Spontaneous hemoperitoneum in a pregnancy with endometriosis.

The protective effect of pregnancy on endometriosis is well known, but complications related to the pregnant state, such as hemoperitoneum, uroperitoneum and bowel perforation may occur.

A first-principles study of pristine and Al-doped activated carbon interacting with 5-Fluorouracil anticancer drug.

The adsorption of the 5-Fluorouracil (5-FU) molecule on the pristine and Al-doped activated carbon (AC) was investigated by using the Vienna Ab-initio Simulation Package. It is found that the 5-FU molecule is only weakly adsorbed on the pristine AC with high adsorption energy and large surface distance. The adsorption of the 5-FU molecule on pristine AC is highly disfavored. In contrast, the molecule shows strong interactions with the Al-doped AC confirmed by the lesser adsorption energy, the charge transfers on the Al-modified zone and the significant changes in the DOS at the Fermi level. The results of our study suggest that the Al dopant increases the adsorption capacity of AC enhancing its interactions with polar atoms of the adsorbate, hence improving its adsorption properties.

S-p-bromobenzyl-glutathione cyclopentyl diester (BBGC) as novel therapeutic strategy to enhance trabectedin anti-tumor effect in soft tissue sarcoma preclinical models.

Trabectedin, approved for the treatment of soft tissue sarcoma (STS), interferes with cell division and genetic transcription processes. Due to its strong anti-tumor activity in only certain histotypes, several studies on trabectedin combinations are currently ongoing to improve its efficacy. In this study, we aimed to investigate novel potential therapeutic strategies to enhance the anti-tumor effect of trabectedin using integrated in silico, in vitro, and in vivo approaches. For in silico analysis, we screened two public datasets, GSEA M5190 and TCGA SARC. Fibrosarcoma, leiomyosarcoma, dedifferentiated, and myxoid liposarcoma cell lines were used for in vitro studies. For in vivo experiments, fibrosarcoma orthotopic murine model was developed. In silico analysis identified Glo1 as the only druggable target upregulated after trabectedin treatment and correlated with poor prognosis. The specific Glo1 inhibitor, S-p-bromobenzylglutathione cyclopentyl diester (BBGC), increased trabectedin cytotoxicity in STS cells, and restored drug sensitivity in myxoid liposarcoma cells resistant to trabectedin. Moreover, the combined treatment with BBGC and trabectedin had a synergistic antitumor effect in vivo without any additional toxicity to mice. Based on these results, we believe that BBGC warrants further investigation to evaluate its potential clinical use in combination with trabectedin.

Prognostic role of sentinel node biopsy in patients with thick melanoma: a meta-analysis.

OBJECTIVES: Sentinel lymph node (SLN) biopsy is a prognostic tool for patients with intermediate-thickness melanomas. However, controversies exist regarding its role in patients with thick melanomas (tumour thickness greater than 4.0 mm). We performed a meta-analysis to assess the prognostic role of SLN in thick melanoma in terms of disease-free survival (DFS) and overall survival (OS). METHODS: An electronic search in MEDLINE and EMBASE databases using the terms 'melanoma' and 'sentinel lymph node' was performed. Studies were considered if they reported data on thick melanoma and SLN biopsy results (positive and negative) and outcomes (DFS or OS). A proportion meta-analysis was used to calculate weighted means and an incidence rate ratio meta-analysis was used to compare outcomes according to SLN biopsy results. RESULTS: Nine studies were included. The weighted mean thickness of melanoma was 4.4 mm, 42% of patients had ulcerated melanoma. SLN was positive in 36% of the patients. Overall, DFS was 71% in patients with a negative SLN and 39% in patients with a positive SLN after a median follow-up of 33 months (IRR 1.83, 95% CI = 1.56-2.14). OS was 71% in patients with a negative SLN and 49% in patients with a positive SLN (IRR 1.44, 95% CI = 1.25-1.65). CONCLUSIONS: The results of this analysis showed that thick melanoma patients with a positive SLN had a significantly worse survival compared with SLN negative patients, thus supporting the routine adoption of SLN biopsy as a prognostic tool also for this subgroup of patients.

Evaluation of potential synergistic action of a combined treatment with alpha-methyl-prednisolone and taurine on the mdx mouse model of Duchenne muscular dystrophy.

