Navigational predictors in determining the necessity for collateral ligament release in total knee replacement.

The requirement for release of collateral ligaments to achieve a stable, balanced total knee replacement has been reported to arise in about 50% to 100% of procedures. This wide range reflects a lack of standardised quantitative indicators to determine the necessity for a release. Using recent advances in computerised navigation, we describe two navigational predictors which provide quantitative measures that can be used to identify the need for release. The first was the ability to restore the mechanical axis before any bone resection was performed and the second was the discrepancy in the measured medial and lateral joint spaces after the tibial osteotomy, but before any femoral resection. These predictors showed a significant association with the need for collateral ligament release (p < 0.001). The first predictor using the knee stress test in extension showed a sensitivity of 100% and a specificity of 98% and the second, the difference between medial and lateral gaps in millimetres, a sensitivity of 83% and a specificity of 95%. The use of the two navigational predictors meant that only ten of the 93 patients required collateral ligament release to achieve a stable, neutral knee.

Nicotine modulation of cytokine induction by LPS-stimulated human monocytes and coronary artery endothelial cells.

Nicotine, the major addictive component of tobacco, is an immunomodulator that impacts on many cells, including immune cells involved in inflammatory processes. Nicotine also induces oxidative damage to the vascular endothelium and accentuates lipid peroxidation, resulting in vascular cell dysfunction. Furthermore, vascular endothelial cells produce growth factors, such as cytokines and chemokines capable of stimulating and recruiting immune cells to atheromatous lesions. In addition, bacterial products including lipopolysaccharides (LPS), a major component of Gram negative bacterial cell walls, activate gene expression resulting in inflammatory cytokine production causing further damage to the vasculature. In the present study, the combined effects of nicotine and bacterial LPS on the expression of IL-6, IL-8, GRO-alpha and MCP-1 in cell lines of human coronary artery endothelial cells (HCAEC) and pulmonary monocytes (THP-1) were examined by quantitative real-time PCR and ELISA. Results showed that nicotine suppressed the LPS induced production of IL-6 and IL-8 in both cell lines. Since cytokines which alter homeostasis of both vascular endothelial and immune cells are critical for the atherogenic process, further studies are warranted to examine in detail the role of nicotine in terms of effects on inflammatory reactions, including those induced by bacterial infection.

Nicotine modulation of apoptosis in human coronary artery endothelial cells.

It has been recently reported that nicotine, the addictive component of tobacco, is an important modulator at the level of immune cell apoptosis or programmed cell death. Apoptosis is a process that helps maintain the homeostasis of the vascular endothelium and vascular smooth muscle cells, and alteration of the apoptotic process has been associated with cardiovascular diseases. The present study examined the effects and the mechanisms of action of nicotine on apoptosis in human coronary artery endothelial cells (HCAECs). Cultured HCAECs were treated with nicotine at a concentration that correlates with the tissue level of smokers (1 microg/ml), concurrently with tumor necrosis factor-alpha (TNF-alpha) and dexamethasone to induce apoptosis. The data showed that nicotine significantly inhibited apoptosis in HCAECs, as verified by the decreased expression level of active caspases compared to cells treated with the apoptosis inducers alone. This decrease was blocked by the addition of d-tubocurarine chloride (d-TC), a general nicotinic receptor antagonist, providing evidence that this action of nicotine was receptor-mediated. The findings were further confirmed by TUNEL assay for DNA fragmentation, a biochemical marker of apoptosis. This action of nicotine on apoptosis in human coronary artery endothelial cells suggests that nicotine may have an impact on cardiovascular pathology and atherogenesis.

Nicotine inhibition of apoptosis in murine immune cells.

Nicotine, the addictive component of tobacco, is thought to be at least partially responsible for the deleterious effects of smoking such as heart disease and cancer. Evidence shows that nicotine is an immunomodulator and that one of its possible mechanisms is regulation of apoptosis, or programmed cell death, in immune cells. This study examined the effects and the mechanisms of action of nicotine on dexamethasone (DEX)-induced apoptosis in murine immune cells by examining the expression of levels of the 17-kDa active caspase-3, a marker of apoptosis. Thymocytes and splenocytes from adult BALB/c female mice were incubated with concentrations of nicotine correlating to those found in the blood and tissue of smokers (0.01 microg/ml [0.022 microM] and 1 microg/ml [2.2 microM]), concurrently with 100 nM DEX, to induce apoptosis. Cytosolic protein fractions were analyzed by Western blotting with polyclonal antibodies that recognize the active form of caspase-3. The data showed that nicotine significantly blocked the formation of the DEX-induced 17-kDa caspase-3 subunit expression. This downregulation ranged from 65% to 100% of the active caspase-3 expressed in cultures treated with DEX alone. Addition of d-tubocurarine chloride (dTC), a general nicotinic receptor antagonist, inhibited nicotine downregulation of the DEX-induced active caspase-3 expression, providing evidence that this action of nicotine was receptor-mediated. These data support that nicotine is an important immunomodulator at the level of immune cell apoptosis, a process thought to be a contributory mechanism of autoimmunity, cardiovascular disease, and carcinogenesis.

