TBS as a Tool to Differentiate the Impact of Antiresorptives onCortical and Trabecular Bone in Children With OsteogenesisImperfecta

Introduction/Background: Osteogenesis imperfecta is a hereditary connective tissue disorder, resulting in low bone mass and high bone fragility. Dual-energy X-ray absorptiometry (DXA) and in adulthood also the trabecular bone score (TBS) are well established to assess bone health and fracture risk. The purpose of this investigation was to assess the usefulness of TBS in respect to different treatment regimes in children with osteogenesis imperfecta. Changes of areal bone mineral density (aBMD) and TBS using DXA scans of children treated with antiresorptive therapies were evaluated. Methodology: DXA scans (aBMD, TBS) of 8 children with OI were evaluated. The scans were taken during a 1 yr period of treatment with bisphosphonates and during 1 yr pilot trial using denosumab. Changes of aBMD and TBS during both treatment regimens were compared. Results: During bisphosphonate treatment aBMD increased about 6.2%, while TBS increased about 2.1%. The difference between aBMD and TBS before and after bisphosphonate treatment was not significant (p?=?0.25). During denosumab treatment aBMD increased around 25.1%, while TBS increased 6.7%. The change of aBMD was significant (p?=?0.007), as was the difference between aBMD and TBS (p < 0.001). Conclusions: Denosumab had a significant effect on both aBMD and TBS but was significantly more pronounced in aBMD. These results suggest a stronger effect of denosumab on cortical bone and the growth plate in comparison to bisphosphonates. Beside the lack of paediatric reference data and the small sample size, the results suggest TBS to be a useful tool for monitoring skeletal changes during development, growth, and antiresorptive therapy in children with OI.     

Evaluation of a novel flow-controlled syringe infusion pump for precise and continuous drug delivery at low flow rates: a laboratory study

Syringe infusion pumps are used for the administration of short-acting drugs in anaesthesia and critical care medicine, but are prone to flow irregularities at low flow rates. A flow-controlled syringe infusion pump using an integrated flow sensor for feedback control represents a new approach to overcoming these limitations. This study compares the performance of a prototype flow-controlled syringe pump both at start-up, and during vertical displacement manoeuvres, with that of a standard infusion syringe pump. The novel pump almost completely eliminated delays at start-up and flow irregularities during hydrostatic pressure changes. Related fluctuations in plasma drug concentration were minimised and the known disadvantages of standard syringe infusion pumps currently used in clinical practice were reduced. Besides providing fast start-up to steady-state flow and precise continuous drug delivery at low flow rates during hydrostatic pressure changes, the new pump offers the potential for the development of target-controlled infusion algorithms for short-acting cardiovascular and other drugs.     

Postremission therapy with repeated courses of high-dose cytarabine,idarubicin, and limited autologous stem cell support achieves a very good long-term outcome in European leukemia net favorable and intermediate-risk acute myeloid leukemia

Consolidation treatment in acute myeloid leukemia (AML) patients achieving complete remission (CR) is warranted. High-dose cytarabine (HDAC) is considered first choice in favorable risk and an option in intermediate-risk AML. However, its optimal dose and schedule, as well as the benefit of additional chemotherapy agents remain controversial. Herein, we report on the long-term outcome of consecutive unselected AML patients treated with repeated courses of HDAC, with the addition of idarubicin, followed by autologous peripheral blood stem cell (PBSC) support, in order to limit toxicity, according to Northern Italy Leukemia Group (NILG) AML-01/00 study (EUDRACT number 00400673). Among 338 patients consecutively diagnosed from 2001 to 2017 at our center, 148 with high-risk AML (adverse cytogenetic, isolated FLT3-internal tandem duplication mutation, refractory to first induction) were addressed to allogeneic stem cell transplant. All other cases, 186 patients (55%), median age 53 (range 19–75), were considered standard-risk and received the NILG AML-01/00 program. After achieving CR, patients were mobilized with cytarabine 8 g/sqm to collect autologous CD34+-PBSC and received three consolidation cycles with HDAC (20 g/sqm) plus idarubicin (20 mg/sqm) per cycle, followed by reinfusion of limited doses of CD34+ PBSC (1-2x106/kg). The program was completed by 160 (86%) patients. Toxicity was acceptable. Neutrophils recovered a median of 10 days. Treatment-related mortality was 3/160 (1.8%). After a median follow-up of 66.4 months, overall survival (OS) and relapse-free survival (RFS) at 5-years were 61.4% and 52.4%, respectively. Twenty-eight selected patients aged >65 had similar outcomes. According to European leukemia net-2010 classification, the OS and RFS at 5-years were 76.4% and 65% in favorable risk, without differences between molecular subgroups, 52.3% and 47.2% in Intermediate-I, 45.2% and 36.5% in Intermediate-II risk patients, respectively. In conclusion, consolidation including repeated courses of high dose cytarabine and idarubicin, with limited PBSC support, proved feasible and very effective in nonhigh risk patients. The incorporation of novel agents in its backbone may be tested to further improve patient's prognosis.     