AIMS: Glucocorticoids are the sole drugs clinically used in Duchenne muscular dystrophy, in spite of the relevant side effects. Combination of glucocorticoids with synergistic drugs may be one strategy to lower doses and control side effects, meanwhile providing wider control of the complex pathology. This study is a preclinical evaluation of the effect of a combined treatment of α-methyl-prednisolone (PDN) with taurine, a safe aminoacid with positive effects on some pathology-related events. METHODS: PDN (1 mg/kg/day i.p.) and taurine (1 g/kg/day orally) were administered either alone or in combination, for 4-8 weeks to male dystrophic mdx mice chronically exercised on a treadmill. Effects were assessed in vivo and ex vivo with a variety of methodological approaches. RESULTS: In vivo, each treatment significantly increased fore limb strength, a marked synergistic effect being observed with the combination PDN + taurine. Ex vivo, PDN + taurine completely restored the mechanical threshold, an electrophysiological index of calcium homeostasis, of extensor digitorum longus myofibres and the benefit was greater than for PDN alone. In parallel, the overactivity of voltage-independent cation channels in dystrophic myofibres was reduced. No effects were observed on plasma levels of creatine kinase, while lactate dehydrogenase was decreased by taurine and, to a minor extent, by PDN + taurine. A similar histology profile was observed in PDN and PDN + taurine-treated muscles. PDN + taurine significantly increased taurine level in fast-twitch muscle and brain, by high-pressure liquid chromatography analysis. CONCLUSIONS: The combination PDN + taurine has additive actions on in vivo and ex vivo functional end points, with less evident advantages on histopathology and biochemical markers of the disease.

Relevance of silica surface morphology in Ampyra adsorption. Insights from quantum chemical calculations.

Theoretical calculations are performed using the Vienna Ab-initio simulation package (VASP) to understand the mechanisms that control the adsorption of Ampyra drug on the different crystallographic planes of ß-cristobalite: the hydroxylated (111) and (100) surfaces. The Ampyra-silica interaction is most favored on the (100) surface where the entire ring of the molecule interacts with the surface while on the (111) face, lesser exchange and fewer non-polar atoms are involved. Calculations show that the interactions mainly occur at the interface between the Ampyra and the closest silanol groups, according to the formation of the H-bonding interactions. The results indicate that the H-bonds have an important influence on the adsorption of the Ampyra. In consequence, adsorption on the (111) surface is observed to a lesser extent than on the (100) surface according the smaller hydroxyl density.

Topical cidofovir for severe warts in a patient affected by AIDS and Hodgkin's lymphoma.

We describe a 42-year-old man with AIDS and Hodgkin's lymphoma whose severe and recalcitrant cutaneous warts resolved following treatment with local 1% cidofovir. Clinically significant improvements were observed in a two-week period of therapy. In advanced HIV disease complicated by additional haematological malignancy, cutaneous warts may be difficult to treat and present a challenge for the attending physicians. In similar clinical condition topical anti-human papillomavirus therapy may prove to be safe and curative.

Clinico-pathological features of the intradiaphragmatic bronchogenic cysts: report of a case and review of the literature.

Bronchogenic cysts represent congenital malformations deriving from an abnormal development of the primitive foregut during embryogenesis. These lesions are rarely found and they are most frequently localized in the mediastinum, or in lung parenchyma. Intramuscular localization is extremely rare, especially within the diaphragm. We report a case of a 54 year old man showing a large lobulated cystic lesion in the left hemidiaphragm. Complete surgery was performed and histological diagnosis of intradiaphragmatic bronchogenic cyst was made during surgery and confirmed after a total section analysis. Moreover we reviewed the other cases published in the English literature, including clinical, surgical and pathological data.

Primary signet-ring cell carcinoma of the uterine cervix with long term follow-up: case report.

BACKGROUND: The uterine cervix represents an exceptional localization of signet-ring cell adenocarcinoma (SRCA). Most commonly, endocervical tumors with such morphology are metastatic from the breast or gastrointestinal tract while primary pure or almost pure tumors are extremely rare. No previous case of primary pure endocervical SRCA with follow-up longer than three years has been found in the literature. CASE REPORT: The present report describes such a case of a 46-year-old woman without evidence of recurrence eight years after the diagnosis. The patient was referred to the Gynecology Department for persistent abnormal vaginal bleeding of three months duration. Specular examination and colposcopy revealed a cervical polypoid lesion occupying the posterior lip of the cervix and protruding from the external uterine orifice. A biopsy of the lesion was interpreted by the pathologist as SRCA. An extensive search for an extrapelvic primary cancer was undertaken but revealed no evidence of malignancy. The patient underwent radical hysterectomy with bilateral salpingo-oophorectomy and pelvic and paraaortic lymph node sampling for FIGO Stage 1B1 cervical cancer without any adjuvant chemo- or radiotherapy. The histological diagnosis showed neoplastic signet-ring cells confined in the head of the cervical polyps with minimal stromal infiltration. After surgery the patient underwent close followup including periodic cervicovaginal smears, bimanual vaginal examination, complete laboratory tests, ultrasound and abdominopelvic computed tomography. CONCLUSIONS: The prognostic relevance of primitive pure SRCA in the uterine cervix is unclear because of the relatively small number of cases. However the two early deaths out of six reported cases and the absence of follow-up longer than three years for the other affected patients, seem to suggest an aggressive behavior. The present case represents an exceptional long-term survival, probably related to an early diagnosis and a prominent polypoid growth of the neoplasia outside the uterus.

