Pin-track infection in HIV-positive and HIV-negative patients with open fractures treated by external fixation: a prospective, blinded, case-controlled study.

Patients infected with HIV presenting with an open fracture of a long bone are difficult to manage. There is an unacceptably high rate of post-operative infection after internal fixation. There are no published data on the use of external fixation in such patients. We compared the rates of pin-track infection in HIV-positive and HIV-negative patients presenting with an open fracture. There were 47 patients with 50 external fixators, 13 of whom were HIV-positive (15 fixators). There were significantly more pin-track infections requiring pharmaceutical or surgical intervention (Checketts grade 2 or greater) in the HIV-positive group (t-test, p = 0.001). The overall rate of severe pin-track infection in the HIV-positive patients requiring removal of the external-fixator pins was 7%. This contrasts with other published data which have shown higher rates of wound infection if open fractures are treated by internal fixation. We recommend the use of external fixation for the treatment of open fractures in HIV-positive patients.

Alprazolam in panic disorder and agoraphobia: results from a multicenter trial. III. Discontinuation effects.

Preliminary reports of discontinuation of alprazolam therapy in patients with panic disorder have revealed worsening of symptoms despite gradual withdrawal of medication. In this study, 126 patients with panic disorder and phobic avoidance received either alprazolam or placebo in doses of 2 to 10 mg daily for eight weeks. The medication was tapered over a period of four weeks, and patients were observed for another two weeks after all medication was discontinued. Sixty of the 63 alprazolam-treated patients and 49 of the 63 placebo-treated patients entered the taper and discontinuation study. After improvement in the active treatment period, the alprazolam-treated group had significant relapse between the first and last week of taper. However, during the second postdiscontinuation week, outcome scores were not significantly different from those of the placebo-treated group who did not deteriorate during taper. Twenty-seven percent of the alprazolam-treated group reported a rebound of panic attacks during taper and 13% reported a rebound of anxiety on the Hamilton Anxiety Scale. No serious or life-threatening withdrawal symptoms were reported, but distinct, transient, mild to moderate withdrawal syndrome occurred in 35% of the alprazolam-treated group and in none of the placebo-treated group. The coexistence of symptom rebound and a withdrawal syndrome occurred in 10% of the alprazolam-treated group, but both subsided by the end of the second week without alprazolam. We recommend that patients with panic disorder be treated for a longer period, at least six months, and that medication be tapered over a more prolonged period, at least eight weeks, especially where high doses are employed.

Potentiation of oxidant-induced toxicity in hamster lung slices by dimethylthiourea.

Dimethylthiourea (DMTU) is an effective scavenger of reactive oxygen metabolites. This property has been successfully exploited, experimentally, in the protection of cells and tissues against oxidative damage. In this study, however, we have observed that levels of nonprotein sulfhydryls (NPSH) in hamster lung slices were markedly decreased by incubation with 10 or 40 mM DMTU. These changes were associated with morphological signs of injury, increased levels of oxidised glutathione (GSSG), and an increased activity of the pentose phosphate pathway (PPP), suggesting that the loss of NPSH was due to their oxidation. Incubation with 40 mM, but not 10 mM DMTU, also resulted in a decreased ability to oxidise [6-14C]glucose or to synthesise proteins, suggesting that at the high concentration, DMTU may cause functional impairment of the tissue. Furthermore, the ability of the slices to accumulate putrescine decreased after incubation with the oxidative toxins paraquat (PQ), tert-butyl hydroperoxide (t-BOOH) or hydrogen peroxide (H2O2) and was further decreased by co-incubation with DMTU. Putrescine uptake, a function specific to the alveolar type I and II epithelial cells, was not affected by incubation with DMTU alone. DMTU did not exacerbate the effect of the nonoxidative toxin iodoacetamide (IAA) on putrescine uptake but it did affect markers of general cell damage or dysfunction. We suggest, therefore, that the toxicity of oxidants toward lung tissue is potentiated in alveolar epithelial cells by DMTU.

The role of thiol oxidation in Cobalt(II)-induced toxicity in hamster lung.

