Human leukocyte antigen class-I variation is associated with atopic dermatitis: A case-control study.

Atopic dermatitis (AD) is a common immune-medicated skin disease. Previous studies have explored the relationship between Human Leukocyte Antigen (HLA) allelic variation and AD with conflicting results. The aim was to examine HLA Class I genetic variation, specifically peptide binding groove variation, and associations with AD. A case-control study was designed to evaluate HLA class I allelic variation and binding pocket polymorphisms, using next generation sequencing on 464 subjects with AD and 388 without AD. Logistic regression was used to evaluate associations with AD by estimating odds ratios (95% confidence intervals). Significant associations were noted with susceptibility to AD (B*53:01) and protection from AD (A*01:01, A*02:01, B*07:02 and C*07:02). Evaluation of polymorphic residues in Class I binding pockets revealed six amino acid residues conferring protection against AD: A9F (HLA-A, position 9, phenylalanine) [pocket B/C], A97I [pocket C/E], A152V [pocket E], A156R [pocket D/E], B163E [pocket A] and C116S [pocket F]. These findings demonstrate that specific HLA class I components are associated with susceptibility or protection from AD. Individual amino acid residues are relevant to protection from AD and set the foundation for evaluating potential HLA Class I molecules in complex with peptides/antigens that may initiate or interfere with T-cell responses.

Association of diabetic foot ulcer and death in a population-based cohort from the United Kingdom.

AIMS: The presence of diabetic foot ulcers is strongly associated with an increased risk of death. In this study, we investigate whether the effects of diabetes-associated complications can explain the apparent relationship between diabetic foot ulcers and death. METHODS: We analysed data from 414 523 people with diabetes enrolled in practices associated with The Health Improvement Network in the United Kingdom. Our methods were designed to control for potential confounders in order to isolate the relationship between diabetic foot ulcers and death. Using proportional hazards models and the area under the receiver operator curve, we evaluated the effects of diabetic foot ulcers and the covariates on death. RESULTS: Among the patients, 20 737 developed diabetic foot ulcers; 5.0% of people with new ulcers died within 12 months of their first foot ulcer visit and 42.2% of people with foot ulcers died within 5 years. After controlling for major known complications of diabetes that might influence mortality, the correlation between diabetic foot ulcers and death remained strong with a fully adjusted hazard ratio of 2.48 (95% confidence interval: 2.43, 2.54). Geographic variance existed but was not spatially associated. CONCLUSIONS: Diabetic foot ulcers are linked to an increased risk of death. This cannot be explained by other common risk factors. These results suggest that either there are major unknown risk factors associated with both diabetic foot ulcers and death, or that diabetic foot ulceration itself is a serious threat, which seems unlikely. A diabetic foot ulcer should be seen as a major warning sign for mortality, necessitating closer medical follow-up.

Association or lack of association between tetracycline class antibiotics used for acne vulgaris and lupus erythematosus.

BACKGROUND: Previous studies have associated tetracyclines and, perhaps more specifically, minocycline use for the treatment of acne with onset of drug-induced lupus erythematosus (LE). OBJECTIVES: To determine the frequency of LE among those with acne who used antibiotics from the tetracycline class of antibiotics. METHODS: A retrospective cohort study of individuals aged 15-35 years with acne within the practices of the general practice physicians in the U.K. who participate in The Health Information Network (THIN). Our outcome measure was physician reports of LE. RESULTS: We identified 97 694 subjects with acne who were followed for about 520 000 person-years. They were on average about 22 years old and 57.5% were female. Minocycline exposure was noted in 24.8% of our subjects, doxycycline exposure in 15.6%, other tetracyclines in 42.3%, and 17.3% had not received a tetracycline antibiotic. The overall hazard ratio for the association of minocycline to LE was 2.64 (95% confidence interval 1.51-4.66) and when adjusted for age and gender was 3.11 (1.77-5.48). Those affected were often treated for LE. No association was noted for doxycycline and the other tetracyclines. CONCLUSIONS: The use of minocycline and not the other tetracyclines is associated with LE. LE as reported in THIN often required systemic therapy. Overall, the event is uncommon but the risk and benefit of minocycline therapy must be carefully considered.

Healing diabetic neuropathic foot ulcers: are we getting better?

AIM: To benchmark by year the likelihood that an individual with a diabetic neuropathic foot ulcer will heal over more than a 10-year period. PATIENTS AND METHODS: A cohort study within a multicentre wound care network of individuals with a diabetic neuropathic foot ulcer who were treated by a standard wound care algorithm. The main outcome was a healed wound by the 20th week of care stratified by calendar year. RESULTS: We evaluated 27 193 individuals with a neuropathic foot ulcer. Between 1988 and 1990 approximately 66% of patients did not heal. By 1999 this percentage had decreased to 49%. The change in the rate of failure to heal is very closely associated with an increase over time in the proportion of patients seen with wounds identified as prognostically favourable using a previously published prognostic model (i.e. individuals with wounds < or = 2 cm2, wounds < or = 2 months old, and wounds of grade < or = 2). Nevertheless, even among those most likely to heal, the likelihood of failing to heal went from 62% prior to 1991 to 32% in 2000. CONCLUSIONS: We have shown that individuals with a diabetic neuropathic foot ulcer seeking care are more likely to heal today than 10 years ago. The primary reason for this improvement is that individuals are seeking care when their wounds are most easily treated and these are now more likely to heal.

