Appendectomy and asthma: a search for an association in older subjects.

INTRODUCTION: Several risk factors found to be associated with postoperative complications and cancer surgery, which carry a significant morbidity risk to cancer patients. Therefore, prehabilitation is necessary to improve the functional capability and nutritional status of a patient prior to surgery, so that the patient can withstand any postoperative activity and associated deterioration. Thus, this study aims to assess the effectiveness of prehabilitation interventions on the functional status of patients with gastric and oesophageal cancer who underwent esophagectomy and gastrectomy. MATERIAL AND METHODS: An interventional study was carried out among oesophageal and gastric cancer patients who had undergone surgery at the National Cancer Institute of Malaysia. The prehabilitation process took a maximum of two weeks, depending on the patient's optimisation before surgery. The prehabilitation is based on functional capacity (ECOG performance status), muscle function (handgrip strength), cardio-respiratory function (peak flow meter) and nutritional status (calorie and protein). Postoperative outcomes are measured based on the length of hospital stay, complications, and Clavien-Dindo Classification. RESULTS: Thirty-one patients were recruited to undergo a prehabilitation intervention prior to gastrectomy (n=21) and esophagectomy (n=10). Demographically, most of the cancer patients were males (67.7%) with an ideal mean of BMI (23.5±6.0). Physically, the majority of them had physical class (ASA grade) Grade 2 (67.7%), ECOG performance status of 1 (61.3%) and SGA grade B (51.6%). The functional capacity and nutritional status showed a significant improvement after one week of prehabilitation interventions: peak expiratory flow meter (p<0.001), handgrip (p<0.001), ECOG performance (p<0.001), walking distance (p<0.001), incentive spirometry (p<0.001), total body calorie (p<0.001) and total body protein (p=0.004). However, those patients who required two weeks of prehabilitation for optimization showed only significant improvement in peak expiratory flow meter (p<0.001), handgrip (p<0.001), and incentive spirometry (p<0.001). Prehabilitation is significantly associated postoperatively with the length of hospital stay (p=0.028), complications (p=0.011) and Clavien-Dindo Classification (p=0.029). CONCLUSION: Prehabilitation interventions significantly increase the functional capacity and nutritional status of cancer patients preoperatively; concurrently reducing hospital stays and complications postoperatively. However, certain cancer patients might require over two weeks of prehabilitation to improve the patient's functional capacity and reduce complications postoperatively.

[Clinical efficacy and safety of venetoclax combined with multidrug chemotherapy in the treatment of 15 patients with relapsed or refractory early T-cell precursor acute lymphoblastic leukemia].

Objective: To explore the efficacy and safety of Venetoclax combined with multidrug chemotherapy in patients with relapsed or refractory early T-cell precursor acute lymphoblastic leukemia (R/R ETP-ALL) . Methods: This study retrospectively analyzed 15 patients with R/R ETP-ALL who received Venetoclax combined with multidrug chemotherapy from December 2018 to February 2022. Among them, eight cases were combined with demethylated drugs, four cases were combined with demethylated drugs and HAAG chemotherapy regimen, two cases were combined with demethylated drugs and CAG regimen, and one case was combined with Cladribine. Specific usage and dosage of Venetoclax: 100 mg on day 1, 200 mg on day 2, 400 mg on day 3-28, orally; when combined with azole antifungal drugs, dosage was reduced to 100 mg/d. Results: Fifteen patients (10 males and 5 females) with R/R ETP-ALL were treated with Venetoclax and multidrug chemotherapy with a median age of 35 (12-42) years old. Of 4 refractory and 11 relapsed patients, the efficacy was evaluated on the 21th day following combined chemotherapy: the overall response rate, the complete response (CR) rate, and the CR with incomplete hematological recovery (CRi) rate were 67.7% (10/15), 60.0% (9/15), and 6.7% (1/15), respectively. For the overall study population, the 12-month overall survival (OS) rate was 60.0%, and the median OS was 17.7 months. The disease-free survival (DFS) rate of all CR patients at 12 months was 60.0%, and the median DFS did not reach. About 14 patients had Ⅲ-Ⅳ hematological toxicity, but these adverse reactions were all controllable. No adverse reaction in the nervous system and tumor lysis syndrome occurred in this study, and no adverse reaction of organs above grade Ⅲ occurred. Conclusion: Venetoclax combined with multidrug chemotherapy may be a safe and promising treatment option for patients with R/R ETP-ALL.

An evaluation of direct PCR assays for the detection and quantification of Porphyromonas gingivalis.

