A case of sudden cardiac death due to mitochondrial disease

A 25-year-old, emaciated man without medical treatment was found to have died suddenly at home by his mother. At autopsy, there were no injuries to his body, but significant circulatory insufficiency was observed. Electron microscopy revealed abnormal mitochondria in cells of the cardiac conduction system. The conduction system was filled with mitochondrial size abnormalities and mitochondrial cristae abnormalities. No notable abnormal findings were observed in other organs. Genetic examination of the blood revealed the mitochondrial pathogenetic variant m.3243A>G. Epileptic seizures, diabetic ketoacidosis, and hyperosmolar hyperglycemic state were unlikely to be the cause of sudden death. The cause of death was diagnosed as arrhythmia possibly induced by the failure of the cardiac conduction system due to mitochondrial disease. This is a rare case of sudden death caused by an accumulation of abnormal mitochondria in the cardiac conduction system.     

Prognosis Comparison Between Chronic Hepatitis B Patients Receiving a Finite Course of Tenofovir and Entecavir Treatment: A Nationwide Cohort Study in Taiwan

PurposeEntecavir (ETV) and tenofovir disoproxil fumarate (TDF) are both recommended as first-line treatments for patients with chronic hepatitis B virus (CHB) infection according to international HBV treatment guidelines. However, recent studies reported conflicting results regarding the preferred antiviral in the prevention of hepatocellular carcinoma (HCC). This cohort study aimed to investigate this issue by using Taiwan's National Health Insurance Research Database, wherein a “finite” but not life-long treatment policy was applied.MethodsFrom January 2008 to December 2013, a total of 12,388 consecutive adult patients with CHB who received a finite course of TDF treatment (n = 1250) or ETV treatment (n = 11,138) were analyzed through screening for study eligibility followed by the 1:4 propensity score matching method.FindingsIn the entire cohort, the annual incidence and survival between the ETV and TDF groups were not significantly different regarding HCC occurrence (2.05 vs 2.74 per 100 patient-years [PY]; P = 0.055; hazard ratio [HR], 0.975; log-rank, P = 0.966), cirrhosis-related complications (1.9 vs 2.4 per 100 PY; P = 0.149; HR, 0.869; log-rank, P = 0.388), or all-cause mortality (2.16 vs 1.6 per 100 PY; P = 0.119; HR, 0.831; log-rank, P = 0.342), respectively. Propensity score matching analyses yielded similar results regarding HCC occurrence, cirrhosis-related complications, and all-cause mortality. In addition, these findings were consistently reproduced in the subgroups of patients with chronic hepatitis and cirrhosis that developed before antiviral treatment.ImplicationsETV and TDF did not significantly differ in prevention of HCC occurrence or reduction of cirrhosis-related complications and all-cause mortality in patients with CHB receiving a finite period of treatment.     

Clinical Practice Guideline for the Therapeutic Drug Monitoring of Voriconazole in Non-Asian and Asian Adult Patients: Consensus Review by the Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring

PurposeVoriconazole, an antifungal drug, is metabolized by a cytochrome P450 isozyme. Increased adverse effects are observed in Asians because of the high rate of poor metabolizers. In this therapeutic drug monitoring (TDM) guideline, recommendations were made according to ethnic group.MethodsFive clinical questions were used. For the preparation of the guideline, the performance of TDM in multicenter studies was surveyed (study 1). We also conducted a systematic review and meta-analysis (study 2) to establish recommendations for non-Asians and Asians.FindingsIn study 1, 401 patients were surveyed. A risk of supratherapeutic concentrations was found in Japanese patients who adhered to the recommended dose. Target trough levels were achieved in 87% of patients with dose reductions. Although the trough level measured at the onset of adverse effects (AEs) was significantly associated with hepatotoxicity, no significant correlation was found between the initial trough level and hepatotoxicity, which indicated that hepatotoxicity was successfully prevented by the trough-guided dosing. In study 2, 22 studies (11 Asian locations and 11 non-Asian locations) were included in meta-analysis for the relationship between trough cutoff level (3, 4, 5, 5.5, and 6 µg/mL) and AEs. Significant differences were found for all cutoff levels, with the highest odds ratio for 4.0 µg/mL in Asian locations. In contrast, in non-Asian locations, no more than 1 study was available for any trough cutoff level, except for 5.5 µg/mL, at which level a significant increase in AEs was found. These findings indicate that TDM is strongly recommended to prevent AEs in Asians, and TDM is generally recommended for non-Asians to address subtherapeutic concentrations. TDM on day 3 is recommended to assess pharmacokinetic properties, including loading and maintenance doses. If the patient condition permits, delaying until day 5 is suggested for Asians because of the prolonged t_½ in poor metabolizers. A trough level ≥1.0 µg/mL is strongly recommended to improve efficacy. Trough levels ≥2.0 µg/mL are suggested for invasive aspergillosis. To decrease adverse effects, trough levels <4.0 µg/mL are strongly recommended in Asians, whereas trough levels <5.5 µg/mL are generally recommended in non-Asians. Maintenance doses of 4 and 3 mg/kg twice daily are recommended in non-Asians and Asians, respectively.ImplicationsDifferent indications, timings, and target trough levels for TDM and different regimens are suggested for Asians and non-Asians.     

