Cytokine Regulation of Metastasis and Tumorigenicity.

The human body combats infection and promotes wound healing through the remarkable process of inflammation. Inflammation is characterized by the recruitment of stromal cell activity including recruitment of immune cells and induction of angiogenesis. These cellular processes are regulated by a class of soluble molecules called cytokines. Based on function, cell target, and structure, cytokines are subdivided into several classes including: interleukins, chemokines, and lymphokines. While cytokines regulate normal physiological processes, chronic deregulation of cytokine expression and activity contributes to cancer in many ways. Gene polymorphisms of all types of cytokines are associated with risk of disease development. Deregulation RNA and protein expression of interleukins, chemokines, and lymphokines have been detected in many solid tumors and hematopoetic malignancies, correlating with poor patient prognosis. The current body of literature suggests that in some tumor types, interleukins and chemokines work against the human body by signaling to cancer cells and remodeling the local microenvironment to support the growth, survival, and invasion of primary tumors and enhance metastatic colonization. Some lymphokines are downregulated to suppress tumor progression by enhancing cytotoxic T cell activity and inhibiting tumor cell survival. In this review, we will describe the structure/function of several cytokine families and review our current understanding on the roles and mechanisms of cytokines in tumor progression. In addition, we will also discuss strategies for exploiting the expression and activity of cytokines in therapeutic intervention.

Effects of organic pollutants on soil microbial activity: the influence of sorption, solubility, and speciation.

The Fe(III) reduction test was used to measure the toxicity of 12 organic chemicals [dichlorophenoxyacetic acid (2,4-D), trichlorophenoxyacetic acid (2,4,5-T), atrazine, picloram, 4-chlorobenzeneamine, pentachlorophenol (PCP), hexachlorobenzene (HCB), 1,1-bis-4-chlorophenyl-2,2,2-trichloroethane (DDT), trichloroethene, benzene, phenol, linear alkylbenzenesulfonate (LAS)]. The different inherent toxicity of the pollutants is strongly modified by interactions with the soils. The total amounts that cause 10, 50, and 90% inhibitions (effective doses, ED10, ED50, ED90) can be statistically related to soil parameters that control the sorption and solubility of the chemicals. Sorption experiments with 2,4-D, 2,4,5-T, PCP, and LAS confirm that the degree of sorption and the concentration in the soil solution are important for potential toxic effects. However, toxic solution concentrations of a chemical (effective concentrations, EC10, EC50, EC90) also vary considerably. For some chemicals the influence of soil pH on their speciation in the soil solution is mainly responsible for this, e.g., the transformation from anionic to nonionic species with decreasing pH. The nonionic species of 2,4-D, 2,4,5-T, and PCP formed under acidic conditions are more toxic than the anionic species. Thus, depending on the chemical parameters of the soils that determine the degree of sorption and the speciation of toxicants in the liquid phase, soils either can "buffer" high loads of toxicants or can be very sensitive toward contamination.

Toxicity of increased amounts of chemicals and the dose-response curves for heterogeneous microbial populations in soil.

The paper deals with the interpretation and classification of dose-response curves in order to understand the way in which the heterogeneous soil microbial population behaves under chemical stress. The evaluation is based on a set of about 500 toxicity tests, in which geometrically increasing doses of toxicants were applied to soil samples. The responses of the microflora were measured by various methods, e.g., Fe(III) reduction, substrate induced respiration, arginine ammonification, and several enzyme activities. The data reveal that microbial populations in soil react more complexly than homogeneous groups of test subjects which are common in classical toxicology. The diverse types of dose-response curves are attributed to a varying sensitivity of different parts of the soil microflora and influences of the habitat soil. A proposal for the interpretation and classification of microbial dose-response curves is presented. Four basic types of dose-dependent effects and several combined sequences of them can describe the reaction patterns found up to now. Since experiments with heterogeneous populations are lacking in classical toxicology, the results can be used as a key for further research regarding the toxicity of chemicals against plant, animal, and human populations.

Laryngo-pharyngeal complaints following laryngeal mask airway and endotracheal intubation.