Vampires 2.0? The ethical quandaries of young blood infusion in the quest for eternal life

Medicine, Health Care and Philosophy - Can transfusions of blood plasma slow down ageing or even rejuvenate people? Recent preclinical studies and experimental tests inspired by the technique known...     

Resilience Intervention for Parents of Children with Autism: Findings from a Randomized Controlled Trial of the AMOR Method

Journal of Autism and Developmental Disorders - Parents of children with autism spectrum disorder (ASD) experience elevated stress, yet parent-specific interventions are sparse. Thirty-five parents...     

Functional genetic evaluation of DNA house-cleaning enzymes in the malaria parasite: dUTPase and Ap4AH are essential in Plasmodium berghei but ITPase and NDH are dispensable

Background: Cellular metabolism generates reactive oxygen species. The oxidation and deamination of the deoxynucleoside triphosphate (dNTP) pool results in the formation of non-canonical, toxic dNTPs that can cause mutations, genome instability, and cell death. House-cleaning or sanitation enzymes that break down and detoxify non-canonical nucleotides play major protective roles in nucleotide metabolism and constitute key drug targets for cancer and various pathogens. We hypothesized that owing to their protective roles in nucleotide metabolism, these house-cleaning enzymes are key drug targets in the malaria parasite.

Methods: Using the rodent malaria parasite Plasmodium berghei we evaluate here, by gene targeting, a group of conserved proteins with a putative function in the detoxification of non-canonical nucleotides as potential antimalarial drug targets: they are inosine triphosphate pyrophosphatase (ITPase), deoxyuridine triphosphate pyrophosphatase (dUTPase) and two NuDiX hydroxylases, the diadenosine tetraphosphate (Ap4A) hydrolase and the nucleoside triphosphate hydrolase (NDH).

Results: While all four proteins are expressed constitutively across the intraerythrocytic developmental cycle, neither ITPase nor NDH are required for parasite viability. dutpase and ap4ah null mutants, on the other hand, are not viable suggesting an essential function for these proteins for the malaria parasite.

Conclusions: Plasmodium dUTPase and Ap4A could be drug targets in the malaria parasite.     

