Pre-clinical evaluation of 99mTc-labeled chalcone derivative for amyloid-ß imaging post-head trauma.

Aß42 plaque formation is one of the preliminary pathologic events that occur post traumatic brain injury (TBI) which is also among the most noteworthy hallmarks of AD. Their pre symptomatic detection is therefore vital for better disease management. Chalcone-picolinic acid chelator derivative, 6-({[(6-carboxypyridin-2-yl)methyl](2-{4-[(2E)-3-[4-(dimethyl amino)phenyl]prop-2-enoyl]phenoxy}ethyl)amino}methyl)pyridine-2-carboxylic acid, Py-chal was synthesized to selectively identify amyloid plaques formed post head trauma using SPECT imaging by stable complexation to 99mTc with > 97% efficiency without compromising amyloid specificity. The binding potential of the Py-chal ligand to amyloid plaques remained high as confirmed by in vitro binding assay and photophysical spectra. Further, the Py-chal complex stained amyloid aggregates in the brain sections of rmTBI mice model. In vivo scintigraphy in TBI mice model displayed high uptake followed by high retention while the healthy rabbits displayed higher brain uptake followed by a rapid washout attributed to absence of amyloid plaques. Higher uptake in brain of TBI model was also confirmed by ex vivo biodistribution analysis wherein brain uptake of 3.38 ± 0.2% ID/g at 2 min p.i. was observed for TBI mice model. This was followed by prolonged retention and more than twofold higher activity as compared to sham mice brain. This preliminary data suggests the specificity of the radiotracer for amyloid detection post head trauma and applicability of 99mTc labeled Py-chal complex for TBI-induced ß-amyloid SPECT imaging.

Efficacy and Toxicity of Calcitonin Treatment in Children with Cherubism: A Single-Center Cohort Study.

Cherubism is a rare autosomal dominant disease characterized by expansile osteolytic jawbone lesions. The effect and safety of off-label calcitonin treatment during the progressive phase of the disease are not well described. In this retrospective study, we present data on the radiological response and adverse effects of subcutaneously administered calcitonin in a cohort of nine cherubism children (three female, six male). Two of the nine patients underwent two separate treatment courses with a significant off-treatment interval in between; therefore, a total of 11 treatment courses with a mean duration of 17.9 months (range <1 to 35, SD 10.8) were studied. To measure the response, the cumulative volume of cherubism lesions was calculated from available three-dimensional imaging. The primary outcome was the change in the volume of lesions during calcitonin treatment and only assessed for the eight treatment courses with a minimal duration of 6 months. A statistically significant reduction in the mean cumulative volume of lesions was seen regardless of treatment duration. Average volume reduction was highest in the first half year of treatment, with a gradual, ongoing reduction thereafter. For the secondary outcome, the change in the cumulative volume of lesions after treatment cessation was assessed for the seven treatment courses with follow-up imaging available. After six of these seven treatment courses, the cumulative volume increased again but remained undoubtedly smaller than the initial volume at the start of therapy. Adverse effects were assessed for all 11 treatment courses and occurred in 73% of them. Most adverse effects were mild and low grade, with the most severe being one grade 3 symptomatic hypocalcemia requiring hospitalization and early treatment termination. Calcitonin treatment seems effective and tolerable in treating actively progressing cherubism in children. However, further research is required to better understand the pharmacological treatment of cherubism, including also other drugs, dosing, and protocols. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Mitochondrial uncoupler DNP induces coexistence of dual-state hyper-energy metabolism leading to tumor growth advantage in human glioma xenografts.

Introduction: Cancer bioenergetics is an essential hallmark of neoplastic transformation. Warburg postulated that mitochondrial OXPHOS is impaired in cancer cells, leading to aerobic glycolysis as the primary metabolic pathway. However, mitochondrial function is altered but not entirely compromised in most malignancies, and that mitochondrial uncoupling is known to increase the carcinogenic potential and modifies treatment response by altering metabolic reprogramming. Our earlier study showed that transient DNP exposure increases glycolysis in human glioma cells (BMG-1). The current study investigated the persistent effect of DNP on the energy metabolism of BMG-1 cells and its influence on tumor progression in glioma xenografts. Methods: BMG-1 cells were treated with 2,4-dinitrophenol (DNP) in-vitro, to establish the OXPHOS-modified (OPM-BMG) cells. Further cellular metabolic characterization was carried out in both in-vitro cellular model and in-vivo tumor xenografts to dissect the role of metabolic adaptation in these cells and compared them with their parental phenotype. Results and Discussion: Chronic exposure to DNP in BMG-1 cells resulted in dual-state hyper-energy metabolism with elevated glycolysis++ and OXPHOS++ compared to parental BMG-1 cells with low glycolysis+ and OXPHOS+. Tumor xenograft of OPM-BMG cells showed relatively increased tumor-forming potential and accelerated tumor growth in nude mice. Moreover, compared to BMG-1, OPM-BMG tumor-derived cells also showed enhanced migration and invasion potential. Although mitochondrial uncouplers are proposed as a valuable anti-cancer strategy; however, our findings reveal that prolonged exposure to uncouplers provides tumor growth advantage over the existing glioma phenotype that may lead to poor clinical outcomes.

