Heterogeneity, Cell Biology and Tissue Mechanics of Pseudostratified Epithelia: Coordination of Cell Divisions and Growth in Tightly Packed Tissues.

Pseudostratified epithelia (PSE) are tightly packed proliferative tissues that are important precursors of the development of diverse organs in a plethora of species, invertebrate and vertebrate. PSE consist of elongated epithelial cells that are attached to the apical and basal side of the tissue. The nuclei of these cells undergo interkinetic nuclear migration (IKNM) which leads to all mitotic events taking place at the apical surface of the epithelium. In this review, we discuss the intricacies of proliferation in PSE, considering cell biological, as well as the physical aspects. First, we summarize the principles governing the invariability of apical nuclear migration and apical cell division as well as the importance of apical mitoses for tissue proliferation. Then, we focus on the mechanical and structural features of these tissues. Here, we discuss how the overall architecture of pseudostratified tissues changes with increased cell packing. Lastly, we consider possible mechanical cues resulting from these changes and their potential influence on cell proliferation.

Short-term outcome of painful bone marrow oedema of the knee following oral treatment with iloprost or tramadol: results of an exploratory phase II study of 41 patients.

OBJECTIVES: To compare the therapeutic effects of oral iloprost and tramadol on the outcome of bone marrow oedema (BME) of the knee by MR imaging and clinical assessment. METHODS: Forty-one patients with painful ischemic or mechanical BME of the knee were enrolled in a double-blind, randomized controlled study. Patients were randomized either to iloprost (n = 21, group 1) or tramadol (n = 20, group 2). The treatment duration was 4 weeks. The Larson knee score was used to assess function before treatment and then 3 days, 1, 2, 3, 4 weeks and 3 months after the start of treatment. Short tau inversion recovery and T1-weighted MR images of the affected knees were obtained before and 3 months after the start of treatment. Bone marrow oedema was assessed visually and by computer-assisted quantification for baseline and follow-up MR examinations. RESULTS: Thirty-three patients completed the study as scheduled. The mean Larson score improved from 58.6 points to 81.8 points in group 1, and from 59.6 points to 86.8 points in group 2, after 3 months (no significant difference between the treatment groups). On MR images, complete BME regression in at least one bone was observed in nine patients (52.9%) in group 1, as opposed to three patients (18.7%) in group 2, after 3 months (P = 0.034). Correspondingly, the median BME volume decreased by 58.0% in group 1, and by 47.5% in group 2. CONCLUSIONS: The analgesic effect of iloprost and tramadol was similar. BME regression on MR images was more pronounced under iloprost treatment.

Linezolid in the treatment of osteomyelitis: results of compassionate use experience.

BACKGROUND: This case series examines osteomyelitis patients enrolled into a prospective, open label, noncomparative, non-randomized compassionate use program. Patients received 600 mg bid iv or po linezolid. PATIENTS AND METHODS: 89 patients were enrolled into the compassionate use program with the diagnosis of osteomyelitis and were evaluated for clinical efficacy, safety and tolerability. Informed consent was obtained from the patients or their guardians and guidelines for human experimentation of the US Department of Health and Human Services and/or those of the investigators' institutions were followed in the conduct of this clinical research. RESULTS: 55 cases of osteomyelitis met the inclusion criteria for clinical assessment. The 55 courses included long bone (53%), diabetic foot (18%), sternal wound (14.5%) and vertebral osteomyelitis (15%). Clinical assessment at longterm follow-up occurred at a median of 195 days after the last dose, and the clinical cure rate in 22 evaluable cases was 81.8% and failure rate 18.2%. The most common clinical adverse drug events (ADEs) were gastrointestinal disturbances. Reduction in hemoglobin/hematocrit and in platelet counts were the most common laboratory ADEs. CONCLUSION: Linezolid iv or po was successful in treating patients with osteomyelitis caused by resistant grampositive organisms or those with intolerance or nonresponsiveness to other potentially effective treatments. Larger comparator controlled studies should be performed to confirm these findings.

Clinical infections in the noninstitutionalized geriatric age group: methods utilized and incidence of infections. The Pittsburgh Good Health Study.

Because noninstitutionalized senior citizens comprise over 95% of the population 65 years of age and older, their health needs are a major concern. Data regarding infections in this population including the epidemiology, morbidity, and mortality are lacking. The authors recruited a study population of 417 free-living persons, all 65 years of age or older, from two neighborhoods in Pittsburgh, Pennsylvania. After the collection of self-reported baseline information from these persons, they were monitored for all clinical infections for 2 years, beginning July 1986 and through June 1988, using clinic visits, hospitalizations, or phone calls when needed. The baseline information showed the study population of 417 persons to be comparable with a neighborhood comparison group and with established populations for epidemiologic studies of the elderly in three other states. The 24 months of infection surveillance yielded 494 diagnosed infections in 224 or 54% of the subjects. Respiratory infections were most frequent with 259 or 52% of the total, followed by genitourinary infections with 24%, skin infections with 18%, gastrointestinal infections with 4%, and other types of infection with 2%. By comparing 22 self-reported baseline conditions with the occurrence of infection, 10 historic factors were univariately significant for infection. Of these 10 factors, only history of a lung problem (relative risk = 1.7, 95% confidence interval (CI) 1.1-2.9) and history of difficulty controlling urination (relative risk = 2.7, 95% CI 1.3-4.9) were statistically significant in multivariate analysis. To our knowledge, this study represents the first prospective data on infections in the noninstitutionalized elderly. The data demonstrate the wide variety of infections that occurred in this population and suggest that persons with a history of any one of several medical problems were possibly at greater risk for infection.

