Abnormal liver function tests associated with severe rhabdomyolysis

Rhabdomyolysis is a syndrome of skeletal muscle injury with release of cellular constituents such as potassium,phosphate,urate and intracellular proteins such as myoglobin into the circulation,which may cause complications including acute kidney injury,electrolyte disturbance and cardiac instability.Abnormal liver function tests are frequently observed in cases of severe rhabdomyolysis.Typically,there is an increase in serum aminotransferases,namely aspartate aminotransferase and alanine aminotransferase.This raises the question of liver injury and often triggers a pathway of investigation which may lead to a liver biopsy.However,muscle can also be a source of the increased aminotransferase activity.This review discusses the dilemma of finding abnormal liver function tests in the setting of muscle injury and the potential implications of such an association.It delves into some of the clinical and experimental evidence for correlating muscle injury to raised aminotransferases,and discusses pathophysiological mechanisms such as oxidative stress which may cause actual liver injury.Serum aminotransferases lack tissue specificity to allow clinicians to distinguish primary liver injury from muscle injury.This review also explores potential approaches to improve the accuracy of our diagnostic tools,so that excessive or unnecessary liver investigations can be avoided.     

Bone Microarchitecture Phenotypes Identified in Older Adults Are Associated With Different Levels of Osteoporotic Fracture Risk

Prevalence of osteoporosis is more than 50% in older adults, yet current clinical methods for diagnosis that rely on areal bone mineral density (aBMD) fail to detect most individuals who have a fragility fracture. Bone fragility can manifest in different forms, and a “one-size-fits-all” approach to diagnosis and management of osteoporosis may not be suitable. High-resolution peripheral quantitative computed tomography (HR-pQCT) provides additive information by capturing information about volumetric density and microarchitecture, but interpretation is challenging because of the complex interactions between the numerous properties measured. In this study, we propose that there are common combinations of bone properties, referred to as phenotypes, that are predisposed to different levels of fracture risk. Using HR-pQCT data from a multinational cohort (n = 5873, 71% female) between 40 and 96 years of age, we employed fuzzy c-means clustering, an unsupervised machine-learning method, to identify phenotypes of bone microarchitecture. Three clusters were identified, and using partial correlation analysis of HR-pQCT parameters, we characterized the clusters as low density, low volume, and healthy bone phenotypes. Most males were associated with the healthy bone phenotype, whereas females were more often associated with the low volume or low density bone phenotypes. Each phenotype had a significantly different cumulative hazard of major osteoporotic fracture (MOF) and of any incident osteoporotic fracture (p < 0.05). After adjustment for covariates (cohort, sex, and age), the low density followed by the low volume phenotype had the highest association with MOF (hazard ratio = 2.96 and 2.35, respectively), and significant associations were maintained when additionally adjusted for femoral neck aBMD (hazard ratio = 1.69 and 1.90, respectively). Further, within each phenotype, different imaging biomarkers of fracture were identified. These findings suggest that osteoporotic fracture risk is associated with bone phenotypes that capture key features of bone deterioration that are not distinguishable by aBMD. © 2021 American Society for Bone and Mineral Research (ASBMR).     

A Simple Dressing Technique Following Dermofasciectomy and Full Thickness Skin Grafting of the Fingers in the Treatment of Severe Dupuytren’s Contracture

Dupuytren’s disease with severe finger contractures and recurrent contractures following previous surgery often have extensive skin involvement. In these severe cases, excision of the diseased chord along with the involved skin is a good option to reduce the risk of recurrance. The resulting skin defect can be covered with a full thickness skin graft (FTSG) or a cross finger flap. Cross finger flaps have donor finger morbidity and hence a full thickness graft is usually preferred. The FTSG extending to the midlateral margins on both sides of the finger reduces the risk of joint contracture due to graft shrinkage. Once the FTSG is sutured in place, the standard practice is to compress and secure the graft to its recipient bed with a tie-over dressing and this can be time consuming. We present a simple dressing technique to secure the FTSG without the need for a tie-over dressing.     