Anti-tumorigenic action of 2-[piperidinoethoxyphenyl]-3-[4-hydroxyphenyl]-2H-benzo(b)pyran: evidence for involvement of GPR30/EGFR signaling pathway.

OBJECTIVE: The aim of the present study was to investigate the effect of non-steroidal, pure antiestrogenic benzopyran derivative i.e., 2-[piperidinoethoxyphenyl]-3-[4-hydroxyphenyl]-2H-benzo(b)pyran (K-1) on the growth of human endometrial cancer cells in vivo and in vitro and to elucidate its mechanism of action. METHODS: Cell proliferation was assayed by measuring the incorporation of 5'-bromo-2'-deoxyuridine in Ishikawa and primary endometrial cancer cells. The expression of proliferation and apoptotic markers was analyzed by immunoblotting. The effect of K-1 on GPR30-regulated proteins was analyzed by ELISA and by immunoblotting. Nude mice bearing subcutaneous implanted-Ishikawa tumors, were treated for 14days with K-1 (200µg/kg body weight/day/orally). The proliferation markers, GPR30-regulated proteins and apoptotic markers were analyzed by immunoblotting in tumor xenograft. The apoptotic effect of compound K-1 was determined by TUNEL assay. RESULTS: Compound K-1 inhibited proliferation of endometrial adenocarcinoma cells and decreased the expression of proliferation markers. It caused apoptosis by increasing the expression of apoptotic markers (NOXA, PUMAα) and reducing the expression of p-CREB and BclxL. Compound interfered with GPR30-regulated-EGFR activation, decreased p-ERK, p-c-jun, c-fos, cyclinD1 and c-myc expression. Treatment of tumor-bearing mice with K-1 resulted in a significant decrease in tumor volume and weight. Decreased expression of p-ERK and its downstream molecules and increased expression of apoptotic markers were observed in tumor in K-1 treated animals. CONCLUSION: Findings suggest the potent inhibitory effect of compound K-1 on endometrial cancer cellular growth (in-vitro) and on tumor size (in-vivo) which is mediated at least, in part, by interference with GPR30-signaling.

Timing of arthroplasty, what is the influence of nocturnal pain and pain at rest on the outcome?

PURPOSE: The purpose of this study was to investigate whether nocturnal pain and pain at rest preoperatively influence the satisfaction in patients after joint arthroplasty. The second research question is whether subjective outcome (VAS/WOMAC) after hip (THA) or knee arthroplasty (TKA) differs in patients with or without nocturnal pain and pain at rest preoperatively compared to those who do not. METHODS: A consecutive group of 189 TKAs and 189 THAs was evaluated. The influence of pain at rest and nocturnal pain preoperatively on the outcome was evaluated by means of a one-way ANOVA. Outcome measurements used were WOMAC, VAS pain and VAS Satisfaction. RESULTS: The results show that satisfaction at follow up was not influenced by the presence of nocturnal pain or pain at rest preoperatively. The presence of nocturnal pain and pain at rest preoperatively did result in a poorer WOMAC pain score WOMAC physical impairment score and a higher VAS pain at rest and activity after surgery for both THA and TKA. CONCLUSION: The results show that the presence of pain at night and pain at rest in symptomatic osteoarthritic patients results in worse VAS and WOMAC scores, but with similar amounts of satisfaction at follow up.

The validation of the visual analogue scale for patient satisfaction after total hip arthroplasty.

INTRODUCTION: Patient satisfaction becomes more important in our modern health care system. The assessment of satisfaction is difficult because it is a multifactorial item for which no golden standard exists. One of the potential methods of measuring satisfaction is by using the well-known visual analogue scale (VAS). In this study, we validated VAS for satisfaction. PATIENT AND METHODS: In this prospective study, we studied 147 patients (153 hips). The construct validity was measured using the Spearman correlation test that compares the satisfaction VAS with the Harris hip score, pain VAS at rest and during activity, Oxford hip score, Short Form 36 and Western Ontario McMaster Universities Osteoarthritis Index. The reliability was tested using the intra-class coefficient. RESULTS: The Pearson correlation test showed correlations in the range of 0.40-0.80. The satisfaction VAS had a high correlation between the pain VAS and Oxford hip score, which could mean that pain is one of the most important factors in patient satisfaction. The intra-class coefficient was 0.95. CONCLUSIONS: There is a moderate to mark degree of correlation between the satisfaction VAS and the currently available subjective and objective scoring systems. The intra-class coefficient of 0.95 indicates an excellent test-retest reliability. The VAS satisfaction is a simple instrument to quantify the satisfaction of a patient after total hip arthroplasty. In this study, we showed that the satisfaction VAS has a good validity and reliability.

Subjective alveolar nerve function after bilateral sagittal split osteotomy or distraction osteogenesis of mandible.

