Adsorption kinetics of plasma proteins on ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles.

In this study the kinetics of plasma protein adsorption onto ultrasmall superparamagnetic iron oxide (USPIO) particles have been analyzed and compared to previously published kinetic studies on polystyrene particles (PS particles), oil-in-water nanoemulsions and solid lipid nanoparticles (SLNs). SPIO and USPIO nanoparticles are commonly used as magnetic resonance imaging (MRI) enhancers for tumor imaging as well as in drug delivery applications. Two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) has been used to determine the plasma protein adsorption onto the citrate/triethylene glycol-stabilized iron oxide surface. The results indicate that the existence of a Vroman effect, a displacement of previously adsorbed abundant proteins, such as albumin or fibrinogen, respectively, on USPIO particles has to be denied. Previously, identical findings have been reported for oil-in-water nanoemulsions. Furthermore, the protein adsorption kinetics differs dramatically from that of other solid drug delivery systems (PS, SLN). More relevant for the in vivo fate of long circulating particles is the protein corona after several minutes or even hours. Interestingly, the patterns received after an incubation time of 0.5 min to 240 min are found to be qualitatively and quantitatively similar. This leads to the assumption of a long-lived ("hard") protein corona around the iron oxide nanoparticles.

Intracoronary formation and retention of micro aggregates of leukocytes and platelets contribute to postischemic myocardial dysfunction.

OBJECTIVE: Cardiac pump function and coronary regulation can be impaired after short-term ischemia. Recent studies with platelets (P) and neutrophils (PMN) yielded contradicting results about the "cellular" contribution to reperfusion injury. METHODS: Isolated guinea pig hearts performing pressure-volume work were employed, external heart work (EHW), aortic flow (AF), coronary flow (CF) and heart rate (HR) serving as parameters of cardiac function. After global ischemia, human blood cells were given as bolus (1 min) during reperfusion (intracoronary hematocrit 7%). Expression of specific adhesion molecules (P: CD62P, CD41; PMN: integrin CD11b) was measured on cells before and after coronary passage (FACS analysis). RESULTS: Postischemic recovery of pump function was significantly reduced in hearts with blood cell application (EHW: -cells 54 +/- 14%, +cells 41 +/-12%, p <0.05). Coronary response to bradykinin and reactive hyperemia were not effected. The blood-cell dependent functional loss was partly reduced by blocking CD18 (anti-CD 18) and completely abrogated by blockage of CD41 (lamifiban). The expression of CD11b on PMN and monocytes (M) and CD62P on platelets was significantly reduced in the coronary effluent and a significant decrease of CD41 on leukocytes occurred during coronary passage after ischemia. Increases in CD41 on PMN in the presence of lamifiban demasked intracoronary formation of micro aggregates (P/PMN). These micro aggregates were visualized by light microscopy. Electron microscopy revealed no significant microvascular plugging. CONCLUSION: 1) A specifically blood-cell induced loss of myocardial pump function has been demonstrated after short-term ischemia. 2) CD41 (= GpIIbIIIa) on P is responsible for this cardiac reperfusion damage. 3) The effect is causally linked to the formation of micro aggregates between PMN and P, but seems attenuated in the presence of erythrocytes as compared to effects reported from experiments in which PMN and P were applied singly or co-perfused. 4) Intracoronary retention of PMN, M and platelet-leukocyte micro aggregates seems to be transient, as adherence was not confirmed by electron microscopy.

[Changes and complication rate in surgery for thoracic esophageal carcinoma]. / Veränderungen und Komplikationsrate in der Chirurgie des thorakalen Osophaguskarzinoms.

AIM: In an analysis over 22 years it was investigated which parameters have changed in the operative treatment of thoracic esophageal carcinoma over time and in how far they have influenced complication rate. PATIENTS AND METHODS: Between 1978 and 1999 386 patients (350 men, 36 women) underwent resection for thoracic esophageal carcinoma (squamous cell carcinoma n=300, adenocarcinoma n=86). Cervical tumors were excluded from analysis. The time periods from 1978 to 1988 (n=242) and from 1989 to 1999 (n=144) were separately analyzed and compared with respect to age, sex, histological type, main tumor location, neoadjuvant therapy, method of operation, esophageal substitute and positioning of the substitute, R-status, pT/pN classification, UICC stage, number of dissected lymph nodes, complication rate, postoperative mortality and survival. RESULTS: Comparison of the two time periods showed a significant increase in adenocarcinomas and main tumor location in the lower thoracic third of the esophagus. Furthermore, significant changes concerning the indication of neoadjuvant chemoradiation, operative approach, esophageal substitute, R-status and number of dissected lymph nodes were observed. Tumor stage (pT/pN classification and UICC stage) significantly shifted towards earlier stages. Total complication rate dropped tendentially form 68.5 % to 59.0 % (p=0.061). Hospital mortality was significantly reduced from 24 % to 12.5 %, whereas anastomotic leakages and multiorgan failure remained on a constant level. Median survival of R0 resected patients was significantly prolonged from 19 months to 34 months. CONCLUSIONS: The increase of esophageal adenocarcinoma, a more strict patient selection (staging, functional status), standardization of operative technique as well as an optimized intensive care management are among the important changes in the operative management of thoracic esophageal carcinoma that have resulted in an improvement of prognosis of curatively resected patients. In spite of a more aggressive operative approach, i. e. lymph node dissection, operative mortality could be reduced by nearly 50 % in the face of a tendentially declining total complication rate.

