On the rise and fall of the apnea−hypopnea index: A historical review and critical appraisal

The publication of “The Sleep Apnea Syndromes” by Guilleminault et al. in the 1970s hallmarked the discovery of a new disease entity involving serious health consequences. Obstructive sleep apnea was shown to be the most important disorder among the sleep apnea syndromes (SAS). In the course of time, it was found that the prevalence of obstructive sleep apnea reached the proportions of a global epidemic, with a major impact on public health, safety and the economy. Early on, a metric was introduced to gauge the seriousness of obstructive sleep apnea, based on the objective measurement of respiratory events during nocturnal sleep. The apnea index and later on the apnea?hypopnea index, being the total count of overnight respiratory events divided by the total sleep time in hours, were embraced as principle measures to establish the diagnosis of obstructive sleep apnea and to rate its severity. The current review summarises the historical evolution of the apnea?hypopnea index, which has been subject to many changes, and has been criticised for not capturing relevant clinical features of obstructive sleep apnea. In fact, the application of the apnea?hypopnea index as a continuous exposure variable is based on assumptions that it represents a disease state of obstructive sleep apnea and that evocative clinical manifestations are invariably caused by obstructive sleep apnea if the apnea?hypopnea index is above diagnostic threshold. A critical appraisal of the extensive literature shows that both assumptions are invalid. This conclusion prompts a reconsideration of the role of the apnea?hypopnea index as the prime diagnostic metric of clinically relevant obstructive sleep apnea.     

Optimized dualCEST‐MRI for imaging of endogenous bulk mobile proteins in the human brain

Dual‐frequency irradiation chemical exchange saturation transfer (dualCEST) allows imaging of endogenous bulk mobile proteins by selectively measuring the intramolecular spin diffusion. The resulting specificity to changes in the concentration, molecular size, and folding state of mobile proteins is of particular interest as a marker for neurodegenerative diseases and cancer. Until now, application of dualCEST in clinical trials was prevented by the inherently small signal‐to‐noise ratio and the resulting comparatively long examination time. In this study, we present an optimized acquisition protocol allowing 3D dualCEST‐MRI examinations in a clinically relevant time frame. The optimization comprised the extension of the image readout to 3D, allowing a retrospective co‐registration and application of denoising strategies. In addition, cosine‐modulated dual‐frequency presaturation pulses were implemented with a weighted acquisition scheme of the necessary frequency offsets. The optimization resulted in a signal‐to‐noise ratio gain by a factor of approximately 8. In particular, the application of denoising and the motion correction were the most crucial improvement steps. In vitro experiments verified the preservation of specificity of the dualCEST signal to proteins. Good‐to‐excellent intra‐session and good inter‐session repeatability was achieved, allowing reliable detection of relative signal differences of about 16% or higher. Applicability in a clinical setting was demonstrated by examining a patient with glioblastoma. The optimized acquisition protocol for dualCEST‐MRI at 3 T enables selective imaging of endogenous bulk mobile proteins under clinically relevant conditions.     

Clinical glycomics for the diagnosis of congenital disorders of glycosylation

Clinical glycomics comprises a spectrum of different analytical methodologies to analyze glycan structures, which provides insights into the mechanisms of glycosylation. Within clinical diagnostics, glycomics serves as a functional readout of genetic variants, and can form a basis for therapy development, as was described for PGM1-CDG. Integration of glycomics with genomics has resulted in the elucidation of previously unknown disorders of glycosylation, namely CCDC115-CDG, TMEM199-CDG, ATP6AP1-CDG, MAN1B1-CDG, and PGM1-CDG. This review provides an introduction into protein glycosylation and presents the different glycomics methodologies ranging from gel electrophoresis to mass spectrometry (MS) and from free glycans to intact glycoproteins. The role of glycomics in the diagnosis of congenital disorders of glycosylation (CDG) is presented, including a diagnostic flow chart and an overview of glycomics data of known CDG subtypes. The review ends with some future perspectives, showing upcoming technologies as system wide mapping of the N- and O-glycoproteome, intact glycoprotein profiling and analysis of sugar metabolism. These new advances will provide additional insights and opportunities to develop personalized therapy. This is especially true for inborn errors of metabolism, which are amenable to causal therapy, because interventions through supplementation therapy can directly target the pathogenesis at the molecular level.     