STUDY OBJECTIVE: To investigate the incidence and severity of laryngo-pharyngeal complaints following anesthesia with the use of a laryngeal mask airway (LMA) compared with endotracheal intubation in adults. DESIGN: Prospective study with randomized patient selection. SETTING: University medical center. PATIENTS: 202 adult ASA physical status I, II, and III patients scheduled for elective surgery of either an extremity or breast, or a transurethral resection. INTERVENTIONS: Following intravenous induction of anesthesia, a standard LMA size #3, #4, or #5 corresponding to the patient's body weight, was inserted in 103 patients; 99 patients were intubated with a polyvinylchloride endotracheal tube [7.5 mm inner diameter (ID) in women and 8.0 mm ID in men]. Cuff pressures in the LMA group were initially reduced to a minimum pressure at which an air-tight seal between the LMA and the laryngeal inlet was provided at a positive pressure of 20 cm H2O during manual bag ventilation. Cuffs of endotracheal tubes were inflated and controlled to a volume needed to prevent gas leak at 35 cm H2O pressure. MEASUREMENTS AND MAIN RESULTS: Cuff pressures were continuously monitored in both groups. Patients assessed their laryngo-pharyngeal complaints on a 101-point numerical rating scale on the evening after surgery and the following two days. No difference was found in the incidence and severity of sore throat on the evening following surgery or on the two following days. Dysphonia was more frequent following intubation than following LMA insertion on the day of surgery (46.8% vs. 25.3%) and on the first postoperative day (28.1% vs. 11.6%) (p < 0.05). However, the incidence of dysphonia increased with the duration of anesthesia in LMA patients but not in intubated patients. The incidence of dysphagia was significantly higher following LMA insertion compared with endotracheal intubation on the day of surgery (23.8% vs. 12.5%), and on the first postoperative day (22.3% vs. 10.4%). The severity of the individual complaints of minor laryngo-pharyngeal morbidity was comparable between groups. The type of airway management during anesthesia did not affect patient satisfaction with the anesthesia received. CONCLUSIONS: There is a distinct pattern of laryngo-pharyngeal complaints following the use of the LMA and endotracheal intubation. With regard to minor laryngo-pharyngeal morbidity, the advantage of the LMA to endotracheal intubation is questionable.

Microbial toxicity of Cd and Hg in different soils related to total and water-soluble contents.

Microbial toxicity tests with Cd and Hg and up to 18 soil samples were combined with sorption and solubility measurements. The data ought to indicate to what extent toxic effects of the metals are influenced by sorption and the other factors that may alter their biocidal action. The microbial reduction of Fe(III) oxides to Fe2+ ions was used as a parameter of microbial activity to calculate the total amounts of Cd and Hg that cause 10, 50, and 90% inhibition [effective doses (ED)10, ED50, ED90]. The corresponding solution concentrations [effective concentrations: (EC)10, EC50, EC90] were derived from Freundlich adsorption isotherms. The very large variability in ED values in different soils (ED10: Cd, 5-95 mg/kg; Hg, 0.125-125 mg/kg) can be related to the sorption and solubility behavior of the metals. Nevertheless, the EC values of both metals also indicate a considerable variation (EC10: Cd, 0.01-1.13 mg/liter; Hg, < 0.001-0.041 mg/liter). The influence of soluble soilborne substances on metal speciation is the main reason for their varying toxic potential in different soil solutions. The strong and complex influence of soil properties on the toxicity of heavy metals in soils indicates that both chemical and biological methods of soil analysis are needed to assess the risks of soil contamination adequately.

Marked increases in heart rate associated with sevoflurane but not with halothane following suxamethonium administration in children.

The changes in heart rate and arterial blood pressure following the administration of suxamethonium in healthy children (mean age 3.8 +/- 0.3 years) during inhalational induction with either sevoflurane (n = 22) or halothane (n = 19) were studied. Heart rate 60s following suxamethonium administration increased significantly in the sevoflurane but not in the halothane group. In the halothane group, four children required intravenous (i.v.) atropine as as result of bradycardia. None of the children in the sevoflurane group developed bradycardia following suxamethonium (P < 0.05). Values of oxygenation, ventilation and age corrected minimal alveolar concentration were comparable at all measurement times. The haemodynamic response to the administration of suxamethonium in children anaesthetized with sevoflurane seems to reflect the stimulation of the autonomic ganglia by suxamethonium whereas this positive chronotropic effect is attenuated or reversed by halothane.

Intensive care unit stay is prolonged in chronic alcoholic men following tumor resection of the upper digestive tract.