Cutaneous eccrine glands of the foot pads of the rock hyrax (Procavia capensis, Hyracoidea, Mammalia).

In order to find correlations between skin gland morphology and specific ethological features, the cutaneous glands of the foot pads of Procavia capensis were studied by histological and various histochemical methods and by electron microscopy. In the foot pads, abundant specific eccrine skin glands occur, which consist of coiled tubular secretory portions and coiled ducts. The wall of the secretory part is composed of cuboidal glandular cells and myoepithelial cells. Among the glandular cells two types occur: clear and dark cells. Clear cells have numerous mitochondria and form a basal labyrinth, indicating fluid transport. Dark cells, which stain strongly with periodic acid-Schiff, contain a highly developed perinuclear Golgi apparatus, large amounts of rough endoplasmic reticulum and many secretory granules indicating production of glycoproteins. Cytokeratin (CK) 19 was found in secretory compartments and ducts, CK14 only in duct cells. Single cells of the secretory coils and ducts may be stained with antibodies against antimicrobial peptides. Some glandular cells contain proliferating cell nuclear antigen-positive nuclei especially in the ducts indicating an increased cell proliferation. Terminal transferase (TdT)-mediated d-UTP nick-end labeling-positive nuclei can be detected predominantly in the secretory coils and rarely in the transitional portions between ducts and end pieces. We suppose that proliferating cells migrate from the ducts to the secretory coils. The secretory product of the eccrine cutaneous glands seems to improve the traction between the foot pads of these animals and the steep and smooth rock formations among which they live.

Pneumococcal immunizations at flu clinics: the impact of community-wide outreach.

This study examined the effectiveness of a community-wide outreach campaign to promote the use of pneumococcal vaccine at public flu immunization clinics, and assessed whether this intervention was more effective than simply making pneumococcal vaccination available at such clinics. In 1997, a community-wide outreach campaign promoting pneumococcal and influenza immunizations was launched in a 17 zip code area of Dutchess County, NY. The campaign was aimed at 7,961 Medicare beneficiaries urging them to obtain pneumococcal immunization from local flu clinics. Medicare reimbursement data were used to assess the countywide pneumococcal vaccination rate, and to analyze differences between rates for beneficiaries in the target area and elsewhere in the county. Between 1996 and 1997 there was a 94% increase in pneumococcal vaccination billed to Medicare beneficiaries in Dutchess County. The 1997 annual rate of pneumococcal immunization in the target area reached 16.3% versus 12.2% elsewhere in the county (p < 0.001), with an increase over the previous year of 8.7% and 5.6%, respectively. Nearly all of the increase is accounted for by pneumococcal vaccination delivered at flu clinics. It is possible to significantly increase the use of pneumococcal immunization by linking its delivery to community-based flu clinics and by developing local outreach strategies. The outreach campaign has a significant additive effect over simply making PPV available at flu shot clinics. Additional community-wide outreach can further improve pneumococcal immunization utilization rates.

Interstitial buffer capacity influences Na+/H+ exchange kinetics and oxyntic cell pHi in intact frog gastric mucosa.

We studied the influence of interstitial buffer capacity and CO2-HCO3- on oxyntic cell intracellular pH (pHi) in intact frog gastric mucosa. Oxyntic cells in stripped gastric mucosa of Rana esculenta were loaded with the pH-sensitive dye 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein, and pHi was assessed fluorometrically. In the presence of a constant serosal and luminal pH, oxyntic cell pHi was dependent on the serosal but not the luminal concentration of cell-impermeable buffer ions such as N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES), tris(hydroxymethyl)aminomethane, N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid, and 3-(N-morpholino)propanesulfonic acid. The stepwise increase in oxyntic cell pHi from 6.74 +/- 0.05 with 1 mM HEPES to 7.23 +/- 0.08 was almost completely inhibited by removal of serosal Na+ and by amiloride and dimethyl amiloride, suggesting that it was largely due to Na+/H+ exchange. Increasing the serosal concentration of a CO2-HCO3- buffer from 1% CO2-4 mM HCO3- to 10% CO2-40 mM HCO3- increased oxyntic cell pHi from 7.03 +/- 0.06 to 7.39 +/- 0.07. This CO2-HCO(3-)-dependent pHi increase was also Na+ and amiloride sensitive, but high HCO3- concentrations increased pHi even in the absence of Na+, K+, or Cl-, and in the presence of omeprazole, bafilomycin A1, or acetazolamide. We suggest that in intact frog gastric mucosa, cellular proton extrusion acidifies the interstitial pH immediately adjacent to the basolateral membrane of the oxyntic cells in the absence of a high interstitial buffer capacity.(ABSTRACT TRUNCATED AT 250 WORDS)

Compliance problems with hormone replacement therapy.