Porphyromonas gingivalis has been linked to the development and progression of oesophageal squamous cell carcinoma (ESCC), and is considered to be a high-risk factor for ESCC. Currently, the commonly used methods for P. gingivalis detection are culture or DNA extraction-based, which are either time and labour intensive especially for high-throughput applications. We aimed to establish and evaluate a rapid and sensitive direct quantitative polymerase chain reaction (qPCR) protocol for the detection of P. gingivalis without DNA extraction which is suitable for large-scale epidemiological studies. Paired gingival swab samples from 192 subjects undergoing general medical examinations were analysed using two direct and one extraction-based qPCR assays for P. gingivalis. Tris-EDTA buffer-based direct qPCR (TE-direct qPCR), lysis-based direct qPCR (lysis-direct qPCR) and DNA extraction-based qPCR (kit-qPCR) were used, respectively, in 192, 132 and 60 of these samples for quantification of P. gingivalis. The sensitivity and specificity of TE-direct qPCR was 95.24% and 100% compared with lysis-direct qPCR, which was 100% and 97.30% when compared with kit-qPCR; TE-direct qPCR had an almost perfect agreement with lysis-direct qPCR (κ = 0.954) and kit-qPCR (κ = 0.965). Moreover, the assay time used for TE-direct qPCR was 1.5 h. In conclusion, the TE-direct qPCR assay is a simple and efficient method for the quantification of oral P. gingivalis and showed high sensitivity and specificity compared with routine qPCR.

Impairment of brain mitochondrial function by hydrogen peroxide.

Hydrogen peroxide, at concentrations comparable to those observed under some pathological conditions, produced a concentration-dependent inhibition of state 3 (ADP-stimulated) and uncoupled mitochondrial respiratory activity. The ADP:O ratio was also substantially reduced. In contrast, the organic peroxide, t-butylhydroperoxide at the same concentrations produced no significant changes in respiratory activity. Intramitochondrial glutathione was oxidised to a similar extent in the presence of hydrogen peroxide or t-butylhydroperoxide. Thus, changes in this endogenous antioxidant apparently did not underlie the different responses to these peroxides. The effects of hydrogen peroxide were not altered by deferoxamine indicating that the extramitochondrial generation of hydroxyl radicals was not likely to be involved. However, modifications arising from the generation of hydroxyl radicals within the mitochondria remain a likely contributor to the observed deleterious effects on respiratory function. The inhibitory effects of hydrogen peroxide were greatest when pyruvate plus malate were present as respiratory substrates. Lesser inhibition was seen with glutamate plus malate and no significant inhibitory effects were detected in the presence of succinate. The findings suggest that mitochondrial components involved in pyruvate oxidation were particularly sensitive to the hydrogen peroxide treatment. However, no significant change was seen in activity of either the pyruvate dehydrogenase complex or NADH-ubiquinone oxidoreductase (complex I) when measured directly following treatment of the mitochondria with hydrogen peroxide.

Thapsigargin enhances camptothecin-induced apoptosis in cardiomyocytes.

Topoisomerase I inhibitors are promising new chemotherapeutic agents for the treatment of certain malignancies. The present study investigated the impact of the topoisomerase I inhibitor camptothecin on cell death in cardiomyocytes and sought to determine whether the sesquiterpene gamma-lactone--thapsigargin, that alter sarcoplasmic reticulum calcium flux, modulates the effect of camptothecin on the cardiomyocyte. Camptothecin-induced cell death was demonstrated in cardiomyocytes maintained in culture, from 7 day old embryonic chick hearts, by the trypan blue and the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assay, two independent indicators of the loss of cell viability. The type of cell death was attributed to apoptosis based on cell structure, DNA fragmentation and flow cytometry studies. Camptothecin-treated cardiomyocytes were shrunken with membrane blebs and nuclear fragmentation. Camptothecin produced a dose-dependent increase in DNA fragments of 180 base pairs, or multiples thereof, which are characteristic of apoptosis. A two-fold increase in this type of DNA fragmentation was produced by camptothecin (10 microM) compared to control (diluent-treated) cells. Flow cytometry analysis of populations of 10,000 cardiomyocytes stained with propidium iodide demonstrated a significant increase in the proportion of the population with alterations of DNA content consistent with apoptosis. Pretreatment of cells with thapsigargin, which selectively inhibits sarcoplasmic reticulum and endoplasmic reticulum Ca+2-dependent ATPase, significantly augmented camptothecin-induced apoptosis. Exploring further the role of calcium in camptothecin-induced cell death, we found that the Ca+2 chelator EGTA decreased camptothecin-induced DNA fragmentation. These data indicate the potential for cardiotoxicity from camptothecin through the process of apoptosis and suggest that agents which affect cellular calcium regulation enhance camptothecin-induced apoptosis.

Chemosensitizing activity of caffeic acid in multidrug-resistant MCF-7/Dox human breast carcinoma cells.