Differential effects of nicotine and aging on splenocyte proliferation and the production of Th1- versus Th2-type cytokines.

Nicotine has a multitude of biological actions in the central and peripheral nervous systems where nicotinic acetylcholine receptors are found. Nicotinic acetylcholine receptors have also been identified on immune cells, but the effects of nicotine on immune responses are not well characterized. These studies tested the hypotheses that nicotine has an effect on both T-lymphocyte proliferation and the production of cytokines by activated T cells, processes that are necessary for effective T-cell-mediated immune responses. In addition, the effects of nicotine on these immune responses in aging animals and the effects of nicotine exposure prior to immunostimulation were investigated. Murine splenocytes were exposed to nicotine and stimulated with concanavalin A (ConA). The highest concentration of nicotine (128 microg/ml) significantly depressed proliferation of T cells both when nicotine and ConA were added concurrently and when nicotine was added 3 hr prior to ConA. Nicotine, added concurrently with ConA at concentrations between 0. 25 and 64 microg/ml, significantly inhibited the production of IL-10 by splenocytes from young adult mice, whereas the inhibition of production of IL-10 by splenocytes from old mice was significantly inhibited, but the response was more variable, depending on the nicotine concentration. In contrast, the production of IFN-gamma by splenocytes from either young adult or old mice was not affected when nicotine (0.016-64 microg/ml) was added concurrently with ConA. Pre-exposure to 1 microg/ml of nicotine for 3 hr significantly enhanced the production of IFN-gamma by splenocytes from young adult mice, whereas pre-exposure to 0.016 microg/ml of nicotine tended to but did not significantly enhance IFN-gamma production. Nicotine is now being used as an over-the-counter drug by people who differ in age and general immunocompetence. Therefore, the effects of nicotine on immune responses, independent from the effects of the other chemicals found in tobacco, need to be investigated.

Differential impact of nicotine on cellular proliferation and cytokine production by LPS-stimulated murine splenocytes.

The immunoregulatory effects of nicotine have not been fully clarified and the reported data are often conflicting. The present study investigated the role of nicotine as an immunomodulator of murine splenocytes stimulated by lipopolysaccharide (LPS), the endotoxin component of gram-negative bacteria. BALB/c female mice of two different ages, young (2-3 months) and old (18-22 months), were used. The cells were incubated with nicotine at two different time points, 3 h pre-incubation and concurrent incubation relevant to LPS stimulation, before further incubation for 48 or 72 h. Treatment of murine splenocytes with nicotine showed an impact on cellular proliferation as well as on the production of the pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). The results indicated that nicotine significantly inhibited cellular proliferation of murine splenocytes in a concentration-related manner (32, 64 and 128 microg/ml). Timing of nicotine exposure prior to LPS stimulation was critical in terms of immunological impact on cytokine production. TNF-alpha and IL-6 production were significantly enhanced by 1 microg/ml of nicotine when cells were pre-incubated with nicotine for 3 h compared to concurrent incubation relative to LPS stimulation. The alteration in cytokine production varied with the age of the mouse. TNF-alpha production was significantly inhibited by nicotine in young mice, while IL-6 production was significantly inhibited by nicotine in old mice. Since any immunomodulation that alters the profile of these cytokines may cause an imbalance in the immune system impinging on health status, these findings may be important when dealing with the concept of nicotine as a therapeutic agent.

Nitazoxanide, a nitrothiazolide antiparasitic drug, is an anti-Helicobacter pylori agent with anti-vacuolating toxin activity.

Nitazoxanide (NTZ), a synthesized drug of the nitrothiazolide class, was initially developed as an antiparasitic compound. This compound has recently been shown to have antibacterial activities against some bacterial pathogens. In the present study, NTZ and its main metabolite tizoxanide (TIZ) were found to have strong minimum inhibitory concentrations (MICs) against both metronidazole (MTZ)-resistant strains and sensitive clinical isolates of Helicobacter pylori. The MIC90 of both NTZ and TIZ against 37 clinical isolates was 8 microg/ml. Vacuolating toxin activity of H. pylori assayed by HeLa cell vacuole formation was inhibited by NTZ at a sub-MIC. In contrast, urease production by H. pylori was not specifically affected by the sub-MIC of NTZ. An acidic pH (pH 5.0) medium reduced the antimicrobial activity of the drug in terms of growth inhibition due to the low growth rate of the bacteria, but killing activity of NTZ against the bacteria was still observed. Thus, it was apparent that both NTZ and TIZ are highly effective against H. pylori, even when the bacteria are resistant to MTZ.

