Stress-opioid interactions: a comparison of morphine and methadone

The utility of methadone and morphine for analgesia and of methadone for substitution therapy for heroin addiction is a consequence of these drugs acting as opioid receptor agonists.We compared the cataleptogenic and antinociceptive effects of single subcutaneous doses of methadone hydrochloride (1–4 mg/kg) and morphine sulfate (2.5–10 mg/kg) using catalepsy and hot-plate tests, and examined the effects of the highest doses of the drugs on Fos protein expression in selected brain regions in male Sprague-Dawley rats. Methadone had greater cataleptogenic and analgesic potency than morphine. Fos immunohistochemistry revealed substantial effects on the Fos response of both the stress induced by the experimental procedures and of the drug exposure itself. There were three response patterns identified: 1) drug exposure, but not stress, significantly elevated Fos-positive cell counts in the caudate-putamen; 2) stress alone and stress combined with drug exposure similarly elevated Fos-positive cell counts in the nucleus accumbens and cingulate cortex; and 3) methadone and morphine (to a lesser extent) counteracted the stimulatory effect of nonpharmacological stressors on Fos protein expression in the somatosensory cortex barrel field, and Fos-positive cell counts in this region correlated negatively with both the duration of catalepsy and the latency time in the hot-plate test. The overlap between brain regions reacting to nonpharmacological stressors and those responding to exogenous opioids suggests that stress contributes to opioid-induced neuronal activation.     

Stankiewicz-Isidor syndrome: expanding the clinical and molecular phenotype

PurposeHaploinsufficiency of PSMD12 has been reported in individuals with neurodevelopmental phenotypes, including developmental delay/intellectual disability (DD/ID), facial dysmorphism, and congenital malformations, defined as Stankiewicz-Isidor syndrome (STISS). Investigations showed that pathogenic variants in PSMD12 perturb intracellular protein homeostasis. Our objective was to further explore the clinical and molecular phenotypic spectrum of STISS.MethodsWe report 24 additional unrelated patients with STISS with various truncating single nucleotide variants or copy-number variant deletions involving PSMD12. We explore disease etiology by assessing patient cells and CRISPR/Cas9-engineered cell clones for various cellular pathways and inflammatory status.ResultsThe expressivity of most clinical features in STISS is highly variable. In addition to previously reported DD/ID, speech delay, cardiac and renal anomalies, we also confirmed preaxial hand abnormalities as a feature of this syndrome. Of note, 2 patients also showed chilblains resembling signs observed in interferonopathy. Remarkably, our data show that STISS patient cells exhibit a profound remodeling of the mTORC1 and mitophagy pathways with an induction of type I interferon-stimulated genes.ConclusionWe refine the phenotype of STISS and show that it can be clinically recognizable and biochemically diagnosed by a type I interferon gene signature.     

The outcome of a bilateral leg amputation according to Syme;s technique as a result of posttraumatic complications: a case report

Background. The purpose of this article is to present the problems encountered in treatment and rehabilitation, including prosthesis fitting, in the case of a 17-year-old female patient who underwent a bilateral leg amputation using Syme's method. Case history. The patient incurred crushing injuries of both feet and the knee joints, resulting from a severe multi-organ injury. As a result of post-traumatic changes and deformations of the feet, including algodystrophic changes, amputation proved to be the only procedure that would restore the patient locomotive capacity. Outcome. As a result of the treatment applied, the patient regained the ability to move about, while the primary limitation on her locomotive abilities turned out to be the status of her knee joints, which had been severely damaged in the accident.     

Mitogenomic differences between the normal and tumor cells of colorectal cancer patients

So far, a reliable spectrum of mitochondrial DNA mutations in colorectal cancer cells is still unknown, and neither is their significance in carcinogenesis. Indeed, it remains debatable whether mtDNA mutations are “drivers” or “passengers” of colorectal carcinogenesis. Thus, we analyzed 200 mitogenomes from normal and cancer tissues of 100 colorectal cancer patients. Minority variant mutations were detected at the 1% level. We showed that somatic mutations frequently occur in colorectal cancer cells (75%) and are randomly distributed across the mitochondrial genome. Mutational signatures of somatic mitogenome mutations suggest that they might arise through nucleotide deamination due to oxidative stress. The majority of somatic mutations localized within the coding region (in positions not known from the human phylogeny) and was potentially pathogenic to cell metabolism. Further analysis suggested that the relaxation of negative selection in the mitogenomes of colorectal cancer cells may allow accumulation of somatic mutations. Thus, a shift in glucose metabolism from oxidative phosphorylation to glycolysis may create advantageous conditions for accumulation of mtDNA mutations. Considering the fact that the presence of somatic mtDNA mutations was not associated with any clinicopathological features, we suggested that mtDNA somatic mutations are “passengers” rather than the cause of colorectal carcinogenesis.     