PURPOSE: The present retrospective cohort study compared the subjective inferior alveolar nerve (IAN) function after distraction osteogenesis (DOG) and bilateral sagittal split osteotomy (BSSO) in mandibular advancement surgery. MATERIALS AND METHODS: Treatment consisted of correction of a retrognathic mandible using DOG (30 patients) or BSSO (35 patients). Subjective IAN function was recorded using a questionnaire 1 year after surgery. A total of 130 IANs were evaluated. RESULTS: In 37 nerves (28.5%), an IAN disturbance was observed. In this group of 37 nerves, BSSO had been performed in 26 (70.3%) and DOG in 11 (29.7%). After eliminating confounders (eg, age, amount of advancement, gender), no significant difference (odds ratio 0.652, 95% confidence interval 0.221 to 1.920) was found. Age was significantly related to subjective IAN disturbances for women but not for men. This was seen in women older than 22 years and increased for women older than 36 years to an odds ratio of 22.8 (95% confidence interval 2.580 to 201.488). Satisfaction also correlated with age, independent of gender. CONCLUSION: No difference was found in subjective IAN disturbances after 1 year between DOG and BSSO for lengthening the mandible.

Surgeon's expectations do not predict the outcome of a total knee arthroplasty.

INTRODUCTION: It is fascinating for both the patient and the surgeon to predict the outcome of a TKA at an early stage. Satisfaction after TKA is primarily determined by the preoperative expectations of the patient. The purpose of this study was to investigate if the peri-operative expectations of the surgeon predicted the outcome of a TKA. PATIENTS AND METHODS: A prospective study of 53 primary TKAs was performed. Preoperatively, the surgeon described the assessment of the difficulty of the TKA on a VAS. Immediately postoperative, the surgeon gave his satisfaction VAS about the procedure. After 1 year the surgeon's satisfaction VAS, the patient's satisfaction VAS and the KSCRS were determined. RESULTS: The Spearman's correlation coefficients between the preoperative difficulty assessment, the immediate postoperative satisfaction and the outcome measurements after 1 year were all very poor (-0.01 to 0.23). CONCLUSIONS: The outcome of a TKA depends on multiple factors. Both the surgeon's preoperative assessment of the difficulty and the surgeon's immediate postoperative satisfaction do not independently predict the outcome of a TKA.

Effect of N-acetylcysteine on human diaphragm strength and fatigability.

Free radical injury is believed to be important in diaphragm dysfunction. N-Acetylcysteine (NAC) is a potent free radical scavenger shown in animal models to attenuate diaphragm fatigue; however, its effects on human diaphragm function are unknown. We assessed diaphragm function by electrophrenic twitch stimulation (PdiT) and twitch occlusion (to yield Pdimax) in four healthy subjects 35 +/- 3 yr of age (mean +/- SD). We intravenously administered NAC (150 mg/kg in 250 ml D5W) or placebo (CON) (250 ml D5W) in a randomized manner after subjects were premedicated with antihistamines. There were no significant side effects with the infusion. After infusion, we measured baseline Pdimax and PdiT at FRC. Diaphragm fatigue was then induced by subjects breathing through an inspiratory resistive load. Pdimax and PdiT were then measured at 15 to 30 min and 1, 2, 3, 4, and 20-25 h after fatigue. Times to fatigue were 13 +/- 4 min (CON) and 21 +/- 6 min (NAC) (p = 0.04). At 15 min after fatigue, PdiT was reduced to 40% (CON) compared with 30% (NAC) initial PdiT value (p = 0.05). Other twitch characteristics (maximal rate of relaxation and maximal contraction rate) were reduced to a greater degree after placebo compared with NAC. There were no significant differences in the rate of recovery between CON and NAC. Pdimax at 30 min after fatigue was significantly greater with NAC; however, at 1 h after fatigue, Pdimax for CON and NAC were not different, suggesting similar rates of recovery in high-frequency fatigue. These data suggest that NAC may attenuate low-frequency human diaphragm fatigue.

Involvement of calcium, calmodulin and protein phosphorylation in morphogenesis of Candida albicans.

N-Acetyl-D-glucosamine-induced germ tube formation in Candida albicans at 37 degrees C was accompanied by an increase in the rate of protein phosphorylation. The calmodulin antagonist trifluoperazine and the Ca2+ ionophore A23187, which inhibited germ tube formation, also reduced the rate of phosphorylation. The rate of phosphorylation was also reduced when cells were incubated at 25 degrees C, which favoured yeast-phase growth. Two-dimensional SDS-PAGE analysis of phosphoproteins from germ-tube-forming and yeast cells revealed two germ-tube-specific and three yeast-specific phosphoproteins. Germ tubes and hyphae had more calmodulin activity than yeast cells, irrespective of the germ-tube-inducing condition used. As a first step towards understanding the inhibitory effect of trifluoperazine on germ tube formation, calmodulin from C. albicans was purified to homogeneity. It was heat stable, and displayed a pronounced Ca2(+)-induced shift in electrophoretic mobility.