Preclinical and clinical role of interleukin-6 in the development of delayed cerebral vasospasm and neuronal cell death after subarachnoid hemorrhage: towards a potential target therapy?

Delayed cerebral vasospasm (DCVS), early brain injury (EBI), and delayed cerebral ischemia (DCI) are devastating complications after aneurysmal subarachnoid hemorrhage (SAH). Interleukin (IL)-6 seems to be an important interleukin in the inflammatory response after SAH, and many studies describe a strong correlation between IL-6 and worse outcome. The aim of this study was to systematically review preclinical and clinical studies that evaluated systemic and cerebral IL-6 levels after SAH and their relation to DCVS, neuronal cell death, and DCI. We conducted two systematic literature searches using PubMed to identify preclinical and clinical studies evaluating the role of IL-6 after SAH. Suitable articles were selected based on predefined eligibility criteria following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A total of 61 and 30 preclinical and clinical articles, respectively, were included in the systematic reviews. Of the preclinical studies in which IL-6 was measured in cerebrospinal fluid (CSF), parenchyma, and systemically, 100%, 94.4%, and 81.3%, respectively, showed increased expression of IL-6 after SAH. Preclinical results were mirrored by clinical findings in which elevated levels of IL-6 in CSF and plasma were found after SAH, correlating with DCVS, DCI, and worse outcome. Only two preclinical studies analyzed the direct inhibition of IL-6, which resulted in reduced DCVS and neuronal cell death. IL-6 is a marker of intracranial inflammation and plays a role in the pathophysiology of DCVS and DCI after SAH in preclinical animal models and clinical studies. Its inhibition might have therapeutic potential to improve the outcome of SAH patients.

     

Plasma thymosin-α1 level as a potential biomarker in urothelial and renal cell carcinoma

ObjectivesTo determine the plasma levels of thymosin-α1 (TA1) and prothymosin-α (PTMA) proteins in renal cell carcinoma (RCC) or urothelial carcinoma (UC) patients, and explore the potential of these 2 molecules as biomarkers.Materials and methodsBlood samples were taken from 50 consecutive patients with RCC, 97 with UC, and 55 with benign urologic diseases before surgery. Their clinical characteristics were obtained from medical record review. Plasma TA1 and PTMA levels were measured using enzyme-linked immunosorbent assay and their correlation with tumor grade, pathologic stage, and survival were explored.ResultsPlasma TA1 levels were significantly lower in RCC patients than in UC or benign patients, particularly in UC of the renal pelvis patients (P < 0.0001). Plasma PTMA levels were also significantly lower in UC patients compared with RCC patients and benign patients (P < 0.05). Plasma TA1 levels inversely correlated with pathologic stage both in bladder cancer and RCC patients (P = 0.03 and 0.02, respectively). Both plasma TA1 and PTMA did not correlate with tumor grade. Plasma TA1 was a prognostic indicator for progression-free and disease-specific overall survival in bladder cancer patients (P = 0.008 and 0.04, respectively).ConclusionsPlasma TA1 level may be a biomarker for differentiating between UC and RCC. It may also be a prognostic factor for disease progression and disease-specific survival in bladder cancer patients. These findings warrant more studies for validation.     

Can the kidney function as a lung? Systemic oxygenation and renal preservation during retrograde perfusion of the ischaemic kidney in rabbits

OBJECTIVE: To investigate renal preservation by a novel method of perfusion using an oxygenated perfluorocarbon (PFC) emulsion via retrograde access to the kidney, as preserving renal function during urological surgery has been elusive, and the recognized technique of nephron-sparing surgery has increased its application and practice in modern urology. MATERIALS AND METHODS: After institutional review and approval, 30 New Zealand White rabbits were studied. In a solitary kidney model, each rabbit had the ureter catheterized before 40 min of renal artery occlusion. Each rabbit was randomized to one retrograde perfusion group, i.e. sham, normothermic PFC, chilled PFC, normothermic saline, and chilled saline. The rabbits were maintained for 2 weeks, during which renal function, urine output, systemic blood gases, weight and serum creatinine level were measured. After death, the kidneys were individually examined and graded by one renal pathologist unaware of the treatment. RESULTS: The rabbits treated with retrograde PFC perfusion (normothermic and chilled) had less change in their creatinine clearance, at 3.6 and 4.0 mL/min per kg, than the sham group, at 7.8 mL/min per kg, while also having significantly higher systemic venous oxygenation, at 26.3 and 10.0 mmHg, than the sham group, at 0.2 mmHg. Normothermic and chilled perfusion with PFC was also associated with less histological evidence of ischaemic damage, with mean (sd) scores of 13.0 (13.5) and 8.7 (4.5), respectively, than in the sham group, at 33.3 (16.8), while favourably matching the contralateral control kidney group, at 5.5 (2.3). The rabbits treated with saline retrograde perfusion also had better outcomes than the sham cohort. There were no adverse effects in any of the study arms or with the use of PFC. CONCLUSION: Retrograde oxygen delivery to the kidney through the urinary collecting system was successful in this pilot study. Renal function, laboratory and histological data indicate a trend towards renal preservation and even systemic oxygenation in the experimental groups compared with the sham rabbits, with no adverse effects attributed to this technique.     