Treatment of hospitalized patients with complicated skin and skin structure infections: double-blind, randomized, multicenter study of piperacillin-tazobactam versus ticarcillin-clavulanate. The Piperacillin/Tazobactam Skin and Skin Structure Study Group.

We compared the efficacy and safety of two beta-lactam-beta-lactamase inhibitor combinations, namely, piperacillin-tazobactam and ticarcillin-clavulanate, in the treatment of complicated bacterial infections of skin that required hospitalization. The study was a randomized, double-blind, comparative trial involving 20 centers. The infections were classified as (i) cellulitis with drainage, (ii) cutaneous abscess, (iii) diabetic or ischemic foot infection, and (iv) infected wounds and ulcers with drainage. The clinical response rates were comparable for the two treatment regimens (61% of the patients were cured with piperacillin-tazobactam and ticarcillin-clavulanate and improvement was seen in 15 and 16% of patients treated with piperacillin-tazobactam and ticarcillin-clavulanate, respectively). Both regimens were found to be safe and well tolerated. These data support the use of piperacillin-tazobactam for initial empiric therapy of hospitalized patients with complicated skin and skin structure infections.

Evaluation of new anti-infective drugs for the treatment of selected infections of the skin and skin structure. Infectious Diseases Society of America and the Food and Drug Administration.

No method for classifying infections of the skin and skin structure is uniformly accepted. Therefore, each protocol for the evaluation of new anti-infective drugs must include definitions of the skin and skin-structure infections to be treated. Clinical findings may suggest the etiology. Cultures should be performed by the best available technique. Because the yield of pathogens from sites of skin and skin-structure infection is often low, monitoring of the clinical response to therapy is paramount. Randomized, double-blind, active-control comparative studies are needed, and maintenance of blinding is recommended, even with a change in the route of administration of the study and/or control drugs. The period of follow-up should be defined for each type of infection.

Evaluation of new anti-infective drugs for the treatment of osteomyelitis in adults. Infectious Diseases Society of America and the Food and Drug Administration.

Cases of osteomyelitis can be divided into four categories: acute hematogenous, vertebral, secondary to a contiguous focus of infection without vascular disease, and secondary to a contiguous focus of infection with vascular disease. Each category may be further divided into acute and chronic forms. Clinical symptoms persisting for > or = 10 days correlate roughly with the development of necrotic bone and chronic osteomyelitis. Patients enrolled in clinical trials should generally be > or = 12 years of age. Prior antimicrobial treatment does not exclude patients if the culture of a bone sample obtained at the time of enrollment yields pathogenic bacteria. Randomized, double-blind, active-control comparative studies are encouraged. Clinical outcome should be assessed during therapy and within 5-9 days, 4-6 weeks, and 11-13 months after completion of therapy. In the final assessment, clinical appraisal is paramount.

Evaluation of new anti-infective drugs for the treatment of acute hematogenous osteomyelitis in children. Infectious Diseases Society of America and the Food and Drug Administration.

Most children with acute hematogenous osteomyelitis have no preceding illness. Their early symptoms are pain and fever. A bacterial etiology is established in approximately 75% of cases by needle aspiration of the affected site or blood culture. Clinical trials should be limited to cases of bacterial origin. The antimicrobial agents studied should be active against Staphylococcus aureus and streptococci. If children < 5 years of age are included, the drug should also be active against beta-lactamase-negative and -positive strains of Haemophilus influenzae. Randomized, prospective, double-blind comparative studies are preferable to open, evaluator-blinded trials. Clinical outcome is appraised by physical signs and symptoms. A successful microbiological outcome consists of presumptive eradication. The final assessment should be made 1 year after completion of therapy.

Evaluation of new anti-infective drugs for the treatment of infectious arthritis in adults. Infectious Diseases Society of America and the Food and Drug Administration.

This guideline describes clinical trials of new anti-infective drugs for the treatment of septic arthritis due to bacteria other than Neisseria gonorrhoeae in adults. Septic arthritis is associated with fever and with physical findings at the affected joint. Diagnosis is established by culture of synovial fluid. Treatment includes the administration of antimicrobial drugs and drainage of the joint by needle aspiration or surgery. Multicenter, randomized comparative clinical trials that are single-, double-, or evaluator-blinded should be performed. However, an open trial of a new antimicrobial agent with historical controls is acceptable. Patients should receive treatment for at least 2-3 weeks. After 5 days of antimicrobial therapy, synovial fluid should be sterile and clinical signs and symptoms should have diminished. Patients should be followed for 2-4 weeks after completion of therapy.

