Recent insights into interactions of deferoxamine with cellular and plasma iron pools: Implications for clinical use.

Despite the availability of deferoxamine (DFO) for more than three decades, its rates of interaction with cellular iron pools in different tissues, and the effects of its pharmacokinetics on the interaction with plasma iron pools, remain incompletely understood. The positive charge of DFO, together with the negative resting potential in vertebrate cells, favors cellular uptake, whereas the low lipophilicity and high molecular weight counter this effect. The findings presented suggest a facilitated uptake of DFO into hepatocytes, being several hundred-fold faster than into red cells. Antibodies that selectively recognize ferrioxamine (FO) show that initial hepatocellular iron chelation is cytosolic, but later transposes to lysosomal and ultimately canalicular compartments. Strong FO staining is visible in myocytes within 4-8 h after commencing a subcutaneous DFO infusion, indicating effective chelation of myocyte iron. A methodology was developed to study the interaction of DFO and its metabolites with plasma iron pools by stabilizing DFO with aluminum ions, thereby preventing iron shuttling from non-transferrin-bound iron (NTBI) onto DFO after plasma collection. DFO removes only about a third of NTBI rapidly, and NTBI is rarely cleared completely. Increasing DFO dosing does not increase NTBI removal, but instead leads to a greater rebound in NTBI on cessation of intravenous infusion. Thus, intermittent infusions of high-dose DFO are less desirable than continuous infusions at low doses, particularly in high-risk patients. Here the benefits of continuous DFO on heart function occur before changes in T2*-visible storage iron, consistent with early removal of a toxic labile iron pool within myocytes.

Effect of a pharmacist-managed diabetes care program in a free medical clinic.

Diabetes care, morbidity, and mortality are usually worse in poor minority populations compared with non-minority ones. This report evaluates evidence-based process and outcome measures of diabetes care in diabetic patients followed in a free medical clinic and compares them to published results. The following process measures compared favorably with measures of the general population: dilated eye and foot exams and measurements of glycated hemoglobin levels; concentrations of total cholesterol; fasting triglycerides and low density lipoprotein (LDL) cholesterol; and proteinuria (by dipstick). Process and outcome measures in 89 diabetic patients referred to a Diabetes Management Program in which diabetes care was delivered by pharmacists following detailed algorithms (experimental group) were compared with measures in 92 diabetic patients who received diabetes care in the general clinic setting (control group). The patients in the experimental group had a slightly longer duration of diabetes and more microvascular and neuropathic complications, and more diabetic patients were taking insulin than were patients in the control group. All of the process measures listed above were more frequent in the experimental group. Compared with the control group, the initial glycated hemoglobin level (% +/- SE) in the experimental group was significantly (P < .001) higher (8.8 +/- 0.2 versus 7.9 +/- 0.2) but fell significantly (P < .03) more (-0.8 +/- 0.2 versus -0.05 +/- 0.3). The lack of a greater decrease in the glycated hemoglobin levels in the experimental group was not related to the inability of the pharmacists to follow the algorithms, the patients' refusal to follow the recommended medication adjustments, or the lack of appropriate self-monitoring of blood glucose in insulin-requiring patients. It was inversely related (r = -0.36, P < .03) to the number of missed visits, i.e., the greater the number of broken appointments, the less the glycated hemoglobin fell. In conclusion, diabetes care for a poor minority population in a free clinic setting can compare favorably to care in the general population. Pharmacists following detailed algorithms can enhance this care further. Administrative and support system changes that minimize the number of missed visits might further improve diabetes care in this population.

The effects of different sampling techniques on smear quality and the diagnosis of cytological abnormalities in cervical screening.

A major cause of false-negative cervical smear is sampling error. We examined the results obtained with three different instruments in 126,608 smears from general practitioners. The spatula/brush combination yielded the highest proportion of smears showing cytological abnormalities, and the Cervex brush the lowest. Although not a randomized study, this paper highlights the shortcomings of the Cervex brush. We postulate a mechanical deficiency. Diagnostic accuracy rather than a high proportion of good quality smears should dictate the choice of instrument.

An assessment of partial rescreening as an internal quality control method for cervical smears.

Partial screening was performed on 10,800 cervical smears, comprising 8640 filed negative and unsatisfactory smears and 2160 newly received smears prior to conventional screening. Each slide was screened for 30 s and those considered abnormal were reviewed by standard screening. Partial screening led to the detection of 27 additional infections and 44 additional cytological abnormalities. These detection rates are better than those obtained with the traditional method of rescreening only a proportion of smears. Amongst the smears partially screened before conventional screening, partial screening detected 37-66% of infections and 22-71% of cytological abnormalities. We recommend the use of partial rescreening of all negatively reported smears as a method of internal quality control in cervical cytology laboratories.

p53 immunostaining as a marker of malignancy in cytologic preparations of body fluids.

The accurate identification of suspicious cells in cytologic preparations is a common problem in diagnostic cytopathology. Recent studies have shown that mutation of the p53 gene may be the most common genetic event in human malignancy. Mutation leads to altered conformation and increased half-life of the p53 protein, resulting in detectability by immunocytochemistry. The usefulness of p53 immunocytochemical staining as a marker of malignancy in the cytologic analysis of body fluids was investigated in the present study. One hundred fifty-four serial samples of body fluids submitted for cytologic diagnosis were also examined for p53 immunoreactivity. Of 121 cases reported as cytologically benign, 3 (2.5%) stained positively for p53; 16 samples were cytologically malignant, and 7 (43.7%) of these were positive for p53 (P < .001). Of those reported as suspicious but not conclusively malignant, 4 of 17 (23.5%) showed p53 immunoreactivity. On review, two of the three patients whose samples were benign cytologically yet showed positive p53 staining had histologic evidence of malignancy. The third patient died without a postmortem examination. Of the 17 cytologically suspicious cases, 16 (94.1%) were later proven to be malignant, and p53 was positive in 4 (25%). These results suggest that p53 immunostaining could be of value as a marker of malignancy in the cytologic examination of body fluids. The presence of p53 immunoreactivity in cytologic samples is strongly suggestive of malignancy, though its absence does not exclude neoplasia.

Free peritoneal tumour cell identification in patients with gastric and colorectal cancer.

The finding of free tumour cells within the peritoneum at the time of laparotomy for gastrointestinal cancer is an important indicator of prognosis and may help select treatment. The aim of this study was to improve the methods whereby these cells could be retrieved and identified. Free peritoneal cancer cells were found in 6 out of 18 gastric cancer patients. All 6 patients had tumour invasion through to the serosa and subsequently died of tumour recurrence. None of the 18 Dukes' B and C colorectal cancer patients had free peritoneal cancer cells. Only 2 of a further 5 patients with extensive colorectal tumour spread had positive cytologies. The conventional mucin stain Periodic Acid Schiff (after diastase digestion) and the monoclonal antibody stain B72.3 were the most useful in identifying free peritoneal cancer cells. Peritoneal brushings did not offer any advantages over conventional peritoneal washings in the retrieval of free tumour cells.