Autologous incubated macrophage therapy in acute, complete spinal cord injury: results of the phase 2 randomized controlled multicenter trial.

STUDY DESIGN: Randomized controlled trial with single-blinded primary outcome assessment. OBJECTIVES: To determine the efficacy and safety of autologous incubated macrophage treatment for improving neurological outcome in patients with acute, complete spinal cord injury (SCI). SETTING: Six SCI treatment centers in the United States and Israel. METHODS: Participants with traumatic complete SCI between C5 motor and T11 neurological levels who could receive macrophage therapy within 14 days of injury were randomly assigned in a 2:1 ratio to the treatment (autologous incubated macrophages) or control (standard of care) groups. Treatment group participants underwent macrophage injection into the caudal boundary of the SCI. The primary outcome measure was American Spinal Injury Association (ASIA) Impairment Scale (AIS) A-B or better at ≥6 months. Safety was assessed by analysis of adverse events (AEs). RESULTS: Of 43 participants (26 treatment, 17 control) having sufficient data for efficacy analysis, AIS A to B or better conversion was experienced by 7 treatment and 10 control participants; AIS A to C conversion was experienced by 2 treatment and 2 control participants. The primary outcome analysis for subjects with at least 6 months follow-up showed a trend favoring the control group that did not achieve statistical significance (P=0.053). The mean number of AEs reported per participant was not significantly different between the groups (P=0.942). CONCLUSION: The analysis failed to show a significant difference in primary outcome between the two groups. The study results do not support treatment of acute complete SCI with autologous incubated macrophage therapy as specified in this protocol.

A phase 2 autologous cellular therapy trial in patients with acute, complete spinal cord injury: pragmatics, recruitment, and demographics.

STUDY DESIGN: Post hoc analysis from a randomized controlled cellular therapy trial in acute, complete spinal cord injury (SCI). OBJECTIVES: Description and quantitative review of study logistics, referral patterns, current practice patterns and subject demographics. SETTING: Subjects were recruited to one of six international study centers. METHODS: Data are presented from 1816 patients pre-screened, 75 participants screened and 50 randomized. RESULTS: Of the 1816 patients pre-screened, 53.7% did not meet initial study criteria, primarily due to an injury outside the time window (14 days) or failure to meet neurological criteria (complete SCI between C5 motor/C4 sensory and T11). MRIs were obtained on 339 patients; 51.0% were ineligible based on imaging criteria. Of the 75 participants enrolled, 25 failed screening (SF), leaving 50 randomized. The primary reason for SF was based on the neurological exam (51.9%), followed by failure to meet MRI criteria (22.2%). Of the 50 randomized subjects, there were no significant differences in demographics in the active versus control arms. In those participants for whom data was available, 93.8% (45 of 48) of randomized participants received steroids before study entry, whereas 94.0% (47 of 50) had spine surgery before study enrollment. CONCLUSION: The 'funnel effect' (large numbers of potentially eligible participants with a small number enrolled) impacts all trials, but was particularly challenging in this trial due to eligibility criteria and logistics. Data collected may provide information on current practice patterns and the issues encountered and addressed may facilitate design of future trials.

The value of leadership in implementing and maintaining a successful health promotion program in the Naval Surface Force, U.S. Pacific Fleet.

A health promotion program called the "Green H Award" was implemented in 1996 for the SURFPAC commands, which represented 35,000 Navy and Marine personnel serving in the Naval Surface Force of the U.S. Pacific Fleet, in an effort to reduce rates of smoking, alcohol abuse, obesity, and poor fitness. Commands which had leadership involvement in their health promotion effort had higher levels of implementation, success, and maintenance. Measures of all these health risks improved substantially between 1996 and 1999; however, the response rates for the measures was highly variable.

Effectiveness of monitored anesthesia care in cataract surgery.

OBJECTIVE: To determine the need for monitored anesthesia care in cataract surgery by evaluating the incidence of intervention by anesthesia personnel and by looking for associated risk factors. DESIGN: Nonrandomized, prospective case series with analysis of consecutive cataract surgery cases. PARTICIPANTS: A total of 1006 consecutive cataract surgery patients at an ambulatory surgery center over a 6-month period. METHODS: Routine cataract surgery was performed with the patient under local anesthesia. A detailed questionnaire was completed by the anesthesia personnel at the conclusion of each phase (before, during, and after) of cataract surgery. MAIN OUTCOME MEASURES: Age, medical history, and preoperative electrocardiogram (EKG) were analyzed as predictors for intervention by anesthesia personnel. The nature of the patient's problem and the type of intervention by anesthesia personnel were recorded. RESULTS: In 1006 consecutive cataract surgery cases, intervention by anesthesia personnel was required in 376 (37.4%) cases. No preoperative identifying characteristics were found to be reliable predictors of the need for intervention. There were no statistically significant differences in preoperative EKG and some medical conditions such as heart disease, diabetes, and thyroid disease between patients who received intervention and those who did not. Certain subgroups of patients did show a statistically significantly greater incidence of intervention, including systemic hypertensives (41.4%) versus nonhypertensives (34.5%) (P = 0.030), patients with pulmonary disease (49.3%) versus no pulmonary disease (36.5%) (P = 0.043), patients with renal disease (68.8%) versus no renal disease (36.9%) (P = 0.019), and patients with cancer (61.9%) versus no cancer (36.3%) (P = 0.001). Intervention was also required in 61.1 % of patients younger than 60 years of age compared to 36.5% of those patients 60 years of age and older (P = 0.005). CONCLUSIONS: Because intervention is required in more than one third of cataract surgery cases and the authors cannot reliably predict those patients at risk, monitored anesthesia care seems justified in cataract surgery with the patient under local anesthesia.

