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Biomedical subjects

M Singer

Publications and source records attributed to M Singer.

At least 55 records · Page 3Linked to original sources

The asgE locus is required for cell-cell signalling during Myxococcus xanthus development.

In response to starvation, Myxococcus xanthus undergoes a multicellular developmental process that produces a dome-shaped fruiting body structure filled with differentiated cells called myxospores. Two insertion mutants that block the final stages of fruiting body morphogenesis and reduce sporulation efficiency were isolated and characterized. DNA sequence analysis revealed that the chromosomal insertions are located in open reading frames ORF2 and asgE, which are separated by 68 bp. The sporulation defect of cells carrying the asgE insertion can be rescued phenotypically when co-developed with wild-type cells, whereas the sporulation efficiency of cells carrying the ORF2 insertion was not improved when mixed with wild-type cells. Thus, the asgE insertion mutant appears to belong to a class of developmental mutants that are unable to produce cell-cell signals required for M. xanthus development, but they retain the ability to respond to them when they are provided by wild-type cells. Several lines of evidence indicate that asgE cells fail to produce normal levels of A-factor, a cell density signal. A-factor consists of a mixture of heat-stable amino acids and peptides, and at least two heat-labile extracellular proteases. The asgE mutant yielded about 10-fold less heat-labile A-factor and about twofold less heat-stable A-factor than wild-type cells, suggesting that the primary defect of asgE cells is in the production or release of heat-labile A-factor.

Bacterial Proteins↗

Inhibition by unsaturated fatty acids of type II secretory phospholipase A2 synthesis in guinea-pig alveolar macrophages evidence for the eicosanoid-independent pathway.

The effect of arachidonic acid (C20:4) on the production of secretory type II phospholipase A2 (sPLA2-II) by guinea-pig alveolar macrophages was investigated. We show that incubation of these cells with 1-30 microM of arachidonic acid inhibits the synthesis of sPLA2-II in a concentration-dependent manner with an IC50 of approximately 7.5 microM. The inhibition by low concentrations (5 microM) of arachidonic acid was partially reduced by pretreatment of alveolar macrophages with cyclooxygenase or cytochrome P450 inhibitors (aspirin and 1-aminobenzotriazole, respectively), but not by lipoxygenase inhibitor, BW A4C. However, these inhibitors failed to interfere with the effect of high concentrations (30 microM) of arachidonic acid, suggesting that the latter may act on the expression of sPLA2-II, at least in part, independently of eicosanoid generation. Indeed, a similar inhibitory effect on sPLA2-II activity and mRNA expression was observed with other unsaturated fatty acids such as eicosapentaenoic (C20:5) and oleic (C18:1) acids, but not with the saturated fatty acid, palmitic acid (C16:0). In addition, arachidonic acid partially reduced the secretion of tumor necrosis factor alpha, an important intermediate in the induction of sPLA2-II synthesis by guinea-pig alveolar macrophages. However, addition of recombinant tumor necrosis factor alpha failed to reverse the inhibitory effect of arachidonic acid on sPLA2-II expression, suggesting that this process occurs downstream of tumor necrosis factor alpha secretion. We conclude that the expression of sPLA2-II in alveolar macrophages is down-regulated at the transcriptional level by arachidonic acid either directly or via its cyclooxygenase and cytochrome P450-derived metabolites.

Animals↗

A comparison of hemodynamic data derived by pulmonary artery flotation catheter and the esophageal Doppler monitor in preeclampsia.

OBJECTIVE: This study was undertaken to compare hemodynamic data derived with the esophageal Doppler monitor against those obtained with a pulmonary artery flotation catheter in women with complicated preeclampsia. STUDY DESIGN: Seventeen women with severe preeclampsia who had a pulmonary artery flotation catheter placed for clinical indications also had an esophageal Doppler monitor inserted. Hemodynamic data were recorded on 2 occasions separated by several hours with both the pulmonary artery flotation catheter and the esophageal Doppler monitor simultaneously. RESULTS: The esophageal Doppler monitor underestimated cardiac output by 36% +/- 14% (mean +/- SD). The esophageal Doppler monitor accurately estimated cardiac output in 3 women >40 years old, whereas in the remaining women (all <35 years old) the esophageal Doppler monitor underestimated cardiac output by 38% +/- 11%. The esophageal Doppler monitor accurately reflected changes in cardiac output with time when compared with the pulmonary artery flotation catheter. CONCLUSION: In women with preeclampsia the esophageal Doppler monitor consistently underestimated cardiac output by approximately 40%. It is not known whether the apparent increase in accuracy among the women >40 years old arose by chance or reflected a real improvement in performance. The esophageal Doppler monitor accurately reflected the direction and magnitude of the changes in cardiac output with time.

