Kimura Disease Presenting with Buccal Mass: A Case Report and Literature Review

A 52-year-old man with a 2-year history of left buccal swelling was admitted to our department. An elastic hard oral mass was palpated under the intact buccal mucosa. A CT scan with enhancement revealed a solid mass measuring 2.0 × 1.5 × 1.3 cm between the left masseter muscle and the maxilla. Laboratory examination showed elevated peripheral blood eosinophil count of 1070/μL (12.3%) and serum immunoglobulin (Ig)E level of 1374 IU/mL. Histologic examination of transorally excised mass revealed lymphoid follicular hyperplasia with reactive germinal centers and eosinophilic infiltration with eosinophilic micro-abscesses in the germinal centers. Abundant IgE deposition in a reticular fashion was observed in the germinal centers and c-kit positive mast cells was observed in the paracortical area in the excised mass. The patient was diagnosed with Kimura disease (KD) and treated with oral prednisolone, tapering from 10 mg/day for approximately 8 months. Eosinophil count and serum IgE level decreased to 435/μL (5%) and 520 IU/dL, respectively. He is free from symptoms at the time of this submission. KD, a rare, benign, and chronic inflammatory disorder, occurs predominantly in young male adults in Asia. Patients with KD who presents with buccal mass are relatively rare. Immunohistologic analyses suggested that an allergic reaction played an important role in the etiology of KD in this case.     

Genetic Evidence for a Normal-Weight “Metabolically Obese” Phenotype Linking Insulin Resistance,Hypertension, Coronary Artery Disease,and Type 2 Diabetes

The mechanisms that predispose to hypertension, coronary artery disease (CAD), and type 2 diabetes (T2D) in individuals of normal weight are poorly understood. In contrast, in monogenic primary lipodystrophy—a reduction in subcutaneous adipose tissue—it is clear that it is adipose dysfunction that causes severe insulin resistance (IR), hypertension, CAD, and T2D. We aimed to test the hypothesis that common alleles associated with IR also influence the wider clinical and biochemical profile of monogenic IR. We selected 19 common genetic variants associated with fasting insulin–based measures of IR. We used hierarchical clustering and results from genome-wide association studies of eight nondisease outcomes of monogenic IR to group these variants. We analyzed genetic risk scores against disease outcomes, including 12,171 T2D cases, 40,365 CAD cases, and 69,828 individuals with blood pressure measurements. Hierarchical clustering identified 11 variants associated with a metabolic profile consistent with a common, subtle form of lipodystrophy. A genetic risk score consisting of these 11 IR risk alleles was associated with higher triglycerides (β = 0.018; P = 4 × 10⁻²⁹), lower HDL cholesterol (β = −0.020; P = 7 × 10⁻³⁷), greater hepatic steatosis (β = 0.021; P = 3 × 10⁻⁴), higher alanine transaminase (β = 0.002; P = 3 × 10⁻⁵), lower sex-hormone-binding globulin (β = −0.010; P = 9 × 10⁻¹³), and lower adiponectin (β = −0.015; P = 2 × 10⁻²⁶). The same risk alleles were associated with lower BMI (per-allele β = −0.008; P = 7 × 10⁻⁸) and increased visceral-to-subcutaneous adipose tissue ratio (β = −0.015; P = 6 × 10⁻⁷). Individuals carrying ≥17 fasting insulin–raising alleles (5.5% population) were slimmer (0.30 kg/m²) but at increased risk of T2D (odds ratio [OR] 1.46; per-allele P = 5 × 10⁻¹³), CAD (OR 1.12; per-allele P = 1 × 10⁻⁵), and increased blood pressure (systolic and diastolic blood pressure of 1.21 mmHg [per-allele P = 2 × 10⁻⁵] and 0.67 mmHg [per-allele P = 2 × 10⁻⁴], respectively) compared with individuals carrying ≤9 risk alleles (5.5% population). Our results provide genetic evidence for a link between the three diseases of the “metabolic syndrome” and point to reduced subcutaneous adiposity as a central mechanism.     

Platelet-rich plasma increases transforming growth factor-beta1 expression at graft-host interface following autologous osteochondral transplantation in a rabbit model

AIM: To explore the effect of platelet-rich plasma on protein expression patterns of transforming growth factor-beta1 (TGF-β1) in cartilage following autologous osteochondral transplantation (AOT) in a rabbit knee cartilage defect model.METHODS: Twelve New Zealand white rabbits received bilateral AOT. In each rabbit, one knee was randomized to receive an autologous platelet rich plasma (PRP) injection and the contralateral knee received saline injection. Rabbits were euthanized at 3, 6 and 12 wk post-operatively. Articular cartilage sections were stained with TGF-β1 antibody. Histological regions of interest (ROI) (left, right and center of the autologous grafts interfaces) were evaluated using MetaMorph. Percentage of chondrocytes positive for TGF-β1 was then assessed.RESULTS: Percentage of chondrocytes positive for TGF-β1 was higher in PRP treated knees for selected ROIs (left; P = 0.03, center; P = 0.05) compared to control and was also higher in the PRP group at each post-operative time point (P = 6.6 × 10^-4, 3.1 × 10^-4 and 7.3 × 10^-3 for 3, 6 and 12 wk, respectively). TGF-β1 expression was higher in chondrocytes of PRP-treated knees (36% ± 29% vs 15% ± 18%) (P = 1.8 × 10^-6) overall for each post-operative time point and ROI.CONCLUSION: Articular cartilage of rabbits treated with AOT and PRP exhibit increased TGF-β1 expression compared to those treated with AOT and saline. Our findings suggest that adjunctive PRP may increase TGF-β1 expression, which may play a role in the chondrogenic effect of PRP in vivo.     

