Vaginal foreign body in the pediatric patient: A systematic review.

BACKGROUND: Vaginal foreign bodies represent a clinical and diagnostical challenge in pediatric gynecology. Several case reports, case series and retrospective studies have been published, highlighting rare or complex cases. A comprehensive systematic review is lacking. METHODS: Published English-language articles on vaginal foreign objects in patients aged 16 years and younger, with full-text availability were included. Articles on adult patients and patients with an object migrating from the abdominal cavity into the vagina were excluded. RESULTS: Out of the 215 screened articles 75 were included, comprising a total of 522 patients. The age ranged from 6 months to 16 years, with an average of 6 years and 3 months. The presenting symptoms were documented in 340 patients, with the two most common being vaginal bleeding (n = 172) and vaginal discharge (n = 134). Toilet paper or tissue was the most common object, in 155 out of 447 patients. Ultrasonography was the most utilized diagnostic method, with a sensitivity of 79.9 %. Radiography showed more false-negative than true-positive results, with a sensitivity of 33.3 %. Complications were reported in 35 patients. Evidence of sexual abuse was found in a small group of 16 patients. Vaginoscopy under sedation was the most frequently used therapeutic approach. CONCLUSION: A swift and accurate diagnosis is crucial, with clinical examination and ultrasonography playing pivotal roles. Vaginoscopy is the gold standard for definitive diagnosis and therapy. Attention should be given to a potential context of sexual abuse.

Intrauterine device (IUD) migration in cesarean delivery scar: What to do with the niche?

BACKGROUND: The presence of a niche after cesarean section is a common and mostly asymptomatic finding. However, it can cause symptoms or result in impaired fertility or obstetric complications in following pregnancies. At present there is no uniform consensus on when to treat and which way of repair is most suitable. The aim of this systematic review of literature was to provide an overview of current knowledge about cesarean scar niches and about the modalities of niche repair. METHODS: On the second of January 2019 Pubmed and Cochrane databases were searched for relevant studies published until December 2018. Search terms were cesarean scar defect, niche, niche repair. As combination key words `hysteroscopy ´, `laparoscopy ´ and `vaginal repair ´ were used. RESULTS: Eight articles were included in this review. The publications were very heterogeneous. Most of them stated that hysteroscopic niche repair with resection of the lower (and upper) rim is suggested for abnormal uterine bleeding. In symptomatic women who wish to conceive, different authors suggest laparoscopic niche repair with double layer closure to increase myometrial thickness. Also, one report on vaginal repair was included, none of the included patients had child wish. Nothing was reported on residual myometrial thickness after surgery. CONCLUSION: The current literature is not sufficient to draw strong conclusions on what to do about cesarean scar niches, yet, they justify the role of hysteroscopic as well as laparoscopic niche repair dependent on different pre- operative factors. We conclude that further large randomized controlled trials are necessary.

Leptin receptor antagonism of iNKT cell function: a novel strategy to combat multiple myeloma.

A hallmark of bone marrow changes with aging is the increase in adipocyte composition, but how this impacts development of multiple myeloma (MM) is unknown. Here, we report the role of the adipokine leptin as master regulator of anti-myeloma tumor immunity by modulating the invariant natural killer T (iNKT) cell function. A marked increase in serum leptin levels and leptin receptor (LR) expression on iNKT cells in MM patients and the 5T33 murine MM model was observed. MM cells and leptin synergistically counteracted anti-tumor functionality of both murine and human iNKT cells. In vivo blockade of LR signaling combined with iNKT stimulation resulted in superior anti-tumor protection. This was linked to persistent IFN-γ secretion upon repeated iNKT cell stimulation and a restoration of the dynamic antigen-induced motility arrest as observed by intravital microscopy, thereby showing alleviation of iNKT cell anergy. Overall our data reveal the LR axis as novel therapeutic target for checkpoint inhibition to treat MM.

USA300, A strain of community-associated methicillin-resistant Staphylococcus aureus, crossing Belgium's borders: outbreak of skin and soft tissue infections in a hospital in Belgium.