BACKGROUND: The prevalence of chronic alcohol misuse in patients with oral, pharyngeal, laryngeal or esophageal carcinomas exceeds 60%. No data is available, to our knowledge, on the morbidity and mortality of chronic alcoholics in surgical intensive care units (ICU) following tumor resection. We investigated whether the subsequent ICU stay in chronic alcoholics following tumor resection was prolonged and whether the incidence of pneumonia and sepsis was increased. METHODS: 213 patients with carcinomas of the upper digestive tract were evaluated regarding their drinking habits. Chronic alcoholics met either the DSM-III-R criteria for alcohol abuse or dependence. Conventional laboratory markers and serum carbohydrate-deficient transferrin were determined preoperatively. Major intercurrent complications during ICU stay such as an alcohol withdrawal syndrome, pneumonia and sepsis as well as the frequency of death were documented. RESULTS: Patients did not differ significantly between groups regarding age or APACHE score on admission to the ICU.121 patients were diagnosed as being chronic alcoholics, 39 as being social drinkers and 61 as being non-alcoholics. In chronic alcoholics the frequency of death was significantly increased. Due to the increased incidence of pneumonia and sepsis the ICU stay was significantly prolonged in chronic alcoholics by approximately 8 days. CONCLUSIONS: The increased mortality and morbidity rate demonstrates that chronic alcoholics undergoing major tumor surgery have to be considered as high-risk patients during their postoperative ICU stay. Further studies are required with respect to the immuno-competence of chronic alcoholics and the prevention of alcohol withdrawal syndrome, pneumonia and sepsis in these patients.

Therapy of alcohol withdrawal syndrome in intensive care unit patients following trauma: results of a prospective, randomized trial.

OBJECTIVES: To assess the effect of three different alcohol withdrawal therapy regimens in traumatized chronic alcoholic patients with respect to the duration of mechanical ventilation and the frequency of pneumonia and cardiac disorders during their intensive care unit (ICU) stay. DESIGN: A prospective, randomized, blinded, controlled clinical trial. SETTING: A university hospital ICU. PATIENTS: Multiple-injured alcohol-dependent patients (n=180) transferred to the ICU after admission to the emergency room and operative management. A total of 180 patients were included in the study; however, 21 patients were excluded from the study after assignment. INTERVENTIONS: Patients who developed actual alcohol withdrawal syndrome were randomized to one of the following treatment regimens: flunitrazepam/clonidine (n=54); chlormethiazole/haloperidol (n=50); or flunitrazepam/haloperidol (n=55). The need for administration of medication was determined, using a validated measure of the severity of alcohol withdrawal (Revised Clinical Institute Withdrawal Assessment for Alcohol Scale). MEASUREMENTS AND MAIN RESULTS: The duration of mechanical ventilation and major intercurrent complications, such as pneumonia, sepsis, cardiac disorders, bleeding disorders, and death, were documented. Patients did not differ significantly between groups regarding age, Revised Trauma and Injury Severity Score and Acute Physiology and Chronic Health Evaluation II score on admission. In all except four patients in the flunitrazepam/clonidine group, who continued to hallucinate, the Revised Clinical Institute Withdrawal Assessment for Alcohol Scale decreased to <20 after initiation of therapy. ICU stay did not significantly differ between groups (p=.1669). However, mechanical ventilation was significantly prolonged in the chlormethiazole/haloperidol group (p=.0315) due to an increased frequency of pneumonia (p=.0414). Cardiac complications were significantly (p=.0047) increased in the flunitrazepam/clonidine group. CONCLUSIONS: There was some advantage in the flunitrazepam/clonidine regimen with respect to pneumonia and the necessity for mechanical ventilation. However, four (7%) patients had to be excluded from the study due to ongoing hallucinations during therapy. Also, cardiac complications were increased in this group. Thus, flunitrazepam/haloperidol should be preferred in patients with cardiac or pulmonary risk. Further studies are required to determine which therapy should be considered.

Patient-controlled intranasal analgesia (PCINA) for the management of postoperative pain: a pilot study.

STUDY OBJECTIVE: To compare patient-controlled intranasal analgesia (PCINA) for post-operative pain management with ward-provided pain therapy. DESIGN: Randomized, prospective pilot study. SETTING: University medical center. PATIENTS: 20 ASA status I and II orthopedic patients. INTERVENTIONS: On the first postoperative day, 20 patients were randomized to receive either PCINA for 4 hours followed by 5 hours of ward-provided pain therapy (Group 1; n = 10) or ward-provided pain therapy for 5 hours followed by 4 hours of PCINA (Group 2; n = 10). The PCINA device used permits self-administration up to a maximum 0.025 mg dose of fentanyl every 6 minutes. Pain intensity (101-point numerical rating scale) and vital signs, as well as possible side effects, were registered at 30-minute intervals. MEASUREMENTS AND MAIN RESULTS: Within 30 minutes after the start of PCINA, pain intensity had decreased significantly in both groups. At the 60, 150, 210, 240, 270, 390, 420, and 480 minute measuring points, there was a significant intergroup difference in pain intensity, the level being significantly lower in the PCINA period. The handling of the PCINA device presented no problem to any patient. The PCINA fentanyl requirement was 0.415 +/- 0.083 mg (Group 1) and 0.408 +/- 0.06 mg (Group 2), respectively (NS). The ward-provided pain therapy included pethidine, tramadol, metamizole, acetaminophen, codeine, and diclofenac alone or in combination. Patient satisfaction was greater with PCINA than with ward-provided pain therapy (p < 0.0005). CONCLUSIONS: PCINA provides an adequate, noninvasive mode of postoperative pain management. The PCINA device is easy to handle and offers new perspectives in the management of postoperative pain.