A systematic analysis of orphan cyclins reveals CNTD2 as a new oncogenic driver in lung cancer.

As lung cancer has increased to the most common cause of cancer death worldwide, prognostic biomarkers and effective targeted treatments remain lacking despite advances based on patients' stratification. Multiple core cyclins, best known as drivers of cell proliferation, are commonly deregulated in lung cancer where they may serve as oncogenes. The recent expansion of the cyclin family raises the question whether new members might play oncogenic roles as well. Here, we investigated the protein levels of eight atypical cyclins in lung cancer cell lines and formalin-fixed and paraffin-embedded (FFPE) human tumors, as well as their functional role in lung cancer cells. Of the new cyclins evaluated, CNTD2 was significantly overexpressed in lung cancer compared to adjacent normal tissue, and exhibited a predominant nuclear location. CNTD2 overexpression increased lung cancer cell viability, Ki-67 intensity and clonogenicity and promoted lung cancer cell migration. Accordingly, CNTD2 enhanced tumor growth in vivo on A549 xenograft models. Finally, the analysis of gene expression data revealed a high correlation between elevated levels of CNTD2 and decreased overall survival in lung cancer patients. Our results reveal CNTD2 as a new oncogenic driver in lung cancer, suggesting value as a prognostic biomarker and therapeutic target in this disease.

ß-Cristobalite (001) surface as 4-formaminoantipyrine adsorbent: First principle study of the effect on adsorption of surface modification.

Silica based materials find applications as excipients and particularly as drug delivery agents for pharmaceutical drugs. Their performance can be crucially affected by surface treatments, as it can modify the adsorption (and release) of these formulations. The role of surface modification on the features of 4-formaminoantipyrine (FAA) adsorbed on ß-cristobalite (001) surface is studied by means of simulations based on the Density Functional Theory (DFT). Starting from the results of FAA in interaction with a dehydroxylated surface; a fully hydroxylated surface and a functionalized surface with benzalkonium chloride (BC) surfactant have been added to study the configurational landscape. Calculations suggest that the trend for FAA preferential adsorption on silica surfaces is: dehydroxylated>hydroxylated>BC-functionalized. The potential for hydrogen bonding causes the main contribution to the bonding while dispersion forces present an additional contribution independently of whether the drug is hydrogen-bonded or BC-bonded to the surface. Adsorption takes mainly place through nitrogen atoms in the heterocyclic ring, the carbonyl and amine functional groups. Associated mode's shifts and concurrent changes in bond length are also observed showing accordance between electronic and geometrical structure results. BC surfactant reduces the number of formed H-bonds and lowers the attractive molecule-surface interaction being it useful to prevent particle agglomeration and could favor drug release in therapies that requires faster but controlled delivery.

Accumulation of deletions in human mitochondrial DNA during normal aging: analysis by quantitative PCR.

We have developed a quantitative PCR technique to measure the amount of a specific mitochondrial DNA deletion (delta mtDNA), the so-called 'common deletion', in human tissues. Using this method, we estimate that there is a 10,000-fold increase in this delta mtDNA species in muscle during the course of the normal human lifespan. The maximum amount of common deletion observed in aged muscle was approx. 0.1%. Tissues that turn-over slowly, such as skeletal muscle and heart, contained more delta mtDNA than more rapidly dividing tissues, such as liver, in agreement with studies performed by others.

Alteration of excitation-contraction coupling mechanism in extensor digitorum longus muscle fibres of dystrophic mdx mouse and potential efficacy of taurine.

No clear data is available about functional alterations in the calcium-dependent excitation-contraction (e-c) coupling mechanism of dystrophin-deficient muscle of mdx mice. By means of the intracellular microelectrode "point" voltage clamp method, we measured the voltage threshold for contraction (mechanical threshold; MT) in intact extensor digitorum longus (EDL) muscle fibres of dystrophic mdx mouse of two different ages: 8 - 12 weeks, during the active regeneration of hind limb muscles, and 6 - 8 months, when regeneration is complete. The EDL muscle fibres of 8 - 12-week-old wildtype animals had a more negative rheobase voltage (potential of equilibrium for contraction- and relaxation-related calcium movements) with respect to control mice of 6 - 8 months. However, at both ages, the EDL muscle fibres of mdx mice contracted at more negative potentials with respect to age-matched controls and had markedly slower time constants to reach the rheobase. The in vitro application of 60 mM taurine, whose normally high intracellular muscle levels play a role in e-c coupling, was without effect on 6 - 8-month-old wildtype EDL muscle, while it significantly ameliorated the MT of mdx mouse. HPLC determination of taurine content at 6 - 8 months showed a significant 140% rise of plasma taurine levels and a clear trend toward a decrease in amino acid levels in hind limb muscles, brain and heart, suggesting a tissue difficulty in retaining appropriate levels of the amino acid. The data is consistent with a permanent alteration of e-c coupling in mdx EDL muscle fibres. The alteration could be related to the proposed increase in intracellular calcium, and can be ameliorated by taurine, suggesting a potential therapeutic role of the amino acid.