Adult↗

Long-term results of tendon transfers for radial nerve palsy in patients with limited rehabilitation.

The authors reviewed the long-term functional results of 22 patients who underwent tendon transfer for isolated radial nerve palsy. The average number of postoperative visits was eight (range of postoperative visits, 3-16), and the mean follow-up was 6.3 years. All but 1 patient had improved function after the tendon transfers, and could cope with the activities of daily living. Radial deviation of the wrist at rest was present in 10 of the 15 patients with flexor carpi ulnaris transfer and in 2 of 7 patients with flexor carpi radialis transfer, with a mean of 14.5 deg (range of radial deviation, 5-30 deg). Although a global decrease in wrist power and power grip was noted, 13 of 17 previously employed patients were able to work after transfer; however, only 1 of 7 heavy manual laborers was able to return to his previous employment. Despite the poor clinic attendance, the overall functional results compared favorably with other published series. It appears that tendon transfer for radial nerve palsy is a viable option, even in patients with limited rehabilitation.

Adult↗

Intravenous crocetinate prolongs survival in a rat model of lethal hypoxemia.

OBJECTIVE: To examine whether a carotenoid, trans-sodium crocetinate, has beneficial effects on hemodynamic status and short-term outcome in a rat model of lethal hypoxemia. DESIGN: Randomized, placebo-controlled study. SETTING: Medical school laboratory. SUBJECTS: Eighteen spontaneously breathing, anesthetized Sprague-Dawley rats (six per group). INTERVENTIONS: Rats underwent instrumentation to measure blood pressure, aortic and renal blood flow, arterial blood gases, bladder epithelial oxygen tension (by an intraluminal Clark electrode), and hepatic microvascular oxygen tension (measured by porphyrin phosphorescence). After stabilization, the rats were subjected to breathing 10% inspired oxygen concentration. After 10 mins, they were administered 1.25 mL/kg intravenous boluses of either isotonic saline (control), normal strength crocetinate (40 microg/mL), or a concentrated crocetinate solution (60 microg/mL). These boluses were repeated at 30-min intervals until either death or 3 hrs had elapsed. MEASUREMENTS AND MAIN RESULTS: With the onset of hypoxemia, we observed a rapid reduction in blood pressure and renal blood flow, maintenance of aortic blood flow, an increase in arterial base deficit, and falls in oxygen tensions in arterial blood, bladder epithelium, and hepatic microvasculature. A progressive deterioration in the control rats was noted, with only two of the six animals surviving for 3 hrs. However, all 12 rats in the two crocetinate groups survived for 3 hrs, with hemodynamic stability until 150 mins and a slow decline thereafter. CONCLUSIONS: Trans-sodium crocetinate improved hemodynamic status and prolonged survival in this model of severe acute hypoxic hypoxia. To our knowledge, this is the first demonstration of an intravenous agent having such an effect.

Animals↗

Control of asgE expression during growth and development of Myxococcus xanthus.