Does PSA play a role as a promoting agent during the initiation and/or progression of prostate cancer?

Prostate cancer cells, like normal prostate epithelial cells, produce high levels of the differentiation marker and serine protease prostate-specific antigen (PSA). PSA is used extensively as a biomarker to screen for prostate cancer, to detect recurrence following local therapies, and to follow response to systemic therapies for metastatic disease. While much is known about PSA's role as a biomarker, only a relatively few studies address the role played by PSA in the pathobiology of prostate cancer. Autopsy studies have documented that not only do prostate cancer cells maintain production of high amounts of PSA but they also maintain the enzymatic machinery required to process PSA to an enzymatically active form. A variety studies performed over the last 10 years have hinted at a role for PSA in growth, progression, and metastases of prostate cancer. A fuller understanding of PSA's functional role in prostate cancer biology, however, has been hampered by the lack of appropriate models and tools. Therefore, the purpose of this review is not to address issues related to PSA as a biomarker. Instead, by reviewing what is known about the genetics, biochemistry, and biology of PSA in normal and malignant prostate tissue, insights may be gained into the role PSA may be playing in the pathobiology of prostate cancer that can connect measurement of this biomarker to an understanding of the underlying etiology and progression of the disease.     

In vitro and ex vivo gene delivery into proximal tubular cells by means of laser energy—a potential approach for curing cystinuria?

Cystinuria is the cause of 1–2% of stones observed in adults and about 10% of those occurring in children. Recurrent stone formation and multiple operations cause considerable morbidity. We investigated the transfection efficiency of naked plasmid DNA in porcine kidney cells by applying holmium laser (Ho:YAG) energy in vitro as well as ex vivo in a porcine kidney papilla model. In the in vitro experiments, naked plasmid DNA was added to LLC-PK1 cells suspended in a medium and Ho:YAG laser applied with varying pulses. The transfection efficiency was measured by the expression of EGFP reporter gene in the cells by FACScan analysis and fluorescence microscopy. Ex vivo, papilla from porcine kidney was excised and naked plasmid DNA was added to the tissue in the medium. The laser was then applied and the cryosectioned tissue observed under fluorescence microscope. The efficiency of transfection in vitro significantly improved with the increase in impulses (P<0.01). Transfection at 50 impulses averaged 0.7±0.3%, at 200 impulses 28.3±7.7%, and at 500 impulses 36.1±3.1%. The cell mortality rate increased with higher pulse rate up to 70%. Ex vivo trials showed transfection in extended regions of the tissue and also in the peripheral layers of the papilla. Our study indicates that the transfection of benign kidney cells by Ho:YAG is a promising new gene transfer strategy. The ex vivo trials showed that peripheral renal tissue layers are susceptible to transfection by Ho:YAG applied from the papillary surface.     

Can repeat biopsy be skipped after initial complete resection of T1 bladder cancer? The role of a novel urinary mRNA biomarker

ObjectivesTo prospectively investigate the role of a urinary mRNA biomarker (Xpert Test) after initial complete resection of T1 bladder cancer (BC) for the prediction of positive repeat biopsy for malignancy.MethodsPatients who underwent TURBT for NMIBC between September 2018 and April 2020 were included. Patients with benign pathology, incomplete resection, concomitant CIS/upper tract urothelial tumor or muscle invasive BC, were excluded. 2 to 6 weeks after primary TURBT, voided urine sample was retrieved for Xpert analysis and patients were scheduled for repeat biopsy. The primary outcome was to determine the role of positive Xpert test to predict positive repeat biopsy for malignancy.ResultsDuring the study period, 254 patients met the study inclusion criteria of which 61 (24%) patients had recurrent NMIBC. Complete resection was censured by the presence of detrusor muscle in the specimen with documented T1 disease in all study participants. Xpert test was positive in 128 patients; of whom 85 (66.4%) showed positive repeat biopsy (HR=6.2, 95%CI=3.46-9.4, P = 0.002). The sensitivity, specificity, positive and negative predictive values of Xpert test for repeat biopsy were 85.9% (95%CI: 82-89), 72.3% (95%CI: 68-76), 66.4% (95%CI: 62-71) and 88.9% (95%CI: 85-94), respectively. On median (range) follow up of 12(3-25) months, tumor recurrence was encountered in 84 (35%) patients. On multivariate Cox regression analysis, Xpert test was significantly associated with tumor recurrence (HR= 9.7, 95%CI=5-18, P <0.001).ConclusionsPositive Xpert test after primary complete resection of T1 BC is significantly associated with positive repeat biopsy for malignancy. In addition, Xpert test is an independent predictor of early tumor recurrence. Xpert test might be applied after initial complete resection of NMIBC to minimize unnecessary repeat biopsy with potential saving of healthcare costs and reduction in patient morbidity.     