Exposure of lung tissue to Co(II) ions both in vivo and in vitro results in toxicity, a relatively early event of which is the oxidation of cellular glutathione. In this study we have attempted to delineate the relationship between this oxidation of glutathione and the subsequent development of cellular dysfunction. Simultaneous incubation with H2O2 potentiated Co(II)-induced increases in both levels of oxidized glutathione (GSSG) and the activity of the pentose phosphate pathway in hamster lung slices. This effect was initially synergistic and, thereafter, both parameters were maintained at significantly greater levels than with either treatment alone throughout the incubation period until the onset of detectable cellular dysfunction. When dysfunction occurred, however, it was not quantitatively increased by the co-treatment over that occurring with CoCl2 alone. Similarly, pretreatment of slices with the glutathione reductase inhibitor 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) potentiated the Co(II)-induced increase in levels of GSSG. However, this effect was again not associated with an enhancement of cell dysfunction. Since the Co(II)-induced cell damage appeared not to be related directly to the oxidation of glutathione, the quantitative significance of the latter was investigated by comparison with the known oxidant tert-butyl hydroperoxide (t-BOOH). At a concentration of 100 microM, t-BOOH caused an increase in the concentration of GSSG in BCNU-pretreated lung slices which was comparable to that after treatment with Co(II)/H2O2 or CO(II)/BCNU. None of these treatments resulted in a loss of protein thiols. Furthermore, in contrast to Co(II), t-BOOH/BCNU treatment did not result in impaired cell functions. However, at a t-BOOH concentration of 250 microM, t-BOOH/BCNU treatment caused a significantly greater increase in the level of GSSG than that caused by the previous treatments and was associated with both a loss of protein thiols and increased cell dysfunction. We have concluded from these data that under our experimental conditions, Co(II)-induced cell dysfunction is not a consequence of oxidation of cellular glutathione. The reason for this appears to be that the extent of glutathione oxidation by Co(II) even at a concentration which induces cell dysfunction is not of sufficient magnitude to result in the oxidation of protein thiol groups, an event which is likely to constitute the critical consequence of glutathione oxidation in the toxic process.

Putrescine and paraquat uptake in human lung slices and isolated type II pneumocytes.

Paraquat is accumulated into the lungs of various species by an active uptake system which also appears to mediate the uptake of endogenous polyamines, such as putrescine. The accumulation of putrescine in the human lung has been previously shown to be mainly located in the type II cells. In the present study, we have studied the mutually competitive inhibition of putrescine and paraquat in human lung slices and the inhibition of putrescine by paraquat or cystamine in isolated human type II pneumocytes. Peripheral lung tissue taken from patients undergoing pneumectomy or lobectomy was used. The initial steps of the cell isolation procedure differed from the literature in that the tissue was first sliced in 0.7 mm thick slices, which were washed in phosphate buffered saline without calcium and magnesium (PBS-), followed by incubations with trypsin. The type II cells were purified and isolated by differential adherence on plastic followed by Percoll gradient centrifugation. Uptake was determined 48 hr after cell isolation. The accumulation of radiolabelled putrescine showed saturation kinetics, with the following apparent kinetic parameters: Km 6.7 and 6.2-7.6 microM and Vmax 2.7 and 3.0-3.4 mumol/g prot/hr for slices and isolated cells, respectively. In the presence of paraquat, putrescine uptake was reduced, in both systems, in a manner compatible with competitive inhibition, with calculated inhibition constants (Ki) of 549-614 and 659-895 microM paraquat for slices and isolated cells, respectively. The accumulation of putrescine in isolated human pneumocytes was strongly reduced in the presence of cystamine, with calculated Ki of 3.7 microM cystamine. These data indicate that putrescine, paraquat and cystamine accumulate in the human lung by the same uptake system, but that the affinities for the three substrates differ. The presence of an uptake system for putrescine in cultured human pulmonary type II is probably useful as a functional viability test.

The identification and characterization of an uptake system for taurine into rat lung slices.

The objective of this study was to determine whether taurine was accumulated by rat lung slices and if so, to establish the role of this uptake as a source of pulmonary taurine. We have shown that taurine is accumulated into rat lung by an active uptake process that was both ATP and Na(+)-dependent and obeyed saturation kinetics, exhibiting an apparent Km of 186 microM and Vmax of 970 nmol/g wet wt/hr. Substrate specificity of the system was high and only compounds possessing anionic and cationic groups separated by two methylene groups were able to competitively inhibit taurine uptake. Subsequent to its uptake, taurine was not significantly metabolized, and since the apparent Km for the uptake process is similar to the known plasma concentration of taurine, it can be inferred that this system will contribute to pulmonary taurine uptake in vivo. Taurine has been suggested to possess antioxidant and antiinflammatory properties, and we suggest that this uptake system may contribute to the defence of pulmonary tissue against oxidative stress.