OBJECTIVE: to investigate an outbreak of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) USA300 in a hospital setting, and the effect of infection control measures. DESIGN: outbreak investigation and retrospective chart review. SETTING: local inpatient and outpatient clinic. PATIENTS: all patients with a history of skin and soft tissue infections with culture-confirmed methicillin-resistant Staphylococcus aureus USA 300 infection from September, 2014, through June, 2015. INTERVENTIONS: an outbreak investigation with a "search and destroy" policy was carried out. A review of infection control practices was conducted. Chart reviews were conducted to study the management and outcomes of the patients. Infection control measures included education and cultures of skin colonization sites (anterior nares, pharynx, perineum). Specific decontamination schemes for uncomplicated and complicated carriers were enforced. Separate decontamination schemes for neonates and children under 5 years of age were implemented. RESULTS: between September 2014 and June 2015, 12 clinical cases and six carriers were identified. Of the twelve clinical presentations with positive cultures, eight were children. Of the four patients who had a relapse, three were children (75%). After outbreak investigation and infection control measures have been implemented, three persistent carriers remained. A policy of periodic screening, consultation, and watchful waiting for skin infections was instituted for these patients. No new cases linked to the CA-MRSA outbreak have since been reported. CONCLUSION: we report the first Belgian outbreak of CA-MRSA USA300 in this article. A strict search and destroy strategy and continued surveillance are required in the management of CA-MRSA USA300.

Chorangiocarcinoma of the placenta: a case report and clinical review.

OBJECTIVE: We describe a case of chorangiocarcinoma, a complex lesion consisting of a trophoblastic proliferation within a chorangioma, presenting in a term placenta. MATERIALS AND METHODS: The lesion was diagnosed by ultrasound at a second trimester check-up after amniocentesis, performed because of increased combined risk at first trimester screening for trisomy 21. After uncomplicated vaginal delivery, a healthy child was born and the placenta was expelled spontaneously. RESULTS: Gross examination of the placenta showed a well-demarcated mass, bulging paracentrally from the fetal surface. Histology revealed a trophoblastic proliferation inside a chorangioma, consisting of multiple nodules with characters of focal multinucleation and pleomorphic cell nuclei, extensive central necrosis and high mitotic activity. Immunohistochemical staining showed strong intensity for hCG; Ki-67 (MIB-1) demonstrated a high proliferation index. Histopathological and immunohistochemical profile was compatible with a malignant trophoblastic proliferation. CONCLUSIONS: This is only the fifth reported case of so-called "chorangiocarcinoma" of the placenta (Table 1). However, histopathologically only one reported case was identical to ours. A proliferation of atypical trophoblast was observed inside a chorangioma, which formed as it were a shield around the trophoblast. No extravascular stromal invasion was present. Follow-up revealed no metastases, either in the mother or the child, up to 3 months after birth.

Drug design and identification of potent leads against mycobacterium tuberculosis thymidine monophosphate kinase.

Antiviral chemotherapy often relies on nucleoside analogues, which, once phophorylated by intracellular kinases, target viral polymerases impeding DNA synthesis. In contrast, nucleoside analogues are much less explored as antibacterial drugs. Thymidine monophosphate kinase from Mycobacterium tuberculosis (TMPKmt), which is essential to DNA replication, was selected as a promising target for the design of new inhibitors. This review describes stepwise modifications of the TMPKmt substrate, guided by the feedback of enzyme assays and crystallographic analysis to afford potent enzyme inhibitors some of which also exhibited antitubercular activity. More importantly, several of the reported thymidine analogues provided a deeper understanding of the structure and catalytic mechanism of this intriguing enzyme.

Abnormal first trimester screen in partial deletion of chromosome 6p21: a case-report.