The chemosensitizing activity of caffeic acid was examined in parent MCF-7 and multidrug-resistant MCF-7/Dox human breast carcinoma cells. In clonogenic assays, MCF-7/Dox cell was about 135-fold less sensitive to doxorubicin than MCF-7 cells. Caffeic acid (10 microM) slightly altered the colony-forming ability of MCF-7 cells, and markedly reduced the IC50 of doxorubicin (Dox) from 10.8 +/- 1.3 microM to 0.83 +/- 0.21 microM in MCF-7/Dox cells. When compared to MCF-7/Dox cells, intracellular accumulations of [14C] Dox in MCF-7 cells for 1 hour and 12 hours were elevated 2.3-fold and about 6.4-fold, respectively. Doxorubicin accumulations in MCF-7 and MCF-7/Dox cells were not altered in the presence of 10 microM caffeic acid. Both TGF beta 1 and TGF beta 2 isotypes were detected in MCF-7/Dox cells, while only TGF beta 1 was found in MCF-7 cells. The level of TGF beta 1 in MCF-7/Dox cells was about 3-fold greater than that in MCF-7 cells. In cells pretreated with caffeic acid (10 microM), TGF beta 1 and TGF beta 2 levels were overexpressed only in MCF-7/Dox cells by 90% and 60%, respectively. These results suggest that caffeic acid is potentially a chemosensitizing agent with greater selectivity to drug-resistant MCF-7/Dox cells over parent MCF-7 cells and that the chemosensitizing effect is not mediated by altered drug concentrations in the cells, but may be possibly correlated to the induction of TGF beta isotypes.

Selective inhibition of the effects of phorbol ester on doxorubicin resistance and P-glycoprotein by the protein kinase C inhibitor 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H7) in multidrug-resistant MCF-7/Dox human breast carcinoma cells.

The possible regulation of the multidrug-resistant (MDR) phenotype and P-glycoprotein by protein kinase C (PKC) was investigated in the doxorubicin (Dox)-resistant MCF-7 cell line (MCF-7/Dox). In a clonogenic assay, cells exposed to 100 nM phorbol 12-myristate 13-acetate (PMA) for 1 hr were about 3-fold more resistant to Dox than were cells exposed to Dox alone. The PKC inhibitor 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H7, 30 microM) completely blocked the PMA-induced effect, but did not reverse the MDR phenotype. Complete down-regulation of PKC from MCF-7/Dox cells by 24-hr preincubation with PMA did not alter the degree of Dox resistance. Intracellular accumulation of [14C]Dox decreased from a baseline of 28 pmol/10(6) cells to 15 pmol/10(6) cells in the presence of 100 nM PMA. The reduced Dox accumulation in the presence of PMA was not blocked by pretreatment of cells with H7. Following a 24-hr pretreatment with PMA, the cells accumulated almost equal amounts of [14C]Dox in the absence or presence of PMA. Cells from PMA-treated colonies showed significantly higher levels of expression of P-glycoprotein when compared with those from control colonies. H7 did not affect the basal level of P-glycoprotein in cells from control colonies or PMA-induced overexpression of P-glycoprotein in cells from PMA-treated colonies. Upon stimulation with PMA (100 nM), PKC alpha and beta translocated to the cell membrane and nucleus and PKC delta and epsilon to the perinuclear membrane and the nucleus, respectively. H7 (30 microM) completely inhibited PMA-induced translocations of PKC delta and epsilon, whereas it only partially blocked the translocations of PKC alpha and beta. These results suggest that PMA appears to alter Dox resistance and intracellular Dox accumulation in a PKC-dependent manner and to induce increased expression of P-glycoprotein in MCF-7/Dox cells. Differential effects of H7 on the PMA-induced changes suggest that different isoforms of PKC may be involved in cell growth and drug accumulation processes as well as P-glycoprotein expression.

Differential distribution of neuropeptides and serotonin in pig adrenal glands.

A differential distribution of vasoactive neuropeptides and serotonin in chromaffin cells and nerve fibers within the adrenal glands of the pig (Sus scrofa) was found using immunohistochemical methods. Met- and leu-enkephalins, present at high levels in the medulla (measured by radioimmunoassay), occurred in adrenaline storing cells, some of which contained calcitonin gene-related peptide. Islets of chromaffin cells beneath the capsule also contained enkephalins and calcitonin gene-related peptide. Nerve fibers with enkephalin-like immunoreactivity were sparse, but many varicose fibers in the inner cortex and medulla showed calcitonin gene-related peptide immunofluorescence in a pattern similar to vasoactive intestinal polypeptide. Neuropeptide Y was mainly associated with perivascular fibers and neither neuropeptide Y nor vasoactive intestinal polypeptide immunoreactive chromaffin cells were detected. In contrast to the neuropeptides, most serotonin-like immunoreactivity coincided with noradrenaline histofluorescence. It is concluded that the distribution of nerve fibers with calcitonin gene-related peptide and vasoactive intestinal polypeptide would allow interactions between chromaffin and inner cortical cells. Stimuli activating noradrenaline chromaffin cells could release serotonin while stimulation of adrenaline storage cells would release enkephalin and, to a lesser extent, calcitonin gene-related peptide. Met-enkephalin, which occurs 3 4:1 over leu-enkephalin, is the most likely of the co-released peptides to reach distant receptors via the venous outflow.