Characterization of a Novel Model of Lumbar Ligamentum Flavum Hypertrophy in Bipedal Standing Mice

ObjectiveTo explore the main causes of hypertrophied ligamentum flavum (HLF) and the possibility of using bipedal standing mouse model to simulate the pathological changes in human HLF.MethodsThirty‐two 8‐week‐old C57BL/6 male mice were randomly assigned to the experimental group (n = 16) and control group (n = 16). In the experimental group, mice were induced to adopt a bipedal standing posture by their hydrophobia. The experimental mice were maintained bipedal standing for 8 h a day with an interval of 2 h to consume food and water. The control mice were placed in a similar environment without bipedal standing. Eight 18‐month‐old C57BL/6 male mice were compared to evaluate the LF degeneration due to aging factor. Three‐dimensional (3D) reconstruction and finite element models were carried out to analyze the stress and strain distribution of the mouse LF in sprawling and bipedal standing postures. Hematoxylin and Eosin (HE), Verhoeff‐Van Gieson (VVG), and immunohistochemistry (IHC) staining were used to evaluate the LF degeneration of mice and humans. RT‐qPCR and immunofluorescence analysis were used to evaluate the expressions of fibrosis‐related factors and inflammatory cytokines of COL1A1, COL3A1, α‐SMA, MMP2, IL‐1β, and COX‐2.ResultsThe von Mises stress (8.85 × 10⁻² MPa) and maximum principal strain (6.64 × 10⁻¹) in LF were increased 4944 and 7703 times, respectively, in bipedal standing mice. HE staining showed that the mouse LF area was greater in the bipedal standing 10‐week‐old group ([10.01 ± 2.93] × 10⁴ μm²) than that in the control group ([3.76 ± 1.87] × 10⁴ μm²) and 18‐month‐old aged group ([6.09 ± 2.70] × 10⁴ μm²). VVG staining showed that the HLF of mice (3.23 ± 0.58) and humans (2.23 ± 0.31) had a similar loss of elastic fibers and an increase in collagen fibers. The cell density was higher during the process of HLF in mice (39.63 ± 4.81) and humans (23.25 ± 2.05). IHC staining showed that the number of α‐SMA positive cells were significantly increased in HLF of mice (1.63 ± 0.74) and humans (3.50 ± 1.85). The expressions of inflammatory cytokines and fibrosis‐related factors of COL1A1, COL3A1, α‐SMA, MMP2, IL‐1β, and COX‐2 were consistently higher in bipedal standing group than the control group.ConclusionOur study suggests that 3D finite element models can help analyze the abnormal stress and strain distributions of LF in modeling mice. Mechanical stress is the main cause of hypertrophied ligamentum flavum compared to aging. The bipedal standing mice model can reflect the pathological characteristics of human HLF. The bipedal standing mice model can provide a standardized condition to elucidate the molecular mechanisms of mechanical stress‐induced HLF in vivo.     

Hyperhomocysteinemia and Hyperglycemia Induce and Potentiate Endothelial Dysfunction via μ-Calpain Activation

Plasma homocysteine (Hcy) levels are positively correlated with cardiovascular mortality in diabetes. However, the joint effect of hyperhomocysteinemia (HHcy) and hyperglycemia (HG) on endothelial dysfunction (ED) and the underlying mechanisms have not been studied. Mild (22 µmol/L) and moderate (88 µmol/L) HHcy were induced in cystathionine β-synthase wild-type (Cbs^+/+) and heterozygous-deficient (Cbs^−/+) mice by a high-methionine (HM) diet. HG was induced by consecutive injection of streptozotocin. We found that HG worsened HHcy and elevated Hcy levels to 53 and 173 µmol/L in Cbs^+/+ and Cbs^−/+ mice fed an HM diet, respectively. Both mild and moderate HHcy aggravated HG-impaired endothelium-dependent vascular relaxation to acetylcholine, which was completely abolished by endothelial nitric oxide synthase (eNOS) inhibitor N^G-nitro-L-arginine methyl ester. HHcy potentiated HG-induced calpain activation in aortic endothelial cells isolated from Cbs mice. Calpain inhibitors rescued HHcy- and HHcy/HG-induced ED in vivo and ex vivo. Moderate HHcy- and HG-induced μ-calpain activation was potentiated by a combination of HHcy and HG in the mouse aorta. μ-Calpain small interfering RNA (μ-calpsiRNA) prevented HHcy/HG-induced ED in the mouse aorta and calpain activation in human aortic endothelial cells (HAECs) treated with DL-Hcy (500 µmol/L) and d-glucose (25 mmol) for 48 h. In addition, HHcy accelerated HG-induced superoxide production as determined by dihydroethidium and 3-nitrotyrosin staining and urinary 8-isoprostane/creatinine assay. Antioxidants rescued HHcy/HG-induced ED in mouse aortas and calpain activation in cultured HAECs. Finally, HHcy potentiated HG-suppressed nitric oxide production and eNOS activity in HAECs, which were prevented by calpain inhibitors or μ-calpsiRNA. HHcy aggravated HG-increased phosphorylation of eNOS at threonine 497/495 (eNOS-pThr497/495) in the mouse aorta and HAECs. HHcy/HG-induced eNOS-pThr497/495 was reversed by µ-calpsiRNA and adenoviral transduced dominant negative protein kinase C (PKC)β₂ in HAECs. HHcy and HG induced ED, which was potentiated by the combination of HHcy and HG via μ-calpain/PKCβ₂ activation–induced eNOS-pThr497/495 and eNOS inactivation.     