Clinical course of masticatory function recovery following arthrocentesis in patients with unilateral mandibular condyle head fracture

The aim of this study was to investigate the clinical course of masticatory function recovery following arthrocentesis. Patients with a unilateral condylar head fracture who underwent arthrocentesis for therapeutic reasons were evaluated and compared with patients with a unilateral condylar head fracture who did not undergo arthrocentesis. At 3 months after treatment, the occlusal contact area and maximum bite force in patients with a fracture treated with arthrocentesis were greater than in those who did not receive arthrocentesis at the same time points, although the differences were not significant. Moreover, at 1 and 3 months following arthrocentesis, mean (±SD) occlusal contact area (1 month: 1.99 ± 0.55 mm², p = 0.01; 3 months: 2.90 ± 1.36 mm², p = 0.03) and maximum bite force (1 month: 82.45 ± 15.04 N, p = 0.01; 3 months: 101.11 ± 14.53 N, p = 0.01) on the fractured side in patients who underwent that treatment were significantly reduced when compared with those on the non-fractured side. The authors conclude that if the priority is to avoid open reduction and internal fixation, then the arthrocentesis approach might be a less invasive alternative, albeit with the price of a prolonged healing interval.     

Partial breast irradiation: An updated consensus statement from the American brachytherapy society

PurposeIn recent years, results with mature follow-up have been reported for several Phase III trials randomizing women to receive whole breast irradiation (WBI) versus varying modalities of partial breast irradiation (PBI). It is important to recognize that these methods vary in terms of volume of breast tissue treated, dose per fraction, and duration of therapy. As such, clinical and technical guidelines may vary among the various PBI techniques.MethodsMembers of the American Brachytherapy Society with expertise in PBI performed an extensive literature review focusing on the highest quality data available for the numerous PBI options offered in the modern era. Data were evaluated for strength of evidence and published outcomes were assessed.ResultsThe majority of women enrolled on randomized trials of WBI versus PBI have been age >45 years with tumor size <3 cm, negative margins, and negative lymph nodes. The panel also concluded that PBI can be offered to selected women with estrogen receptor negative and/or Her2 amplified breast cancer, as well as ductal carcinoma in situ, and should generally be avoided in women with extensive lymphovascular space invasion.ConclusionsThis updated guideline summarizes published clinical trials of PBI methods. The panel also highlights the role of PBI for women facing special circumstances, such as history of cosmetic breast augmentation or prior breast irradiation, and discusses promising novel modalities that are currently under study, such as ultrashort and preoperative PBI. Updated consensus guidelines are also provided to inform patient selection for PBI and to characterize the strength of evidence to support varying PBI modalities.     

Adjunctive therapies for in vitro carious lesions: Antimicrobial activity,activation of dentin metalloproteinases and effects on dental pulp cells

BackgroundAdjunctive therapies used before dental restorative procedures may encourage carious tissue removal. Beyond promising antimicrobial properties, treatments could positively modulate the dentin-pulp complex while not interfering with restoration survival. Herein, we evaluated a set of substances and their effects on carious lesions and the underlying dentin or pulp cells.MethodsArtificial caries lesions were developed in bovine teeth cavities immersed in Streptococcus mutans and Lactobacillus casei co-cultures. The cavities were treated according to the following groups: Phosphate Buffer Saline (PBS), Chlorhexidine (CHX), Papacárie® (Papain gel), Ozone (O₃), and antimicrobial Photodynamic Therapy (aPDT). After treatments, samples were cultivated to count isolated microbial colonies. The zymography assay evaluated the activity of dentin metalloproteinases (MMP-2 and MMP-9). Cell viability was indirectly assessed on human dental pulp cells after 24, 72, or 120 h, whereas the odontodifferentiation potential was evaluated after ten days of cell culture.ResultsCHX and aPDT led to around 1 log bacterial load reduction. PBS, CHX, and aPDT showed the eventual expression of MMP-2 and MMP-9. Cell viability was reduced (< 30%) after 120 h for all groups compared to the control. CHX, O3, and aPDT induced greater odontodifferentiation (≈ 20% higher) than PBS and papain gel.ConclusionAdjunctive therapies presented little or no biological significance in reducing bacterial load in artificial carious lesions. Although the activation of endogenous metalloproteinases may represent a possible concern for adhesive restorations, some of these treatments may have a positive role in dental pulp tissue repair.