The accumulation of cystamine and its metabolism to taurine in rat lung slices.

The objective of these studies was to determine the accumulation and fate of the disulphide, cystamine by rat lung slices. Cystamine was accumulated by two active uptake systems that obeyed saturation kinetics, with apparent Km values of 12 and 503 microM, and maximal rates of 530 and 5900 nmol/g wet weight/hr respectively. The high affinity system was competitively inhibited by the diamine, putrescine and the herbicide paraquat, which are themselves accumulated. Thus, this pulmonary uptake process appears to be identical for all three compounds. In contrast, the low affinity process was not inhibited by putrescine, and this process results from the diffusion of cystamine into the cell and its subsequent metabolism. Upon accumulation, cystamine was metabolised, predominantly to the sulphonic acid, taurine, with 10-20% of the intracellular label covalently binding to protein. Conversion to taurine was unaffected by amine oxidase inhibitors, but was decreased after GSH depletion, suggesting that pulmonary cystamine metabolism is glutathione-dependent, and is not mediated by diamine oxidase. Both cystamine and taurine have been implicated as antioxidants, and we suggest that cystamine is actively accumulated by the lung as part of the process to protect pulmonary tissue against oxidative stress.

The importance of epithelial uptake systems in lung toxicity.

The discovery that the herbicide paraquat was selectively accumulated by the lung, both in vivo and in vitro, in comparison with other tissues, provided an explanation for its selective toxicity to the lung. This uptake process is energy dependent and obeys saturation kinetics. A characterization of the process led to the identification of endogenous chemicals that are the natural substrates for the system. Among these are a series of diamines and polyamines, as well as the diaminodisulfide cystamine. It appears that paraquat, because of specific structural similarities to these endogenous polyamines, is mistakenly accumulated by the lung. This uptake process is specifically located in the alveolar Type II cell, the Clara cell, and probably the alveolar Type I cell. With the development of knowledge of the structural requirements of chemicals to be accumulated by this system, it is possible to predict which chemicals will be accumulated by the lung or design molecules that are targeted to the alveolar epithelial and Clara cells. In the wider perspective, this polyamine uptake system has been found on a number of cancerous cells or tissues. With the knowledge of the uptake system in the lung, it should be possible to design drugs that will be specifically concentrated in cells that possess this system.

Relationship of past depressive episodes to symptom severity and treatment response in panic disorder with agoraphobia.

BACKGROUND: Many investigators have reported that panic disorder (PD) patients with comorbid major depression (MD) have more severe symptoms and a poorer response to treatment than patients with PD alone. It is not known if this is due to a distinct and more serious underlying disorder in these patients or simply a result of the simultaneous presence of the two disorders. METHOD: Nondepressed patients presenting for treatment of panic disorder with agoraphobia (PDA) were studied before treatment (N = 180) and after 4 weeks of treatment with adinazolam sustained release (N = 89) or placebo (N = 91). Twenty-nine percent (N = 53) of the patients had a past history of MD. Symptom severity and treatment outcome were compared in patients with primary, secondary, single, recurrent, or no past MD. RESULTS: There were no consistent differences in symptom severity or treatment outcome in patients with a past history of primary, secondary, or single episode MD compared with patients with no history of MD. However, a small number of patients with history of recurrent MD exhibited consistently greater symptom severity and poorer response to treatment than patients with no history of MD. CONCLUSION: The greater severity and worse outcome of comorbid PD and MD observed in earlier studies are more likely due to the simultaneous presence of the two disorders than to a more serious and enduring underlying disorder. However, our results suggest that recurrent MD may indicate a more serious condition in patients with PDA. This possibility warrants further study.

Wound healing after implant surgery in HIV-positive patients.

We performed a prospective, blind, controlled study on wound infection after implant surgery involving 41 procedures in patients infected with the human immunodeficiency virus (HIV) and 141 in HIV-negative patients. The patients were staged clinically and the CD4 cell count determined. Wound infection was assessed using the asepsis wound score. A risk category was allocated to account for presurgical contamination. In HIV-positive patients, with no preoperative contamination, the incidence of wound infection (3.5%) was comparable with that of the HIV-negative group (5%; p = 0.396). The CD4 cell count did not affect the incidence of infection (r = 0.16). When there was preoperative contamination, the incidence of infection in HIV-positive patients increased markedly (42%) compared with that in HIV-negative patients (11%; p = 0.084). Our results show that when no contamination has occurred implant surgery may be undertaken safely in HIV-positive patients.