The Screening of Fixation‐Related Infection in Patients Undergoing Conversion Total Hip Arthroplasty after Failed Internal Fixation of Hip Fractures: A Single‐Central Retrospective Study

ObjectiveTo evaluate the diagnostic values of preoperative plasma fibrinogen and platelet count for screening fixation‐related infection (FRI) in patients undergoing conversion total hip arthroplasty (cTHA) after failed internal fixation of hip fractures.MethodThis was a single‐center retrospective study. Data were retrospectively analyzed for 435 patients who underwent cTHA in our hospital from January 2008 to September 2020. They were divided into infected (n = 30) and non‐infected groups (n = 405) according to the 2013 International Consensus Meeting (ICM) criteria. The diagnostic sensitivity and specificity of plasma fibrinogen and platelet count were determined using receiver operating characteristic (ROC) curves. Optimal predictive cutoffs of these two markers were determined based on the Youden index. In addition, the diagnostic value of preoperative serum C‐reactive protein (CRP) and erythrocyte sedimentation rate (ESR) for screening FRI were also evaluated based on the cutoffs recommended by the 2013 ICM Criteria. Finally, the diagnostic ability of various combinations of the plasma fibrinogen and platelet count as well as serum CRP and ESR was re‐assessed.ResultsThe numbers of patients with and without FRI were 30 (6.9%) and 405 (93.1%), respectively. Areas under the ROC curves were 0.770 for fibrinogen, 0.606 for platelet, 0.844 for CRP and 0.749 for ESR. The optimal predictive cutoff of fibrinogen was 3.73 g/L, which gave sensitivity of 60.0% and specificity of 90.5%. The optimal predictive cutoff for platelet was 241.5 × 10⁹/L, which gave sensitivity of 46.7% and specificity of 83.7%. The CRP gave sensitivity of 66.7% and specificity of 92.5% with the predetermined cutoff of 10 mg/L, while the ESR gave sensitivity of 67.5% and specificity of 72.4% % with the predetermined cutoff of 30 mm/h. The combination of CRP and ESR showed high specificity of 93.2% but low sensitivity of 66.7%, while the corresponding values for CRP with fibrinogen were satisfied both for sensitivity of 80.0% and specificity of 78.7%. The combination of these four biomarkers gave sensitivity of 73.3% and specificity of 85.7%.ConclusionPreoperative serum CRP, ESR, plasma fibrinogen and platelet count have low sensitivity on their own for screening FRI in patients, but the combination of CRP with fibrinogen shows promise for that.     

Lower-Dose Mepivacaine Plus Fentanyl May Improve Spinal Anesthesia for Knee Arthroscopy

Background

Previous work indicates that 30 mg isobaric mepivacaine 1.5% plus 10 μg fentanyl produces reliable anesthesia for knee arthroscopy with a more rapid recovery profile than 45 mg mepivacaine.

Questions/Purposes

This randomized controlled trial compared plain mepivacaine to three reduced doses of mepivacaine with 10 μg fentanyl for spinal anesthesia.

Methods

Following written informed consent, subjects undergoing outpatient knee arthroscopy were prospectively randomized into one of four groups: mepivacaine 37.5 mg (M37.5); mepivacaine 30 mg plus fentanyl 10 μg (M30/F10); mepivacaine 27 mg plus fentanyl 10 μg (M27/F10); and mepivacaine 24 mg plus fentanyl 10 μg (M24/F10). The spinal was evaluated by the blinded anesthetist and surgeon. In the post-anesthesia care unit, sensory and motor block resolution was assessed. Subjects rated their satisfaction with the overall experience.

