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.     

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.     

Limited unilateral approach for extramedullary spinal tumours

Traditionally, spinal extramedullary tumours are approached by a wide multilevel laminectomy and a midline dural incision. This exposure may result in immediate or delayed instability of the spine, and exposes the spinal cord to the possibility of inadvertent injury during surgery. To avoid these complications the authors have, in 27 patients, used a limited unilateral approach to remove extramedullary tumours. The approach entails bone removal which is limited to the lateral half of the lamina on the side of the tumour and may or may not include the medial part of the facet joint. A lateral dural flap exposes the tumour without exposing the cord. Extraspinal extensions of the lesion may be approached by extending the laminectomy further laterally to the facet joint. This technique has been used in the cervical, thoracic and the lumbar spine to radically remove the lesion in all cases. There were no complications. The authors conclude that extramedullary lesions of the spine can be removed radically by this approach which allows direct access without cord or root retraction, and with little disturbance to the normal anatomy.     

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.     

Mycobacterial pseudotumor of the plantar fascia: how common is it?

Mycobacterial spindle cell pseudotumor (MSCP) is an extremely rare complication of mycobacterial infections. It has been reported to occur in various sites such as skin, lymph nodes, bone marrow, lungs, and spleen. This tumor-like lesion can be confused clinically as well as radiographically with dermatofibroma, nodular fasciitis, xanthogranuloma, and Kaposi's sarcoma.While this lesion is rare and has been previously reported to occur only in superficial skin, we emphasize its consideration and inclusion in the differential diagnoses when a deep soft tissue mass is complicated by symptoms of deep tissue infection secondary to abscess formation in immunocompromised hosts. Here, we present the clinical and radiologic findings of a case of MSCP involving the deep plantar sheaths.     

Neonatal brain: color Doppler imaging. Part I. Technique and vascular anatomy

Color Doppler imaging (CDI) can demonstrate the relative direction and velocity of blood flow in color, superimposed on a conventional gray-scale ultrasound image that depicts stationary tissue. Twenty-five infants were studied with portable CDI in the coronal, sagittal, and axial planes. Bilateral antegrade flow was noted in the anterior, middle, and posterior cerebral arteries in all patients. Multiplanar CDI can image flow in the circle of Willis and its tributaries and branches.