Lipopolysaccharide delays demyelination and promotes oligodendrocyte precursor proliferation in the central nervous system

Systemic infection can influence the course in many diseases of the central nervous system (CNS) such as multiple sclerosis (MS), yet the relationship between infection outside the CNS and potential damage and/or protection within the CNS is still not understood. Activation of microglia is a characteristic feature of most CNS autoimmune disorders, including MS, and both protective and degenerative functions of microglia have been proposed. Hence, we analyzed the effects of a systemic inflammatory reaction induced by peripheral treatment with lipopolysaccharide (LPS) on microglial reaction and cuprizone induced de- and remyelination. We found that LPS administration delayed demyelination, which was linked with inhibition of microglial proliferation and reduced numbers of activated microglia. The phenotype of microglia changed as an increase of Toll-like receptor 4 was found. During remyelination, LPS treatment delayed the onset of myelin protein re-expression, but later there was a beneficial effect via an increase of proliferating oligodendrocyte precursor cells (OPC) and mature oligodendrocytes. Moreover, the expression of ciliary neurotrophic factor was increased in response to LPS, a growth factor known to mediate OPC proliferation. Additional experiments showed that the time window to induce LPS effects was limited and associated with the presence of microglia. In conclusion, LPS delayed demyelination and caused beneficial effects on remyelination via increasing the proliferation of OPC. These differences seem to be an effect of LPS induced microglial modulation and indicate that exposure to certain infectious agents within a given time window may be beneficial in promoting tissue repair.     

Off-label-dosing of non-vitamin K-dependent oral antagonists in AF patients before and after stroke: results of the prospective multicenter Berlin Atrial Fibrillation Registry

Aims

We aimed to analyze prevalence and predictors of NOAC off-label under-dosing in AF patients before and after the index stroke.

Methods

The post hoc analysis included 1080 patients of the investigator-initiated, multicenter prospective Berlin Atrial Fibrillation Registry, designed to analyze medical stroke prevention in AF patients after acute ischemic stroke.

Results

At stroke onset, an off-label daily dose was prescribed in 61 (25.5%) of 239 NOAC patients with known AF and CHA₂DS₂-VASc score ≥ 1, of which 52 (21.8%) patients were under-dosed. Under-dosing was associated with age ≥ 80 years in patients on rivaroxaban [OR 2.90, 95% CI 1.05–7.9, P = 0.04; n = 29] or apixaban [OR 3.24, 95% CI 1.04–10.1, P = 0.04; n = 22]. At hospital discharge after the index stroke, NOAC off-label dose on admission was continued in 30 (49.2%) of 61 patients. Overall, 79 (13.7%) of 708 patients prescribed a NOAC at hospital discharge received an off-label dose, of whom 75 (10.6%) patients were under-dosed. Rivaroxaban under-dosing at discharge was associated with age ≥ 80 years [OR 3.49, 95% CI 1.24–9.84, P = 0.02; n = 19]; apixaban under-dosing with body weight ≤ 60 kg [OR 0.06, 95% CI 0.01–0.47, P < 0.01; n = 56], CHA₂DS₂-VASc score [OR per point 1.47, 95% CI 1.08–2.00, P = 0.01], and HAS-BLED score [OR per point 1.91, 95% CI 1.28–2.84, P < 0.01].

Conclusion

At stroke onset, off-label dosing was present in one out of four, and under-dosing in one out of five NOAC patients. Under-dosing of rivaroxaban or apixaban was related to old age. In-hospital treatment after stroke reduced off-label NOAC dosing, but one out of ten NOAC patients was under-dosed at discharge.

Clinical trial registration

NCT02306824.