Beta-carbolines in chronic alcoholics following trauma.

In our society every second polytraumatized patient is a chronic alcoholic. A patient's alcohol-related history is often unavailable and laboratory markers are not sensitive or specific enough to detect alcohol-dependent patients who are at risk of developing alcohol withdrawal syndrome (AWS) during their post-traumatic intensive care unit (ICU) stay. Previously, it has been found that plasma levels of norharman are elevated in chronic alcoholics. We investigated whether beta-carbolines, i.e. harman and norharman levels, could identify chronic alcoholics following trauma and whether possible changes during ICU stay could serve as a predictor of deterioration of clinical status. Sixty polytraumatized patients were transferred to the ICU following admission to the emergency room and subsequent surgery. Chronic alcoholics were included only if they met the DSM-III-R and ICD-10 criteria for alcohol dependence or chronic alcohol abuse/harmful use and their daily ethanol intake was > or =60 g. Harman and norharman levels were assayed on admission and on days 2, 4, 7 and 14 in the ICU. Harman and norharman levels were determined by high pressure liquid chromatography. Elevated norharman levels were found in chronic alcoholics (n = 35) on admission to the hospital and remained significantly elevated during their ICU stay. The area under the curves (AUC) showed that norharman was comparable to carbohydrate-deficient transferrin (CDT) and superior to conventional laboratory markers in detecting chronic alcoholics. Seventeen chronic alcoholics developed AWS; 16 of these patients experienced hallucinations or delirium. Norharman levels were significantly increased on days 2 and 4 in the ICU in patients who developed AWS compared with those who did not. An increase in norharman levels preceded hallucinations or delirium with a median period of approximately 3 days. The findings that elevated norharman levels are found in chronic alcoholics, that the AUC was in the range of CDT on admission and that norharman levels remained elevated during the ICU stay, support the view that norharman is a specific marker for alcoholism in traumatized patients. Since norharman levels increased prior to the onset of hallucinations and delirium it seems reasonable to investigate further the potential role of norharman as a possible substance which triggers AWS.

Prophylaxis of alcohol withdrawal syndrome in alcohol-dependent patients admitted to the intensive care unit after tumour resection.

Prophylaxis of alcohol withdrawal syndrome (AWS) in alcohol-dependent patients shortens the duration of stay in the intensive care unit (ICU). The objective of this study was to assess the effect of four different prophylactic regimens on the duration of ICU stay, prevention of AWS and rate of major intercurrent complications in alcohol-dependent patients admitted to the ICU after tumour resection. A total of 197 alcohol-dependent patients, diagnosed by the Diagnostic and Statistical Manual of Mental Disorders (third revised edition) with a daily ethanol intake of 60 g, were allocated randomly to one of the following regimens which were commenced on admission to the ICU: flunitrazepam-clonidine, chlormethiazole-haloperidol, flunitrazepam-haloperidol or ethanol. The duration of ICU stay, prevention of AWS, incidence of tracheobronchitis and major intercurrent complications such as pneumonia, sepsis, cardiac disorders, bleeding disorders and death were documented. On admission, patients did not differ significantly in age, APACHE II and multiple organ failure scores. ICU stay, incidence of AWS, severity of AWS (revised clinical institute withdrawal assessment for alcohol scale > 20) and major intercurrent complication rate did not differ significantly between groups. Although there was no advantage in any of the four regimens with respect to the primary outcome measures, pulmonary and cardiac patients were not included in the study. Patients in the chlormethiazole-haloperidol group had a significantly increased incidence of tracheobronchitis (P = 0.0023), probably because of an increased incidence of hypersecretion.

[Endotracheal intubation with propofol and fentanyl]. / Endotracheale Intubation unter Propofol und Fentanyl.

