Combination Therapy Reverses Hyperglycemia in NOD Mice With Established Type 1 Diabetes

An increasing number of therapies have proven effective at reversing hyperglycemia in the nonobese diabetic (NOD) mouse model of type 1 diabetes (T1D), yet situations of successful translation to human T1D are limited. This may be partly due to evaluating the effect of treating immediately at diagnosis in mice, which may not be reflective of the advanced disease state in humans at disease onset. In this study, we treated NOD mice with new-onset as well as established disease using various combinations of four drugs: antithymocyte globulin (ATG), granulocyte-colony stimulating factor (G-CSF), a dipeptidyl peptidase IV inhibitor (DPP-4i), and a proton pump inhibitor (PPI). Therapy with all four drugs induced remission in 83% of new-onset mice and, remarkably, in 50% of NOD mice with established disease. Also noteworthy, disease remission occurred irrespective of initial blood glucose values and mechanistically was characterized by enhanced immunoregulation involving alterations in CD4⁺ T cells, CD8⁺ T cells, and natural killer cells. This combination therapy also allowed for effective treatment at reduced drug doses (compared with effective monotherapy), thereby minimizing potential adverse effects while retaining efficacy. This combination of approved drugs demonstrates a novel ability to reverse T1D, thereby warranting translational consideration.     

Factors influencing decision‐making processes for unwell residents in residential aged care: Hospital transfer or Residential InReach referral?

Objective

To investigate decision‐making around hospital transfer and/or referral of residents to a Residential InReach (RiR) service in north‐eastern metropolitan Melbourne, Australia, from the perspectives of residential aged care facility (RACF) staff, general practitioners (GPs) and RiR registered nurses (RNs).

Methods

Thirty‐one staff from eight RACFs, five GPs and four RiR RNs participated in individual or group interviews.

Results

Residential aged care facility staff and GPs valued and relied upon RiR to manage unwell residents. Thematic analysis identified RiR utilisation was driven by the following: (i) complexity of decision‐making processes in RACFs; (ii) variability in facility‐based medical and nursing care; and (iii) impact of RiR service outcomes on patients and referrers.

Conclusion

Availability of timely and appropriate medical and nursing care in RACFs was reported to influence transfers to the hospital and/or referrals to RiR. RiR was used to complement or substitute usual care available to residents. Further research and improvements in RACF and RiR resources are required.

     

RCS1, a substrate of APC/C, controls the metaphase to anaphase transition

The anaphase-promoting complex/cyclosome (APC/C) controls the onset of anaphase by targeting securin for destruction. We report here the identification and characterization of a substrate of APC/C, RCS1, as a mitotic regulator that controls the metaphase-to-anaphase transition. We showed that the levels of RCS1 fluctuate in the cell cycle, peaking in mitosis and dropping drastically as cells exit into G₁. Indeed, RCS1 is efficiently ubiquitinated by APC/C in vitro and degraded during mitotic exit in a Cdh1-dependent manner in vivo. APC/C recognizes a unique D-box at the N terminus of RCS1, as mutations of this D-box abolished ubiquitination in vitro and stabilized the mutant protein in vivo. RCS1 controls the timing of the anaphase onset, because the loss of RCS1 resulted in a faster progression from the metaphase to anaphase and accelerated degradation of securin and cyclin B. Biochemically, mitotic RCS1 associates with the NuRD chromatin-remodeling complex, and this RCS1 complex is likely involved in regulating gene expression or chromatin structure, which in turn may control anaphase onset. Our study uncovers a complex regulatory network for the metaphase-to-anaphase transition.     

Long-term unpredictable foraging conditions and physiological stress response in mountain chickadees (Poecile gambeli)

Birds respond to short-term deterioration in foraging conditions by increasing their plasma level of corticosterone but the physiological effects of long-term deterioration in food supplies are not well known. In resident passerine birds that winter in temperate climates, such as the mountain chickadee (Poecile gambeli), the food supply may be limited and unpredictable over long periods of time. Whether the long-term limited and unpredictable food supply has an effect on (a) baseline levels of corticosterone and (b) the adrenocortical stress response to a standardized acute stress of handling and restraint in mountain chickadees was assessed. For a period of 94 days, one group of chickadees was maintained on limited and unpredictable food (food-restricted) and the other group was maintained on an ad libitum food supply. The food-restricted birds had significantly higher baseline levels of corticosterone than those maintained on ad libitum food. All birds responded to the acute stressor by an increasing secretion of corticosterone but there were no differences between the treatment groups in their stress response. There was a significant effect of sex on the stress response, with females reaching higher levels of corticosterone and responding at a faster rate than males. These results suggest that permanent resident birds wintering in harsh environments may have elevated levels of corticosterone on a long-term basis. Whereas other factors, such as day length and ambient temperature, may contribute to energetic hardship during the winter, the results showed that limited and unpredictable food alone can trigger significant changes in baseline levels of plasma corticosterone. The potential costs and benefits of long-term increased corticosterone levels in resident food-caching birds are discussed.     

Radiologic abnormalities and autonomic neuropathology in the digestive tract of the ketonuric diabetic Chinese hamster

Summary Barium x-ray patterns of ketonuric diabetic Chinese hamsters displayed marked dilatation of the stomach, small and large intestine. Hypomotility was manifested by flocculation of barium in the small and large bowel. Impaired transit time was further characterized by prolonged emptying of the stomach (mean 570 min diabetics; 200 min controls) and delayed stool formation (mean 230 min diabetics; and 100 min controls) and passage (mean 457 min diabetics; 210 min controls). Ultrastructural analysis of Auerbach's myenteric plexuses of the small intestine indicated acute degeneration in certain distal, unmyelinated axons. Swelling, deposition of glycogen, aggregation of neurofilaments and dense accumulation of lamellar bodies were observed. The severity and frequency of barium flocculation, glycogen deposition, aggregation of neurofilaments and lamellar inclusion bodies in axons were directly related to duration of ketonuria. The data strongly suggest that autonomic neuropathology in the plexuses of Auerbach may be a critical factor underlying gastrointestinal dysfunction in the ketonuric diabetic Chinese hamster.