Results

Group M30/F10 (n = 6) had two “fair” anesthetics, and group M27/F10 (n = 10) had one “fair” and one “inadequate” anesthetic. Both groups were eliminated from further enrollment per study protocol. The recovery profiles showed little difference between groups M37.5 and M30/F10, except for motor block resolution (median (25th percentile, 75th percentile): 171 (135, 195) and 128 (120, 135), respectively). Groups M27/F10 and M24/F10 demonstrated recovery profiles that were faster than group M37.5. Patient satisfaction was 10/10 for all groups.

Conclusions

Adding fentanyl 10 μg to a lower dose of mepivacaine 1.5% can lead to quicker recovery profiles. However, this advantage of a quicker recovery must be weighed against the likelihood of an incomplete anesthetic.

Electronic supplementary material

The online version of this article (doi:10.1007/s11420-015-9454-8) contains supplementary material, which is available to authorized users.     

Lumbar neuraxial procedures in thrombocytopenic patients across populations: A systematic review and meta-analysis

IntroductionThere is currently no consensus regarding the minimum threshold platelet count to ensure safe neuraxial procedures. Numerous reports describe the safe performance of lumbar punctures in severely thrombocytopenic patients but reports of neuraxial anesthetic procedures in thrombocytopenic patients are limited. To date, the focus on specific populations in contemporary reviews has failed to include any actual hematoma cases. This systematic review aggregates reported lumbar neuraxial procedures from diverse thrombocytopenic populations to best elucidate the risk of spinal epidural hematoma.MethodsMEDLINE, Embase, Cochrane, CINAHL databases were searched for articles about thrombocytopenic patients (<100,000 × 10⁶/L) who received a lumbar neuraxial procedure (lumbar puncture; spinal, epidural, or combined spinal-epidural analgesia/anesthesia; epidural catheter removal), whether spinal epidural hematoma occurred.ResultsOf 4167 articles reviewed, 131 met inclusion criteria. 7476 lumbar neuraxial procedures were performed without and 33 procedures with spinal epidural hematoma. Within the platelet count ranges of 1–25,000 × 10⁶/L, 26–50,000 × 10⁶/L, 51–75,000 × 10⁶/L, and 76–99,000 × 10⁶/L there were 14, 6, 9, and 4 spinal epidural hematomas, respectively. An infection point and narrow confidence intervals were observed near 75,000 × 10⁶/L or above, reflecting a low probability of spinal epidural hematoma in this sample. Of the 19 spinal epidural hematoma cases for which the onset of symptoms was reported, 18 (95%) were symptomatic within 48 h of the procedure.ConclusionsSpinal epidural hematoma in thrombocytopenic patients is rare. In this sample of patients, an inflection point and narrow confidence intervals are observed near a platelet count of 75,000 × 10⁶/L or above, reflecting an estimated low spinal epidural hematoma event rate with more certainty given a larger sample size and inclusion of spinal epidural hematoma cases. Thrombocytopenic patients should be monitored, particularly in the first 48 h, and educated about symptoms concerning for spinal epidural hematoma.     

Kasabach-Merritt syndrome: dangers of interferon and successful treatment with pentoxifylline

A girl aged 3 months presented with thrombocytopenia and bruising around a large vascular malformation of her posterior abdominal wall. Treatment was started with corticosteroids and platelet replacement, but with no improvement and a platelet count persistently less than 10 × 10⁹/L over 3 weeks, α-interferon was added. There was an immediate increase in bruising, a fall in platelet count, and an increase in platelet transfusion requirement until interferon was discontinued 11 days later. After a further week, the platelet count returned to the levels before interferon, but the patient did not develop any further symptoms. The platelet count remained low with no clinical change until pentoxifylline was started at the age of 15 months. The platelet count rose to 117 × 10⁹/L within 4 days and remained more than 100 × 10⁹/L thereafter. The patient is now 7 years old and has had no recurrence since stopping the pentoxifylline at the age of 5 years. Although thrombocytopenia is a recognized side effect of interferon therapy, this very dangerous complication has not been previously reported using interferon for the Kasabach-Merritt syndrome.     

Oxygen Cost During Treadmill Walking with Hip and Knee Immobilised

The aim of this study was to determine the effect of immobilising the knee and hip on the oxygen cost (ml·kg^-1·min^-1) to velocity relationship during treadmill walking. The study was a prospective experimental conducted in a Rehabilitation centre. Ten healthy individuals, five men and five women, with no gait abnormality participated. Following familiarisation five men and five women walked on a treadmill and selected their own, free “comfortable walking velocity ”(SSWS). Subjects then performed an incremental test at -60 to +60% of SSWS. Individuals later repeated the test with the knee and hip of one limb immobilised. Samples of expired air were measured at each velocity and the oxygen cost (ml·kg^-1·min^-1) to Froude number (Fr) relationship plotted (where calculation of Fr normalizes for subjects of differing leg length and acts as an index of velocity). There was a higher oxygen cost, and lower Fr at SSWS during immobilised (0.21 ± 0.03 ml·kg^-1·min^-1; Fr = 0.12 ± 0. 03) compared with free walking (0.16 ± 0.02 ml·kg^-1·min^-1; Fr = 0.18 ± 0.04) (p < 0. 01). Statistical analysis demonstrated that during immobilised walking an inverse fit (y = β₀ + β₁/x) and for free walking a cubic fit (y = β₀ + β₁x + β₂x² + β₃x³) best fitted the data. Hip and knee immobilisation increased the oxygen cost at SSWS and altered the oxygen cost to Fr relationship. The results have implications in selecting optimal walking velocities in individuals with impairments affecting mobility such as hemiplegic gait.

