Rituximab in Subepidermal Blistering Diseases.

BACKGROUND: Although rituximab is known to be effective in the treatment of pemphigus, its role in subepidermal autoimmune blistering diseases is unclear and currently limited to off-label use. SUMMARY: This is a meta-analysis of case reports, case series, and retrospective studies on the effectiveness and safety of rituximab in bullous pemphigoid, mucous membrane pemphigoid, ocular pemphigoid, and epidermolysis bullosa acquisita. We compared remission and relapse rates in patients who received rituximab with those who only received conventional medical therapy. Comparisons were also made among disease subgroups. KEY MESSAGE: The present analysis suggests that patients with subepidermal autoimmune blistering diseases treated with rituximab achieve a higher rate of complete remission and encounter their first relapse after a longer time interval. However, time to remission and total relapse rates were similar between groups. Adverse events and mortality rates were no more common in patients who received rituximab. This analysis was limited by the absence of randomized controlled trials and the observation that rituximab was used as a late rescue therapy in most reports. In conclusion, rituximab may be effective in subepidermal blistering disease, but randomized controlled studies are required for the validation of current observational data.

Pulmonary Thrombosis Promotes Tumorigenesis via Myeloid Hypoxia-Inducible Factors.

Cancer patients have a greater risk of thrombosis than individuals without cancer. Conversely, thrombosis is a diagnostic predictor of cancer, but the mechanisms by which thrombosis promotes tumor propagation are incompletely understood. Our previous studies showed that hypoxia-inducible factors (HIF) 1α and HIF2α are stabilized in myeloid cells of murine thrombi. We also previously showed that pulmonary thrombosis increases the levels of HIF1α and HIF2α in murine lungs, enhances the levels of tumorigenic factors in the circulation, and promotes pulmonary tumorigenesis. In this study, we aimed to investigate the regulation of thrombosis-induced tumorigenesis by myeloid cell-specific HIFs (i.e., HIF1 and HIF2 in neutrophils and macrophages). Our in vitro studies showed that multiple tumorigenic factors are upregulated in the secretome of hypoxic versus normoxic neutrophils and macrophages, which promotes lung cancer cell proliferation and migration in a myeloid-HIF-dependent manner. Next, we used a mouse model of pulmonary microvascular occlusion to study the impact of pulmonary thrombosis and myeloid HIFs on lung tumorigenesis. Experiments on mice lacking either HIF1α or HIF2α in myeloid cells demonstrated that loss of either factor eliminates the advantage given to pulmonary tumor formation by thrombotic insult. The myeloid HIF-dependent and tumorigenic impact of pulmonary thrombosis on tumor burden may be partly driven by paracrine thymidine phosphorylase (TP), given that TP levels were increased by hypoxia in neutrophil and macrophage supernates, and that plasma TP levels were positively correlated with multiple measures of tumor progression in wild type mice but not myeloid cell-specific HIF1α or HIF2α knockout mice. These data together demonstrate the importance of thrombotic insult in a model of pulmonary tumorigenesis and the essential role of myeloid HIFs in mediating tumorigenic success.

Use of Phenobarbitone for Palliative Sedation in Dyspneic Crises Due to COVID-19 Pneumonia - A Case Series.

Patients who suffer from dyspnea while dying from COVID-19 are treated with opioids and benzodiazepines. In some instances, patients may experience refractory dyspnea at the end of life. Palliative sedation can be prescribed to alleviate such patients' suffering. We describe two patients being treated for severe COVID-19 pneumonia in a tertiary hospital. Both developed intractable dyspneic crises despite high-dose opioids and benzodiazepines. This led to their requirement of palliative sedation in the general ward using subcutaneous phenobarbitone (phenobarbital). We outline clinical considerations for the use of palliative sedation in COVID-19 related dyspnea. In particular, we discuss the evidence for, benefits and limitations of using phenobarbitone for palliative sedation in COVID-19 patients.

Clinical Manifestations of Early-Onset Dementia With Lewy Bodies Compared With Late-Onset Dementia With Lewy Bodies and Early-Onset Alzheimer Disease.