Failure of adjuvant heparin to reduce myocardial ischemia in the early treatment of patients with unstable angina.

Although the efficacy of long-term administration of antithrombotic agents in unstable angina has been established, short-term effects on myocardial ischemia are unknown. A retrospective analysis was performed in 47 patients undergoing three-channel continuous ST segment monitoring as part of a multicenter trial using esmolol in unstable angina, in which 20 patients received a continuous heparin infusion during the initial assessment of chest pain. Concomitant medications included calcium channel blockers, beta-adrenergic blockers, nitrates, and aspirin in the majority of patients. Clinical variables between the heparin and no heparin groups were similar, except for fewer males and fewer total artery occlusions in the heparin group. No significant differences in the incidence or duration of ischemia were found in a 36 +/- 16 hour monitoring period. Forty percent of the heparin group had 35 episodes of ischemia with a mean of 11 +/- 10 minutes per episode and a total ischemic time of 48 +/- 39 minutes per patient with ischemia. Forty-four percent of the no heparin group had 47 episodes of ischemia with a mean of 13 +/- 13 minutes per episode and a total ischemic time of 58 +/- 47 minutes per patient with ischemia. Multiple linear regression analysis to adjust for intergroup differences did not alter the results. Eighty-five percent of all episodes were asymptomatic. Clinical events, such as episodes of chest pain, emergency coronary arteriography, or coronary revascularization, were also similar between groups. Thus the short-term administration of heparin did not alter the incidence or duration of ischemia in patients with unstable angina.(ABSTRACT TRUNCATED AT 250 WORDS)

Variations on the temporoparietal fascial flap.

An improved understanding of the vascular supply of the layers of the temporal fossa has increased the potential of this region for new and ingenious reconstructive techniques. Separate and independently vascularized layers of this region include hair-bearing scalp, glabrous skin, tempororoparietal fascia (and galea aponeurotica), temporalis muscle and fascia, and pericranium. Island flaps of glabrous skin and scalp provided esthetically appropriate tissue to cover a variety of defects. The malleable bulk of the subcutaneous fascial layers were combined with skin grafts to restore thin lining, and used as a vascularized bed for cartilage grafts in otherwise unsatisfactory recipient sites. Illustrative cases from our 5-year clinical experience are presented to demonstrate various combinations of the temporoparietal fascial pedicle with tissues from the temporal region to reconstruct the eyebrows, eyelids, orbits, cheeks, and lips.

Assessment of intravenous fenoldopam mesylate in the management of severe systemic hypertension.

To evaluate the acute BP response to iv fenoldopam mesylate (FNP), 14 patients with severe hypertension (diastolic BP 120 to 170 mm Hg) were studied in an open-label trial. Initial infusion rate of FNP was 0.1 microgram/kg.min. Titration to diastolic BP goal (95 to 110 mm Hg) was followed by a constant infusion phase (greater than or equal to 6 h), a detitration phase (2 h), and a postinfusion phase. FNP reduced BP by 27/29 mm Hg (p less than .001) with no significant effect on heart rate. Maintenance of the BP effect was noted through the 6 h of constant rate infusion. Mild, transient vasodilating-associated adverse effects were noted with FNP. We conclude that FNP is an effective, well-tolerated iv antihypertensive agent for acute BP reduction in a severely hypertensive population.

Ultrastructural tubular basement membrane lesions in adult polycystic kidney disease.

The pathogenesis of adult polycystic kidney disease (PCKD) remains an enigma. In an attempt to find a defect that might explain the cyst formation, an ultrastructural study was performed on seven fresh bilateral nephrectomies of seven patients suffering from adult PCKD. Marked electron microscopic changes of the tubular basement membranes were detected, including thickening, splitting, fraying, and multilayering of the basement membranes. By contrast, glomerular basement membranes lacked these alterations. The kidneys from two control groups (five donor kidneys harvested for transplantation; 10 patients who suffered from end stage renal disease) showed none of the lesions detected in the polycystic kidneys. The lesions of the tubular basement membrane, the principal support of tubular wall, may be the primary phenotypic expression and cause of the inherited defect.

Relation between myocardial thallium-201 kinetics during exercise and quantitative coronary angiography in patients with one vessel coronary artery disease.