Randomized double-blind prospective trial to evaluate the effects of sargramostim versus placebo in a moderate-dose fluorouracil, doxorubicin, and cyclophosphamide adjuvant chemotherapy program for stage II and III breast cancer.

PURPOSE: To determine the effects of sargramostim (recombinant human granulocyte-macrophage colony-stimulating factor [rhu GM-CSF]) on the incidence, duration, and complications of myelosuppression after moderate-dose fluorouracil, doxorubicin, cyclophosphamide (FAC) adjuvant chemotherapy in patients with node-positive breast cancer. PATIENTS AND METHODS: In this randomized, double-blind, placebo-controlled study, 142 women with stage II and III breast cancer were to receive four 21-day cycles of chemotherapy that consisted of fluorouracil 600 mg/ m2 intravenously (IV), doxorubicin 60 mg/m2 IV, and cyclophosphamide 750 mg/m2 IV on day 1, followed by placebo or GM-CSF 250 micrograms/m2/d daily subcutaneously (SC) on days 3 through 15. All patients received prophylactic ciprofloxacin by mouth when the absolute neutrophil count (ANC) was less than 1,000/microL. RESULTS: Eighty-six percent of GM-CSF patients (n = 62) and 96% of placebo patients (n = 69) completed four assessable cycles of treatment on study. Overall, the median duration of severe neutropenia (ANC < 500/microL) was 2.8 days with GM-CSF and 6.8 days with placebo (P < .001); the duration of ANC less than 1,000/microL was 6.0 versus 9.1 days, respectively (P < .001). Hospitalizations for febrile neutropenia were uncommon in either group: GM-CSF, six; placebo, eight. The only other difference in hematologic toxicity was grade 3/4 thrombocytopenia observed with greater frequency in GM-CSF patients than placebo patients in cycles 3 and 4. GM-CSF increased mean the FAC dose-intensity among patients who completed two or more cycles (P < .001). GM-CSF was generally well tolerated and associated with more injection-site reactions, but less mucositis than placebo. There were no deaths on study. CONCLUSION: GM-CSF significantly enhanced ANC recovery after FAC chemotherapy; it decreased the incidence and duration of associated neutropenia and moderately increased the dose-intensity of adjuvant chemotherapy. Whether these effects will ultimately translate into improved long-term outcome remains to be determined.

TQM: a paradigm for physicians.

Change, even when for the better, is always accompanied by apprehension and even outright fear. It is therefore not surprising to hear health care workers, especially physicians, expressing their concerns about this "new" management philosophy through a spectrum of reactions that vary from skeptical or grudging acceptance to outright dismissal of all of the new "alphabet soup" associated with TQM.

Transhiatal esophagectomy in the management of perforated esophageal cancer.

Instrumental perforation of esophageal malignancy is best managed by immediate esophagectomy. Transthoracic esophagectomy has been the technique most described in the management of patients with this injury. A recent series reported the successful use of transhiatal esophagectomy with primary cervical esophagogastrostomy in four patients with perforated esophageal cancers. We have also used this technique to treat a patient with instrumental perforation of a distal esophageal cancer. This case is presented to add to the published experience using transhiatal esophagectomy in the management of perforated esophageal malignancy. The merits of transhiatal esophagectomy warrant consideration of this approach as a useful alternative to transthoracic resection in the management of selected patients with perforated esophageal cancer.

Olfactomedin: purification, characterization, and localization of a novel olfactory glycoprotein.

We have identified a novel glycoprotein expressed exclusively in frog olfactory neuroepithelium, which we have named "olfactomedin". Olfactomedin is a 57-kDa glycoprotein recognized by seven monoclonal antibodies, previously shown to react solely with proteins of olfactory cilia preparations. It undergoes posttranslational modifications, including dimerization via intermolecular disulfides and attachment of complex carbohydrate moieties that contain N-acetylglucosamine and beta-D-galactoside sugars. Olfactomedin strongly binds to Ricinus communis agglutinin I and has been purified to homogeneity by lectin affinity chromatography. Polyclonal rabbit antiserum raised against purified olfactomedin confirmed that it is expressed only in olfactory tissue. Immunohistochemical studies at the light microscopic and electron microscopic level show that olfactomedin is localized in secretory granules of sustentacular cells, in acinar cells of olfactory glands, and at the mucociliary surface. The massive production of olfactomedin and its striking deposition at the chemosensory surface of the olfactory neuroepithelium suggest a role for this protein in chemoreception.