Importance: Early-onset dementia, presenting in individuals younger than 65 years, is a diagnosis with significant social and financial implications. The early-onset form of dementia with Lewy bodies (DLB) is poorly understood. Objective: To investigate clinical features that distinguish early-onset DLB (onset and diagnosis at age <65 years) from late-onset DLB (onset at age ≥65 years) and from early-onset Alzheimer disease (AD) dementia. Design, Setting, and Participants: This is a retrospective case-control study on patients with pathologically confirmed DLB or AD enrolled in the National Alzheimer's Coordinating Center database from January 2005 to July 2017. The National Alzheimer's Coordinating Center Uniform Data Set comprised deidentified data collected by Alzheimer disease centers in the United States. Of patients fulfilling criteria for all-cause dementia at enrollment (n = 1152), those who at post mortem received a pathological diagnosis of either AD (n = 848) or Lewy body disease (n = 218) were selected. Excluding 52 patients owing to missing data and 12 diagnosed with Parkinson disease dementia, remaining patients were classified by age of symptom onset into early-onset AD, early-onset DLB, and late-onset DLB subgroups. Data were analyzed from June to December 2018 and from November to December 2021. Exposures: Demographics, cognitive, behavioral, and motor features recorded at first clinic visit and neuropathological characteristics at autopsy were analyzed by disease subgroup. Main Outcomes and Measures: Concordance between initial etiologic diagnosis of dementia and final pathological diagnosis was assessed, as was time to death. Results: A total of 542 individuals were categorized as having early-onset AD (n = 363; mean [SD] age, 53.0 [5.8] years; 208 [57.3%] male), early-onset DLB (n = 32; mean [SD] age, 57.9 [3.2] years; 23 [71.9%] male), and late-onset DLB (n = 147; mean [SD] age, 73.5 [5.5] years; 103 [70.1%] male). Early-onset DLB was clinically misdiagnosed in 16 individuals (50%). Features that predicted a diagnosis of early-onset DLB over early-onset AD included visual hallucinations (15 [46.9%] vs 42 [11.6%]), slowness (23 [71.9%] vs 95 [26.2%]), apathy (23 [71.9%] vs 189 [52.1%]), and motor deterioration that preceded cognitive and behavioral symptoms (7 [21.9%] vs 6 [1.7%]). Late-onset DLB had more amnestic features, but this was accounted for by a higher proportion of neocortical neuritic plaques and diffuse plaques (frequent in 79 [53.7%] vs 8 [25%]) than seen in early-onset DLB. Conclusions and Relevance: This study found that early-onset DLB has clinical features that distinguish it from early-onset AD, whereas features of late-onset DLB are associated with a higher burden of AD copathology.

Assessment of small intestinal bacterial overgrowth in Alzheimer's disease.

There is great interest in crosstalk between the gastrointestinal and immune systems. Small intestinal bacterial overgrowth (SIBO) is a bowel disorder prevalent among patients with Parkinson's disease; SIBO treatment has been shown to modulate neurological inflammation, motor and cognitive outcomes there. However, to date, no link between Alzheimer's dementia and SIBO has been established. This pilot study sought to estimate the prevalence of SIBO in Alzheimer's dementia in the outpatient setting in Singapore General Hospital. It entailed performing a hydrogen breath test and objectively scoring gastrointestinal symptoms and their severity in 48 patients, comparing symptom scores and mean breath test values in those with mild to moderate Alzheimer's against age- and sex-matched controls that did not fulfill DSM-V criteria for probable Alzheimer's. Here, the prevalence of positive breath tests and symptoms of SIBO were no greater among Alzheimer's patients than in controls. This suggests that the gut microbiome changes and increased bowel inflammation seen in previous studies on Alzheimer's patients are likely effected through pathways other than SIBO, and are likely more complex than a mere increase in small bowel bacterial volume. Rather, future research could be directed along the lines of qualitative changes in small bowel microbiota, or pathologies in other parts of the gastrointestinal tract such as the colon or stomach, aspects which are not adequately captured by the hydrogen breath test. Keywords: Alzheimer's disease; dementia; gut-brain axis; small intestinal bacterial overgrowth; microbiome.

The Factor Inhibiting HIF Asparaginyl Hydroxylase Regulates Oxidative Metabolism and Accelerates Metabolic Adaptation to Hypoxia.

Animals require an immediate response to oxygen availability to allow rapid shifts between oxidative and glycolytic metabolism. These metabolic shifts are highly regulated by the HIF transcription factor. The factor inhibiting HIF (FIH) is an asparaginyl hydroxylase that controls HIF transcriptional activity in an oxygen-dependent manner. We show here that FIH loss increases oxidative metabolism, while also increasing glycolytic capacity, and that this gives rise to an increase in oxygen consumption. We further show that the loss of FIH acts to accelerate the cellular metabolic response to hypoxia. Skeletal muscle expresses 50-fold higher levels of FIH than other tissues: we analyzed skeletal muscle FIH mutants and found a decreased metabolic efficiency, correlated with an increased oxidative rate and an increased rate of hypoxic response. We find that FIH, through its regulation of oxidation, acts in concert with the PHD/vHL pathway to accelerate HIF-mediated metabolic responses to hypoxia.

Modelling pulmonary microthrombosis coupled to metastasis: distinct effects of thrombogenesis on tumorigenesis.

