Efficacy of subcutaneous epoetin-zeta on anemia in renal transplant recipients: a single-center experience.

BACKGROUND: Persistent or "de novo" anemia (plasma hemoglobin<11 g/dL) may complicate the graft outcome in a significant number of renal transplant recipients. We describe a single-center experience with epoetin-zeta (EPO-Z), the biosimilar form for epoetin-alfa. METHODS: Twenty patients were included in the study, 10 in treatment with different erythropoiesis-stimulating agents (ESA) and shifted to EPO-Z (shift group) and 10 who started EPO-Z treatment for anemia (naive group). All the patients had stable renal function and normal values of main inflammation markers and were prospectively followed up for 12 months. Iron supplements were administered during the study, as needed. RESULTS: In the shift group, mean plasma hemoglobin levels>11 g/dL were maintained for the entire 1-year follow-up period, with average EPO-Z doses 3.4% higher than the corresponding doses of previous ESA; in the naive group, the target value was reached between the first and third months and remained stable throughout the study. Mean corpuscular volume did not vary in either group. No change was observed in glomerular filtration rate, nor in proteinuria or in main laboratory data. No drug-related side effect was reported. CONCLUSIONS: EPO-Z may be considered a valid alternative to different ESAs in renal transplant recipients, with an interesting pharmaco-economic profile, considering its lower cost.

A randomized controlled double-blind investigation of the effects of vitamin D dietary supplementation in subjects with atopic dermatitis.

BACKGROUND: Subjects with atopic dermatitis (AD) have defects in antimicrobial peptide (AMP) production possibly contributing to an increased risk of infections. In laboratory models, vitamin D can alter innate immunity by increasing AMP production. OBJECTIVE: To determine if AD severity correlates with baseline vitamin D levels, and to test whether supplementation with oral vitamin D alters AMP production in AD skin. METHODS: This was a multi-centre, placebo-controlled, double-blind study in 30 subjects with AD, 30 non-atopic subjects, and 16 subjects with psoriasis. Subjects were randomized to receive either 4000 IU of cholecalciferol or placebo for 21 days. At baseline and day 21, levels of 25-hydroxyvitamin D (25OHD), cathelicidin, HBD-3, IL-13, and Eczema Area and Severity Index (EASI) and Rajka-Langeland scores were obtained. RESULTS: At baseline, 20% of AD subjects had serum 25OHD below 20 ng/mL. Low serum 25OHD correlated with increased Fitzpatrick Skin Type and elevated BMI, but not AD severity. After 21 days of oral cholecalciferol, mean serum 25OHD increased, but there was no significant change in skin cathelicidin, HBD-3, IL-13 or EASI scores. CONCLUSIONS: This study illustrated that darker skin types and elevated BMI are important risk factors for vitamin D deficiency in subjects with AD, and highlighted the possibility that seasonality and locale may be potent contributors to cathelicidin induction through their effect on steady state 25OHD levels. Given the molecular links between vitamin D and immune function, further study of vitamin D supplementation in subjects with AD is warranted.

Treatment of rosacea.

A range of treatment options are available in rosacea, which include several topical (mainly metronidazole, azelaic acid, other antibiotics, sulfur, retinoids) and oral drugs (mainly tetracyclines, metronidazole, macrolides). In some cases, the first choice is a systemic therapy because patients may have sensitive skin and topical medications can be irritant. Isotretinoin can be used in resistant cases of rosacea. Unfortunately, the majority of studies on rosacea treatments are at high or unclear risk of bias. A recent Cochrane review found that only topical metronidazole, azelaic acid, and oral doxycycline (40 mg) had some evidence to support their effectiveness in moderate to severe rosacea and concluded that further well-designed, adequately-powered randomised controlled trials are required. In our practice, we evaluate our patients for the presence of two possible triggers, Helicobacter pylori infection and small intestinal bacterial overgrowth. When they are present we use adapted antibiotic protocols. If not, we use oral metronidazole or oral tetracycline to treat papulopustolar rosacea. We also look for Demodex folliculorum infestation. When Demodex concentration is higher than 5/cm(2) we use topical crotamiton 10% or metronidazole.