Characterization of channel-forming activity in muscle biopsy from a porin-deficient human patient.

A bioptic specimen from the muscles of a patient suffering from severe myopathy was inspected for the presence of human porin 31HL. Western blotting suggested that the specimen was free of the most abundant eukaryotic porin 31HL (HVDAC1). The specimen was treated with detergent and the soluble protein fraction was passed through a dry hydroxyapatite column. The passthrough of this column was inspected for channel formation in artificial lipid-bilayer membranes. The channel observed under these conditions had a single-channel conductance of about 2.5 nS in 1 M KCl, was cation selective, and was found to be virtually voltage independent. Experiments with a control specimen from a healthy human being, without any indication for muscle myopathy, revealed the presence of the voltage-dependent porin 31HL in the sample. It is discussed whether the patient's bioptic specimen contained another human porin, which has not been studied to date in its natural environment.

Correlation of follicular fluid volume with oocyte morphology from follicles stimulated by human menopausal gonadotropin.

The maturity of human oocytes was correlated with corresponding follicular fluid volumes in 547 cycles stimulated with human menopausal gonadotropin, with or without the supplementation of follicle-stimulating hormone. Mature oocytes were found to be associated with larger follicles (average volume, 2.7 ml). Immature or degenerating oocytes were found to be associated with smaller follicles (average volume, 1.0 and 0.8 ml, respectively). Follicles without oocytes were generally quite small (average volume, 1.0 ml). We studied follicular fluid volumes associated with mature oocytes that were responsible for the establishment of pregnancy after single conceptus transfer. Analysis of these data demonstrated that the rate of spontaneous abortion was very high with conceptuses derived from smaller follicles, suggesting that oocytes from larger follicles may be of better quality.

Successful establishment of pregnancy by superovulation and intrauterine insemination with sperm recovered by a modified Hotchkiss procedure from a patient with retrograde ejaculation.

OBJECTIVE: To improve the quality of the sperm recovered from the bladder in a patient with retrograde ejaculation who already had failed to conceive after several attempts at IUI with sperm recovered by conventional techniques. SETTING: University Hospital. PATIENTS: A couple with male infertility due to retrograde ejaculation caused by the Zielke operation, a spinal fixation procedure performed to correct severe kyphoscoliosis. INTERVENTION: Superovulation and IUI of sperm recovered from the bladder using a modified Hotchkiss procedure involving the introduction into the bladder of Earle's balanced salt solution (EBSS) buffered with Hepes in sufficient quantity to bring the urinary pH and osmolarity to those of fresh ejaculate. MAIN OUTCOME MEASURES: Urine pH and osmolarity at baseline and after dilution with EBSS buffered with HEPES. Concentration, motility, and progression score of the sperm recovered from the bladder. RESULTS: Good sperm samples were achieved. Pregnancy was established when IUI was performed in association with superovulation induction. CONCLUSIONS: Determination of urine pH and osmolarity appears to be a useful method for choosing the ideal sperm recovery procedure. The modified Hotchkiss procedure described seems to be a promising alternative method for recovering sperm for artificial insemination.

Follicular atresia associated with concurrent initiation of gonadotropin-releasing hormone agonist and follicle-stimulating hormone for oocyte recruitment.

The ability of gonadotropin-releasing hormone agonist (GnRHa) to cause an initial stimulation of serum gonadotropins was used for follicular recruitment for in vitro fertilization (IVF) in 12 patients with a history of low estradiol (E2) response to conventional gonadotropin stimulation. Stimulation was initiated on cycle day 3 with concurrent administration of leuprolide (1 mg/day subcutaneously) and follicle stimulating hormone (FSH, 4 ampules/day intramuscularly). An 8-fold increase in basal serum luteinizing hormone (LH) and a 4-fold increase in basal serum FSH was seen on cycle day 4. Serum progesterone levels rose significantly by day 6. When compared to prior IVF attempts in these patients, the mean day of human chorionic gonadotropin administration and corresponding E2 levels were not significantly different. More atretic oocytes and fewer preovulatory oocytes were retrieved using GnRHa, and no increase was seen in total oocytes retrieved. One patient was canceled for poor E2 response, and one patient conceived, with a current viable pregnancy. It is concluded that concurrent initiation of leuprolide and FSH stimulation on cycle day 3 in patients with prior low response does not improve oocyte recruitment, and the high LH environment generated from initial stimulation of the agonist may be detrimental to normal oocyte development.