Key Points

• Walking with one limb immobilised requires greater energy cost than normal free walking.
• This has clinical implications when developing rehabilitation strategies for patients who mobility problems such as those with hemi paretic gait.

Key words: Froude number, oxygen cost, immobilisation, hip, knee, walking, hemiplegic gait     

Effect of Local Delivery of Vancomycin and Tobramycin on Bone Regeneration

ObjectiveA bone defect rat model was established to investigate the osteogenic effect of local delivery two antibiotics (vancomycin and tobramycin powder) on bone regeneration.MethodsTwenty‐four Sprague–Dawley (SD) male rats (6 to 8 weeks, 200 to 250 g) were used in this study. All these rats were randomly divided into four groups. Based on dose conversion between rat and human via body surface area, the rat dose of two antibiotics was 88μg/g and 176 μg/g for vancomycin and tobramycin, respectively. Con group (no antibiotic), Van group (vancomycin, 88 μg/g), Tob group (tobramycin 176 μg/g), and Van+Tob group (vancomycin 88μg/g combined with tobramycin 176 μg/g). A 5.0‐mm full‐thickness standardized mandibular bone defect was performed with a drill in each rat and different antibiotic powders were placed over the bone defect space, respectively. All these animals were sacrificed after 12 weeks post‐operation. The mandible bones were harvested for further radiographic and histologic analysis. The bone volume/total volume (BV/TV) ratio, bone volume (BV), and bone fractional area (BFA) in the defect area via micro‐computed tomography (μCT scanning) were further analyzed. Then, we performed a histological assessment via hematoxylin and eosin (H&E) and Masson''s trichrome staining to analyze bone regeneration and also analyze the number of osteoblasts per filed.ResultsThere were no postoperative deaths, signs of vancomycin‐related or tobramycin‐related toxicity, or signs of systemic illness in any of the four groups. All wounds healed well, and no complications or surgical site infection were observed in all rats. From the μCT scans analyses, there was less bone regeneration in the Van group than in the Con group (BV/TV: F = 64.29, R ² = 0.9602; P = 0.0052; BFA: F = 76.17, R ² = 0.9662, P = 0.0007; BV: F = 194.4, R ² = 0.9865, P = 0.0022). However, when the tobramycin and vancomycin were combined, an increase in bone defect re‐ossification was found in the Van+Tob group than in the Van group (BV/TV: F = 64.29, R ² = 0.9602, P = 0.0033; BFA: F = 76.17, R ² = 0.9662, P = 0.0006; BV: F = 194.4, R ² = 0.9865, P = 0.0033). Routine H&E and Masson staining supported the finding of μCT scanning. Quantitative indices confirmed that both the bone regeneration and the number of osteoblasts per filed in the defect area was higher in the Van+Tob group than in the Van group (percentage of bone tissue: F = 145.7, R ² = 0.9562, P = 0.0008; number of osteoblasts per file; F = 67.3, R ² = 0.9098, P < 0.0001). There was no significant difference between the Con group and the Van+Tob group on the number of osteoblasts each field (F = 145.7, R ² = 0.9562, P > 0.9999).ConclusionFor bone defect, local application of vancomycin combined with tobramycin was recommended over vancomycin alone. This animal study presents data suggesting that the use of local delivery of vancomycin and tobramycin should be investigated further in clinical studies.     

The First Genome-Wide Association Study for Type 2 Diabetes in Youth: The Progress in Diabetes Genetics in Youth (ProDiGY) Consortium

The prevalence of type 2 diabetes in youth has increased substantially, yet the genetic underpinnings remain largely unexplored. To identify genetic variants predisposing to youth-onset type 2 diabetes, we formed ProDiGY, a multiethnic collaboration of three studies (TODAY, SEARCH, and T2D-GENES) with 3,006 youth case subjects with type 2 diabetes (mean age 15.1 ± 2.9 years) and 6,061 diabetes-free adult control subjects (mean age 54.2 ± 12.4 years). After stratifying by principal component–clustered ethnicity, we performed association analyses on ∼10 million imputed variants using a generalized linear mixed model incorporating a genetic relationship matrix to account for population structure and adjusting for sex. We identified seven genome-wide significant loci, including the novel locus rs10992863 in PHF2 (P = 3.2 × 10⁻⁸; odds ratio [OR] = 1.23). Known loci identified in our analysis include rs7903146 in TCF7L2 (P = 8.0 × 10⁻²⁰; OR 1.58), rs72982988 near MC4R (P = 4.4 × 10⁻¹⁴; OR 1.53), rs200893788 in CDC123 (P = 1.1 × 10⁻¹²; OR 1.32), rs2237892 in KCNQ1 (P = 4.8 × 10⁻¹¹; OR 1.59), rs937589119 in IGF2BP2 (P = 3.1 × 10⁻⁹; OR 1.34), and rs113748381 in SLC16A11 (P = 4.1 × 10⁻⁸; OR 1.04). Secondary analysis with 856 diabetes-free youth control subjects uncovered an additional locus in CPEB2 (P = 3.2 × 10⁻⁸; OR 2.1) and consistent direction of effect for diabetes risk. In conclusion, we identified both known and novel loci in the first genome-wide association study of youth-onset type 2 diabetes.     