Double-contrast barium enema and computerised tomography in the pre-operative evaluation of rectal carcinoma: are they still useful diagnostic procedures?

PURPOSE: In modern management of rectal carcinoma, the preoperative evaluation of disease parameters is important for selection of therapeutic options. Such parameters are currently defined through endorectal ultrasonography or endoscopic ultrasonography. A retrospective analysis of the parameters obtained with double-contrast barium enema (DCBE) and endorectal balloon computed tomography (CT) was conducted to verify the diagnostic reliability of the radiological techniques and to establish whether there is still an indication for their use. METHODS: 53 consecutive patients with adenocarcinoma of the distal half of the rectal ampulla underwent double contrast barium enema examination and CT of the pelvis with endorectal balloon. On the basis of the DCBE and CT assessment we evaluated: 1) the distance between the cranial extremity of the anal canal and the distal margin of the neoplasm; 2) the radial diffusion of the tumor; 3) the metastatic involvement of the perirectal and inferior mesenteric lymph nodes. RESULTS: 1) CT and DBCE measurements of the distal margin tended to coincide, but both tended to overestimate the measurement when compared to the pathologic examination; 2) in the identification of neoplastic infiltration of perirectal fat (T3) CT had 100% sensitivity, 78.7% specificity and 86.8% accuracy; 3) the CT sensitivity for detecting lymph node metastasis was 52.6%, specificity 85.3% and accuracy 73.6%. CONCLUSIONS: The diagnostic information provided by the radiological examinations is comparable to that of clinical and instrumental methods currently employed for staging of rectal carcinoma, although the latter are preferred because they are more readily accessible and less costly. DCBE and CT can therefore be usefully employed for staging of cancer of the rectum in those cases in which there are limitations of the current standard methods.

Schnitzler's syndrome: no evidence for autoimmune basis in two patients.

We report two cases of Schnitzler's syndrome in which anti-interleukin-1alpha autoantibodies and functional autoantibodies against the high affinity IgE receptor (FcepsilonRIalpha) or against IgE were absent. One patient responded well to TL-01 phototherapy, a treatment which may be considered in patients with Schnitzler's syndrome if, as is usually the case, they are unresponsive to antihistamine therapy.

Effects of various inhibitors of phenylethanolamine N-methyltransferase on pulsatile release of LH in ovariectomized rats.

This study was undertaken to investigate whether hypothalamic adrenaline is involved in pulsatile LH release in rats. Various inhibitors of phenylethanolamine N-methyltransferase (PNMT), the enzyme which catalyses the conversion of noradrenaline to adrenaline, were administered to freely moving ovariectomized rats bearing an atrial cannula. Blood samples were taken continuously from 09.00 to 11.00 h and from 14.30 to 17.00 h. The drugs were administered either at 11.00 h only or at both 11.00 and 14.00 h. The various treatments with the vehicle or an inhibitor of peripheral PNMT, SKF 29661, produced no decrease in any parameter of pulsatile LH release. A single injection of one of the central PNMT inhibitors, SKF 64139 or LY 134046, at 11.00 h had no effect on LH release, but when given at both times the drugs suppressed the mean LH level, pulse frequency and amplitude. The effect of these drugs on the level of dopamine, noradrenaline and adrenaline in the hypothalamus (including preoptic area) was assessed. There was no effect on the concentration of the catecholamines after SKF 29661. None of the treatments with SKF 64139 or LY 134046 resulted in a change in the level of dopamine or noradrenaline; the double dose did, however, produce a significantly greater depletion of adrenaline than that which was achieved with the single injection. These results suggest that the maintenance of normal LH pulses is dependent upon the presence of a sufficient level of hypothalamic adrenaline.(ABSTRACT TRUNCATED AT 250 WORDS)

Establishment of long-term monocyte suspension cultures from normal human peripheral blood.

