Ventilatory responses to hypercapnia and hypoxia in relatives of patients with the obesity hypoventilation syndrome

BACKGROUND: It is unclear why some morbidly obese individuals have waking alveolar hypoventilation while others with similar obesity do not. Some evidence suggests that patients with the obesity hypoventilation syndrome (OHS) may have a measurable premorbid impairment of ventilatory chemoresponsiveness. Such an impairment of ventilatory chemoresponsiveness in OHS, however, may be an acquired and reversible consequence of severe obstructive sleep apnoea (OSA). We hypothesised that, in patients with OHS who do not have coincident severe OSA, there may be a familial impairment in ventilatory responses to hypoxia and hypercapnia. METHODS: Sixteen first degree relatives of seven patients with OHS without severe OSA (mean (SD) age 40 (16) years, body mass index (BMI) 30 (6) kg/m(2)) and 16 subjects matched for age and BMI without OHS or OSA were studied. Selection criteria included normal arterial blood gas tensions and lung function tests and absence of sleep apnoea on overnight polysomnography. Ventilatory responses to isocapnic hypoxia and to hyperoxic hypercapnia were compared between the two groups. RESULTS: The slope of the ventilatory response to hypercapnia was similar in the relatives (mean 2.33 l/min/mm Hg) and in the control subjects (2.12 l/min/mm Hg), mean difference 0.2 l/min/mm Hg, 95% confidence interval (CI) for the difference -0.5 to 0.9 l/min/mm Hg, p=0.5. The hypoxic ventilatory response was also similar between the two groups (slope factor A: 379.1 l/min * mm Hg for relatives and 373.4 l/min * mm Hg for controls; mean difference 5.7 l/min * mm Hg; 95% CI -282 to 293 l/min * mm Hg, p=0.7; slope of the linear regression line of the fall in oxygen saturation and increase in minute ventilation: 2.01 l/min/% desaturation in relatives, 1.15 l/min/% desaturation in controls; mean difference 0. 5 l/min/% desaturation; 95% CI -1.7 to 0.7 l/min/% desaturation, p=0. 8). CONCLUSION: There is no evidence of impaired ventilatory chemoresponsiveness in first degree relatives of patients with OHS compared with age and BMI matched control subjects.     

Allogeneic vaccination with a B7.1 HLA-A gene-modified adenocarcinoma cell line in patients with advanced non-small-cell lung cancer.

PURPOSE: To determine the safety, immunogenicity, and clinical response to an allogeneic tumor vaccine for non-small-cell lung cancer, we conducted a phase I trial in patients with advanced metastatic disease. PATIENTS AND METHODS: We treated 19 patients with a vaccine based on an adenocarcinoma line (AD100) transfected with B7.1 (CD80) and HLA A1 or A2. Patients were vaccinated intradermally with 5 x 10(7) cells once every 2 weeks. Three vaccinations represented one course of treatment. If patients had complete response, partial response, or stable disease, they continued with the vaccinations for up to three courses (nine vaccinations). Immune response was assessed by a change between pre-study and postvaccination enzyme-linked immunospot frequency of purified CD8 T-cells secreting interferon-gamma in response to in vitro challenge with AD100. RESULTS: Four patients experienced serious adverse events that were unrelated to vaccine. Another four patients experienced only minimal skin erythema. All but one patient had a measurable CD8 response after three immunizations. The immune response of six surviving, clinically responding patients shows that CD8 titers continue to be elevated up to 150 weeks, even after cessation of vaccination. Overall, one patient had a partial response, and five had stable disease. Median survival for all patients is 18 months (90% CI, 7 to 23 months), with corresponding estimates of 1-year, 2-year, and 3-year survival of 52%, 30%, and 30%, respectively. HLA matching of vaccine, age, sex, race, and pathology did not bear a significant relation to response. CONCLUSION: Minimal toxicity and good survival in this small population suggest clinical benefit from vaccination.     