One of the earliest events in the Myxococcus xanthus developmental cycle is production of an extracellular cell density signal called A-signal (or A-factor). Previously, we showed that cells carrying an insertion in the asgE gene fail to produce normal levels of this cell-cell signal. In this study we found that expression of asgE is growth phase regulated and developmentally regulated. Several lines of evidence indicate that asgE is cotranscribed with an upstream gene during development. Using primer extension analyses, we identified two 5' ends for this developmental transcript. The DNA sequence upstream of one 5' end has similarity to the promoter regions of several genes that are A-signal dependent, whereas sequences located upstream of the second 5' end show similarity to promoter elements identified for genes that are C-signal dependent. Consistent with this result is our finding that mutants failing to produce A-signal or C-signal are defective for developmental expression of asgE. In contrast to developing cells, the large majority of the asgE transcript found in vegetative cells appears to be monocistronic. This finding suggests that asgE uses different promoters for expression during vegetative growth and development. Growth phase regulation of asgE is abolished in a relA mutant, indicating that this vegetative promoter is induced by starvation. The data presented here, in combination with our previous results, indicate that the level of AsgE in vegetative cells is sufficient for this protein to carry out its function during development.

Bacterial Proteins↗

Open trial of psychodynamic psychotherapy for panic disorder: a pilot study.

OBJECTIVE: This report contains preliminary data from an open trial of brief psychodynamic psychotherapy for panic disorder. METHOD: Fourteen patients with primary DSM-IV panic disorder completed a 24-session, twice-weekly course of psychodynamic psychotherapy. Other psychiatric treatment was not permitted throughout the 12-week treatment period and the 6-month follow-up. Symptoms were assessed at baseline, treatment termination, and 6-month posttermination follow-up (40 weeks). RESULTS: Statistically significant, clinically meaningful improvements appeared in panic, depression, anxiety, and functional impairment both at treatment termination and at 6-month follow-up. CONCLUSIONS: Psychodynamic monotherapy can be used successfully to retain and treat patients with panic disorder. Psychodynamic interventions warrant further study for patients with panic disorder.

Adult↗

The social geography of AIDS and hepatitis risk: qualitative approaches for assessing local differences in sterile-syringe access among injection drug users.

While significant gains have been achieved in understanding and reducing AIDS and hepatitis risks among injection drug users (IDUs), it is necessary to move beyond individual-level characteristics to gain a fuller understanding of the impact of social context on risk. In this study, 6 qualitative methods were used in combination with more traditional epidemiologic survey approaches and laboratory bioassay procedures to examine neighborhood differences in access to sterile syringes among IDUs in 3 northeastern cities. These methods consisted of (1) neighborhood-based IDU focus groups to construct social maps of local equipment acquisition and drug use sites; (2) ethnographic descriptions of target neighborhoods; (3) IDU diary keeping on drug use and injection equipment acquisition; (4) ethnographic day visits with IDUs in natural settings; (5) interviews with IDUs about syringe acquisition and collection of syringes for laboratory analysis; and (6) focused field observation and processual interviewing during drug injection. Preliminary findings from each of these methods are reported to illustrate the methods' value in elucidating the impact of local and regional social factors on sterile syringe access.

Anthropology, Cultural↗

Dummy measurement of chest injuries induced by two-point shoulder belts.

The University of Miami's William Lehman Injury Research Center at the Jackson Memorial Medical Center conducts interdisciplinary investigations to study seriously injured restrained occupants in frontal automobile collisions. Engineering analysis of these crashes is conducted in conjunction with the National Crash Analysis Center at the George Washington University. The multidisciplinary research team includes expertise in crash investigation, crash reconstruction, computer graphics, biomechanics of injuries, crash data analysis, trauma care, and all of the medical specialties associated with the Ryder Trauma Center at Jackson Memorial Hospital. More than 350 injured occupants and their crashes have been studied in depth. The purpose of this paper is to report on an observed pattern of liver lacerations suffered by drivers wearing shoulder belts, without the lap belt fastened and to assess the ability of existing crash test dummies to measure the potential for these injuries. During the initial years of the study, 48 cases of drivers protected by shoulder belts but without the lap belt fastened met the criteria for the study. Fifty percent of these drivers suffered liver lacerations. Further study showed that 22 of the crashes involved damage to the right front of the vehicle. Among the drivers in vehicles with right front damage, 92% sustained injuries to the liver. This observation indicated that 2-point belts were most likely to produce liver injuries in low severity frontal collisions when the crash direction is 1 to 2 o'clock. An analysis of the National Accident Sampling System for the years 1988-95 indicated that liver injuries constitute about 0.5% of the injuries suffered by drivers who are in tow-away crashes. NASS data showed that the risk of chest injury is more likely among drivers with automatic shoulder belts than drivers with 3-point manual belts. The crash test dummies showed no difference in chest injury measures. Finite element computer modeling demonstrated that the high deflection of the right lower rib on the Hybrid III dummy predicts the liver injuries in the 1 o'clock crashes. These higher deflections were less apparent at the location of the center chest deflection measurement device on the Hybrid III.