Delay in skeletal maturity in Malawian children.

The atlas of Greulich and Pyle for skeletal maturity and epiphyseal closure is widely used in many countries to assess skeletal age and to plan orthopaedic surgery. The data used to compile the atlas were collected from institutionalised American children in the 1950s. In order to determine whether the atlas was relevant to subSaharan Africa, we compared skeletal age, according to the atlas, with chronological age in 139 skeletally immature Malawian children and young adults with an age range from 1 year 11 months to 28 years 5 months. The height and weight of each patient were also measured in order to calculate the body mass index. The skeletal age of 119 patients (85.6%) was lower than the chronological age. The mean difference was 20.0+/-24.1 months (t-test, p = 0.0049), and the greatest difference 100 months. The atlas is thus inaccurate for this group of children. The body mass index in 131 patients was below the normal range of 20 to 25 kg/m2. The reasons for the low skeletal age in this group of children are discussed. Poor nutrition and chronic diseases such as malaria and diarrhoea which are endemic in Malawi are likely to be contributing factors. We did not find any correlation between the reduction in body mass index in our patients and the degree of retardation of skeletal age.

Cobalt and possible oxidant-mediated toxicity.

The occurrence of interstitial lung disease similar to hard metal lung disease in diamond polishers who had been exposed to cobalt (in the absence of tungsten carbide) through the use of polishing disks containing microdiamonds sintered with cobalt, led us to experimentally test the hypothesis that cobalt has pro-oxidant activity in lung tissue. Several experiments were carried out in which we measured indices of oxidant stress, mainly changes in the oxidation state of glutathione and in the activity of the pentose phosphate pathway, upon exposure of hamster pulmonary tissue to CoCl2 in vivo by intratracheal instillation, or in vitro by incubating lung slices. These experiments indicated that cobalt ions are capable of causing thiol oxidation in lung tissue as an early manifestation of oxidant stress, but more studies are needed to establish the relevance of this mechanism in the causation of lung disease in subjects exposed to cobalt-containing dusts.

Disaster planning, Part I. Overview of hospital and emergency department planning for internal and external disasters.

The definition and causes for internal and external disasters are discussed in this article. Features of a hospital disaster plan are outlined with special reference to the role of the emergency department. Examples of previous disasters involving hospitals are presented to demonstrate problems that disaster planners should anticipate.

Indices of oxidative stress in hamster lung following exposure to cobalt(II) ions: in vivo and in vitro studies.

Cobalt, a metal with numerous industrial applications, has been associated with lung disease, an extreme form of which is an interstitial fibrosis. The biochemical mechanisms underlying this toxicity are not understood. In vitro studies have suggested that cobalt(II) ions are able to generate reactive oxidant species (possibly hydroxyl radical) in a reaction with hydrogen peroxide, and we have hypothesized that the occurrence of such an event in lung tissue, and the subsequent development of oxidative damage, may contribute to this pulmonary toxicity. The intratracheal instillation of CoCl2 into hamster lungs resulted after 3 h in decreased levels of reduced glutathione and increases in levels of oxidized glutathione and in the activity of the pentose phosphate pathway. These changes, which are compatible with the generation of oxidative stress, were reversed by 48 h at low Co2+ doses (1.0 to 1,000 micrograms/kg). Irreversible changes at higher doses coincided with the onset of pulmonary edema. Incubation of lung slices with CoCl2 (0.1 to 10 mM) resulted in time- and Co2+ concentration-dependent increases in levels of oxidized glutathione and protein-mixed disulfides and a decrease in reduced glutathione. A concentration-dependent stimulation of the pentose phosphate pathway was also observed. These changes preceded the detection of overt cell toxicity, as assessed by various biochemical parameters. These data indicate that thiol oxidation constitutes an early event in the pulmonary toxicity of cobalt(II) ions and are compatible with the hypothesis that the generation of oxidative stress may be of significance to the toxic process.

Disasters within hospitals.

Hospital disaster planning should encompass events that affect the safety of the hospital environment and address those measures that ensure the availability of necessary services. Although most of the emphasis has been placed on general disaster planning, there is little written about disasters occurring within a hospital. In recent years, several incidents at our medical center involving fire, flood, and power failure resulted in a reevaluation of our preparedness to handle such situations. These experiences prompted this discussion and literature review of internal disaster plan because it is likely that at some time an internal emergency may occur.