The routine use of succinylcholine for endotracheal intubation is being increasingly questioned. Initial studies have suggested that a combination of propofol and alfentanil without a muscle relaxant can provide good intubating conditions. However, most of these initial studies either did not have a double-blind design or did not include a control group with muscle relaxants. In this study, intubation conditions using fentanyl/propofol without a muscle relaxant were compared with the combinations of fentanyl/propofol/succinylcholine and sodium thiopental/succinylcholine. MATERIAL AND METHODS. Following approval from the local ethics committee and written consent, 100 gynaecological patients (ASA I, II) were included in this study. The study was carried out in a double blind, randomized and prospective manner. Black perfusor syringes and extension sets were used, and the drugs administered were diluted to equal volumes. For induction, group 1 (n = 25) received 0.1 mg fentanyl, 1 mg vecuronium, sodium thiopental (demand-adapted) and succinylcholine 1 mg/kg; group 2 (n = 25) received 0.1 mg fentanyl and propofol (demand-adapted); group 3 (n = 25) received 0.2 mg fentanyl and propofol (demand-adapted); group 4 (n = 25) received 0.1 mg fentanyl, 1 mg vecuronium, propofol (demand-adapted) and succinylcholine 1 mg/kg. Each patient was assessed prior to induction with regard to visualization of the pharynx (grade I-IV). Following induction, jaw relaxation (grade I-IV) and the laryngoscopic visualization of the glottis (grade I-IV) were assessed. During the intubation, the position and movements of the vocal cords (grade I-IV) and patient movement during and 1 min following the intubation were assessed. The overall assessment of the intubation was graded (grade I-IV) by the anaesthetist and the anaesthetic nurse. Postoperatively the patients were questioned regarding muscle pain (grade I-IV). Before, during and after endotracheal intubation arterial haemoglobin oxygen saturation, heart rate and arterial blood pressure were monitored. RESULTS. There were no intergroup differences with regard to age, height, weight and preanaesthetic visualization of the pharynx. In group 1 an average of 5.5 +/- 1.2 mg/kg sodium thiopental was required. There were no significant differences in group 2, 3 and 4 with respect to the dose of propofol (2.4, 2.2 and 2.2 mg/kg). No intergroup differences were noted with regard to jaw relaxation, laryngoscopic visualization of the glottis and patients' movements during intubation. Statistically significant intergroup differences occurred with regard to the position and movements of vocal cords during intubation (group 3 worse than groups 1, 2, 4) and the patients' movements 1 min after intubation (group 2 worse than group 3). Significant intergroup differences also occurred with regard to the overall assessment of the intubation by the anaesthetist (group 3 worse than groups 2, 4) and the anaesthetic nurse (group 3 worse than group 4) and the postoperative muscle pain (group 1 worse than groups 2, 3). CONCLUSION. The use of 0.1 mg fentanyl/sodium thiopental/succinylcholine results in no better intubating conditions than 0.1 mg fentanyl plus propofol. Under these conditions, without the use of a muscle relaxant, it is possible to carry out safe endotracheal intubation in cases where no complications are anticipated.

The influence of lung injury due to mechanical ventilation on the initiation of ECMO.

Before the entry criteria for extracorporeal membrane oxygenation (ECMO) are met, newborns may require aggressive mechanical ventilation which may result in lung injury. The question arises whether the presence of a pneumothorax in these infants plays a role in the prognosis. Of the 21 newborns transferred to our hospital for ECMO, 8 were treated with ECMO. 9 of the 21 newborns developed a pneumothorax with conventional ventilation and 6 of these 9 newborns subsequently required ECMO. Infants who developed a pneumothorax but did not meet ECMO criteria and remained in the oxygenation index (OI) range between 25 and 40 for more than 2 days had a poorer prognosis. If adequate oxygenation cannot be attained with acceptable mechanical ventilation and a more aggressive ventilation results in a pneumothorax, ECMO should be considered even if the oxygenation index is below 40.

Prediction of heavy metal behavior in soil by means of simple field tests.

Binding and retention against uptake by plants, and groundwater pollution of the metal ions Cd, Mn, Ni, Co, Zn, Cu, Cr(III), Pb, Hg, Fe(III), and Al by soils in relation to pH, redox potential, texture, organic matter, and iron oxide contents can be diagnosed in the form of rough relative values with simple field methods. A comparison with the results of some pot and field trials showed the practicability of this method.

[The development of the omental bursa]. / Zur Entwicklung der Brusa omentalis.

The development of the omental bursa (lesser sac) was studied in serial sections of hybrid mouse embryos of 9-11 1/2 days. The anlage of the bursa is represented by several indentations on the right side of the mesenterium. Further growth and topographic alterations of the adjoining organs determine the definitive shape of the lesser sac. On the left side, the recessus pneumato-entericus is a transient structure which persists only until the 11th day of gestation. In humans, the anlage of the bursa is almost identical with its origin in mice. The bursa facilitates the separation from the digestive tract of several organs developing in the mesentery.