Bioburden Increases Heterotopic Ossification Formation in an Established Rat Model

Background

Heterotopic ossification (HO) develops in a majority of combat-related amputations wherein early bacterial colonization has been considered a potential early risk factor. Our group has recently developed a small animal model of trauma-induced HO that incorporates many of the multifaceted injury patterns of combat trauma in the absence of bacterial contamination and subsequent wound colonization.

Questions/purposes

We sought to determine if (1) the presence of bioburden (Acinetobacter baumannii and methicillin-resistant Staphylococcus aureus [MRSA]) increases the magnitude of ectopic bone formation in traumatized muscle after amputation; and (2) what persistent effects bacterial contamination has on late microbial flora within the amputation site.

Methods

Using a blast-related HO model, we exposed 48 rats to blast overpressure, femur fracture, crush injury, and subsequent immediate transfemoral amputation through the zone of injury. Control injured rats (n = 8) were inoculated beneath the myodesis with phosphate-buffered saline not containing bacteria (vehicle) and treatment rats were inoculated with 1 × 10⁶ colony-forming units of A baumannii (n = 20) or MRSA (n = 20). All animals formed HO. Heterotopic ossification was determined by quantitative volumetric measurements of ectopic bone at 12-weeks postinjury using micro-CT and qualitative histomorphometry for assessment of new bone formation in the residual limb. Bone marrow and muscle tissue biopsies were collected from the residual limb at 12 weeks to quantitatively measure the bioburden load and to qualitatively determine the species-level identification of the bacterial flora.

Results

At 12 weeks, we observed a greater volume of HO in rats infected with MRSA (68.9 ± 8.6 mm³; 95% confidence interval [CI], 50.52–85.55) when compared with A baumannii (20.9 ± 3.7 mm³; 95% CI, 13.61–28.14; p < 0.001) or vehicle (16.3 ± 3.2 mm³; 95% CI, 10.06–22.47; p < 0.001). Soft tissue and marrow from the residual limb of rats inoculated with A baumannii tested negative for A baumannii infection but were positive for other strains of bacteria (1.33 × 10² ± 0.89 × 10²; 95% CI, −0.42 × 10²–3.08 × 10² and 1.25 × 10⁶ ± 0.69 × 10⁶; 95% CI, −0.13 × 10⁶–2.60 × 10⁶ colony-forming units in bone marrow and muscle tissue, respectively), whereas tissue from MRSA-infected rats contained MRSA only (4.84 × 10¹ ± 3.22 × 10¹; 95% CI, −1.47 × 10¹–11.1 × 10¹ and 2.80 × 10⁷ ± 1.73 × 10⁷; 95% CI, −0.60 × 10⁷–6.20 × 10⁷ in bone marrow and muscle tissue, respectively).

Conclusions

Our findings demonstrate that persistent infection with MRSA results in a greater volume of ectopic bone formation, which may be the result of chronic soft tissue inflammation, and that early wound colonization may be a key risk factor.

Clinical Relevance

Interventions that mitigate wound contamination and inflammation (such as early débridement, systemic and local antibiotics) may also have a beneficial effect with regard to the mitigation of HO formation and should be evaluated with that potential in mind in future preclinical studies.     

Genetic Variation in CDH13 Is Associated With Lower Plasma Adiponectin Levels but Greater Adiponectin Sensitivity in East Asian Populations