Evaluation of new anti-infective drugs for the treatment of acute suppurative arthritis in children. Infectious Diseases Society of America and the Food and Drug Administration.

Diagnostic criteria for bacterial suppurative arthritis include the demonstration of an inflammatory exudate by aspiration of synovial fluid and the isolation of bacteria from cultures of synovial fluid and/or blood. Clinical manifestations include joint effusion, swelling, tenderness, and pain, with or without redness of the overlying skin. Management consists of antimicrobial therapy, measures designed to relieve symptoms, surgical drainage of infected fluid, and physical therapy. Studies of new anti-infective therapy should be limited to cases of bacterial origin. Prospective, randomized, double-blind, or evaluator-blinded, active-control comparative clinical trials should be performed. Clinical response is characterized as success (cure), failure, or indeterminate outcome. The most common successful microbiological outcome is presumptive eradication. Follow-up should continue for 1 year before the final assessment.

Evaluation of new anti-infective drugs for the treatment of infections of prosthetic hip joints. Infectious Diseases Society of America and the Food and Drug Administration.

Infections of a prosthetic hip are of three types: acute contiguous, chronic contiguous, and hematogenous. Acute contiguous infections result from contamination of the operative field at the time of surgery; clinical manifestations of infection become apparent within 6 months. Chronic contiguous infections are diagnosed 6-24 months postoperatively and are believed to be caused by intraoperative contamination. Hematogenous seeding of prosthetic joints accounts for infections that develop > or = 2 years after surgery. Fever and pain or dysfunction of the joint may be the only signs or symptoms of prosthetic hip joint infection. Definitive diagnosis is established by culture of a needle aspirate from the joint space or by intraoperative culture. Prospective, randomized, double-blind or evaluator-blinded, active-control comparative studies are preferable to open trials. Success rates 10-14 weeks after completion of a 4- to 6-week course of antimicrobial therapy should be > or = 90%.

Antibiotic prophylaxis in orthopedic surgery.

This review covers four areas: the use of prophylactic antibiotics in orthopedic surgery not involving prosthetic devices; the use of prophylactic antibiotics in prosthetic joint implantation; the use of antibiotic-containing cement in prosthetic joint surgery; and the use of prophylactic antibiotics for dental procedures in individuals with implanted prosthetic joints. The major conclusions are as follows: (1) Prophylactic antimicrobial agents lower the rate of wound infection following surgery for closed hip fractures. (2) Antimicrobial prophylaxis reduces the frequency of deep wound infection following total joint replacement; operating rooms with ultraclean air have a similar effect. (3) Antibiotic-impregnated cement is as effective as systemic antibiotics in preventing early infection following total joint replacement. (4) For routine dental work in most patients with total joint replacement, there is insufficient evidence to support antibiotic prophylaxis; for such individuals with periodontal disease or potential dental infection, antimicrobial prophylaxis seems indicated.

Pharmacokinetics of cephradine administered intravenously and orally to young and elderly subjects.

The pharmacokinetics of IV and oral cephradine in healthy young male and female volunteers (ages 19 to 25, n = 10) were compared to those of older individuals (ages 65 to 81, n = 9). Subjects received 1 gram of cephradine by a 5-minute intravenous (IV) infusion followed the next day by a 1-gram oral dose. Serial serum and urine samples collected over a period of 12 hours after the dose were analyzed for cephradine concentration by a microbiologic assay. After IV administration, mean serum cephradine concentrations in the elderly group were significantly higher at both 6 hours (1.52 +/- 0.41 mcg/mL) and 8 hours (0.73 +/- 0.22 mcg/mL) than in the young group at 6 hours (0.43 +/- 0.11 mcg/mL). Total systemic clearance was significantly lower (2.64 +/- 0.34 vs. 4.81 +/- 0.59 ml/min/kg) and the elimination half-life was significantly longer (1.71 +/- 0.20 vs 1.12 +/- 0.13 hours) in the elderly group (P = .0001). Systemic cephradine clearance correlated positively with creatinine clearance (r2 = 0.34, P = .0110) and negatively with age (r2 = 0.79, P = .0052). The mean volume of distribution was not significantly different between the two groups. Mean renal clearance was significantly lower in the elderly group (P = .0001), but more than 80% of the dose was excreted in the urine within 6 hours in both groups. After oral administration, the mean peak concentration and time to peak concentration did not differ between groups. The relative oral bioavailability was approximately 94% in both groups. The mean serum concentrations in the elderly were higher at both 6 and 8 hours than in the young group at 6 hours. There were no differences in pharmacokinetic parameters between male and female subjects. Because of reduced cephradine clearance secondary to an age-related decline in renal function, administration of cephradine every 8 hours, rather than every 6 hours, may be sufficient in elderly patients.