Cerebral extraction of oxygen, lactate production, and perfusion pressure in gunshot wound to the head: case report.

A case of gunshot wound to the head is presented, in which the patient made a satisfactory recovery after a prolonged period of elevated intracranial pressure and increased cerebral extraction of oxygen. Even though cerebral extraction of oxygen was increased in the most acute phase, the arteriojugular lactate difference was never abnormally decreased (ischemic). This finding indicated that, in this patient, increased cerebral extraction of oxygen was not sufficient to result in global cerebral ischemia (increased cerebral lactate production). To our knowledge, this is the first report on frequent serial assessment of cerebral extraction of oxygen and lactate production in severe penetrating head injury.

Cerebral blood flow, vascular resistance, and oxygen metabolism in acute brain trauma: redefining the role of cerebral perfusion pressure?

OBJECTIVES: To evaluate normal or high cerebral perfusion pressure in relation to cerebral blood flow and oxygen metabolism, as well as other multivariate cerebral hemodynamic and metabolic interrelationships, in acute brain trauma in humans. DESIGN: Prospective, observational study. SETTING: Neuroscience intensive care unit of a university hospital. PATIENTS: Adults (n = 66) with severe acute brain trauma (Glasgow Coma Scale scores from 4 to 8), undergoing multivariate physiologic studies involving cerebral perfusion pressure, cerebral blood flow, cerebral metabolic rate of oxygen consumption, total hemoglobin content, arterio-jugular oxygen content difference, and cerebral vascular resistance, along with other routine procedures. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Statistical analysis did not demonstrate any correlation between cerebral perfusion pressure and cerebral blood flow, between cerebral perfusion pressure and arterio-jugular oxygen content difference, and between cerebral perfusion pressure and cerebral metabolic rate of oxygen consumption, over a broad spectrum of perfusion pressures ranging from 60 to 130 mm Hg. In contrast, a significant negative correlation was found between cerebral vascular resistance and cerebral blood flow, where higher values of cerebral vascular resistance were associated with lower blood flow levels, and vice versa. CONCLUSIONS: In severe acute brain trauma, cerebral hemodynamic and oxygen metabolic variables are not necessarily correlated with normal or even high levels of cerebral perfusion pressure. Under these circumstances, cerebral vascular resistance (not perfusion pressure) is more closely correlated with different patterns of cerebral blood flow and metabolism.

Cerebral lactate-oxygen index in acute brain injury with acute anemia: assessment of false versus true ischemia.

OBJECTIVE: To evaluate the occurrence of global cerebral ischemia in acute brain trauma with acute anemia by combined measurements of cerebral hemodynamics, oxygenation, and lactate production. DESIGN: Prospective, intervention study. SETTING: Neuroscience intensive care unit of a university hospital. PATIENTS: Adults (n = 22) with severe acute brain trauma (Glasgow Coma Scores ranging from 4 to 8), undergoing frequent serial measurements of total hemoglobin content, jugular oxyhemoglobin saturation, arteriojugular oxygen content difference, arteriojugular lactate concentration difference, lactate-oxygen index, and cerebral blood flow, along with other routine procedures. MEASUREMENTS AND MAIN RESULTS: Acute anemia (disclosed by a total hemoglobin content of < 11 g/dL in at least three measurements) was found in 19 (86%) of 22 patients. In 211 serial multivariate physiologic observations, only one (0.4%) disclosed abnormally negative arteriojugular lactate difference consistent with global cerebral ischemia. However, in 18 (8.5%) studies in seven (31.8%) patients, acute anemia resulted in markedly decreased values of arteriojugular oxygen content difference. The latter, in turn, yielded abnormally high values of lactate-oxygen index despite normal cerebral lactate production (arteriojugular lactate difference) and oxygenation (jugular oxyhemoglobin saturation). CONCLUSIONS: In acute brain injury with acute anemia, global cerebral ischemia is a rare finding. However, false cerebral ischemia may be frequently found, if assessed by the lactate-oxygen index, because the denominator of the index (the arteriojugular oxygen content difference) frequently decreases as a function of decreasing hemoglobin, thus yielding false calculated ischemic high values for lactate-oxygen index despite normal cerebral oxygenation and lactate production.

Failure of jugular lactate determinations to disclose cerebral ischemia in posttraumatic cerebral infarction: case report.

A case of acute closed brain trauma is presented in which the patient developed a right middle cerebral artery infarction, while frequent measurements of the arteriojugular lactate difference (AVDL) remained normal, failing to disclose ischemia. To our knowledge, this is the first report on sequential AVDL measurements during evolving cerebral infarction.