Therapeutic cooperation between auranofin,a thioredoxin reductase inhibitor and anti-PD-L1 antibody for treatment of triple-negative breast cancer

Triple-negative breast cancer (TNBCs) is a very aggressive and lethal form of breast cancer with no effective targeted therapy. Neoadjuvant chemotherapies and radiotherapy remains a mainstay of treatment with only 25–30% of TNBC patients responding. Thus, there is an unmet clinical need to develop novel therapeutic strategies for TNBCs. TNBC cells have increased intracellular oxidative stress and suppressed glutathione, a major antioxidant system, but still, are protected against higher oxidative stress. We screened a panel of antioxidant genes using the TCGA and METABRIC databases and found that expression of the thioredoxin pathway genes is significantly upregulated in TNBC patients compared to non-TNBC patients and is correlated with adverse survival outcomes. Treatment with auranofin (AF), an FDA-approved thioredoxin reductase inhibitor caused specific cell death and impaired the growth of TNBC cells grown as spheroids. Furthermore, AF treatment exerted a significant in vivo antitumor activity in multiple TNBC models including the syngeneic 4T1.2 model, MDA-MB-231 xenograft and patient-derived tumor xenograft by inhibiting thioredoxin redox activity. We, for the first time, showed that AF increased CD8^+Ve T-cell tumor infiltration in vivo and upregulated immune checkpoint PD-L1 expression in an ERK1/2-MYC-dependent manner. Moreover, combination of AF with anti-PD-L1 antibody synergistically impaired the growth of 4T1.2 primary tumors. Our data provide a novel therapeutic strategy using AF in combination with anti-PD-L1 antibody that warrants further clinical investigation for TNBC patients.     

Antidepressant and other centrally acting drugs regulate glucocorticoid receptor messenger RNA levels in rat brain

The effect of imipramine, desipramine, ketanserin and lithium on Type II glucocorticoid receptor (GR) mRNA levels was studied in rat brain regions involved in the control of the hypothalamo-pituitary-adrenal (HPA) axis, the dysregulation of which has been implicated in the pathophysiology of major depression. Northern blot analysis of Type II GR mRNA showed that treatment of male rats with either desipramine or imipramine increased hypothalamic and hippocampal GR mRNA levels. Upregulation of GR mRNA following administration of imipramine was found in brain regions of female rats, while desipramine had no effect. Ketanserin increased levels of GR mRNA in hippocampus of male, but not female, rats. Lithium also was able to induce important increases rat brain GR mRNA; this effect was particularly marked in females.

We conclude that desipramine, imipramine, ketanserin and lithium can modulate GR mRNA in regions of rat brain involved in the control of the HPA axis and may have a common mechanism of action at the level of the GR gene. Sexual dimorphism for drug regulation of brain GR mRNA content was shown and may be related to sex differences in the prevalence of certain affective disorders.     

Evaluation of a mass dispensing exercise in a Cities Readiness Initiative setting.

PURPOSE: The effectiveness of a point of dispensing (POD) used in a mass dispensing exercise was evaluated. METHODS: Public Health-Seattle & King County (PHSKC), in conjunction with the University of Washington, conducted a functional exercise of mass dispensing plans to test the effectiveness of a POD. Specifically, the organization and maintenance of patient flow, staffing model, signage, and dissemination of public information were evaluated. A data collection application using cellular telephones was used to record time and patient flow data to evaluate patient flow. Questionnaires distributed to staff and volunteer patients at the end of the exercise obtained feedback regarding the setup, organization, and operations of the POD. RESULTS: The POD was operational for approximately 68 minutes. The majority of POD staff reported feeling comfortable with their specific job tasks and duties within 15 minutes of opening the doors to the POD to the public. Staff questionnaires also revealed a high level of self-reported confidence in their ability and in the ability of their colleagues to perform the job-specific responsibilities required of them or respond to this hypothetical event. The majority of volunteer patients found the signs helpful and easy to follow and the check-in form easy to complete. Despite efforts to provide patients with oral and written information about the medications being dispensed, only 80% indicated that they knew how to take the medication, and only 73% reported understanding the medication instructions for all the individuals for whom they picked up medication. CONCLUSION: The majority of volunteer patients and staff who participated in a functional exercise of mass dispensing plans found the POD to be effective. Time-flow analysis provided preliminary estimates of the total amount of time needed to complete the dispensing process for each head of household.     

Molecular determinants of cetuximab efficacy.