Accidents, Traffic↗

Injuries to restrained occupants in far-side crashes.

Occupants exposed to far-side crashes are those seated on the side of the vehicle opposite the struck side. This study uses the NASS/CDS 1988-98 to determine distributions of AIS 3+ injuries among occupants exposed to far-side crashes and the sources of the injuries. The William Lehman Injury Research Center (WLIRC) data from 1994-98 is used to assess injury mechanisms among seriously injured crash exposed far-side occupants. The NASS/CDS indicated that injury patterns for far-side restrained drivers were different from far-side restrained front passengers. For the driver, the head accounted for 40% of the AIS 3+ injuries in far-side collisions and the chest/abdomen accounted for 45.5%. For the right front passengers, head injuries contributed 27.2%, while chest and abdominal injuries accounted for 64.5%. The opposite-side interior was the most frequent contact associated with driver AIS 3+ injuries (30.5%). The seat belt was second, accounting for 22.6%. Among thirteen WLIRC cases of far-side belted occupants with MAIS 3+ injuries, five of the most serious injuries were attributed to the seat belt. The liver or the spleen was the most seriously injured body organ in all five cases. The seat was the most frequent source of passenger AIS 3+ injuries for the NASS/CDS weighted cases. However, non-contacts, contacts with other occupants, and the seat belt contacts were more frequent sources when considering the raw number of injuries. Overall, contacts with the opposite side of the car interior and with safety belts were the most frequent causes of AIS 3+ injuries in far-side crashes. The presence of an occupant on the near-side changed the injury pattern of the far-side occupant, mitigating injuries from contacts with the opposite side interior of the vehicle.

Accidents, Traffic↗

Mitochondrial dysfunction in sepsis.

The current mainstream view of organ failure induced by sepsis revolves around inflammation and loss of vascular control. However, there has been a resurgence in interest in bioenergetic failure due to mitochondrial dysfunction. This concept is not new--studies date back 30 years; however, the data have been highly conflicting with findings of either decreased, increased or unchanged mitochondrial activity and/or nucleotide levels. These studies are virtually all based on non-human cells, isolated perfused organs or in vivo animal models that have received a variety of insults ranging from mild to severe, and monitored for different durations ranging from minutes to weeks. As a generalization, there does appear to be depression of mitochondrial function with longer-duration models of greater severity. This is confirmed by the scanty human data currently available. This chapter provides an overview, and attempts to relate the biochemical changes to the clinical condition. The potential roles of nitric oxide, intracellular calcium and reactive oxygen species are highlighted.

Adenosine Triphosphate↗

Preliminary UK experience of dexmedetomidine, a novel agent for postoperative sedation in the intensive care unit.

Dexmedetomidine, a highly selective and potent alpha2-adrenergic agonist, has a potentially useful role as a sedative agent in patients requiring intensive care. As part of a larger European multicentre trial, a total of 119 postoperative cardiac and general surgical patients requiring ventilation and sedation in an intensive care unit were enrolled in four centres in the United Kingdom. One hundred and five patients were randomly allocated to receive either dexmedetomidine or placebo with rescue sedation and analgesia provided by midazolam and morphine, respectively. Compared with the control group, intubated patients receiving dexmedetomidine required 80% less midazolam [mean 4.9 (5.8) microg.kg-1.h-1 vs. 23.7 (27.5) microg.kg-1.h-1, p < 0.0001], and 50% less morphine [11.2 (13.4) microg.kg-1.h-1 vs. 21.5 (19.4) microg.kg-1.h-1,p = 0.0006]. Cardiovascular effects and adverse events could be predicted from the known properties of alpha-2 agonists. In conclusion, dexmedetomidine is a useful agent for the provision of postoperative analgesia and sedation.