Cerebral blood flow and oxygen consumption in acute brain injury with acute anemia: an alternative for the cerebral metabolic rate of oxygen consumption?

OBJECTIVE: To comparatively evaluate cerebral metabolic rate of oxygen consumption and a modification of it, cerebral consumption of oxygen, in patients with acute brain injury with acute anemia. DESIGN: Prospective, observational study. SETTING: Neuroscience intensive care unit (ICU) of a university hospital. PATIENTS: Adults (n = 62) with acute brain trauma, undergoing serial 133xenon studies of regional cerebral blood flow and global cerebral oxygen metabolism, along with other routine monitoring techniques. MEASUREMENTS AND MAIN RESULTS: In 173 combined studies of blood flow and oxygen metabolism, in the presence of spontaneous decreases in hemoglobin, cerebral metabolic rate of oxygen consumption and cerebral consumption of oxygen were comparatively evaluated in three groups with different hemoglobin levels. Cerebral metabolic rate of oxygen consumption was calculated as the product of averaged regional cerebral blood flow and arterio-jugular oxygen content difference, while cerebral consumption of oxygen was calculated as the product of averaged regional cerebral blood flow and the arterio-jugular oxyhemoglobin saturation difference, i.e., cerebral extraction of oxygen. Results indicated that a decrease of hemoglobin content is paralleled by a decrease in cerebral metabolic rate of oxygen consumption, even though the level of consciousness (coma score) is essentially unchanged across three hemoglobin groups. On the other hand, cerebral consumption of oxygen does not follow the decrease in hemoglobin and cerebral metabolic rate of oxygen consumption, thus demonstrating better stability to changing hemoglobin content. The low cerebral metabolic rate of oxygen consumption is due to a decrease in arterio-jugular oxygen content difference in anemia, while the cerebral extraction of oxygen does not follow the trend of the arterio-jugular oxygen content difference. CONCLUSIONS: In acute brain trauma with acute anemia, calculated arterio-jugular oxygen content difference and cerebral metabolic rate of oxygen consumption tend to be progressively lower, depending on the extent of anemia, which is in disagreement with coma scores. These changes in hemoglobin tend to have an inverse influence on cerebral consumption of oxygen, which, therefore, constitutes an alternative and independent measure of cerebral oxygen and independent measure of cerebral oxygen consumption under these limiting circumstances.

Cerebral oxygenation monitoring.

OBJECTIVES: To discuss theoretical and practical aspects of cerebral oxygenation, from isolated observational measurements to continuous interventional monitoring. DATA SOURCES: Relevant articles from the pertinent literature, as well as a multivariate physiologic diagram developed in this article. STUDY SELECTION: Theoretical, experimental, and clinical information that further clarifies the physiologic relevance of cerebral oxygenation. DATA EXTRACTION: All basic concepts of cerebral hemometabolism were used, up to cerebral hemodynamic reserve, and were interrelated accordingly. DATA SYNTHESIS: Cerebral perfusion pressure alone does not allow global cerebral hemometabolic optimization. The same situation is true for cerebral blood flow. The reason for this limitation is because these variables lack metabolic information. Cerebral arteriovenous differences do allow global cerebral hemometabolic optimization, because they reflect the exchange between the capillary and the tissue. In addition, cerebral hemodynamic reserve allows quantification of the cerebral microcirculatory tolerance to increases in intracranial "tightness" (decreases in intracranial compliance). CONCLUSIONS: Multivariate optimization of global cerebral oxygenation, primarily based on global cerebral oxygen delivery and extraction, may strongly affect outcome in a variety of predominantly diffuse, acute intracranial disorders. Cerebral hemodynamic reserve may be further explored in experimental and clinical areas, involving not just acute brain trauma.

Lack of relevance of the Bohr effect in optimally ventilated patients with acute brain trauma.

The relationship between jugular bulb oxyhemoglobin saturation (SjO2) and oxygen tension (PjO2) during hyperventilation was prospectively evaluated in 37 adults with acute brain injuries. Hyperventilation was optimized in all patients, based on measured values of the arteriojugular oxyhemoglobin saturation difference, or cerebral extraction of oxygen (CEO2). Most patients initially had variable CEO2 values, in 578 observations carried out in the acute phase. Overall, there was a strong positive correlation between SjO2 and PjO2 at all levels of arterial pH. In 31 (5.3%) of the 578 observations, where the arterial pH was greater than 7.6, the SjO2 was disproportionally higher than the PjO2, despite a good SjO2-PjO2 correlation (moderate Bohr effect). In only 5 of these 31 observations (0.8%) did the SjO2 and PjO2 largely change in opposite directions (marked Bohr effect) during profound hypocapnia. The present findings support the current practice of continuous or intermittent SjO2 monitoring and management, and of optimized hyperventilation for control of intracranial hypertension, provided that hyperventilation is optimized according to the CEO2 values. Only on rare occasions (arterial pH greater than 7.6) is it advisable to replace SjO2 measurements by those of PjO2, because the latter is not affected by the Bohr effect.