Thrombosis can cause localized ischemia and tissue hypoxia, and both of these are linked to cancer metastasis. Vascular micro-occlusion can occur as a result of arrest of circulating tumour cells in small capillaries, giving rise to microthrombotic events that affect flow, creating localized hypoxic regions. To better understand the association between metastasis and thrombotic events, we generated an experimental strategy whereby we modelled the effect of microvascular occlusion in metastatic efficiency by using inert microbeads to obstruct lung microvasculature before, during and after intravenous tumour cell injection. We found that controlled induction of a specific number of these microthrombotic insults in the lungs caused an increase in expression of the hypoxia-inducible transcription factors (HIFs), a pro-angiogenic and pro-tumorigenic environment, as well as an increase in myeloid cell infiltration. Induction of pulmonary microthrombosis prior to introduction of tumour cells to the lungs had no effect on tumorigenic success, but thrombosis at the time of tumour cell seeding increased number and size of tumours in the lung, and this effect was strikingly more pronounced when the micro-occlusion occurred on the day following introduction of tumour cells. The tumorigenic effect of microbead treatment was seen even when thrombosis was induced five days after tumour cell injection. We also found positive correlations between thrombotic factors and expression of HIF2α in human tumours. The model system described here demonstrates the importance of thrombotic insult in metastatic success and can be used to improve understanding of thrombosis-associated tumorigenesis and its treatment.

S-2-hydroxyglutarate regulates CD8+ T-lymphocyte fate.

R-2-hydroxyglutarate accumulates to millimolar levels in cancer cells with gain-of-function isocitrate dehydrogenase 1/2 mutations. These levels of R-2-hydroxyglutarate affect 2-oxoglutarate-dependent dioxygenases. Both metabolite enantiomers, R- and S-2-hydroxyglutarate, are detectible in healthy individuals, yet their physiological function remains elusive. Here we show that 2-hydroxyglutarate accumulates in mouse CD8+ T cells in response to T-cell receptor triggering, and accumulates to millimolar levels in physiological oxygen conditions through a hypoxia-inducible factor 1-alpha (HIF-1α)-dependent mechanism. S-2-hydroxyglutarate predominates over R-2-hydroxyglutarate in activated T cells, and we demonstrate alterations in markers of CD8+ T-cell differentiation in response to this metabolite. Modulation of histone and DNA demethylation, as well as HIF-1α stability, mediate these effects. S-2-hydroxyglutarate treatment greatly enhances the in vivo proliferation, persistence and anti-tumour capacity of adoptively transferred CD8+ T cells. Thus, S-2-hydroxyglutarate acts as an immunometabolite that links environmental context, through a metabolic-epigenetic axis, to immune fate and function.

Through a Clear Cell, Darkly: HIF2α/PLIN2-Maintained Fat Droplets Protect ccRCCs from ER Stress.

Qiu and colleagues describe how a structural component of lipid droplets is markedly induced in pseudohypoxic renal tumors, where it maintains endoplasmic reticulum (ER) homeostasis. This adaptation is indispensable in tumor cells-where growth demands and a fluctuating blood supply place unnatural stresses on ER function-and is therefore an attractive therapeutic target.

The determinants of transverse tubular volume in resting skeletal muscle.

The transverse tubular (t)-system of skeletal muscle couples sarcolemmal electrical excitation with contraction deep within the fibre. Exercise, pathology and the composition of the extracellular fluid (ECF) can alter t-system volume (t-volume). T-volume changes are thought to contribute to fatigue, rhabdomyolysis and disruption of excitation-contraction coupling. However, mechanisms that underlie t-volume changes are poorly understood. A multicompartment, history-independent computer model of rat skeletal muscle was developed to define the minimum conditions for t-volume stability. It was found that the t-system tends to swell due to net ionic fluxes from the ECF across the access resistance. However, a stable t-volume is possible when this is offset by a net efflux from the t-system to the cell and thence to the ECF, forming a net ion cycle ECF→t-system→sarcoplasm→ECF that ultimately depends on Na(+)/K(+)-ATPase activity. Membrane properties that maximize this circuit flux decrease t-volume, including PNa(t) > PNa(s), PK(t) < PK(s) and N(t) < N(s) [P, permeability; N, Na(+)/K(+)-ATPase density; (t), t-system membrane; (s), sarcolemma]. Hydrostatic pressures, fixed charges and/or osmoles in the t-system can influence the magnitude of t-volume changes that result from alterations in this circuit flux. Using a parameter set derived from literature values where possible, this novel theory of t-volume was tested against data from previous experiments where t-volume was measured during manipulations of ECF composition. Predicted t-volume changes correlated satisfactorily. The present work provides a robust, unifying theoretical framework for understanding the determinants of t-volume.

A whiter shade of gray: HIF and coordination of angiogenesis with postnatal myelination.

Oligodendrocyte precursor cells are the primary source of myelinating oligodendrocytes in the neonatal CNS. In a recent issue of Cell, Yuen and coworkers (2014) show that hypoxia-inducible factors and Wnt7a/7b act in developing white matter, promoting angiogenesis in anticipation of the metabolic demands of oligogenesis, before finally allowing precursor differentiation.