PURPOSE: To investigate whether mRNA expression levels of cyclin D1 (CCND1), cyclooxygenase 2 (Cox-2), epidermal growth factor receptor (EGFR), interleukin 8 (IL-8), and vascular endothelial growth factor (VEGF), all members of the EGFR signaling pathway, are associated with clinical outcome in patients with EGFR-expressing metastatic colorectal cancer (CRC) treated with cetuximab. PATIENTS AND METHODS: Thirty-nine patients with metastatic CRC, refractory to both irinotecan and oxaliplatin, were enrolled on IMCL-0144 and treated with single-agent cetuximab. The intratumoral mRNA levels of CCND1, Cox-2, EGFR, IL-8, and VEGF were assessed from paraffin-embedded tissue samples using laser-capture microdissection and quantitative real-time polymerase chain reaction. RESULTS: There were 21 women and 18 men with a median age of 64 years (range, 35 to 83 years). Higher gene expression levels of VEGF were associated with resistance to cetuximab (P = .038; Kruskal-Wallis test). The combination of low gene expression levels of Cox-2, EGFR, and IL-8 was significantly associated with overall survival (13.5 v 2.3 months; P = .028; log-rank test). Both findings were independent of skin toxicity that was itself significantly correlated to survival. Patients with a lower mRNA amount of EGFR had a longer overall survival compared with patients that had a higher mRNA amount (7.3 v 2.2 months; P = .09; log-rank test). Patients with lower expression of Cox-2 had a significantly higher rate of grade 2 to 3 skin reactions under cetuximab treatment. CONCLUSION: This pilot study suggests that gene expression levels of Cox-2, EGFR, IL-8, and VEGF in patients with metastatic CRC may be useful markers of clinical outcome in single-agent cetuximab treatment.     

Priapism: a refined approach to diagnosis and treatment

The recent introduction of intracorporeal injections of papaverine and phentolamine for the diagnosis and treatment of impotence has resulted in an increased incidence of iatrogenic priapism. Based on our research into penile hemodynamics we propose a refined approach to all types of priapism. Intracorporeal blood gas and pressure monitoring should be used to differentiate ischemic (low flow) from nonischemic (high flow) types. Most cases of papaverine-induced or phentolamine-induced priapism will respond to aspiration alone or in combination with intracorporeal instillation of a diluted alpha-adrenergic agent. In spontaneous priapism alpha-adrenergic agents can be tried first if patients have only mild or no ischemia. In patients with severe ischemia stagnant blood should be evacuated and a shunt procedure should be performed to allow metabolic replenishment of tissue. Intracorporeal pressure monitoring will help to determine the size and number of shunts needed to re-establish corporeal circulation.     

Inguinal hernia repair in Hospital Authority hospitals: The role of laparoscopic hernioplasty

Objective: Two major changes have occurred in inguinal hernia repair during the last two decades: (i) the use of tension‐free mesh repair; and (ii) the application of laparoscopic technique for repair. The aims of the present study were to study: (i) how inguinal hernia repair was carried out; and (ii) the outcome of inguinal hernia repair in Hospital Authority (HA) hospitals. Methodology: This was a retrospective analysis on 8311 elective inguinal hernia repairs performed in 16 HA hospitals from January 2001 to December 2003. The mean age was 63.9 ± 14.2 years, and the male to female ratio was 22.0 : 1.0. Among these, 869 (10.5%) repairs were performed with the laparoscopic approach and 7442 (89.5%) repairs with the open approach. The proportion of laparoscopic hernia repair increased from 8.7% to 12.6%. Results: For open repair, 39% of cases were carried out with regional anaesthesia, 32% with general anaesthesia and 29% with local anaesthesia (LA). Furthermore, mesh repair was used in 88% of the patients. For laparosocpic repair, 98.4% of cases were carried out under general anaesthesia, and all patients had mesh repair using the totally extraperitoneal approach. A significantly higher proportion of bilateral repair and recurrent hernia repair was performed with the laparoscopic approach (P = 0.000). For primary unilateral repair, there was no significant difference in the postoperative length of stay (LOS) and the total LOS between the laparoscopic and the open surgery groups. No difference in LOS was found in recurrent hernia repair between the two groups. With respect to bilateral repair, both the preoperative LOS (P = 0.036) and total LOS (P = 0.039) were shorter in the laparoscopic group. Furthermore, a significantly higher proportion of day‐surgery patients was observed in the laparoscopic group than the open surgery group (21.3%vs 16.9%, P = 0.001). Nevertheless, when only the results of 2003 were analyzed, the postoperative LOS (P = 0.000) and total LOS (P = 0.000) were significantly shorter in the laparoscopic group than the open surgery group. The LOS parameters were significantly shorter in the open surgery LA subgroup compared with the non‐LA subgroup (P = 0.000), and they were not different from those in the laparoscopic group. Conclusions: The open mesh repair is the predominant approach for inguinal hernia repair in HA hospitals. The originally described local anaesthetic approach was under utilized, although it resulted in good outcome. The use of laparoscopic hernia repair is increasing and a learning curve was recently observed with improved outcome.