The pectoralis major myocutaneous flap in head and neck reconstruction

The pectoralis major myocutaneous flap (PMMC flap) represents a landmark in the development of head and neck reconstructive surgery. After Stephan Ariyan first described its use for head and neck reconstruction in 1979, it has become tremendously popular and has revolutionised head and neck cancer surgery. Here, we present our initial experience with fourteen PMMC flaps in head and neck reconstruction. In most of the instances it was used for oral or oropharyngeal reconstruction. It was used for five other reconstructive tasks as well. Wound infection was the most common complication. There was no case of total flap loss. It has proven to be a reliable method of reconstuction in the head and neck.     

Hepatitis B and C virus infections transmitted through organ transplantation investigated by CDC,United States, 2014‐2017

We evaluated clinical outcomes among organ recipients with donor‐derived hepatitis B virus (HBV) or hepatitis C virus (HCV) infections investigated by CDC from 2014 to 2017 in the United States. We characterized new HBV infections in organ recipients if donors tested negative for total anti‐HBc, HBsAg and HBV DNA, and new recipient HCV infections if donors tested negative for anti‐HCV and HCV RNA. Donor risk behaviors were abstracted from next‐of‐kin interviews and medical records. During 2014‐2017, seven new recipient HBV infections associated with seven donors were identified; six (86%) recipients survived. At last follow‐up, all survivors had functioning grafts and five (83%) had started antiviral therapy. Twenty new recipient HCV infections associated with nine donors were identified; 19 (95%) recipients survived. At last follow‐up, 18 (95%) survivors had functioning grafts and 14 (74%) had started antiviral treatment. Combining donor next‐of kin interviews and medical records, 11/16 (69%) donors had evidence of injection drug use and all met Public Health Service increased risk donor (IRD) criteria. IRD designation led to early diagnosis of recipient infection, and prompt implementation of therapy, likely reducing the risk of graft failure, liver disease, and death.     

Viscoelastic Imaging of Breast Tumor Microenvironment With Ultrasound

Imaging systems are most effective for detection and classification when they exploit contrast mechanisms specific to particular disease processes. A common example is mammography, where the contrast depends on local changes in cell density and the presence of microcalcifications. Unfortunately the specificity for classifying malignant breast disease is relatively low for many current diagnostic techniques. This paper describes a new ultrasonic technique for imaging the viscoelastic properties of breast tissue. The mechanical properties of glandular breast tissue, like most biopolymers, react to mechanical stimuli in a manner specific to the microenvironment of the tissue. Elastic properties allow noninvasive imaging of desmoplasia while viscous properties describe metabolism-dependent features such as pH. These ultrasonic methods are providing new tools for studying disease mechanisms as well as improving diagnosis.     

Gene Profiling of Human Adipose Tissue During Evoked Inflammation In Vivo

OBJECTIVE

Adipose inflammation plays a central role in obesity-related metabolic and cardiovascular complications. However, few human adipose-secreted proteins are known to mediate these processes. We hypothesized that microarray mRNA profiling of human adipose during evoked inflammation could identify novel adipocytokines.

RESEARCH DESIGN AND METHODS

Healthy human volunteers (n = 14) were treated with intravenous endotoxin (3 ng/kg lipopolysaccharide [LPS]) and underwent subcutaneous adipose biopsies before and after LPS. On Affymetrix U133Plus 2.0 arrays, adipose mRNAs modulated >1.5-fold (with P < 0.00001) were selected. SignalP 3.0 and SecretomeP 2.0 identified genes predicted to encode secreted proteins. Of these, 86 candidates were chosen for validation in adipose from an independent human endotoxemia protocol (N = 7, with 0.6 ng/kg LPS) and for exploration of cellular origin in primary human adipocytes and macrophages in vitro.