The long-term suspension growth of normal, immature myeloid cells from fresh human cord blood was recently reported and required cells separated on supplemented discontinuous Percoll gradients, growth in media containing hydrocortisone and vitamins D3, and gentle, continuous agitation (13). When normal adult bone marrow (six donors) or blood from Epstein-Barr virus (EBV)-seropositive donors (nine donors) was used as a source of fresh human leukocytes, only short-term proliferation of myeloid cells was achieved with the same techniques. However, when leukocytes prepared from EBV seronegative normal adult peripheral blood were used, pure populations of monocytes and macrophages that replicate slowly in liquid suspension culture for greater than 5 mo were repeatedly obtained from three independent donors. These cultures consists of several morphologically distinguishable monocytic cell types, including an approximately 20% adherent macrophage population. The monocytic nature of these cultures was confirmed by cytochemical, immunological, and functional criteria. These monocytes retain a normal chromosome pattern and can be induced to differentiate to phagocytic cells by treatment with tetradecanylphorbal acetate. Eventually, the cultures terminate as nonreplicating mature macrophages. These liquid suspension cultures should be a valuable resource for morphological, biochemical, and functional studies of developing monocyte-macrophages and their interaction with other cell types in normal and various pathological situations.

Effect of electrical stimulation of the dorsomedial hypothalamic nucleus on pulsatile LH release in ovariectomized rats.

The present experiments were carried out to examine the influence of electrical stimulation of the dorsomedial hypothalamic nucleus (DMH) on pulsatile LH release in ovariectomized rats, and the possible involvement of serotonin (5HT) in mediating any observed effects. Unanesthetized animals were bled continuously through jugular vein cannulae for an initial 1 1/2 h control period. Rats were then stimulated for two 1-hour periods, separated by a 45-min nonstimulation period. DMH stimulation suppressed pulsatile LH release and decreased mean blood LH levels during both stimulation periods in control rats as well as animals in which 5HT synthesis was inhibited by p-chlorophenylalanine or 5HT receptors were blocked by metergoline. The decrease in mean blood LH levels in all groups was due solely to an increase in the LH interpulse interval. LH pulses that did occur during the stimulation-induced suppression did not show a decreased LH pulse amplitude. Rather, in control and metergoline-treated animals this parameter increased during stimulation, suggesting a buildup of readily releasable LHRH and/or pituitary LH. Lastly, estradiol benzoate suppressed pulsatile LH secretion but did not reverse the inhibitory LH response to DMH stimulation. These experiments indicate that the DMH, because of neurons originating within this nucleus and/or fibers passing through, may be a brain region that influences pulsatile LH release in a suppressive manner. This effect is exerted solely on the periodicity of the process and not through a 5HT-mediated mechanism.

Muzolimine: a new high-ceiling diuretic suitable for patients with advanced renal disease.

Muzolimine was administered by mouth to 24 patients with creatinine clearances ranging from 4 to 28 ml/min to treat oedema or hypertension, or both. In four of these 24 patients muzolimine was given after intravenous high-dose frusemide had been unsuccessful. Muzolimine significantly increased urine volume and excretions of sodium, chloride, and potassium ions. Its diuretic efficacy was further shown by a mean reduction in body-weight of 8% and by the disappearance of oedema in all affected patients, even those refractory to intravenous frusemide. No rebound phenomenon was observed after the drug was stopped. Mean blood pressure was reduced in all hypertensive patients. Blood pressure was restored to normal in five out of seven patients treated with muzolimine alone and 10 out of 11 in whom muzolimine had been added to previously unsatisfactory antihypertensive treatment. Muzolimine was well tolerated by all patients. Muzolimine appears to be the diuretic of choice when treating patients with advanced renal disease.

Regional differences in response to electrical stimulation within the medial preoptic-suprachiasmatic region on blood luteinizing hormone levels in ovariectomized and ovariectomized, estrogen-primed rats.