     

Comparison of non-surgical methods for the treatment of deep partial thickness skin burns of the hand

This paper describes a randomized, controlled, parallel-group, single-center clinical trial designed to compare non surgical treatment methods of deep partial thickness skin burns of the hand.All patients were scanned with the Laser Doppler Imaging device to determine the depth of the burn wound. Viable keratinocytes sites were determined according to the established Perfusion Units (PU) measurement system. The trial enrolled 87 patients with hand burn wounds in the section of 260–600 PU.Hand burn patients were divided into the following four groups: treated with hydrocolloid dressings; treated with mechanical debridement of monofilament polyester fibers pad and then applying silver sulfadiazine; treated with gauze dressings containing enzymatic collagenase preparation. The fourth group of patients was treated with silver sulfadiazine and gauze dressings. This group was considered as the control group. The wound healing status was assessed after 3, 7, 14 and 21 days. Burn scars and injured extremity function were assessed after six months according to the Vancouver Scar Scale and Disabilities of the Arm, Shoulder and Hand Outcome Measure.The fastest epithelialization of hand burn wounds was observed in the patients group treated with hydrocolloid dressings (15, 7 days, p < 0,05). The patients of this group also had less scars and a better hand function.     

The effect on early renal function of various dynamic preservation strategies in a preclinical pig ischemia–reperfusion autotransplant model

The aims of this study were to determine the most optimal timing to start machine perfusion during kidney preservation to improve early graft function and to evaluate the impact of temperature and oxygen supply during machine perfusion in a porcine ischemia–reperfusion autotransplant model. The left kidney of an approximately 40‐kg female Belgian Landrace pig was exposed to 30 minutes of warm ischemia via vascular clamping and randomized to 1 of 6 study groups: (1) 22‐hour static cold storage (SCS) (n = 6), (2) 22‐hour hypothermic machine perfusion (HMP) (n = 6), (3) 22‐hour oxygenated HMP (n = 7), (4) 20‐hour HMP plus 2‐hour normothermic perfusion (NP) (n = 6), (5) 20‐hour SCS plus 2‐hour oxygenated HMP (n = 7), and (6) 20‐hour SCS plus 2‐hour NP (n = 6). Graft recovery measured by serum creatinine level was significantly faster for continuous HMP preservation strategies compared with SCS alone and for all end‐ischemic strategies. The active oxygenated 22‐hour HMP group demonstrated a significantly faster recovery from early graft function compared with the 22‐hour nonactive oxygenated HMP group. Active oxygenation was also found to be an important modulator of a faster increase in renal flow during HMP preservation. Continuous oxygenated HMP applied from the time of kidney procurement until transplant might be the best preservation strategy to improve early graft function.     

Cryoablation treatment of benign breast lesions with 12-month follow-up

OBJECTIVE: Eighty percent of all breast biopsies reveal benign findings. The most common benign tumor is a fibroadenoma. Despite their benign nature, many women eventually choose to have their bothersome lumps surgically removed. We report the use of cryoablation to treat these benign breast lesions with minimum 12-month follow-up. METHODS: After receiving Institutional Review Board approval, a prospective nonrandomized trial was initiated in June 2000. Ultrasound-guided cryoablation of core biopsy-proven benign fibroadenomas, other benign breast nodules, or nodular fibrocystic change was performed on 78 lesions in 63 patients. Eighty-five percent of lesions treated were benign fibroadenomas. The cryoablation procedure consisted of a double freeze-thaw cycle that lasted between 6 and 30 minutes and was performed most often in an office setting. Each patient was serially evaluated for treatment efficacy, complications, and patient satisfaction. RESULTS: Sixty-four of 78 lesions (mean size 2.0 cm [range 0.8 to 4.2]) were followed-up for at least 12 months after cryoablation per protocol, which included 53 fibroadenomas. At 1 year, ultrasound tumor volume resorption was 88.3% overall (87.3% for fibroadenomas), and 73% of the entire group became nonpalpable to both clinician and patient (75% for fibroadenomas). Two of the fibroadenoma patients had their palpable residual nodule excised, both revealing necrotic debris and no viable tumor in the treated volume. Serial mammograms showed resorption of the lesion leaving minimal residual density without calcifications. Cosmesis was excellent with only a small scar remaining at the probe insertion site. There was no report of visual or palpable volumetric deficit. Patient satisfaction was good to excellent in 92% of cases. CONCLUSIONS: Cryoablation was successful in treating core biopsy-proven benign breast lesions in 63 patients. At 12 months, we found gradual resorption of treated tissue with no cosmetic deficit. Ultrasound-guided cryoablation is an effective and safe treatment for benign breast lesions, as seen at 12-month follow-up, and offers an office-based, minimally invasive alternative to surgical excision.     