Variants in the CDH13 gene have been identified as determinants of blood levels of adiponectin, an insulin-sensitizing adipokine. However, their association with other metabolic risk factors remains unclear. We examined variants at CDH13 in relation to total and high-molecular-weight (HMW) adiponectin using data from a genome-wide association study performed in 2,434 Singaporean Chinese with replication in up to 3,290 Japanese and 1,610 Koreans. The top signal rs4783244 in CDH13 showed strong associations with total adiponectin (standardized β [β] = −0.34, 95% CI −0.38 to −0.30, P = 2.0 × 10⁻⁷⁰), HMW adiponectin (β = −0.40, 95% CI −0.43 to −0.36, P = 1.1 × 10⁻¹¹⁷), and the HMW-to-total adiponectin ratio (β = −0.44, 95% CI −0.49 to −0.40, P = 3.2 × 10⁻⁸³). In the replication study, this single nucleotide polymorphism explained 4.1% of total and 6.5% of HMW adiponectin levels. No association was observed between rs4783244 and metabolic traits associated with insulin resistance before adjustment for HMW adiponectin levels. After adjustment for HMW adiponectin levels, the minor allele was associated with lower BMI (β = −0.15, 95% CI −0.19 to −0.11, P = 3.5 × 10⁻¹⁴), homeostasis model assessment-insulin resistance index (β = −0.16, 95% CI −0.20 to −0.12, P = 9.2 × 10⁻¹⁶), and triglycerides (β = −0.16, 95% CI −0.19 to −0.12, P = 1.3 × 10⁻¹⁶) and with higher HDL (β = 0.16, 95% CI 0.12 to 0.19, P = 2.1 × 10⁻¹⁷). CDH13 variants strongly influence plasma total and HMW adiponectin levels in East Asian populations but appear to alter adiponectin sensitivity, resulting in better metabolic health than expected based on circulating adiponectin levels.Adiponectin is a protein abundantly secreted by adipose tissue with anti-inflammatory (1) and insulin-sensitizing properties (2). Blood levels of adiponectin are inversely associated with obesity (3), insulin resistance (4), and risk of type 2 diabetes (5). Genetic determinants account for a substantial proportion of the variation in plasma adiponectin (6), and genome-wide association studies (GWAS) have identified several loci associated with plasma adiponectin (7–10). Adiponectin exists in several forms in the blood. High-molecular-weight (HMW) adiponectin has shown stronger associations with insulin sensitivity and suppression of hepatic glucose production than other forms of adiponectin (11). Few existing GWAS have included both total and HMW adiponectin and compared the associations. This may be pertinent because CDH13 has been identified to code for T-cadherin, a specific receptor for hexameric and HMW adiponectin (12). In addition, the effects of variants at the CDH13 locus on insulin resistance and other metabolic risk factors remain unclear.We therefore conducted a GWAS of total and HMW adiponectin in a Singaporean Chinese population. With an extension to other East Asian populations, we also examined the effects of CDH13 variants in relation to insulin resistance and associated metabolic traits.     

Preoperative Platelet to Albumin Ratio Predicts Outcome of Patients with Non-Small-Cell Lung Cancer

Objective: The purpose of this study was to evaluate the predictive power of the platelet to albumin ratio (PAR) on survival outcomes of patients with non-small-cell lung cancer (NSCLC).Patients and Methods: In all, 198 patients with NSCLC were recruited. The X-tile software was performed to identify the optimal cutoff values for PAR, platelet to lymphocyte ratio (PLR), and neutrophil to lymphocyte ratio (NLR). The Kaplan–Meier method, univariate and multivariate analyses Cox regression were used to analyze the prognostic factors for overall survival (OS).Results: In all, 198 patients were enrolled, containing 146 (73.7%) men and 52 (26.3%) women. The optimal cutoff values for PAR, PLR, and NLR were 8.8×10⁹, 147.7, and 3.9, respectively. Patients with PAR > 8.8 × 10⁹ (P <0.001), PLR > 147.7 (P <0.001), and NLR >3.9 (P = 0.007) were associated with poor OS. Multivariate analyses found that PAR was an independent predictor in NSCLC patients (hazard ratio [HR]: 4.604, 95% confidence interval [CI]: 2.557–8.290, P <0.001).Conclusion: Preoperative PAR is a useful and potential prognostic biomarker in NSCLC patients who have received primary resection.     

Serum zinc, bronchiectasis, and bronchial carcinoma

Beeley, J. M., Darke, C. S., Owen, G., and Cooper, R. D. (1974).Thorax, 29, 21-25. Serum zinc, bronchiectasis, and bronchial carcinoma. Serum zinc levels were measured by atomic absorption spectrophotometry in 65 patients with proven bronchiectasis; the mean level was 93 μg/100 ml, while the levels in two groups of healthy control subjects were 88·6 and 92·7 μg/100 ml respectively. The range of individual values was similar in all groups and the differences between the mean serum zinc levels of the two groups of control subjects and the mean level of the group of patients with bronchiectasis were small and did not attain significance at the conventional 0·05 level. In contrast, the mean level in bronchial carcinoma patients (75·9 μg/100 ml) was significantly less than in each of the other groups of subjects.     