The effect of electrical stimulation of the medial preoptic-suprachiasmatic nucleus (MPOA-SCN) region of the forebrain on blood LH levels was studied in ovariectomized, pentobarbital-anesthetized rats. Animals were either not primed with estrogen or previously given 5 micrograms estradiol benzoate (EB)/100 g BW . day for the 2 days before stimulation. Rats were bled continuously (30, 40, or 50 microliter whole blood/5--6 min) through indwelling right atrial cannulae for 1.5 h before stimulation, 1.5 h during stimulation, and up to 1 h afterwards. Whole blood was analyzed for LH by RIA. In ovariectomized, unprimed rats, electrical stimulation of the ventral MPOA consistently increased LH release. In contrast, stimulation of the peri-SCN region (immediately caudal to the MPOA, and lateral and dorsal to, but not within, the SCN), uniformly inhibited pulsatile LH secretion. Activation of the SCN elevated blood LH levels in most unprimed rats tested, but suppression of episodic LH release occasionally occurred. Pretreatment with estrogen resulted in increased LH secretion in response to stimulation of each of these three regions. Estrogen prolonged the LH increase occurring during MPOA stimulation, completely reversed the inhibitory LH response to peri-SCN stimulation, and either reversed any possible inhibitory response to SCN stimulation or greatly increased the magnitude and duration of the increase in blood LH levels produced in the unprimed rat during activation of this nucleus. In summary, the present study indicates that well defined areas in the MPOA-SCN region can have strikingly different effects on LH secretion in the absence of ovarian estrogen and that this steroid is critically important in determining the direction, magnitude, and duration of the LH response to a localized brain stimulus.

Effect of lesions in the suprachiasmatic nucleus-retrochiasmatic area on the inhibition of pulsatile LH release induced by electrical stimulation of the midbrain dorsal raphe nucleus.

The present studies were designed to determine if the inhibition of pulsatile luteinizing hormone (LH) secretion reported to occur during midbrain dorsal raphe nucleus (DRN) stimulation involved some portion of the suprachiasmatic nucleus(SCN)-retrochiasmatic area (RCA). In animals having lesions that completely destroyed the SCN but did not extend into the RCA, dorsal raphe-induced inhibition of pulsatile LH release was still present. If, however, a significant portion (more than 40%) or all of the RCA was encompassed by the lesion (with variable or no SCN damage), the inhibition induced by DRN stimulation was prevented. This indicates that the SCN is not necessary for the inhibitory effect of DRN stimulation on pulsatile LH release to occur. However, the pathway responsible for this inhibition does appear to project to or through the RCA. Furthermore, pulsatile LH release was reduced, but present, during the control period prior to stimulation in rats with SCN lesions (and no damage to the RCA), and mean blood LH levels for this group were significantly decreased during the control bleeding period. Therefore, the neuronal pathway activating episodic LH release involves, but is not restricted solely to, the SCN.

The effect of blockade of dopamine receptors on the inhibition of episodic luteinizing hormone release during electrical stimulation of the arcuate nucleus in ovariectomized rats.

This study examined the possible involvement of dopamine (DA) in mediating the inhibition of episodic LH release that occurs during electrical stimulation of the arcuate nucleus (ARH) in ovariectomized rats. Animals were treated before stimulation with pimozide (1.26--2.0 mg/kg) or d-butaclamol (1 mg/kg), blockers of DA receptors, or l-butaclamol. Apomorphine, which inhibits episodic LH release by activating DA receptors, was given near the end of the experiment to determine if these receptors were blocked. ARH stimulation suppressed pulsatile LH release in six rats when DA receptors were not blocked by pimozide (as well as two in which blockade was not tested). A transient increase occurred in one other animal. When DA receptors were blocked by pimozide, stimulation of the ARH inhibited episodic LH release in nine rats, suggesting that DA may have no role in mediating this inhibition. However, because increased LH release occurred in five additional animals, as well as in one with partial receptor blockade, the possibility remains that DA may perhaps have a minor role in this inhibitory response. Although ARH stimulation increased LH release after DA receptor blockade by d-butaclamol, this effect could not be ascribed to the DA antagonist property of this agent, because elevated blood LH levels also occurred during stimulation in rats treated with l-butaclamol, in which DA receptors were not blocked. d- and l-butaclamol may possess a non-stereospecific action on a non-dopaminergic event, thus reversing the response to ARH stimulation. Finally, whether DA receptors were blocked or not by pimozide, d-, or l-butaclamol, activation of the ventromedial hypothalamic and periventricular nucleus regions suppressed episodic LH release, but did not increase LH secretion. This suggests that the region through which stimulation can inhibit, but not increase, LH release may extend in the hypothalamus to these two areas.

