Artificial Pancreas Systems: Closed-Loop Artificial Pancreas Using Subcutaneous Glucose Sensing and Insulin Delivery and a Model Predictive Control Algorithm: Preliminary Studies in Padova and Montpellier

New effort has been made to develop closed-loop glucose control, using subcutaneous (SC) glucose sensing and continuous subcutaneous insulin infusion (CSII) from a pump, and a control algorithm. An approach based on a model predictive control (MPC) algorithm has been utilized during closed-loop control in type 1 diabetes patients. Here we describe the preliminary clinical experience with this approach.Six type 1 diabetes patients (three in each of two clinical investigation centers in Padova and Montpellier), using CSII, aged 36 ± 8 and 48 ± 6 years, duration of diabetes 12 ± 8 and 29 ± 4 years, hemoglobin A1c 7.4% ± 0.1% and 7.3% ± 0.3%, body mass index 23.2 ± 0.3 and 28.4 ± 2.2 kg/m², respectively, were studied on two occasions during 22 h overnight hospital admissions 2–4 weeks apart. A Freestyle Navigator® continuous glucose monitor and an OmniPod® insulin pump were applied in each trial. Admission 1 used open-loop control, while admission 2 employed closed-loop control using our MPC algorithm.In Padova, two out of three subjects showed better performance with the closed-loop system compared to open loop. Altogether, mean overnight plasma glucose (PG) levels were 134 versus 111 mg/dl during open loop versus closed loop, respectively. The percentage of time spent at PG > 140 mg/dl was 45% versus 12%, while postbreakfast mean PG was 165 versus 156 mg/dl during open loop versus closed loop, respectively. Also, in Montpellier, two patients out of three showed a better glucose control during closed-loop trials. Avoidance of nocturnal hypoglycemic excursions was a clear benefit during algorithm-guided insulin delivery in all cases.This preliminary set of studies demonstrates that closed-loop control based entirely on SC glucose sensing and insulin delivery is feasible and can be applied to improve glucose control in patients with type 1 diabetes, although the algorithm needs to be further improved to achieve better glycemic control.     

Anatomic double-bundle ACL reconstruction using a bone–patellar tendon–bone autograft: a technical note

This article describes an original arthroscopic double-bundle anterior cruciate ligament (ACL) reconstruction technique using a bone–patellar tendon–bone autograft. A rectangular patellar bone block, with a double strand patellar tendon, and a double tibial bone block is harvested. The femoral anteromedial tunnel is made using an all-inside technique by the anteromedial portal. The femoral posterolateral (PL) tunnel is created with an outside-in technique, with a 30° divergence between both tunnels. A single tibial tunnel is drilled, the graft is then passed through the tibial tunnel, and the bundles are separately tensioned and fixed with three bioabsorbable interference screws. The femoral AM bone block is fixed by the anteromedial portal, the tibial bone block is then fixed in an oblique manner in order to mimic the ACL orientation with the knee at 30° of flexion. The femoral PL bone block is fixed at the end with the knee in full extension.     

Neural predictors of motor control and impact of visuo‐proprioceptive information in youth

For successful motor control, the central nervous system is required to combine information from the environment and the current body state, which is provided by vision and proprioception respectively. We investigated the relative contribution of visual and proprioceptive information to upper limb motor control and the extent to which structural brain measures predict this performance in youth (n = 40; age range 9–18 years). Participants performed a manual tracking task, adopting in‐phase and anti‐phase coordination modes. Results showed that, in contrast to older participants, younger participants performed the task with lower accuracy in general and poorer performance in anti‐phase than in‐phase modes. However, a proprioceptive advantage was found at all ages, that is, tracking accuracy was higher when proprioceptive information was available during both in‐ and anti‐phase modes at all ages. The microstructural organization of interhemispheric connections between homologous dorsolateral prefrontal cortices, and the cortical thickness of the primary motor cortex were associated with sensory‐specific accuracy of tracking performance. Overall, the findings suggest that manual tracking performance in youth does not only rely on brain regions involved in sensorimotor processing, but also on prefrontal regions involved in attention and working memory. Hum Brain Mapp 38:5628–5647, 2017. © 2017 Wiley Periodicals, Inc.     

Olaratumab for the treatment of advanced soft tissue sarcoma

Introduction: Olaratumab, a human monoclonal antibody against platelet derived growth factor receptor alpha (PDGFR- α), is the first drug that in combination with doxorubicin for the treatment of patients with advanced/metastatic soft tissue sarcoma (STS) that has showed an improved overall survival compared to doxorubicin alone. These initial results are exciting and have the potential to change the landscape of treatment for patients with STS.