Lupus Nephritis Susceptibility Loci in Women with Systemic Lupus Erythematosus

Lupus nephritis is a manifestation of SLE resulting from glomerular immune complex deposition and inflammation. Lupus nephritis demonstrates familial aggregation and accounts for significant morbidity and mortality. We completed a meta-analysis of three genome-wide association studies of SLE to identify lupus nephritis–predisposing loci. Through genotyping and imputation, >1.6 million markers were assessed in 2000 unrelated women of European descent with SLE (588 patients with lupus nephritis and 1412 patients with lupus without nephritis). Tests of association were computed using logistic regression adjusting for population substructure. The strongest evidence for association was observed outside the MHC and included markers localized to 4q11-q13 (PDGFRA, GSX2; P=4.5×10⁻⁷), 16p12 (SLC5A11; P=5.1×10⁻⁷), 6p22 (ID4; P=7.4×10⁻⁷), and 8q24.12 (HAS2, SNTB1; P=1.1×10⁻⁶). Both HLA-DR2 and HLA-DR3, two well established lupus susceptibility loci, showed evidence of association with lupus nephritis (P=0.06 and P=3.7×10⁻⁵, respectively). Within the class I region, rs9263871 (C6orf15-HCG22) had the strongest evidence of association with lupus nephritis independent of HLA-DR2 and HLA-DR3 (P=8.5×10⁻⁶). Consistent with a functional role in lupus nephritis, intra-renal mRNA levels of PDGFRA and associated pathway members showed significant enrichment in patients with lupus nephritis (n=32) compared with controls (n=15). Results from this large-scale genome-wide investigation of lupus nephritis provide evidence of multiple biologically relevant lupus nephritis susceptibility loci.     

Exciting Performance of Plasma Fibrinogen in Periprosthetic Joint Infection Diagnosis

ObjectiveTo test the significance of serum C‐reactive protein (CRP), the erythrocyte sedimentation rate (ESR), the platelet count/mean platelet volume ratio (PC/MPV), plasma fibrinogen, and D‐Dimer in periprosthetic joint infection (PJI) diagnosis.MethodsWe retrospectively analyzed the clinical data of 149 patients diagnosed from July 2016 to December 2019 with primary osteoarthritis (OA group, average age 63.18 years [range, 53–82 years] 18 males, 46 females), PJI (PJI group, average age 63.74 years [range, 52–81 years], 16 males, 31 females), and aseptic loosening (aseptic group, average age 63.18 years [range, 53–80 years], 12 male, 26 female) in our department. Demographic data and the sensitivity and specificity of preoperative CRP, ESR, PC/MPV, fibrinogen, and D‐Dimer in PJI diagnosis were compared.ResultsThere were no significant differences when the demographic data of the three groups were compared. The expression level of CRP (50.67 ± 58.98 mg/L), ESR (50.55 ± 25.81 mm/h), PC/MPV (35.79 ± 18.00), and fibrinogen (4.85 ± 1.33 μg/mL) in the PJI group were higher than in the OA group (CRP: 4.09 ± 9.68 mg/L; ESR:13.44 ± 9.32 mm/1 h; PC/MPV: 24.97 ± 7.58; fibrinogen: 3.09 ± 0.55 μg/mL) and the aseptic group (CRP: 7.01 ± 11.83 mg/L; ESR: 22.47 ± 17.53 mm/1 h; PC/MPV: 25.18 ± 11.48; fibrinogen: 3.39 ± 0.80 μg/mL), respectively. The expression level of plasma D‐dimer (1.60 ± 1.29 mg/L) in the PJI group was higher than in the OA group (0.49 ± 0.42 mg/L) but similar to that in the aseptic group (1.21 ± 1.35 mg/L). Receiver operating characteristic (ROC) curve analysis demonstrated that the areas under the ROC curve (AUC) for CRP, ESR, PC/MPV, fibrinogen, and D‐dimer were 0.892 (95% confidence interval, 0.829–0.954), 0.888 (0.829–0.947), 0.686 (0.589–0.784), 0.873 (0.803–0.943), and 0.835 (0.772–0.899), respectively. When PC/MPV > 31.70, fibrinogen >4.01 μg/mL, and D‐dimer >1.17 mg/L were set as the threshold values for the diagnosis of PJI, the sensitivity of PC/MPV in PJI diagnosis was lower than that of ESR and plasma fibrinogen. In contrast, there was no significant difference when comparing the specificity of CRP, ESR, PC/MPV, fibrinogen, and D‐dimer in PJI diagnosis.ConclusionPlasma fibrinogen is a good new auxiliary diagnostic marker for PJI.     

Dose response of ipratropium bromide assessed by two methods

The dose-response relationships of ipratropium bromide were assessed by two different techniques in two groups of 10 male patients with partially reversible airways obstruction. In a randomised double-blind fashion on four days, 10 patients were given 40 μg, 80 μg, or 120 μg of ipratropium bromide or placebo from identical containers. Baseline FEV₁ and vital capacity were measured and the measurements repeated after 40 minutes, one, two, four, and six hours, and any symptoms were elicited. In the second study, each patient received cumulative doses of 40 μg, 80 μg, and 120 μg. Baseline FEV₁ was obtained and repeated 35 minutes after each dose. The peak increase of the FEV₁ was comparable in both studies. The FEV₁ was slightly greater after 120 μg than after 40 μg. Although this reached statistical significance only in the first study, it was concluded that the cumulative dose-response technique was suitable for determining the peak response. However, this technique was unsuitable for assessing duration of effect, which could be examined only in the first study. After 120 μg of ipratropium bromide, the FEV₁ was significantly greater than after 40 μg at each time interval and it was greater than 80 μg at six hours (p<0·05). No significant side effects were noted in either study. When prolonged effective bronchodilation is sought, a dose of 120 μg of ipratropium bromide may be preferable to the recommended dose of 40 μg.