Carbon monoxide poisoning from waterpipe smoking: a retrospective cohort study

Objective: Waterpipe smoking may increasingly account for unintentional carbon monoxide poisoning, a serious health hazard with high morbidity and mortality. We aimed at identifying waterpipe smoking as a cause for carbon monoxide poisoning in a large critical care database of a specialty care referral center.

Methods: This retrospective cohort study included patients with a history of exposure to waterpipe smoking and carbon monoxide blood gas levels >10% or presence of clinical symptoms compatible with CO poisoning admitted between January 2013 and December 2016. Patients’ initial symptoms and carbon monoxide blood levels were retrieved from records and neurologic status was assessed before and after hyperbaric oxygen treatment.

Results: Sixty-one subjects with carbon monoxide poisoning were included [41 males, 20 females; mean age 23 (SD?±?6) years; range 13–45] with an initial mean carboxyhemoglobin of 26.93% (SD?±?9.72). Most common symptoms included syncope, dizziness, headache, and nausea; 75% had temporary syncope. Symptoms were not closely associated with blood COHb levels.

Conclusion: CO poisoning after waterpipe smoking may present in young adults with a wide variability of symptoms from none to unconsciousness. Therefore diagnosis should be suspected even in the absence of symptoms.     

Melanoma diagnosed in lesions previously treated by laser therapy

Laser therapy has become a routine procedure in dermatological practice and is frequently also used for pigmented lesions. Few reports exist of melanomas diagnosed in lesions previously treated by laser therapy. Between 2007 and 2014, we identified 11 patients who presented to our department with a melanoma diagnosed in a region previously treated by laser therapy. The course of events until the diagnosis of melanoma was assessed as well as patient outcome including treatment for disease progression. No histological assessment had been performed prior to laser therapy in nine of 11 (82%) cases. Benign melanocytic lesions had been diagnosed by biopsy prior to laser therapy in the other two cases. Time from laser therapy to diagnosis of melanoma ranged from less than 1 to 10 years. Stage of disease at diagnosis varied from stage IA to IIIC. Four patients progressed to stage IV disease, of whom at least one died of melanoma. We conclude that laser treatment of pigmented lesions can complicate the diagnosis of melanoma and lead to diagnosis delay with potentially fatal consequences. Considering this risk, we believe laser therapy for pigmented lesions should either be avoided entirely or at a minimum performed only after prior histological assessment.     

Lessons from human coronary aspirate

The interventional implantation of a stent into an atherosclerotic coronary artery is a unique and paradigmatic scenario of plaque rupture in humans. The use of protection devices not only prevents the released plaque particles and the superimposed thrombotic material from being washed and embolized into the coronary microcirculation of the individual patient, but permits also the retrieval and ex vivo analysis of particulate plaque debris and soluble substances. The particulate debris comprises typical cholesterol crystals, foam cells, hyalin material and calcium deposits from the atheroma as well as platelets and coagulation material; soluble substances include vasoconstrictors, such as serotonin and thromboxane, as well as inflammatory mediators, such as TNFα which amplifies vasoconstriction by inducing endothelial dysfunction. The vasoconstriction observed in a bioassay ex vivo correlates to clinical symptoms, angiographic stenosis and plaque burden, as assessed by intravascular ultrasound. The release of TNFα into the aspirate correlates to restenosis. Detailed analysis of the human coronary aspirate may promote a better understanding of the pathophysiology of the vulnerable atherosclerotic plaque and help to better antagonize the microvascular consequences of coronary microembolization, including the no reflow phenomenon. This article is part of a Special Issue entitled “Coronary Blood Flow.”