This study examined the relation between the kinetics of thallium-201 and coronary stenosis in 30 patients with one vessel coronary artery disease; 25 patients had no visible collateral vessels. The myocardial thallium concentration in the postexercise images and percent washout were determined in the distribution of the diseased vessel and a normal vessel, and each was expressed as a ratio. Coronary stenosis was assessed as minimal diameter stenosis, minimal area stenosis and percent diameter stenosis. The correlations between the myocardial concentration ratio or washout ratio and the descriptors of coronary stenosis improved when the patients with collateral vessels were excluded. There were significant correlations between the myocardial thallium concentration ratio and minimal diameter stenosis (r = 0.73, p less than 0.001), minimal area stenosis (r = 0.72, p less than 0.001) and, to a lesser degree, percent diameter stenosis (r = -0.51, p less than 0.01). Similarly, there were significant correlations between washout ratio and minimal diameter stenosis (r = 0.50, p less than 0.01) and minimal area stenosis (r = 0.45, p less than 0.02) but not percent diameter stenosis (r = 0.37, p = 0.06). Thus, variation in thallium kinetics in relation to the severity of coronary stenosis can be demonstrated with conventional imaging in patients with one vessel disease. The myocardial thallium concentration and washout are physiologic expressions of the severity of perfusion deficit and are dependent on collateral flow. The myocardial thallium concentration ratio and washout ratio correlate better with minimal diameter and area stenosis than with percent diameter stenosis.

Lack of antibodies to Legionella pneumophila and Legionella micdadei in hemodialysis patients.

In 231 adult hemodialysis patients and 134 healthy adults, we measured antibodies to Legionella pneumophila (serogroups 1-6) and Legionella micdadei by indirect immunofluorescent antibody tests to assess the risk of Legionnaires' disease. One of the patients had a titer of 1:512 to Legionella pneumophila but he had no history of Legionnaires' disease. Two had a titer of 1:64 to Legionella pneumophila, and none had a titer of greater than or equal to 1:64 to Legionella micdadei. By contrast, none of the control group had a titer greater than or equal to 1:64 to Legionella pneumophila and two had a titer of 1:64 to Legionella micdadei. Thus, our population of maintenance hemodialysis patients did not display increased prevalence of antibodies of Legionella pneumophila and Legionella micdadei, but prospective studies of pneumonia in hemodialysis patients might further evaluate possible risk of Legionnaires' disease.

Transitional epithelial lesions of the ureter in renal transplant rejection.

The spectrum of ureteric lesions of human renal allografts, long attributed exclusively to postsurgical complications such as ischemia, has recently been shown to include the types of rejection seen in the kidney. Since the rejected ureter also exhibits transitional epithelial lesions that may impact on renal and ureteral function, we studied, by light, immunohistochemical, immunofluorescent, and electron microscopic techniques, ureters of 65 irreversibly rejected kidneys. Seven unused cadaver kidneys served as controls. Urothelial lesions, noticed in 57 of 65 ureters (88%), ranged from minimal basal vacuolization to complete sloughing with or without necrosis of the epithelial lining. Epithelial exfoliation was noticed in 31 cases (54.4%), and basal vacuolization, severe enough to produce cleavage of the epithelial junctions and thus create bullae, was noticed in 21 cases (36.8%). Immunofluorescent and immunoperoxidase stains, performed in 16 cases, were all positive for immunoglobulins but yielded varied results ranging from granular to linear staining, particularly in the region of the basal cells and the basement membrane. Electron microscopic findings confirmed the light microscopic alterations. By contrast, control ureters showed no lesions. Urothelial ureteric lesions might impede ureteral functions and result in obstruction or infection, thus compounding the consequences of renal allograft rejection. Moreover, elucidation of the pathophysiology of the process will advance the understanding of various cutaneous and transitional epithelial autoimmune conditions.

The temporal fossa in head and neck reconstruction: twenty-two flaps of scalp, fascia, and full-thickness cranial bone.

We reviewed 22 consecutive flaps based on the blood supply of the temporal fossa. Our purpose was to demonstrate reliability of the vascular supply and to illustrate the versatility of these tissues for reconstruction of specialized structures, including eyelids, eyebrow, ear, lips, oral lining, orbit, and mandible. For these complex problems, all but one patient required multiple-stage surgery to obtain their final aesthetic and functional results. All flaps proved reliable and versatile. Their advantages include proximity to the reconstructive site, ease of bilateral reconstructions, and well-camouflaged donor deficit. In particular, the ability to transfer vascularized full-thickness cranial bone for total or bilateral mandibular reconstructions presents an additional possibility for this difficult problem. We conclude that the reconstructive potential of these flaps is limited only by the surgeon's ingenuity.