In this case-report we describe a 21-year-old primigravida with an abnormal first trimester screen: combined risk for Downs Syndrome was 1:90. Karyotype revealed 46,XX,del(6)(p21). Termination with Cytotec was offered because of the risk of congenital malformations and subsequent abnormalities associated with deletions in chromosome 6p. As to our knowledge no report has been written about the prenatal diagnosis of deletions on the short arm of chromosome six based on the first trimester screen. By publishing our experience we want to create awareness. This case-report shows the importance of combining prenatal screening with the biochemical tests, instead of only measuring nuchal translucency. It also shows the need for full karyotyping when invasive prenatal testing is done.

Structure-aided design of inhibitors of Mycobacterium tuberculosis thymidylate kinase.

Antiviral chemotherapy often relies on nucleoside analogues, which, once phophorylated by intracellular kinases, target viral polymerases and preclude DNA synthesis. In contrast, common antibacterial drugs are rarely related to such compounds. In this work TMPKmt, which is essential to DNA replication, was selected as a promising target for inhibitor design. Our work demonstrates that judicious and stepwise modifications of the substrate structure of TMPKmt, guided by the feedback of the enzyme assays as well as by the enzyme's X-ray structure, proved a valuable approach to produce a submicromolar inhibitor of this target enzyme. This inhibitor was also capable to inhibit bacterial growth. Perhaps more importantly, some of the reported thymidine analogues also represent valuable tools to better understand the structure and the mechanism of this intriguing enzyme.

Development of a liquid chromatography/tandem mass spectrometry method for the quantification of fumonisin B1, B2 and B3 in cornflakes.

A liquid chromatography/tandem mass spectrometry (LC/MS/MS) method for the determination of fumonisin B1 (FB1), B2 (FB2) and B3 (FB3) in cornflakes is described. During method development, special attention was paid to the selection of a suitable internal standard (IS) in order to offer a good alternative for deuterated FB1. In this respect, the C12-sphinganine analogue (2S,3R)-2-aminododecane-1,3-diol was chosen because of its structural similarity to the fumonisin backbone and its chromatographic elution between the target analytes. For the extraction of the fumonisins from the cornflakes matrix, MeOH/H2O (adjusted to pH 4 with 0.1 M HCl; 70:30, v/v), ACN/MeOH/H(2)O (25:25:50, v/v/v) and acidified ACN/MeOH/H2O (25:25:50, v/v/v; pH 4) were evaluated. Preference was given to acidified MeOH/H2O (70:30, v/v) with mean recoveries (n=12) for FB1, FB2 and FB3 of, respectively, 84+/-10, 78+/-7 and 85+/-9%. Cleanup was performed using immunoaffinity columns (FumoniTest, VICAM). The chromatography was performed under isocratic conditions at a flow of 0.3 mL min-1 with a mobile phase consisting of ACN/H2O (60:40, v/v) containing 0.3% formic acid. The mass spectrometer was operated in the positive electrospray ionization (ESI+) mode using multiple reaction monitoring (MRM). An intralaboratory validation was conducted with fortified samples determining limits of detection (LOD), limits of quantification (LOQ), precision, trueness, specificity and measurement uncertainty. The LOD concentrations for FB1, FB2 and FB3 were 20, 7.5 and 12.5 microg/kg. The LOQs were 40 microg/kg for FB1, 15 microg/kg for FB2 and 25 microg/kg for FB3. The coefficients of variation (CVs) under repeatability conditions varied from 11 to 13% for FB1, from 9 to 14% for FB2 and from 7 to 10% for FB3. Under within-laboratory reproducibility conditions, the CVs ranged from 12 to 17% for FB1, from 9 to 16% for FB2 and from 7 to 13% for FB3. The percent bias for FB1 varied from -12 to -10%, while for FB2 and FB3 bias ranged, respectively, from -4 to -2% and from -12 to -5%. The expanded measurement uncertainties for FB1, FB2 and FB3 were, respectively, 19, 18 and 22%.

Fatality due to combined use of the designer drugs MDMA and PMA: a distribution study.