Areas covered: This article reviews the development of olaratumab for oncology use by reviewing articles in PubMed for ‘platelet derived growth factor’ and ‘receptor’ and ‘soft tissue sarcoma’. We provide an overview of the published studies to date for olaratumab and specifically the use in soft tissue sarcoma.

Expert commentary: Olaratumab is a well-tolerated drug that, when combined with doxorubicin, has shown an improved overall survival compared to doxorubicin alone and the phase III confirmatory study is eagerly awaited.     

Effects of four carbamate compounds on antioxidant parameters

The effect of four carbamates, aldicarb and its metabolites (aldicarb sulfone and aldicarb sulfoxide) and propoxur on glutathione content and the activity of the enzymes involved in the sulfur-redox cycle in the mammalian cellular model CHO-K1 cells after 24-h exposure were determined. Carbamate exposure resulted in a depletion of intracellular reduced glutathione (GSH) content, no change was observed in oxidized glutathione (GSSG) and a decrease in GSH/GSSG ratio was detected. After carbamates exposition a GSH/GSSG decreases in ranged from 12.44% to 21.35% of control was observed. Depletion of GSH levels was accompanied by the induction of glutathione reductase (GR) after 24h exposure with each of the four carbamates to CHO-K1 cells. After aldicarb sulfone, aldicarb sulfoxide, and propoxur exposure, glutathione peroxidase (GPx) activity increased in CHO-K1 cells by 198%, 32%, and 228% of control, respectively. After aldicarb sulfone and propoxur exposure, glutathione transferase (GST) activities increased by 49% and 230% of control, respectively. Due to the role played by GSH in preventing cytotoxicity via free-radical scavenging, results obtained suggest that high concentrations of aldicarb sulfone and propoxur closely resembling oxidative stress in CHO-K1 cells.     

Transcription factor E4F1 is essential for epidermal stem cell maintenance and skin homeostasis

A growing body of evidence suggests that the multifunctional protein E4F1 is involved in signaling pathways that play essential roles during normal development and tumorigenesis. We generated E4F1 conditional knockout mice to address E4F1 functions in vivo in newborn and adult skin. E4F1 inactivation in the entire skin or in the basal compartment of the epidermis induces skin homeostasis defects, as evidenced by transient hyperplasia in the interfollicular epithelium and alteration of keratinocyte differentiation, followed by loss of cellularity in the epidermis and severe skin ulcerations. E4F1 depletion alters clonogenic activity of epidermal stem cells (ESCs) ex vivo and ends in exhaustion of the ESC pool in vivo, indicating that the lesions observed in the E4F1 mutant skin result, at least in part, from cell-autonomous alterations in ESC maintenance. The clonogenic potential of E4F1 KO ESCs is rescued by Bmi1 overexpression or by Ink4a/Arf or p53 depletion. Skin phenotype of E4F1 KO mice is also delayed in animals with Ink4a/Arf and E4F1 compound gene deficiencies. Our data identify a regulatory axis essential for ESC-dependent skin homeostasis implicating E4F1 and the Bmi1-Arf-p53 pathway.     

Subdural hematoma in infants: can it occur spontaneously? Data from a prospective series and critical review of the literature

Background

Subdural hematomas (SDH) in infants often result from nonaccidental head injury (NAHI), which is diagnosed based on the absence of history of trauma and the presence of associated lesions. When these are lacking, the possibility of spontaneous SDH in infant (SSDHI) is raised, but this entity is hotly debated; in particular, the lack of positive diagnostic criteria has hampered its recognition. The role of arachnoidomegaly, idiopathic macrocephaly, and dehydration in the pathogenesis of SSDHI is also much discussed.

Purpose

We decided to analyze apparent cases of SSDHI from our prospective databank.

Materials and methods

We selected cases of SDH in infants without systemic disease, history of trauma, and suspicion of NAHI. All cases had fundoscopy and were evaluated for possible NAHI. Head growth curves were reconstructed in order to differentiate idiopathic from symptomatic macrocrania.

Results

Sixteen patients, 14 males and two females, were diagnosed with SSDHI. Twelve patients had idiopathic macrocrania, seven of these being previously diagnosed with arachnoidomegaly on imaging. Five had risk factors for dehydration, including two with severe enteritis. Two patients had mild or moderate retinal hemorrhage, considered not indicative of NAHI. Thirteen patients underwent cerebrospinal fluid drainage. The outcome was favorable in almost all cases; one child has sequels, which were attributable to obstetrical difficulties.

Conclusion

SSDHI exists but is rare and cannot be diagnosed unless NAHI has been questioned thoroughly. The absence of traumatic features is not sufficient, and positive elements like macrocrania, arachnoidomegaly, or severe dehydration are necessary for the diagnosis of SSDHI.