The interaction of ethanol with central histaminergic stimulation of the pituitary-adrenocortical and hyperlipemic activity

Ethanol introduced intragastrically (i.g.) in rats increased the pituitary-adrenocortical activity, measured indirectly through corticosterone concentration in blood serum. Since this increase reached only about 40% of the maximum hormone levels observed in that species after another stimuli, ethanol may be considered as a relatively weak stimulus. Ethanol induced also a significant decrease in serum free fatty acid (FFA) levels which was blocked totally by a prior intracerebroventricular (i.c.v.) administration of either H₁- or H₂-histamine receptor antagonists, mepyramine or metiamide and cimetidine. The ethanol-induced increase in serum corticosterone was insensitive to a central histamine H₁- and H₂-receptors blockade. Ethanol abolished the rise in serum FFA levels induced by an i.c.v. administration of histamine, pyridylethylamine (PEA)-a H₁-receptor agonist, and dimaprit — a H₂-receptor agonist. The histamine- and histamine-agonists induced increases of serum coricosterone were generally slightly intensified by a prior i.g. administration of ethanol.     

Analyzing the learning curves of a novice and an experienced urologist for transrectal magnetic resonance imaging-ultrasound fusion prostate biopsy

BackgroundThe aim of the current study was to evaluate and compare the learning curves of transrectal magnetic resonance imaging-ultrasound fusion biopsy for two urologists with different backgrounds (Operator 1: experienced, self-trained and Operator 2: novice, trained by a mentor/MRI reading courses).MethodsA cohort of 400 patients who underwent fusion prostate biopsy in our department was analyzed. The learning curves were assessed in terms of overall and clinically significant prostate cancer (PCa) detection rates, percentage of positive biopsy cores/targeted and the percentage of PCa tissue on positive targeted cores.ResultsIncreasing trends were observed for both urologists in terms of all biopsy outcomes during the study time. For the novice urologist, a significant increase was observed for overall PCa detection rate, but not for clinically significant disease (25.44%, P=0.04/15%, P=0.145). Operator 1 showed an increasing diagnosis yield of clinically significant disease up to 104 cases. Similar cancer detection rates were observed when comparing the first and last biopsies performed by both operators. Multivariate analysis adjusted for age, PSA, prostate volume, lesion diameter and PIRADS score showed an increase of PCa detection with 51% for every 52 biopsies performed (P=0.022).ConclusionsWhen starting with magnetic resonance imaging-ultrasound fusion prostate biopsy, mentoring and prostate magnetic resonance imaging reading training allow a novice urologist to demonstrate a good initial PCa detection rate. After about 52 cases, he reached a stable PCa and clinically significant PCa detection rate, that was similar to that of an experienced urologist.     

Combined liver–kidney transplantation versus liver transplant alone based on KDIGO stratification of estimated glomerular filtration rate: data from the United Kingdom Transplant registry – a retrospective cohort study

Patient selection for combined liver–kidney transplantation (CLKT) is a current issue on the background of organ shortage. This study aimed to compare outcomes and post‐transplant renal function for patients receiving CLKT and liver transplantation alone (LTA) based on native renal function using estimated glomerular filtration rate (eGFR) stratification. Using the UK National transplant database (NHSBT) 6035 patients receiving a LTA (N = 5912; 98%) or CLKT (N = 123; 2%) [2001–2013] were analysed, and stratified by KDIGO stages of eGFR at transplant (eGFR group‐strata). There was no difference in patient/graft survival between LTA and CLKT in eGFR group‐strata (P > 0.05). Of 377 patients undergoing renal replacement therapy (RRT) at time of transplantation, 305 (81%) and 72 (19%) patients received LTA and CLKT respectively. A significantly greater proportion of CLKT patients had severe end‐stage renal disease (eGFR < 30 ml/min/1.73 m²) at 1 year post‐transplant compared to LTA (9.5% vs. 5.7%, P = 0.001). Patient and graft survival benefit for patients on RRT at transplantation was favouring CLKT versus LTA (P = 0.038 and P = 0.018, respectively) but the renal function of the long‐term survivors was not superior following CLKT. The data does not support CLKT approach based on eGFR alone, and the advantage of CLKT appear to benefit only those who are on established RRT at the time of transplant.