We present a fatal case involving the combined ingestion of amphetamine, 3,4-methylenedioxymethylamphetamine, 3,4-methylenedioxyamphetamine, and paramethoxyamphetamine. Various postmortem specimens (e.g., several blood samples, urine, and tissue samples) were analyzed to study the distribution of the compounds and their metabolites in the human body. Quantitation took place using liquid chromatography-sonic spray ionization-mass spectrometry after pretreatment with a liquid-liquid extraction. The medico-legal findings were compatible with a disseminated intravascular coagulation induced by hyperthermia caused by the simultaneous intake of the amphetamine analogues.

Color Doppler imaging is a valuable tool for the diagnosis and management of uterine vascular malformations.

OBJECTIVE: The aim of this study was to assess the spontaneous outcome of uterine vascular malformations detected with ultrasonography and color Doppler, and to investigate the predictive value of color Doppler imaging as to which patients require invasive treatment. METHODS: This was a prospective observational study conducted between January 1999 and February 2001 comprising all consecutive patients diagnosed with a uterine vascular malformation by ultrasonography and color Doppler imaging. Spectral analysis included measurement of flow velocities, pulsatility index (PI) and resistance index (RI). Close follow-up was arranged in all cases and the outcomes were recorded. RESULTS: A total of 30 consecutive patients with uterine vascular malformations were included in the study. Spectral analysis of the vessels in the vascular malformations within the myometrium and endometrium revealed the presence of a low-impedance and high-velocity flow. The average values for PI, RI, peak systolic velocity (PSV) and time-averaged maximum velocity (TAMXV) were 0.50, 0.38, 0.63 m/s and 0.46 m/s, respectively. Eight patients (27%) eventually required embolization of the uterine arteries and three of them had true arteriovenous malformations confirmed at angiography. PSV values of >/= 0.83 m/s were associated with higher probabilities of further treatment, such as an embolization, whereas no vascular malformation with a PSV value < 0.39 m/s required embolization. CONCLUSION: Conservative management is possible in more than two-thirds of patients presenting with uterine vascular malformations diagnosed by color Doppler sonography. Despite considerable overlap, PSV values appear to be useful in distinguishing between low- and high-risk patients.

Neoceptor concept based on molecular complementarity in GPCRs: a mutant adenosine A(3) receptor with selectively enhanced affinity for amine-modified nucleosides.

Adenosine A(3) receptors are of interest in the treatment of cardiac ischemia, inflammation, and neurodegenerative diseases. In an effort to create a unique receptor mutant that would be activated by tailor-made synthetic ligands, we mutated the human A(3) receptor at the site of a critical His residue in TM7, previously proposed to be involved in ligand recognition through interaction with the ribose moiety. The H272E mutant receptor displayed reduced affinity for most of the uncharged A(3) receptor agonists and antagonists examined. For example, the nonselective agonist 1a was 19-fold less potent at the mutant receptor than at the wild-type receptor. The introduction of an amino group on the ribose moiety of adenosine resulted in either equipotency or enhanced binding affinity at the H272E mutant relative to wild-type A(3) receptors, depending on the position of the amino group. 3'-Amino-3'-deoxyadenosine proved to be 7-fold more potent at the H272E mutant receptor than at the wild-type receptor, while the corresponding 2'- and 5'-amino analogues did not display significantly enhanced affinities. An 3'-amino-N(6)-iodobenzyl analogue showed only a small enhancement at the mutant (K(i) = 320 nM) vs wild-type receptors. The 3'-amino group was intended for a direct electrostatic interaction with the negatively charged ribose-binding region of the mutant receptor, yet molecular modeling did not support this notion. This design approach is an example of engineering the structure of mutant receptors to recognize synthetic ligands for which they are selectively matched on the basis of molecular complementarity between the mutant receptor and the ligand. We have termed such engineered receptors "neoceptors", since the ligand recognition profile of such mutant receptors need not correspond to the profile of the parent, native receptor.

An intracranial tumour--an uncommon cause of hyperemesis in pregnancy.

Brain tumours in pregnancy are rare. In this case vomiting and headache were the only signs. An assessment of the patient with vomiting in pregnancy to help reach a diagnosis when faced with vomiting in pregnancy is given. Following the diagnosis of a brain tumour during pregnancy, management should be tailored to the individual patient.