The effect of multimodal balanced anaesthesia and long term gabapentin on neuropathic pain,nitric oxide and interleukin-1β following breast surgery

ObjectivesTo evaluate the effect of multimodal balanced anaesthesia and gabapentin (6 months) on neuropathic pain qualities, nitric oxide (NO) and interleukin 1-beta (IL-1β).MethodologyThis randomized study was conducted on 50 women scheduled for conservative breast surgery for cancer followed by chemotherapy and/or radiotherapy. Women enrolled into two groups; either to receive balanced general anaesthesia (GA) (control group) or ultrasound guided thoracic paravertebral with GA, multimodal balanced anaesthesia, (intervention group). Nociceptive pain was evaluated for 24 h. Neuropathic pain was evaluated using pain questionnaire 1 month postoperatively and neuropathic pain scale at 1, 3, 6 and 9 months. Gabapentin was prescribed to women reporting neuropathic pain 1 month postoperatively and for 6 months. NO and IL-1β were measured before operation, 1, 3, 6 & 9 months, postoperatively. Their relationship with neuropathic pain was assessed.ResultsNociceptive pain was less in intervention group than control group immediately post operative, 4 h after surgery at rest and 8 h with movement. Neuropathic pain started few days postoperatively, in both groups. Its onset, sites, duration and precipitating factors did not differ between the groups. Sensitive, hot pain and unpleasantness reduced significantly 1 month postoperatively, in intervention group. Two months later, itchy, dull and sharp pain was significantly less in intervention group. At 6 months, most of neuropathic pain items except sharp and deep pain lowered significantly in intervention group. At 9 months, hot and superficial pain was still less in intervention group. NO decreased significantly 1 and 3 months postoperatively, while IL-1β was significantly lower through different times, in intervention group. IL-1β correlated well with neuropathic pain intensity and unpleasantness.ConclusionBreast surgery for cancer was associated with neuropathic pain that continued for 9 months after surgery. Multimodal balanced GA had positive impact on acute nociceptive and neuropathic pain. Gabapentin reduced almost all neuropathic pain qualities.     

The association of neurofibromatosis 1 and spinal deformity with primary hyperparathyroidism and osteomalacia: might melatonin have a role?

A 35-year-old woman with neurofibromatosis 1 and thoracic kyphoscoliosis had incomplete paraplegia. She had a history of hyperparathyroidism due to a parathyroid adenoma which had been excised 4 years previously. Plain radiographs of the spine revealed kyphoscoliosis from the third to sixth thoracic vertebrae. Kyphosis and scoliosis angles were 86° and 28°, respectively. Radiographs of the skull and hands showed radiological changes suggestive of hyperparathyroidism. Laboratory tests showed low-normal serum calcium, hypophosphatemia, elevated serum alkaline phosphatase, and low serum 25-hydroxyvitamin D. Retrospective review of the patient's laboratory data showed that she had osteomalacia at the time of diagnosis of primary hyperparathyroidism. The patient had been treated by anterior and posterior decompression and fusion with posterior instrumentation through a single posterior approach. The postoperative kyphosis and scoliosis angles were 30° and 12°, respectively. Neurological recovery and spinal fusion had been achieved. Osteomalacia responded well to vitamin D therapy. This is the first case of coexisting neurofibromatosis 1, primary hyperparathyroidism due to parathyroid adenoma and osteomalacia to be reported in the literature. The osteomalacia in this patient could be related to primary hyperparathyroidism, and not to neurofibromatosis 1. A drop in melatonin level after parathyroidectomy may have been the cause of spinal curvature progression in this patient. Received: June 28, 2000 / Accepted: November 21, 2000