Reconstruction of large bone defects with arthroplasty in the treatment of bone tumors of the hip joint

Background. In a retrospective study of the time of survival, the quality of life and the methods used to reconstruct large bone defects around the hip joint, we examined 13 patients treated surgically in our orthopedic ward between 1989 and 2004 for primary and secondary bone tumors. Material and methods. The study group included 11 women and 7 men, mean age 56.4 years. 5 patients (22%) had primary tumors: myeloma in 2 patients, chondrosarcoma in 2 patients, and MFH in 1 patient. In 13 patients (87%) there were metastatic lesions. The technical solutions used to reconstruct large bone defects included post-resection endoprothesis in 5 cases, total endoprothesis in 10 cases, and partial endoprosthesis in 3 cases. The treatment outcome was evaluated using the authors' own clinical scoring system, which covers pain, range of motion, muscle strength, ambulation, and activities of daily living. Results. There were no deaths in the early post-operative period. The mean post-operative follow-up time was 15 months. Excellent or good outcomes were achieved in 92.3% of cases: good ambulation, independence in activities of daily living, and no pain. The mean time of patient survival was 16.5 months (range: 10-42 months). Conclusions. Surgical reconstruction of large bone defects due to a malignant tumor around the hip joint is very effective in relieving pain, improving ambulation and increasing daily activities. The time of survival of patients after resection of bone tumor and hip replacement confirms the usefulness of this treatment method.     

Interphase FISH screening for the LCR-mediated common rearrangement of isochromosome 17q in primary myelofibrosis

Non-allelic homologous recombination (NAHR) between low-copy repeats (LCRs) has been implicated recently in somatic rearrangements including isochromosome i(17q), which is associated with hematologic malignancies as well as solid tumors. In hematological malignancies, the most common i(17q) breakpoint results from LCR-mediated NAHR, which creates a dicentric chromosome, idic(17)(p11.2). We report an elderly patient who presented with primary myelofibrosis (MF) with myeloid metaplasia (MMM), associated with idic(17)(p11.2) as the sole chromosomal abnormality, making this the first idic(17)(p11.2) myeloproliferative case reported in which the breakpoints are mapped to the breakpoint cluster region in proximal 17p. The rearrangement breakpoint maps to the previously defined LCR cluster, further suggesting that the genomic architecture of proximal 17p may be responsible for the formation of the majority of i(17q) cases. We describe our development of a rapid screening test using interphase FISH to detect idic(17)(p11.2), discuss the potential prognostic value of this molecular diagnostic test, and examine the relevance of LCR-mediated NAHR to common rearrangements in neoplasms.     

EPR studies of free radicals decay and survival in gamma irradiated aminoglycoside antibiotics: sisomicin, tobramycin and paromomycin

Radiation sterilization technology is more actively used now that any time because of its many advantages. Gamma radiation has high penetrating power, relatively low chemical reactivity and causes small temperature rise. But on the other hand radiosterilization can lead to radiolytic products appearing, in example free radicals. Free radicals in radiative sterilized sisomicin, tobramycin and paromomycin were studied by electron paramagnetic resonance (EPR) spectroscopy. Dose of gamma irradiation of 25kGy was used. Concentrations and properties of free radicals in irradiated antibiotics were studied. EPR spectra were recorded for samples stored in air and argon. For gamma irradiated antibiotics strong EPR lines were recorded. One- and two-exponential functions were fitted to experimental points during testing and researching of time influence of the antibiotics storage to studied parameters of EPR lines. Our study of free radicals in radiosterilized antibiotics indicates the need for characterization of medicinal substances prior to sterilization process using EPR values. We propose the concentration of free radicals and other spectroscopic parameters as useful factors to select the optimal type of sterilization for the individual drug. The important parameters are i.a. the τ time constants and K constants of exponential functions. Time constants τ give us information about the speed of free radicals concentration decrease in radiated medicinal substances. The constant K(0) shows the free radicals concentration in irradiated medicament after long time of storage.