Cystic lymphoepithelial lesions of the parotid gland in HIV-1 infection

The benign cystic lymphoepithelial lesion (BLL) of the parotid gland is a rare disorder affecting HIV-1-infected patients. Here we describe the clinical and histopathological features of 10 cases of BLL, who presented to our observation between November 1992 and December 1996, before the combination antiretroviral therapy was introduced.     

Spigelian hernia: a case report and review of the literature

Spigelian hernia is a rare abdominal hernia that occurs through Spigelian aponeurosis. The Authors present a case of Spigelian hernia associated with narrowing of sigmoid colon and diverticular pathology. They also described historical background, surgical anatomy and etiopathogenesis of this hernia. By a remarkable revision of literature, they sum up epidemiology and clinical features of Spigelian hernia. Furthermore, they discuss diagnostic and therapeutic principles.     

Endogenous thiols and MRP transporters contribute to Hg2+ efflux in HgCl2-treated tubular MDCK cells

Tubular epithelium represents the primary target of mercuric ions (Hg(2+)) nephrotoxicity. Although widely investigated, the mechanisms of Hg(2+) cell uptake, accumulation and excretion all along the nephron remain largely unknown. In the present study, native distal tubular-derived Madin-Darby canine kidney (MDCK) cells exposed to subcytotoxic (micromolar) HgCl(2) concentrations were used for investigating specific mechanisms involved in the tubular response to toxic metals. Inductively coupled plasma-mass spectrometry (ICP-MS) was firstly used for assessing HgCl(2) solubility and then for quantifying Hg(2+) cell uptake. Exposed to HgCl(2), MDCK cells showed a rapid, but transient, Hg(2+) accumulation. The metallic cation was found to affect cell density and morphology, being these effects related to the dose and the time of exposure. In parallel, an Hg(2+)-induced up-regulation of endogenous MRP1 and MRP2 export pumps, a significant HgCl(2)-dependent induction of protective cellular thiols and an increase in the glutathione conjugates metabolism were also observed. The functional suppression of MRPs activity, obtained by MK-571 treatment, increased the Hg(2+) cell content and the sensitivity of MDCK cells to HgCl(2). Our results demonstrate that, in MDCK cells, inorganic Hg(2+) promotes the activation of specific detoxifying pathways that may, at least partly, depend on the activity of MRP transporters.     

Cumulus cell-oocyte complexes retrieved from antral follicles in IVM cycles: relationship between COCs morphology, gonadotropin priming and clinical outcome

Purpose

To assess retrospectively the developmental potential of different types of cumulus cell-oocyte complexes (COCs) derived from IVM cycles.

Methods

IVM cycles were performed in natural cycles or after HCG, FSH, or FSH/HCG priming. COCs recovered were morphologically characterized in different types: compact (CC) or expanded (EC) cumulus mass but including an immature oocyte, and expanded cumulus mass enclosing a mature oocyte (EC-MII). Embryo developmental competence was investigated analysing exclusively cycles in which all transferred embryos derived from the same COC category.

Results

Fertilization rates did not differ significantly. Significant differences in pregnancy rates (14.5 %, 10.0 % and 27.6 % in the CC, EC, and EC-MII categories, respectively) were observed. Likewise, significant differences in implantation rates (8.9 %, 6.3 % and 19.1 % in the CC, EC, and EC-MII categories, respectively) were found. Overall, priming with FSH/HCG had a beneficial effect on pregnancy and implantation rates, while no priming or HCG alone generated oocytes with poor competence.

Conclusions

In IVM cycles, morphological evaluation at the time of collection can predict the developmental ability of different COCs. FSH/HGC priming has a positive effect on oocyte competence.     

Novel Antimalarial Aminoquinolines: Heme Binding and Effects on Normal or Plasmodium falciparum-Parasitized Human Erythrocytes

