Spatial architectures of somatic mutations in normal prostate, benign prostatic hyperplasia and coexisting prostate cancer.

This study aimed to identify somatic mutations in nontumor cells (NSMs) in normal prostate and benign prostatic hyperplasia (BPH) and to determine their relatedness to prostate cancer (PCA). From 22 PCA patients, two prostates were sampled for 3-dimensional mapping (50 normal, 46 BPH and 1 PCA samples), and 20 prostates were trio-sampled (two normal or BPH samples and one PCA sample) and analyzed by whole-genome sequencing. Normal and BPH tissues harbored several driver NSMs and copy number alterations (CNAs), including in FOXA1, but the variations exhibited low incidence, rare recurrence, and rare overlap with PCAs. CNAs, structural variants, and mutation signatures were similar between normal and BPH samples, while BPHs harbored a higher mutation burden, shorter telomere length, larger clone size, and more private NSMs than normal prostates. We identified peripheral-zonal dominance and right-side asymmetry in NSMs, but the asymmetry was heterogeneous between samples. In one normal prostate, private oncogenic RAS-signaling NSMs were detected, suggesting convergence in clonal maintenance. Early embryonic mutations exhibited two distinct distributions, characterized as layered and mixed patterns. Our study identified that the BPH genome differed from the normal prostate genome but was still closer to the normal genome than to the PCA genome, suggesting that BPH might be more related to aging or environmental stress than to tumorigenic processes.

Radiological Risk Factors for Neurological Deficits After Traumatic Mid and Low Lumbar Fractures.

STUDY DESIGN: Retrospective study. OBJECTIVE: We identified radiological risk factors for neurological deficits in mid and low lumbar spinal fractures. SUMMARY OF BACKGROUND DATA: Although numerous studies have focused on radiological risk factors for neurological deficits in spinal cord injury or thoracolumbar junction area fractures, few have examined mid and low lumbar fractures at the cauda equina level. METHODS: We retrospectively reviewed 71 consecutive patients who suffered acute traumatic mid and low lumbar fractures (L2-L5) corresponding to the cauda equina level, as confirmed on magnetic resonance imaging. We defined a neurological deficit as present if the patient had any sensory or motor deficit in the lower extremity or autonomic system at the initial assessment. Various computed tomography parameters of canal stenosis, vertebral body compression, sagittal alignment, interpedicular distance, and presence of vertical laminar fractures were analyzed as independent risk factors to predict neurological deficits using multivariate logistic regression analyses. RESULTS: At the initial assessment, 31 patients had neurological deficits. Fracture level, AO fracture type, canal encroachment ratio, vertebral compression ratio, interpedicular distance ratio, and presence of a vertical laminar fracture were significantly associated with the presence of neurological deficits (all P < 0.05). Multivariate logistic regression identified fracture level, canal encroachment ratio (adjusted odds ratio [aOR] 1.072, 95% confidence interval [CI] 1.018-1.129), and vertebral compression ratio (aOR 0.884, 95% CI 0.788-0.992) as independent predictors of a neurological deficit. Receiver operating characteristic curve analyses revealed that only the canal encroachment ratio had good discriminatory ability (area under the curve 0.874, 95% CI 0.791-0.957), and the optimal cutoff was 47% (canal diameter 6.6 mm) with 90.3% sensitivity and 80% specificity. CONCLUSION: The canal encroachment ratio was most strongly associated with neurological deficits in traumatic mid and low lumbar fractures, with an optimal cutoff of 47%. LEVEL OF EVIDENCE: 4.

Morphological Patterns of Anterior Femoral Condylar Resection in Kinematically and Mechanically Aligned Total Knee Arthroplasty.