Open fractures of the tibia in HIV positive patients: a prospective controlled single-blind study.

Twenty-seven patients with severe open fractures were studied prospectively analysing infection and union as outcome measures. A standard treatment regime was applied. Seven patients were HIV positive, and 20 patients HIV negative. Wound infection and delayed union were more common in HIV positive patients. The difference in rate of infection was statistically significant (P = 0.020), while that in union did not quite reach significance (P = 0.059). The authors have developed an algorithm for treatment of these injuries in areas of high seroprevalence of HIV infection.

One-year follow-up of orthopaedic implants in HIV-positive patients.

We followed prospectively 38 orthopaedic implants in 36 HIV-positive patients. X-rays and clinical examination were used to assess union, and observation was made for early and late wound sepsis for 12 months from the time of surgery. Two patients died of causes unrelated to the implantation, two patients had implants removed for reasons other than infection and eight cases were lost to follow-up. Of the 26 cases that were reviewed at 1 year, no late sepsis was identified. All of the fractures, non-unions, osteotomies and arthrodeses united. The literature indicates that late sepsis following arthroplasty occurs more frequently in haemophiliacs who are HIV positive than their HIV-negative counterparts. It is still not certain whether or not such a risk also applies to HIV-positive patients who are not haemophiliacs and have undergone internal fixation of fractures or non-unions. This study increases the confidence that fixation in immune-compromised patients with intact skin is safe, at least for the time period that the implant is required. Further studies are required to know whether or not fixation implants should be removed.

Triage: techniques and applications in decision making.

Correct decision making may have far-reaching consequences. Triage is an area in which decision-makers must know what they are doing, why they are doing it, and which actions to take to achieve a satisfactory outcome. Triage has its origins in military history and today is used in a variety of medical settings. In this article we focus on the role of triage in disaster situations, its application in military settings, and its use in disaster medicine. Useful concepts enabling correct decision making by the triage officer include the application of computer technology and a review of methods of patient categorization. The dynamic nature of triage and the role of the triage officer as part of a team approach to disaster patient management are highlighted. We explore techniques for the successful training and education of triage officers and investigate a model of the emergency physician as the triage officer.

Safety trial with the 5HT1B/1D agonist avitriptan (BMS-180048) in patients with migraine who have experienced pressure, tightness, and/or pain in the chest, neck, and/or throat following sumatriptan.

We investigate whether symptoms of pressure, tightness, and/or pain in the chest, neck, and/or throat after administration of the 5HT1B/1D agonist avitriptan were associated with objective impairment of the myocardial function on 12-lead electrocardiogram (ECG), continuous ECG (Holter) monitoring, and echocardiography. Migraine sufferers who in two-thirds of all attacks treated with sumatriptan had experienced chest/throat/neck symptoms were chosen for study. Baseline measures included vital signs, a 12-lead ECG and an echocardiogram. Patients (n = 51) who had no clinically significant abnormality at baseline received a high dose (150 mg) of avitriptan orally outside of a migraine attack. If pressure, tightness, and/or pain in the chest, neck, and/or throat occurred, an ECG was obtained, and a repeat echocardiogram was done while the symptoms were present in order to monitor for impairment of myocardial function. If symptoms of these types did not occur within 60 min after administration of the study drug, a second echocardiogram was obtained. Forty-five patients (88%) reported at least one adverse event and 23 (45%) experienced pressure, tightness, and/or pain in the chest, neck, and/or throat after administration of avitriptan. No clinically significant myocardial abnormalities were observed in any patients, even in those who had experienced the targeted symptoms. No other serious adverse event occurred. We concluded that the typical 5HT1B/1D agonist-induced chest/throat/neck symptoms are most unlikely to be of cardiovascular origin.

Hemorrhage from recanalized umbilical vein in a patient with cirrhosis.

The formation of portosystemic collaterals occurs frequently in portal hypertension; however, the finding of a patent or recanalized umbilical vein has more often been incidental, with only six cases of recanalized umbilical veins or patent paraumbilical veins demonstrated with clinical significance This is only the second documented case of an umbilical vein with external hemorrhage significant enough to cause hemodynamic instability. It raises important questions with regard to prognostic indices for rebleeding at the umbilicus as well as at other, more common, portosystemic collateral sites.