Two new quinolizidinyl-alkyl derivatives of 7-chloro-4-aminoquinoline, named AM-1 and AP4b, which are highly effective in vitro against both the D10 (chloroquine [CQ] susceptible) and W2 (CQ resistant) strains of Plasmodium falciparum and in vivo in the rodent malaria model, have been studied for their ability to bind to and be internalized by normal or parasitized human red blood cells (RBC) and for their effects on RBC membrane stability. In addition, an analysis of the heme binding properties of these compounds and of their ability to inhibit beta-hematin formation in vitro has been performed. Binding of AM1 or AP4b to RBC is rapid, dose dependent, and linearly related to RBC density. Their accumulation in parasitized RBC (pRBC) is increased twofold compared to levels in normal RBC. Binding of AM1 or AP4b to both normal and pRBC is higher than that of CQ, in agreement with the lower pK_a and higher lipophilicity of the compounds. AM1 or AP4b is not hemolytic per se and is less hemolytic than CQ when hemolysis is accelerated (induced) by hematin. Moreover, AM-1 and AP4b bind heme with a stoichiometry of interaction similar to that of CQ (about 1:1.7) but with a lower affinity. They both inhibit dose dependently the formation of beta-hematin in vitro with a 50% inhibitory concentration comparable to that of CQ. Taken together, these results suggest that the antimalarial activity of AM1 or AP4b is likely due to inhibition of hemozoin formation and that the efficacy of these compounds against the CQ-resistant strains can be ascribed to their hydrophobicity and capacity to accumulate in the vacuolar lipid (elevated lipid accumulation ratios).Chloroquine (CQ) has been effectively used for decades as an antimalarial drug for its efficacy, safety, and stability but is now largely ineffective because of widespread parasite resistance. This has led to the necessity of utilizing artemisinin-based combination therapy as a first-line treatment for uncomplicated malaria (20). However, the recent reports of artemisinin-based combination therapy treatment failure in southeast Asia and the potential emergence of artemisinin resistance (26) indicate that the search for new drugs or new drug combinations is still highly necessary (40, 41). Quinoline-type antimalarials remain an attractive class of compounds because their mechanism of action and resistance are unrelated (14) and resistance has emerged very slowly over time. CQ and quinoline antimalarial drugs are thought to kill parasites by inhibiting the process of crystallization necessary to detoxify ferriprotoporphyrin IX (FP) into hemozoin (HZ) (5, 30, 34). This process is vital for Plasmodium falciparum and can be reproduced in vitro with hematin under acidic conditions, leading to the formation of beta-hematin (BH), a crystal product showing physicochemical properties identical to those of HZ (29).FP in the food vacuole of the parasite is considered the target of quinoline antimalarials (6, 15). The inhibition of HZ formation leads to the accumulation of free FP, potentially toxic for its prooxidant and lytic activities (7, 27). The resistance mechanism of CQ is based on the reduced drug accumulation at the site of action, the food vacuole, due to mutation of PfCRT (P. falciparum CQ resistance transporter) (5, 16, 39) and does not involve modification of the target.In the last few years, the research of our group has been directed to the study of new quinolizidinyl and quinolizidinyl-alkyl derivatives of 7-chloro-4-aminoquinoline (33). The terminal quinolizidine ring (octahydro-2H-quinolizine) confers basicity and lipophilicity to the molecules and prevents the metabolic oxidative dealkylation known to limit the usefulness of quinoline derivatives (28). Lead candidates have been obtained that are very stable and highly effective in vitro against both the D10 (CQ susceptible [CQ-S]) and W2 (CQ resistant [CQ-R]) strains of P. falciparum (33) and in vivo in the murine Plasmodium berghei model (23). Two of these compounds, named AM-1 and AP4b, have been selected for further characterization (Fig. ​(Fig.1):1): AM-1, a pure enantiomer, is semisynthetic and derives from l-lupinine, a natural alkaloid extracted from the seeds of Lupinus luteus; AP4b is synthetic and a racemate.Open in a separate windowFIG. 1.Molecular structures of the compounds used in the study.For the present article, we evaluated the binding of these compounds to human red blood cells (RBC), normal or parasitized by the P. falciparum strain D10 or W2. In addition, an analysis of the heme binding properties of these compounds and of their ability to affect RBC membrane stability and inhibit FP crystallization in vitro has been performed.     

Endocrinology: Evidence suggesting an additional control mechanism regulating episodic secretion of luteinzing hormone and follicle stimulating hormone in pre-pubertal children and post-menopausal women

The possible differential regulation of pulsatile follicle stimulatinghormone (FSH) and luteinizing hormone (LH) secretion in pre-pubertalchildren and in post-menopausal women was investigated. Childrenwere studied for 4 h and post-menopausal women for 6 h; bloodsamples were taken every 10 min. Post-menopausal women werestudied before and 21 days after administration of a singlei.m. dose of gonadotrophin-releasing hormone(GnRH) analogue.Eight post-menopausal women and 18 children (nine boys and ninegirls) were enrolled. The children were divided into two groups:A, at Tanner stages 0–1 (four boys and three girls); B,at Tanner stage 2–3 (five boys and six girls). PlasmaLH and FSH concentrations were determined using an immunofluorimetricassay. Time series were analysed and the specific concordance(SC) index was computed to determine the degree of concordancebetween episodes of LH and FSH secretion. While children ofgroup A had LH concentrations below the minimal detectable doseof 0.1 IU/I, group B showed measurable LH plasma concentrations(1.4 ± 0.3 IU/1, mean ± SEM). Plasma FSH concentrationswere detectable in both groups. Group A showed FSH plasma concentrationssignificantly lower than those of group B (0.75 ± 0.2and 1.95 ± 0.4 IU/1 respectively; P < 0.05), but FSHpulse frequency was higher in group A (P < 0.05). Childrenof group B showed significant concomitance of LH and FSH secretoryevents at time 0 (P < 0.05). Post-menopausal women showedboth LH and FSH plasma concentrations to be reduced after GnRHanalogue administration (P < 0.01), but only LH pulse frequency,not FSH pulse frequency, was significantly decreased (P <0.01). In these patients LH and FSH were co-secreted before(P < 0.05) but not after GnRH analogue administration. Inconclusion, this study confirms that during pre-puberty FSHis episodically secreted while LH is not. Following pubertaldevelopment, plasma LH concentrations increase and pulses ofthe two gonadotrophins are synchronized. The co-secretion ofLH and FSH is also observed in post-menopausal women, but notafter the single administration of a GnRH analogue. These datasuggest that FSH might have an additional stimulatory pathwaythat is independent of GnRH.