Glargine and detemir: Safety and efficacy profiles of the long-acting basal insulin analogs

Diabetes mellitus is a growing public health concern in the US and worldwide. Insulin therapy is the cornerstone of diabetes therapy, and the use of basal insulins will increase as clinicians strive to help their patients reach glycemic goals. Basal insulins have been continually improved upon over the years, and the long-acting basal insulin analogs, glargine and detemir, have many pharmacokinetic and pharmacodynamic advantages over neutral protamine Hagedorn insulin, namely, less variable absorption profiles, a less pronounced peak in effect, and a longer duration of action. Overall, glargine and detemir do not differ greatly in their safety and efficacy profiles. Major differences between the two include lower within-subject variability, lower risk of hypoglycemia, and a weight-sparing effect with insulin detemir. This review summarizes data from the key pharmacokinetic and pharmacodynamic studies, as well as clinical and observational studies to elucidate the role of each basal insulin analog in therapy

Sensitivity and specificity of MRI in detecting malignant spinal cord compression and in distinguishing malignant from benign compression fractures of vertebrae

The accuracy of magnetic resonance (MR) imaging in the detection of metastatic compression of the spinal cord and the cauda equina (MCCE) in 75 patients with known primary maglignancy outside the central nervous system is determined retrospectively by comparing the MR results with findings of myelography, surgery, clinical follow-up and autopsy. The sensitivity is 93%, the specificity 97% and the overall accuracy 95%. The signal intensity measured in the sagittal MR images of a collapsed vertebral body is divided by that of an average of three adjacent normal vertebrae to form a signal intensity ratio (SIR). The SIRs of 41 metastatic and 15 post-traumatic collapsed vertebrae are calculated. A ratio of 0.8 has the most differentiating power. All benign and one malignant compressed vertebrae have SIRs greater than 0.8.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27167/1/0000162.pd

Henry Kandrup's Ideas About Relaxation of Stellar Systems

Henry Kandrup wrote prolifically on the problem of relaxation of stellar systems. His picture of relaxation was significantly more refined than the standard description in terms of phase mixing and violent relaxation. In this article, I summarize Henry's work in this and related areas.Comment: 11 pages. To appear in "Nonlinear Dynamics in Astronomy and Physics, A Workshop Dedicated to the Memory of Professor Henry E. Kandrup", ed. J. R. Buchler, S. T. Gottesman and M. E. Maho

MYCN expression induces replication stress and sensitivity to PARP inhibition in neuroblastoma

This study investigates the influence expression of the MYCN oncogene has on the DNA damage response, replication fork progression and sensitivity to PARP inhibition in neuroblastoma. In a panel of neuroblastoma cell lines, MYCN amplification or MYCN expression resulted in increased cell death in response to a range of PARP inhibitors (niraparib, veliparib, talazoparib and olaparib) compared to the response seen in non-expressing/amplified cells. MYCN expression slowed replication fork speed and increased replication fork stalling, an effect that was amplified by PARP inhibition or PARP1 depletion. Increased DNA damage seen was specifically induced in S-phase cells. Importantly, PARP inhibition caused a significant increase in the survival of mice bearing MYCN expressing tumours in a transgenic murine model of MYCN expressing neuroblastoma. Olaparib also sensitized MYCN expressing cells to camptothecin- and temozolomide-induced cell death to a greater degree than non-expressing cells. In summary, MYCN expression leads to increased replication stress in neuroblastoma cells. This effect is exaggerated by inhibition of PARP, resulting in S-phase specific DNA damage and ultimately increased tumour cell death. PARP inhibition alone or in combination with classical chemotherapeutics is therefore a potential therapeutic strategy for neuroblastoma and may be more effective in MYCN expressing tumours

Treatment of Chinese adolescents with anorexia nervosa in Hong Kong: The gap between treatment expectations and outcomes.

BACKGROUND AND OBJECTIVE: Anorexia nervosa (AN) is one of the most difficult-to-treat psychiatric disorders. AN is associated with individual vulnerability, societal and family factors. There has been limited research in Asia regarding the patients or their families' perceptions on its treatment. This study explored the perceived treatment outcomes among Chinese families having adolescents with AN. METHODS: Qualitative interviews were conducted on parents of adolescents with AN recruited through an eating disorder association in Hong Kong to understand their views and experiences regarding the help-seeking and treatment process. RESULTS: The parents expressed dissatisfaction towards help-seeking and treatment outcomes, including relationships with health professionals, hospitalization, health professionals' knowledge of AN, understanding of the treatment model and parents' role, amount of psychological support, and coordination among health professionals. The parents were unclear about the treatment plan as they received little explanation from the health professionals. The parents perceived that the AN treatment only focused on weight restoration with limited psychological support. Home diet monitoring was seen as a harsh task which worsened the relationship with their children. The parents often needed to take up the coordinator role and search around for different health professionals and integrate their advices by themselves. CONCLUSIONS: The study shows that limited psychoeducation, communication and coordination in the treatment for AN are major problems in a Chinese context. Open communication between the health professionals and the parents about the expected treatment outcomes and limitations is needed to enhance their mutual trust. Besides, treatment should emphasize not only family involvement but also empower them to fight against AN