RESULTS

Microarray identified 776 adipose genes modulated by LPS; 298 were predicted to be secreted. Of detectable prioritized genes, 82 of 85 (96% [95% CI 90–99]) were upregulated (fold changes >1.0) during the lower-dose (LPS 0.6 ng/kg) validation study and 51 of 85 (59% [49–70]) were induced greater than 1.5-fold. Treatment of primary adipocytes with LPS and macrophage polarization to M1 proinflammatory phenotype increased expression by 1.5-fold for 58 and 73% of detectable genes, respectively.

CONCLUSIONS

We demonstrate that evoked inflammation of human adipose in vivo modulated expression of multiple genes likely secreted by adipocytes and monocytes. These included established adipocytokines and chemokines implicated in recruitment and activation of lymphocytes, adhesion molecules, antioxidants, and several novel genes with unknown function. Such candidates may represent biomarkers and therapeutic targets for obesity-related complications.Activation of innate and adaptive immunity is a crucial link between adiposity and its metabolic complications (1–4). In rodents, modulation of toll-like receptor-4 (5), tumor necrosis factor (TNF) receptors (6), chemokines, and downstream kinases (7) attenuate diet-induced obesity and insulin resistance. Further, cross talk between immune cells and adipocytes promotes an inflammatory, insulin-resistant state in obesity. A key initiating event in adipose inflammation is recruitment of T-lymphocytes (8,9) and monocyte/macrophages (10,11) with elaboration of inflammatory adipocytokines that modulate metabolic signaling (12–15). Despite experimental evidence in rodent models, most evidence supporting these concepts in humans derives from observational and correlative studies (16–18). Indeed, validated adipokines that mediate, or serve as biomarkers for, complications of human adiposity remain limited.Expression of inflammatory, insulin-signaling, and lipid genes are perturbed in adipose of obese humans (19–21). Recently, the in vitro secretome of subcutaneous and visceral primary human adipocytes was described and includes many unexplored proteins modulated during adipogenesis (1,22). Remarkably, less than half of genes found in the human subcutaneous adipocyte secretome were previously found in the murine 3T3-L1 preadipocyte secretome (22), underscoring the importance of studies in human tissue.Experimental human endotoxemia can provide unique insights into the relationship of inflammation to metabolic disturbance in man (23,24). Others and we have shown that endotoxemia induces acute metabolic, lipoprotein, and oxidant responses that resemble the chronic changes in insulin resistance and metabolic syndrome (25,26). Notably, endotoxemia induces adipose inflammation (27) with activation of several adipose inflammatory cascades, including cytokines, chemokines, and suppressor of cytokine signaling (SOCS) molecules (26) that attenuate insulin signaling and are implicated in obesity and type 2 diabetes (28).We applied microarray mRNA profiling of human adipose during endotoxemia to identify novel inflammation-induced adipose genes. We focused on genes predicted to be secreted and validated our findings in vivo through independent experiments of low-grade human inflammation. Finally, we identified in vitro the likely human adipose cellular source of these top candidates.     

From the Cover: Bumblebees perceive the spatial layout of their environment in relation to their body size and form to minimize inflight collisions

Animals that move through complex habitats must frequently contend with obstacles in their path. Humans and other highly cognitive vertebrates avoid collisions by perceiving the relationship between the layout of their surroundings and the properties of their own body profile and action capacity. It is unknown whether insects, which have much smaller brains, possess such abilities. We used bumblebees, which vary widely in body size and regularly forage in dense vegetation, to investigate whether flying insects consider their own size when interacting with their surroundings. Bumblebees trained to fly in a tunnel were sporadically presented with an obstructing wall containing a gap that varied in width. Bees successfully flew through narrow gaps, even those that were much smaller than their wingspans, by first performing lateral scanning (side-to-side flights) to visually assess the aperture. Bees then reoriented their in-flight posture (i.e., yaw or heading angle) while passing through, minimizing their projected frontal width and mitigating collisions; in extreme cases, bees flew entirely sideways through the gap. Both the time that bees spent scanning during their approach and the extent to which they reoriented themselves to pass through the gap were determined not by the absolute size of the gap, but by the size of the gap relative to each bee’s own wingspan. Our findings suggest that, similar to humans and other vertebrates, flying bumblebees perceive the affordance of their surroundings relative their body size and form to navigate safely through complex environments.