Catecholamine involvement in episodic luteinizing hormone release in adult ovariectomized rats.

This study was intended to examine the role of hypothalamic norepinephrine (HNE) and dopamine (HDA) in episodic luteinizing hormone (LH) release in adult ovariectomized rats. Unrestrained, unanesthetized rats with indwelling right atrial cannulae were bled continuously (30, 50, or 100 mul of whole blood/4-6 min for 3-4 hours), and the blood samples were analyzed for LH by radio-immunoassay. In other individual rats, changes in the hypothalamic levels of norepinephrine and dopamine after drug administration were determined by a radioisotopic-enzymatic catechol-O-methyl transferase assay. alpha-Methyl-p-tyrosine significantly decreased HNE and HDA concentrations but failed to alter episodic LH release. Two dopamine-beta-hydroxylase inhibitors (U-14,624 and FLA-63) caused marked reductions in HNE, small but not statistically significant increases in HDA, and an inhibition of episodic LH secretion. Apomorphine, a dopamine receptor stimulator, caused a transient (50-60 min) but marked inhibition of episodic LH release. Saline injection had no effect. Pimozide, a blocker of dopamine receptors, prevented the inhibitory effects seen following apomorphine. Although not studied in detail, pimozide alone did not appear to alter episodic LH secretion. These data suggest that in adult ovariectomized rats norepinephrine may be an excitatory neurotransmitter in the modulation of episodic LH release. The activation of dopamine receptors may be capable of inhibiting this release process. However, the apparent inability of pimozide alone to alter episodic LH discharge suggests that under physiological conditions dopamine may not play a role in the modulation of episodic LH secretion.

Electrical stimulation of the arcuate nucleus in ovariectomized rats inhibits episodic luteinizing hormone (LH) release but excites LH release after estrogen priming.

The effect of electrical stimulation of the arcuate nucleus of the hypothalamus (ARH) on the blood levels of luteinizing hormone (LH) was studied in ovariectomized (ovx) rats. Unanesthetized, unrestrained rats were bled continuously (30 or 50 mul whole blood/4-6 min) through indwelling right atrial cannulae for 1 1/2-2h prior to the onset of stimulation. The bleeding was continued for the following three hours, during which electrical stimulation was applied for two 60 min periods separated by a 60 min non-stimulation period. Whole blood was analyzed for LH by radioimmunoassay. Electrical stimulation of the ARH in ovx rats inhibited the episodic LH release characteristic of these animals. The inhibition was rapid in onset, beginning within minutes, and lasted for most if not all of the stimulation period or longer. The blood LH levels returned to control values prior to the second stimulation period during which the inhibitory response was again seen. Stimulation in other hypothalamic areas outside the ARH was generally ineffective, although repeatable inhibition of episodic LH release did occur in 2 of 3 rats stimulated in the periventricular nucleus. In a second study, ovx rats were primed with 5 mug estradiol benzoate/100 g body weight/day for 2 days prior to stimulation. In these rats, stimulation of the ARH or median eminence produced increases in LH release, whereas stimulation in other hypothalamic areas outside the ARH was ineffective. The parameters of electrical stimulation that produced increases in LH release were the same as those that caused the inhibition of episodic LH release. The results demonstrate that electrical stimulation of the ARH inhibits LH release in ovx rats, but increases LH release if the animals have been primed with estrogen.