Because menopause and its consequences constitute an endocrinopathy, long-term administration of HRT is often necessary to achieve optimal results. Compliance is therefore an important consideration in the clinical use of HRT. A number of factors appear to influence physicians in their prescribing of HRT, including estimates of benefits and risks that may not be supported by scientific data. In addition, some physicians appear to use patterns of administration of HRT that may diminish the chance of appropriate patient compliance, or of maximizing benefits while minimizing risks. Patients may elect to avoid HRT or stop HRT prematurely because of incorrect impressions about the benefits and risks, or because of bothersome side effects. Although the side effects are more prevent some appropriate candidates from using HRT. Fortunately, a range of possible options is available for prescribing HRT, and modifications may be used for patients who are experiencing problems. In order for patients to receive maximum benefit from HRT, clinicians must be willing to educate and reassure patients, and to adjust therapy when problems occur.

Pharmacokinetics of estrogen.

The main types of pharmacologic therapy used to treat the hormone deficiency of menopause are parenteral and oral administrations of estrogen. Parenteral administration results in predictable absorption without major intermediary metabolism, whereas all oral estrogens are subject to intestinal metabolism before entering the systemic circulation. Various options are available. Injectable estrogens, because of rapid absorption and metabolism, are impractical for long-term replacement therapy. The primary drawback to subcutaneous estradiol pellets is the surgical procedure required for their insertion and removal. Vaginal epithelium is an effective pathway for absorption of estrogen given by solution, tablet, or cream, although only the latter is currently approved for clinical use; relatively constant serum levels of estradiol can be obtained with vaginal rings. Transdermal patches provide controlled hormone levels for up to 3.5 days. Although oral conjugated equine estrogens have been used extensively, they introduce types of estrogen, such as equilin, that are not naturally found in humans and that can produce a pronounced hepatic response. Micronized estradiol, oral estrone, and other estrogens have been used as alternatives to equine estrogens. Clinicians should understand the pharmacokinetics of the various options for replacement therapy and select a course of treatment that is safe, effective, and convenient for the patient.

Mechanisms that subserve estradiol's induction of increased prolactin concentrations: evidence of amplitude modulation of spontaneous prolactin secretory bursts.

Estradiol stimulates hyperprolactinemia in human beings and in experimental animals by mechanism(s) that remain largely undefined. We have tested the hypothesis that estrogen modulates episodic and rhythmic prolactin release. To this end we studied six postmenopausal women by repetitive venous sampling basally and on days 1, 5, 10, and 30 after intravaginal placement of an estradiol-impregnated polymeric silicone (Silastic) ring. Computerized analysis of episodic prolactin pulsatility revealed that estrogen amplified prolactin pulse amplitude threefold without changing prolactin pulse frequency. Fourier analysis disclosed heightened amplitudes of specific ultradian rhythms, and deconvolution analysis demonstrated a sevenfold increase in the mass of prolactin secreted per pulse with no change in its half-life. We conclude that estradiol selectively augments the amplitude of episodic prolactin pulsatility, amplifies ultradian rhythms, and increases the mass of prolactin released per secretory burst.

Estradiol and progesterone replacement regimens for the induction of endometrial receptivity.

Initiation of pregnancy in premature ovarian failure patients by use of donated oocytes fertilized in vitro requires establishment of a normal endometrial environment. We compared administration of estradiol (E2) and progesterone (P) by polysiloxane vaginal rings versus oral micronized E2 and P vaginal suppositories in 10 such patients. Serum E2 levels were similar between groups and similar to normally-cycling controls. With vaginal administration of E2, a burst effect was noted, with marked elevation 1 hour after insertion. The pattern with oral administration was more consistent, although marked conversion to estrone occurred. The P cylinder and suppositories delivered similar levels, with diminution of P in some patients with the cylinder. Despite apparent limitations, endometrial histology was normal after each cycle; both groups achieved pregnancies. Administration of E2 and P by polysiloxane vaginal rings achieved hormonal levels similar to oral micronized E2 and P vaginal suppositories. Endometrial biopsies after the stimulated cycle were appropriately mature.

Incomplete Behcet's syndrome in the differential diagnosis of genital ulceration and postcoital bleeding. A case report.

Behcet's syndrome occasionally produces significant vaginal bleeding requiring operative intervention. Our patient had genital and oral ulcerations but did not have uveitis or iritis, therefore representing incomplete Behcet's syndrome. The oral and genital lesions associated with Behcet's syndrome resemble those produced by herpes infection and must be considered in the differential diagnosis of genital ulceration.