigned into 3 groups: those patients receiving a preoperative regular diet of 900 kcal/day (group 1), those receiving a preoperative balanced energy high-protein formula (group 2) and those receiving preoperative Immunonutrition (group 3). Preoperative weight loss, postoperative pain, complications and analytical acute phase reactants were investigated. Results Sixty patients were included in the study, 20 in each group. Preoperative excess weight loss was 7.7 % in group 1, 12.3 % in group 2 and 15.3 % in group 3 ( p  = 0.014). Median postoperative pain was 3.5 in group 1, 3 in group 2 and 2 in group 3 ( p  = 0.048). C-reactive protein determined 24 h after surgery was significantly lower in group 3 than in the other groups. AST and ALT values were significantly lower in group 3 than in the other groups, without significant differences between groups 1 and 2. Conclusions Preoperative diet with Immunonutrition formulas during 2 weeks achieves a greater preoperative weight loss, lower postoperative pain and lower values of CRP and liver enzymes than high-protein formulas or regular diet, all of them with similar caloric intake.

Purpose Interruption of renal blood flow is often necessary during nephron sparing surgery (NSS) and can induce renal injury. This study examines whether tadalafil, a phosphodiesterase-5 (PDE-5) inhibitor and well-known vasodilator, exerts nephroprotective effects in patients undergoing NSS. Methods This non-randomized study included 49 patients with enhancing solid renal mass. All patients were subjected to open NSS during which clamping the renal artery was performed. Twenty-two patients were pretreated with tadalafil 1 day prior NSS and 2 days following surgery. The other 27 patients underwent the same surgical procedure but did not receive tadalafil (controls). Urine samples were collected before surgery and following renal pedicle clamp removal. Urine levels of NGAL and KIM-1, two novel biomarkers for acute kidney injury (AKI), were determined. Results Clamping the renal artery induced kidney dysfunction as reflected by increases in urinary NGAL and KIM-1 in all participants. These increases in urinary NGAL and KIM-1 excretion were evident 1 h after renal ischemia and lasted for 72 and 24 h, respectively. Pretreatment with tadalafil reduced the absolute urinary excretion of KIM-1, but not of NGAL. Although the incidence of AKI was comparable between tadalafil-treated and untreated NSS subjects, the elevation in serum creatinine (SCr) was significantly attenuated in tadalafil-treated group as compared with NSS controls. Conclusions Tadalafil exerts nephroprotective effects in AKI following NSS, as was evident by reduced urinary excretion of KIM-1 and attenuation of SCr elevation. Carefully controlled large clinical studies are needed before defining the role of PDE-5 inhibition therapy in these patients.