Functional and Patient Reported Outcomes Following Total Glans Resurfacing

BackgroundWhilst there is a trend away from aggressive nonorgan sparing surgical treatments for malignant penile disease, a variety of penile preservation options exist but functional outcomes and patient reported outcomes (PROs) in this area are poorly reported to date.AimThe aim of this study is to report functional outcomes and PROs of total glans resurfacing (TGR) in a consecutive series of patients with lichen sclerosis (LS) or localized penile cancer (PC).MethodsFrom 2004 to 2018 a consecutive series of patients underwent TGR for the management of LS or localized PC in a tertiary referral network. Patient clinical records and operative notes were retrospectively reviewed. Statistical analysis was conducted with Stata 12.OutcomesUrinary and sexual outcomes were recorded utilizing both the International Index of Erectile Function (IIEF) and International Prostate Symptom Score (IPSS) validated questionnaires while PROs were extrapolated from a 5-item “ad hoc” telephone questionnaire administered at 1 year post procedure.Results37 consecutive patients were enrolled. Histology results demonstrated LS in 16 patients, with the remaining 21 having a diagnosis of PC. The most common reasons for patient presentation were local pain (32.4%), pruritus (37.8%) and bleeding (29.7%). Median follow-up was 22 (IQR 13–77) months. Median age was 62 (IQR 55–68).Neither of the questionnaires assessing urinary and sexual function showed any significant deterioration after surgery. Glans sensitivity was fully maintained in 89.2% of cases. 94.5% of patients reported to be fully satisfied with the aesthetic appearance of the penis and would consider undergoing the same procedure again if necessary. 91.9% of patients would recommend the same procedure to someone else. An overall improvement of the quality of life was reported by 86.4% of patients.Clinical ImplicationsTGR should be considered a treatment of choice for selected cases of benign or malignant penile lesionsStrengths and LimitationsOur study has some limitations, the first being its retrospective nature. Furthermore, despite being one of the largest series to date, follow-up duration is somewhat limited and a control group is lacking.ConclusionTGR represents an excellent surgical option ensuring satisfactory voiding and sexual function, as well as cosmesis for selected cases of penile lesions.M. Preto, M. Falcone, G. Blecher, et al. Functional and Patient Reported Outcomes Following Total Glans Resurfacing. J Sex Med 2021;18:1099–1103.     

Immunolocalization of VEGF/VEGFR system in human fetal vomeronasal organ during early development

The vomeronasal system (VNS) is an accessory olfactory structure present in most mammals adhibited to the detection of specific chemosignals implied in social and reproductive behavior. The VNS comprises the vomeronasal organ (VNO), vomeronasal nerve and accessory olfactory bulb. VNO is characterized by a neuroepithelium constituted by bipolar neurons and supporting and stem/progenitor cells. In humans, VNO is present during fetal life and is supposed to possess chemoreceptor activity and participate in gonadotropin-releasing hormone neuronal precursor migration toward the hypothalamus. Instead, the existence and functions of VNO in postnatal life is debated. Vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) have been demonstrated to play fundamental roles in various neurogenic events. However, there are no data regarding the localization and possible function of VEGF/VEGFRs in human fetal VNO. Therefore, this study was conceived to investigate the expression of VEGF/VEGFRs in human VNO in an early developmental period (9–12 weeks of gestation), when this organ appears well structured. Coronal sections of maxillofacial specimens were subjected to peroxidase-based immunohistochemistry for VEGF, VEGFR-1 and VEGFR-2. Double immunofluorescence for VEGF, VEGFR-1 or VEGFR-2 and the neuronal marker protein gene product 9.5 (PGP 9.5) was also performed. VEGF expression was evident in the entire VNO epithelium, with particularly strong reactivity in the middle layer. Strongly VEGF-immunostained cells with aspect similar to bipolar neurons and/or their presumable precursors were detected in the middle and basal layers. Cells detaching from the basal epithelial layer and detached cell groups in the surrounding lamina propria showed moderate/strong VEGF expression. The strongest VEGFR-1 and VEGFR-2 expression was detected in the apical epithelial layer. Cells with aspect similar to bipolar neurons and/or their presumable precursors located in the middle and basal layers and the detaching/detached cells displayed a VEGFR-1 and VEGFR-2 reactivity similar to that of VEGF. The basal epithelial layer exhibited stronger staining for VEGFRs than for VEGF. Cells with morphology and VEGF/VEGFR expression similar to those of the detaching/detached cells were also detected in the middle and basal VNO epithelial layers. Double immunofluorescence using anti-PGP 9.5 antibodies demonstrated that most of the VEGF/VEGFR-immunoreactive cells were neuronal cells. Collectively, our findings suggest that during early fetal development the VEGF/VEGFR system might be involved in the presumptive VNO chemoreceptor activity and neuronal precursor migration.