BACKGROUND: "Grand-piano sign" has been used as a popular benchmark to facilitate correct rotational alignment during total knee arthroplasty (TKA). The purpose was to quantitatively determine morphological patterns on anterior femoral resection in mechanically aligned (MA) and kinematically aligned (KA) TKA. METHODS: Computed tomography scans of 60 TKA candidates were reconstructed into 3D models. Femurs were virtually cut with a 3D imaging program using various anterior flange flexion angles (AFFAs) of 3°, 5°, and 7°. The anterior femoral resection was performed parallel to the surgical epicondylar axis, at an external rotation and internal rotation of 3° relative to surgical epicondylar axis for MA-TKA, and parallel to the cylindrical axis, at an external rotation and internal rotation of 3° to cylindrical axis for KA-TKA. The ratio of vertical distance from the anterior margin of distal femoral resection to the most proximal peak of each medial and lateral condyle of anterior femoral resection was defined as AC/BC ratio. RESULTS: The mean ratios of AC/BC were 0.57, 0.60, and 0.63 respectively, according to 3°, 5°, and 7° of AFFA with standard MA-TKA method and were 0.73, 0.74, and 0.76, respectively, according to 3°, 5°, and 7° of AFFA with standard KA-TKA method. The AC/BC ratios of malrotated planes were significantly different from those of both standard MA- and KA-TKAs (P-values < .01). CONCLUSION: Surgeons can accessorily use the quantifying method for anterior femoral resection intraoperatively to ensure correct rotational alignment of femoral resection in both mechanically and kinematically aligned TKA.

Discovery, Synthesis, and Evaluation of 2,4-Diaminoquinazolines as a Novel Class of Pancreatic ß-Cell-Protective Agents against Endoplasmic Reticulum (ER) Stress.

Pancreatic insulin-producing ß-cell dysfunction and death plays central roles in the onset and progression of both type 1 and type 2 diabetes. Current antidiabetic drugs cannot halt the ongoing progression of ß-cell dysfunction and death. In diabetes, a major cause for the decline in ß-cell function and survival is endoplasmic reticulum (ER) stress. Here, we identified quinazoline derivatives as a novel class of ß-cell protective agents against ER stress-induced dysfunction and death. A series of quinazoline derivatives were synthesized from dichloroquiazoline utilizing a sequence of nucleophilic reactions. Through SAR optimization, 2,4-diaminoquinazoline compound 9c markedly protects ß-cells against ER stress-induced dysfunction and death with 80% maximum rescue activity and an EC50 value of 0.56 µM. Importantly, 9c restores the ER stress-impaired glucose-stimulated insulin secretion response and survival in primary human islet ß-cells. We showed that 9c protects ß-cells by alleviating ER stress through the suppression of the induction of key genes of the unfolded protein response and apoptosis.

Synthesis of apoptotic chalcone analogues in HepG2 human hepatocellular carcinoma cells.

Eight chalcone analogues were prepared and evaluated for their cytotoxic effects in human hepatoma HepG2 cells. Compound 5 had a potent cytotoxic effect. The percentage of apoptotic cells was significantly higher in compound 5-treated cells than in control cells. Exposure to compound 5 for 24h induced cleavage of caspase-8 and -3, and poly (ADP-ribose) polymerase (PARP). Our findings suggest that compound 5 is the active chalcone analogue that contributes to cell death in HepG2 cells via the extrinsic apoptotic pathway.

Synthesis and biological evaluation of chalcone analogues as protective agents against cisplatin-induced cytotoxicity in kidney cells.

Chalcone analogues were prepared and evaluated for any renoprotective effects on cisplatin-treated cultured kidney cells (LLC-PK1); two chalcone analogues exhibited a potent renoprotective effect. In an additional study, we demonstrated that the blocking of MAPKs-p53-caspase-3 signaling cascade plays an important role in mediating the protective effect of these compounds against oxidative cytotoxicity in cultured LLC-PK1 cells.

United Rapid Urease Test Is Superior than Separate Test in Detecting Helicobacter pylori at the Gastric Antrum and Body Specimens.

BACKGROUND/AIMS: The rapid urease test (RUT) is an invasive method to diagnose Helicobacter pylori infection, which relies on the acquisition and examination of gastric antrum and body tissues. We determined and compared the efficacy of RUT when the tissues were examined separately or after being combined. METHODS: Two hundred and fourteen patients were included and underwent esophagogastroduodenoscopy from July 2008 to June 2010. The separate test was defined as evaluating the status of infectivity of H. pylori from the antrum and body separately; whereas the united test was carried out putting both tissues from the antrum and body in the same RUT kit. All RUTs were read by a single observer 1, 3, 6, 12, and up to 24 hours later. We also got two biopsy specimens stained with hematoxylin and eosin and quantified H. pylori density was calculated on a scale of 0 to 3. RESULTS: Overall positivity for H. pylori was 137 (64%) for the separate test and 148 (69.2%) for the united test (p<0.01). The mean time to a positive test was 3.58 hours for the separate test and 1.69 hours for the united test (p<0.01). The correlation between the time to positive RUT and the severity of histology showed r=+0.556 for the antrum (p<0.01) and r=+0.622 for the body (p<0.01). CONCLUSIONS: Combining tissues prior to RUT enhances the detection of H. pylori, as compared with the examination of separate tissues, and shortens the time to develop a positive reaction by approximately 50%. These diagnostic advantages are also accompanied by increased cost-savings.