Protein interactions in Xenopus germ plasm RNP particles

Hermes is an RNA-binding protein that we have previously reported to be found in the ribonucleoprotein (RNP) particles of Xenopus germ plasm, where it is associated with various RNAs, including that encoding the germ line determinant Nanos1. To further define the composition of these RNPs, we performed a screen for Hermes-binding partners using the yeast two-hybrid system. We have identified and validated four proteins that interact with Hermes in germ plasm: two isoforms of Xvelo1 (a homologue of zebrafish Bucky ball) and Rbm24b and Rbm42b, both RNA-binding proteins containing the RRM motif. GFP-Xvelo fusion proteins and their endogenous counterparts, identified with antisera, were found to localize with Hermes in the germ plasm particles of large oocytes and eggs. Only the larger Xvelo isoform was naturally found in the Balbiani body of previtellogenic oocytes. Bimolecular fluorescence complementation (BiFC) experiments confirmed that Hermes and the Xvelo variants interact in germ plasm, as do Rbm24b and 42b. Depletion of the shorter Xvelo variant with antisense oligonucleotides caused a decrease in the size of germ plasm aggregates and loosening of associated mitochondria from these structures. This suggests that the short Xvelo variant, or less likely its RNA, has a role in organizing and maintaining the integrity of germ plasm in Xenopus oocytes. While GFP fusion proteins for Rbm24b and 42b did not localize into germ plasm as specifically as Hermes or Xvelo, BiFC analysis indicated that both interact with Hermes in germ plasm RNPs. They are very stable in the face of RNA depletion, but additive effects of combinations of antisense oligos suggest they may have a role in germ plasm structure and may influence the ability of Hermes protein to effectively enter RNP particles

Nuclear Localization of Cyclin B1 Controls Mitotic Entry After DNA Damage

Mitosis in human cells is initiated by the protein kinase Cdc2-cyclin B1, which is activated at the end of G2 by dephosphorylation of two inhibitory residues, Thr14 and Tyr15. The G2 arrest that occurs after DNA damage is due in part to stabilization of phosphorylation at these sites. We explored the possibility that entry into mitosis is also regulated by the subcellular location of Cdc2-cyclin B1, which is suddenly imported into the nucleus at the end of G2. We measured the timing of mitosis in HeLa cells expressing a constitutively nuclear cyclin B1 mutant. Parallel studies were performed with cells expressing Cdc2AF, a Cdc2 mutant that cannot be phosphorylated at inhibitory sites. Whereas nuclear cyclin B1 and Cdc2AF each had little effect under normal growth conditions, together they induced a striking premature mitotic phenotype. Nuclear targeting of cyclin B1 was particularly effective in cells arrested in G2 by DNA damage, where it greatly reduced the damage-induced G2 arrest. Expression of nuclear cyclin B1 and Cdc2AF also resulted in significant defects in the exit from mitosis. Thus, nuclear targeting of cyclin B1 and dephosphorylation of Cdc2 both contribute to the control of mitotic entry and exit in human cells

Can Generalist Foundation Models Outcompete Special-Purpose Tuning? Case Study in Medicine

Generalist foundation models such as GPT-4 have displayed surprising capabilities in a wide variety of domains and tasks. Yet, there is a prevalent assumption that they cannot match specialist capabilities of fine-tuned models. For example, most explorations to date on medical competency benchmarks have leveraged domain-specific training, as exemplified by efforts on BioGPT and Med-PaLM. We build on a prior study of GPT-4's capabilities on medical challenge benchmarks in the absence of special training. Rather than using simple prompting to highlight the model's out-of-the-box capabilities, we perform a systematic exploration of prompt engineering. We find that prompting innovation can unlock deeper specialist capabilities and show that GPT-4 easily tops prior leading results for medical benchmarks. The prompting methods we explore are general purpose, and make no specific use of domain expertise, removing the need for expert-curated content. Our experimental design carefully controls for overfitting during the prompt engineering process. We introduce Medprompt, based on a composition of several prompting strategies. With Medprompt, GPT-4 achieves state-of-the-art results on all nine of the benchmark datasets in the MultiMedQA suite. The method outperforms leading specialist models such as Med-PaLM 2 by a significant margin with an order of magnitude fewer calls to the model. Steering GPT-4 with Medprompt achieves a 27% reduction in error rate on the MedQA dataset over the best methods to date achieved with specialist models and surpasses a score of 90% for the first time. Beyond medical problems, we show the power of Medprompt to generalize to other domains and provide evidence for the broad applicability of the approach via studies of the strategy on exams in electrical engineering, machine learning, philosophy, accounting, law, nursing, and clinical psychology.Comment: 21 pages, 7 figure