Adolescent↗

Activation of the tissue factor pathway occurs during continuous venovenous hemofiltration.

BACKGROUND: Activation of the tissue factor pathway occurs during continuous venovenous hemofiltration (CVVH). Despite adequate exogenous anticoagulation, the occlusion of CVVH circuits can occur within minutes to a few hours of use and is associated with evidence of thrombin generation. Having found no evidence of activation of the contact factor (intrinsic coagulation) pathway during CVVH, we sought to examine the effect of the first episode of CVVH on the tissue factor (extrinsic) pathway of coagulation and thrombin generation. METHODS: Twelve critically ill patients were studied prior to the commencement of hemofiltration and at regular intervals thereafter until the filter clotted. RESULTS: Prior to hemofiltration, most patients had increased levels of plasma tissue factor, thrombin-antithrombin (TAT) complexes, and tissue factor pathway inhibitor (TFPI); during hemofiltration, further generation of TAT complexes occurred. Initially, levels of activated factor VII (FVIIa) fell and TFPI increased, but during the course of hemofiltration, the levels of TFPI fell and FVIIa increased. Levels of tissue factor increased during CVVH in some patients, but this was not related to the generation of FVIIa. CONCLUSIONS: These data indicate that activation of FVII occurred during CVVH, which was related to levels of TFPI, but not tissue factor, and was coincidental to thrombin generation.

Adult↗

Septic arthritis of the metacarpophalangeal and interphalangeal joints of the hand.

Septic arthritis of the small joints of the hand is not reported frequently. Twenty-eight patients were treated during a 15-month period, from November 1992 to January 1994. Prompt surgical drainage, antibiotics, and early postoperative mobilization (within 24 hours) were the cornerstones of management. Nineteen patients were available for a median follow-up of 10 months. Patients who presented after 10 days all had a poor result. Patients who presented earlier achieved a good result unless they defaulted from treatment or had sustained an associated severe traumatic joint injury. Ten of the 19 patients obtained a good result. Good functional results can be obtained with early postoperative mobilization.

Adolescent↗

Prediction of postoperative cardiac surgical morbidity and organ failure within 4 hours of intensive care unit admission using esophageal Doppler ultrasonography.

OBJECTIVE: To compare esophageal Doppler ultrasonography with standard hemodynamic variables used in postoperative care for the prediction of postoperative complications after cardiac surgery. DESIGN: Prospective, observational pilot study. SETTING: University hospital, multidisciplinary intensive care unit PATIENTS: Postoperative cardiac surgical patients. INTERVENTIONS: Standard postoperative management as guided by routinely measured hemodynamic variables. MEASUREMENTS: An esophageal Doppler ultrasound probe was inserted for measurement of stroke volume (SV), cardiac output (CO), and other flow-related variables. Both these and routine hemodynamic variables (mean arterial pressure, central venous pressure, heart rate, arterial base deficit, urine output, core-toe temperature difference) were recorded at half-hourly intervals for the first 4 postoperative hrs. The incidence of systemic inflammatory response syndrome at 24 hrs, Acute Physiology and Chronic Health Evaluation II, and multiple organ failure scores, postoperative complications, and length of ICU and hospital stays were recorded. MAIN RESULTS: Twenty consecutively admitted patients were studied: eight after emergency bypass grafting and 12 after elective bypass grafts and/or valve replacement. Of the nine patients who developed postoperative complications, two died. At admission, significant differences were seen between patients with a complicated and those with an uncomplicated surgical procedure for SV, heart rate, and standard base excess, but not for cardiac output. By using receiver operator characteristic curves, SV was the best marker for predicting postoperative complications during the initial postoperative period. CONCLUSIONS: A low SV and a high heart rate, both at ICU admission and during the subsequent 4 hrs, were the best prognostic factors for development of complications after cardiac surgery. Cardiac output values were not useful. This pilot study suggests that the minimally invasive technique of esophageal Doppler ultrasonography may be a useful tool to assist early prognostication.

Analysis of Variance↗