Synthesis and biological evaluation of an orally active glycosylated endomorphin-1

The endogenous opioid peptide endomorphin-1 (1) was modified by attachment of lactose to the N-terminus via a succinamic acid spacer to produce compound 2. The carbohydrate modification significantly improved the metabolic stability and membrane permeability of 2 while retaining μ-opioid receptor binding affinity and agonist activity. Analogue 2 produced dose-dependent antinociceptive activity following intravenous administration in a chronic constriction injury (CCI) rat model of neuropathic pain with an ED(50) of 8.3 (± 0.8) μmol/kg. The corresponding ED(50) for morphine was 2.6 (± 1.4) μmol/kg. Importantly, compound 2 produced dose-dependent pain relief after oral administration in CCI rats (ED(50) = 19.6 (± 1.2) μmol/kg), which was comparable with that of morphine (ED(50) = 20.7 (±3.6) μmol/kg). Antineuropathic effects of analogue 2 were significantly attenuated by pretreatment of animals with the opioid antagonist naloxone, confirming opioid receptor-mediated analgesia. In contrast to morphine, no significant constipation was produced by compound 2 after oral administration.     

A placebo-controlled study to assess Standardized Field Sobriety Tests performance during alcohol and cannabis intoxication in heavy cannabis users and accuracy of point of collection testing devices for detecting THC in oral fluid

Rationale

Standardized Field Sobriety Tests (SFST) and oral fluid devices are used to screen for driving impairment and roadside drug detection, respectively. SFST have been validated for alcohol, but their sensitivity to impairment induced by other drugs is relatively unknown. The sensitivity and specificity for Δ⁹-tetrahydrocannabinol (THC) of most oral fluid devices have been low.

Objective

This study assessed the effects of smoking cannabis with and without alcohol on SFST performance. Presence of THC in oral fluid was examined with two devices (Dr?ger Drug Test? 5000 and Securetec Drugwipe? 5).

Methods

Twenty heavy cannabis users (15 males and 5 females; mean age, 24.3?years) participated in a double-blind, placebo-controlled study assessing percentage of impaired individuals on the SFST and the sensitivity of two oral fluid devices. Participants received alcohol doses or alcohol placebo in combination with 400?μg/kg body weight THC. We aimed to reach peak blood alcohol concentration values of 0.5 and 0.7?mg/mL.

Results

Cannabis was significantly related to performance on the one-leg stand (p?=?0.037). Alcohol in combination with cannabis was significantly related to impairment on horizontal gaze nystagmus (p?=?0.029). The Dr?ger Drug Test? 5000 demonstrated a high sensitivity for THC, whereas the sensitivity of the Securetec Drugwipe? 5 was low.

Conclusions

SFST were mildly sensitive to impairment from cannabis in heavy users. Lack of sensitivity might be attributed to tolerance and time of testing. SFST were sensitive to both doses of alcohol. The Dr?ger Drug Test? 5000 appears to be a promising tool for detecting THC in oral fluid as far as correct THC detection is concerned.     

Outbreak of SARS-CoV-2 B.1.1.7 Lineage after Vaccination in Long-Term Care Facility,Germany, February–March 2021

One week after second vaccinations were administered, an outbreak of B.1.1.7 lineage severe acute respiratory syndrome coronavirus 2 infections occurred in a long-term care facility in Berlin, Germany, affecting 16/20 vaccinated and 4/4 unvaccinated residents. Despite considerable viral loads, vaccinated residents experienced mild symptoms and faster time to negative test results.     

Multiband accelerated spin‐echo echo planar imaging with reduced peak RF power using time‐shifted RF pulses

Purpose:

To evaluate an alternative method for generating multibanded radiofrequency (RF) pulses for use in multiband slice‐accelerated imaging with slice‐GRAPPA unaliasing, substantially reducing the required peak power without bandwidth compromises. This allows much higher accelerations for spin‐echo methods such as SE‐fMRI and diffusion‐weighted MRI where multibanded slice acceleration has been limited by available peak power.

Theory and Methods:

Multibanded “time‐shifted” RF pulses were generated by inserting temporal shifts between the applications of RF energy for individual bands, avoiding worst‐case constructive interferences. Slice profiles and images in phantoms and human subjects were acquired at 3 T.

Results:

For typical sinc pulses, time‐shifted multibanded RF pulses were generated with little increase in required peak power compared to single‐banded pulses. Slice profile quality was improved by allowing for higher pulse bandwidths, and image quality was improved by allowing for optimum flip angles to be achieved.

Conclusion:

A simple approach has been demonstrated that significantly alleviates the restrictions imposed on achievable slice acceleration factors in multiband spin‐echo imaging due to the power requirements of multibanded RF pulses. This solution will allow for increased accelerations in diffusion‐weighted MRI applications where data acquisition times are normally very long and the ability to accelerate is extremely valuable. Magn Reson Med 69:1261–1267, 2013 Wiley Periodicals, Inc.     

Does Time Spent on Household Activities or Housework Stress Complicate Recovery Following Coronary Artery Bypass Surgery?

ABSTRACT

Objectives: The purpose of the present study was to examine the role of household activities and housework stress as factors contributing to gender differences in recovery following coronary artery bypass graft (CABG) surgery. Therefore, the impact of time spent on household activities and housework stress on physical functioning (PF) was explored.

Methods: Psychosocial data were measured two months and again one year after CABG in a sample of 351 patients (23% women) recruited within one week before surgery. Self-report questionnaires included assessment of household responsibilities, depression (PHQ–9), and PF (SF-36 subscale).

Results: The results revealed that, following CABG, women spent more time on household activities and experienced markedly more stress due to these activities than men. Surprisingly, only housework stress was associated with poorer PF, whereas the time spent on household activities did not explain differences in PF in men and women. Finally, household responsibilities were not associated with the poorer recovery of the female CABG patient.

Discussion: In conclusion, our results do not support the advice that women should not resume household activities two months after surgery. More research is needed to establish valid guidelines.     

Impact of early intensified postoperative corticosteroids on immune reaction rates after Descemet membrane endothelial keratoplasty (DMEK)

Graefe's Archive for Clinical and Experimental Ophthalmology -     

Combination of an EGFR blocker and a COX‐2 inhibitor for the treatment of advanced cutaneous squamous cell carcinoma

Cutaneous squamous cell carcinoma (SCC) is one of the most common cancers worldwide. Epidermal growth factor receptor (EGFR) is expressed at the cell surface by more than 90% of SCCs and its activation is responsible for cell cycle progression, proliferation, survival, angiogenesis and metastasis. Cyclooxygenase‐2 (COX‐2) is an enzyme up‐regulated through EGFR signaling and responsible for some of the EGFR‐dependent biological effects. An 88‐year‐old man presented with a recurrent, locoregionally meta‐static SCC of the right parietal region, which was resistant to radiotherapy. With a combination therapy of an EGFR blocker (cetuximab) and a COX‐2 inhibitor (celecoxib), the tumor regressed partially and the patient's Karnofsky index improved. We speculate that the combined use of cetuxi‐mab and COX‐2 inhibitors can be a new and effective therapy for advanced and recurrent cutaneous SCCs.