Avoiding collisions with obstacles is a requirement for successful locomotion through most natural habitats, where the physical environment is often cluttered and complex. At the most elemental level, animals moving through their environments need to identify gaps between obstacles and assess their passability. In this context, whether a gap between obstacles “affords” passing is determined by the fit between the spatial layout of the environment and the properties of the organism’s form and action system, as described in classical theses on affordances (1–3). In humans and other highly cognitive vertebrates, the perception of affordances for performing visually guided actions such as grasping, passing through apertures, and climbing is actively shaped throughout ontogeny, as body size, configuration, and experience change (2, 4–7). However, the strategies used by animals with much smaller brains, such as insects, to contend with the challenges of navigating environmental clutter and spatial heterogeneity are unclear.We used bumblebees to investigate whether flying insects take into account their own size during interactions with their surroundings. Bumblebees and other volant insects that travel long distances (8) and frequently encounter regions of dense clutter can be expected to exhibit strategies to avoid collisions, because damage to sensitive structures such as the wings is irreparable and adversely impacts flight performance and lifespan (9, 10). For an animal attempting to navigate through tight spaces, perceiving the relationship between the layout of the environment and its own size can help inform the animal of its potential for collision-free passage. Bumblebee workers naturally display large variation in body size within a given colony (11, 12), and thus are particularly suitable models for testing the effects of insect body size on aerial navigation and for determining whether insects perceive the external environment in relation to their own spatial dimensions.To elicit repeatable flight behavior, we trained foraging bumblebees to fly within a 1.6 × 0.3 × 0.3 m (l × w × h) flight tunnel that separated the hive from a foraging arena (Materials and Methods, SI Appendix, Fig. S1, and Movie S1). After bees were habituated to the setup and began foraging normally, we placed an unexpected obstacle within the tunnel, consisting of a thin vertical wall (5-mm thickness) spanning the tunnel’s width and height. The obstructing wall contained a rectangular gap starting midway up and extending to the top of the wall (Materials and Methods, SI Appendix, Fig. S1, and Movie S1). The width of the gap was varied between 20 and 60 mm over different trials, with the presenting order of gap sizes chosen randomly. A high-speed camera placed above the tunnel was used to record bees’ instantaneous positions, heading/yaw orientations (Fig. 1A), and trajectories as they approached the obstructing wall and passed through the gap. To prevent bees from becoming familiar with the experimental paradigm, the obstructing wall was removed after each flight recording. In total, we recorded and analyzed over 400 flights of bees of varying body sizes flying through seven different gap sizes (SI Appendix, Table S1). For the population of bees recorded, wingspan was the longest dimension of the body and it varied linearly by a factor of 1.9 compared to their longitudinal body length while in flight (SI Appendix, Fig. S2A).Open in a separate windowFig. 1.Bumblebees can safely fly through gaps that are smaller than their wingspan. (A and B) Illustrations indicating the wingspan of bees (Ws), the size of the gap (Gs), and the positive and negative yaw (heading) angles for bees flying in the tunnel, respectively. (C) Schematic illustration of the flight of a bee flying through a gap that is much wider than its wingspan. (D) The instantaneous yaw angle of bee shown in C. (E) Schematic illustrationof the flightofabeeflying through a gap that is smaller than its wingspan. (F) The instantaneous yaw angle of bee shown in E. Flights, in both cases (C and E), consisted of approach, lateral peering, and—for the smaller gap size (E)—body reorientation (an increase in yaw angle) while passing through the gap. The differences in reorientation behavior can be noted at x = 0 (location of the gap), whereas in F the bee displays a large increase in yaw angle that reorients its body to pass through the small gap, and body reorientation in D is minimal. For the flight shown in C and D, Ws = 27.5 mm and Gs = 50 mm, while for the flight shown in E and F, Ws = 27 mm and Gs = 25 mm.