[A case of perforated xanthogranulomatous cholecystitis presenting as biloma].

Xanthogranulomatous cholecystitis is an unusual inflammatory disease of the gallbladder characterized by severe proliferative fibrosis and the accumulation of lipid-laden macrophages in areas of destructive inflammation. Its macroscopic appearance may occasionally be confused with gallbladder carcinoma. We present a case of perforated xanthogranulomatous cholecystitis presenting as biloma. An 80-year-old woman was referred to our hospital with a 1-week history of abdominal pain and febrile sensation. Abdominal CT showed a biloma in the subhepatic area. The follow-up CT showed that the biloma increased in size. Therefore, ultrasonography-guided aspiration was performed. The aspirated fluid/serum bilirubin ratio was greater than 5, which was strongly suggestive of bile leakage complicated by perforated cholecystitis. She underwent a laparoscopic cholecystectomy with cyst aspiration and adhesiolysis. A histological diagnosis of perforated xanthogranulomatous cholecystitis was made.

Intussusception in a young female with Vibrio gastroenteritis and diabetic ketoacidosis.

The incidence of functional intussusception is extremely rare in adults. A 23-year-old woman, previously diagnosed with type 1 diabetes mellitus (DM), complained of colicky abdominal pain associated with vomiting of 1-day duration. Currant jelly stool was observed. Irrespective of hydration and intravenous insulin injection under the diagnosis of diabetic ketoacidosis (DKA), her abdominal pain and laboratory parameters did not improve. Abdominal computerized tomography (CT) revealed a jejunojejunal intussusception. We maintained large-volume fluid administration, and her abdominal pain began to subside. The stool culture was positive for Vibrio parahaemolyticus. We confirm the intussusception that was resolved by supportive management without surgical intervention in a patient with gastroenteritis and diabetic ketoacidosis.

A case of hyperglycemic hyperosmolar state associated with Graves' hyperthyroidism: a case report.

Hyperglycemic hyperosmolar state (HHS) is an acute complication mostly occurring in elderly type 2 diabetes mellitus (DM). Thyrotoxicosis causes dramatic increase of glycogen degradation and/or gluconeogenesis and enhances breakdown of triglycerides. Thus, in general, it augments glucose intolerance in diabetic patients. A 23-yr-old female patient with Graves' disease and type 2 DM, complying with methimazole and insulin injection, had symptoms of nausea, polyuria and generalized weakness. Her serum glucose and osmolarity were 32.7 mM/L, and 321 mosm/kg, respectively. Thyroid function tests revealed that she had more aggravated hyperthyroid status; 0.01 mU/L TSH and 2.78 pM/L free T3 (reference range, 0.17-4.05, 0.31-0.62, respectively) than when she was discharged two weeks before (0.12 mU/L TSH and 1.41 pM/L free T3). Being diagnosed as HHS and refractory Graves' hyperthyroidism, she was treated successfully with intravenous fluids, insulin and high doses of methimazole (90 mg daily). Here, we described the case of a woman with Graves' disease and type 2 DM developing to HHS.

Determination of urinary Myo-/chiro-inositol ratios from Korean diabetes patients.

Of two major forms (myo- and chiro-inositol) of inositols, only chiro-inositol enhances the activity of proteins involved in intracellular glucose metabolism. This study aims to determine the urinary myo-/chiro-inositol ratio in type 1 and type 2 diabetes patients and compare its ratio with the normal control group. The 24-hour urinary myo- and chiro-inositols in 71 Korean diabetes patients and 39 control subjects have been quantified using high-performance liquid chromatography, and their ratios have been evaluated as indices of insulin resistance. The level of 24-hour urinary myo-inositol was significantly higher in both type 1 and type 2 diabetes than with the control group, whereas the urinary chiro-inositol in type 1 or type 2 diabetes was lower than that in normal subjects. The myo-/chiro-inositol ratio in diabetes patients was higher than that in the control group. Twenty four-hour urinary myo-/ chiro-inositol ratios were significantly elevated in type 1 and type 2 diabetes patients compared to the control group, suggesting that a high ratio of urinary myo-/chiro- inositol in type 2 diabetes patients might be used for an index of insulin resistance.