Intermittent claudication caused by atherosclerosis in patients aged forty years and younger.

Intermittent claudication may represent a severe limitation in daily life-style for young, active patients and may result in loss of professional career for members of the armed forces. Our recent experience with young patients with atherosclerotic claudication was reviewed to determine whether more liberal use of angioplasty and surgery is warranted in these patients to salvage their military careers and improve their life-styles. A systemic review was made of patients aged 40 years and younger with atherosclerosis who have undergone arteriography at our institution during the past 67 months. From this study, 22 patients were found with the initial complaint of intermittent claudication. Fifteen of these patients (68%) had occlusive disease confined to the iliac arteries, and six (27%) had single-level occlusive disease in a femoropopliteal distribution. Only one patient had multilevel disease. Symptoms of coronary occlusive disease developed in five patients (23%) within 38 months of the onset of claudication, and two of these patients died of myocardial infarctions. Of 19 patients who underwent interventions to correct symptoms of claudication, 16 (85%) had complete relief of symptoms at the end of follow-up, ranging from 6 months to 7 years. Ten of these patients remained symptom free after a single intervention, but six patients had rapid progression of disease and required secondary procedures. These results indicate that a majority of young patients with claudication caused by atherosclerosis can be returned to full active-duty status in the military after angioplasty or surgery. However, some patients may require secondary procedures to relieve recurrent symptoms caused by rapid progression of disease. We believe that an aggressive interventional approach is warranted in the evaluation and treatment of young patients with work-limiting claudication caused by atherosclerosis. These patients are at significant risk of developing premature coronary occlusive disease and should be monitored closely.

Hypopyon iridocyclitis associated with extended-wear soft contact lenses.

Two patients had corneal erosions and hypopyon iridocyclitis associated with continuous wear of aphakic soft contact lenses. Both patients were treated with cycloplegia and patching without antibiotics or corticosteroids. Both patients fully recovered.

Humoral and cellular immunity studies in patients with Vogt-Koyanagi-Harada syndrome and pars planitis.

We performed a comprehensive immunologic assessment of 17 patients with Vogt-Koyanagi-Harada syndrome (VKH) and nine with pars planitis (PP). Several variations in humoral and cellular immunity were found when the patients were compared with normal controls. Elevated serum IgD levels, positive results from various autoimmune profile assays, and deviations from normal levels of viral antibody titers were noted in both groups of patients. However, only some VKH patients had elevated beta 2 microglobulin, total complement level and E-active and EA rosette counts. HLA haplotype typing revealed no distinct correlation between patients when compared with a normal population.

Vogt-Koyanagi-Harada syndrome.

We studied 20 patients with Vogt-Koyanagi-Harada syndrome. They represented 3.7% of referred patients with uveitis. American Indian ancestry appears to be the link to Oriental racial type. Five patients had a forme fruste retinal detachment. After extensive treatment with corticosteroids, detachments flattened within an average of two to three months. Anterior inflammation continued to persist chronically. Seven of our patients had retinal vasculitis. Pregnancy had a beneficial effect on disease activity. Those patients with diabetes mellitus and sickle cell hemoglobin did not have an adverse effect. Visual outcome was good; of 20 patients, 16 had visual ascuity of 6/21 (20/70) in at least one eye.

An unusual presentation of pseudotumor cerebri.

A 25-year old grossly obese woman presented with decreased visual acuity. She had bilateral total (internal and external) ophthalmoplegia, a left-sided seventh cranial nerve palsy, and florid bilateral papilledema. The diagnosis of pseudotumor cerebri was made on the basis of high cerebrospinal fluid pressure and the absence of other abnormalities on systemic, neurologic, and neuroradiologic examination. The patient responded favorably to corticosteroid treatment; however, bilateral optic atrophy occurred with persistent loss of visual field and acuity.

Follicular and gonadotrophic changes during transition from ovulatory to anovulatory seasons.

Observations of follicular and gonadotrophic changes were conducted on 14 Pony mares for 31-day periods beginning at the penultimate (second last) ovulation and at the last ovulation of the season. There were no main effects or interaction of day or period on the numbers of small follicles (less than 20 mm). Concentrations of FSH, numbers of large follicles (greater than 20 mm), and oestrous behaviour each showed an effect of day (P less than 0.01), but no effect of period. Concentrations of LH and diameter of the largest follicle each showed an interaction (P less than 0.01) between day and period attributable primarily to smaller values on Days 18--24 after the last ovulation than after the penultimate ovulation. It was concluded that, of the factors considered, failure of ovulation at the onset of the anovulatory season was due to lack of an adequate ovulatory LH surge and final growth of a preovulatory follicle.

Vitelliform lesions associated with retinal pigment epithelial detachment.

Two patients with bilateral vitelliform macular lesions had normal electro-oculogram findings. The fluorescein angiograms showed retinal pigment epithelial detachment. Detachment of the retinal pigment epithelium associated with lipid and/or protein accumulation within the subpigment epithelial space represents another mechanism by which a lesion ophthalmoscopically similar to that seen in classical Best's disease can be produced.