Sensitive gas chromatographic--mass spectrometric screening of acetylated benzodiazepines.

GC-MS screening conditions were developed for 15 low-dosed benzodiazepines, covering alprazolam, flunitrazepam, flurazepam, ketazolam, lorazepam and triazolam, and the corresponding metabolites alpha-hydroxyalprazolam, 4-hydroxyalprazolam; 7-aminoflunitrazepam, desmethylflunitrazepam, 7-aminodesmethylflunitrazepam; hydroxyethylflurazepam, N-desalkylflurazepam; oxazepam and alpha-hydroxytriazolam, respectively. Benzodiazepines are analyzed on a polydimethylsiloxane column in both the scan and the multiple ion monitoring modes using on-column injection to attain maximal sensitivity. The reactive compounds are acetylated with pyridine and acetic anhydride for 20 min. The derivatives are stable for at least 4 days. The relative standard deviation observed with standard compounds at the low nanogram-level ranged from 1.13 to 4.87% within-day and from 1.12 to 4.94% between-day. Unequivocal identification potential, high chromatographic resolution and sensitivity are combined with minimal thermal degradation. The presented screening conditions provide the basis for a unique routine screening method for low-dosed benzodiazepines with a broad polarity range.

Determination of the designer drugs 3, 4-methylenedioxymethamphetamine, 3,4-methylenedioxyethylamphetamine, and 3,4-methylenedioxyamphetamine with HPLC and fluorescence detection in whole blood, serum, vitreous humor, and urine.

BACKGROUND: The popular designer drugs 3, 4-methylenedioxymethamphetamine (MDMA) and 3, 4-methylenedioxyethylamphetamine (MDEA) can be determined in serum, whole blood, and urine, but also in vitreous humor. The latter matrix is interesting when dealing with decomposed bodies in a toxicological setting. METHODS: After extraction, chromatographic separation was achieved on a narrow-bore C(18) column by gradient elution with fluorometric detection; results were confirmed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: The method was linear over the range of 2-1000 microg/L for whole blood, serum, and vitreous humor, and 0.1-5 mg/L for urine. Extraction recoveries were >70%, imprecision (CV) was 2.5-19%, and analytical recoveries were 95.5-104.4%. The limit of detection (LOD) and the limit of quantification (LOQ) were 0.8 and 2 microg/L, respectively, for whole blood, serum, and vitreous humor, and 2.5 microg/L and 0.1 mg/L, respectively, for urine. Excellent correlations between the quantitative LC-fluorescence and LC-MS/MS results were obtained. We found the following concentrations in a thanatochemical distribution study in rabbits: in serum, 5.3-685 microg/L for MDMA and from the LOQ to 14.5 microg/L for 3, 4-methylenedioxyamphetamine (MDA); in whole blood, 19.7-710 microg/L for MDMA and from the LOQ to 17.8 microg/L for MDA; in vitreous humor, 12.1-97.8 microg/L for MDMA and from the LOQ to 3.86 microg/L for MDA. In routine toxicological urine samples, concentrations ranged from LOQ to 14.62 mg/L for MDA, from LOQ to 157 mg/L for MDMA, and from LOQ to 32.54 mg/L for MDEA. CONCLUSIONS: The HPLC method described is sensitive, specific, and suitable for the determination of MDMA, MDEA, and MDA in whole blood, serum, vitreous humor, and urine.

Synthesis and biological evaluation of ceramide analogues with substituted aromatic rings or an allylic fluoride in the sphingoid moiety.

The biological activity of synthetic ceramide analogues, having modified sphingoid and N-acyl chains, as well as fluorine substituents in the allylic position, was investigated in hippocampal neurons. Their influence on axonal growth was compared to that of C(6)-N-acyl analogues of natural ceramides. D-erythro-Ceramides with a phenyl group in the sphingoid moiety and a short N-acyl chain were able to reverse the inhibitory effect of fumonisin B(1) (FB(1)), but not of D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), on accelerated axonal growth in hippocampal neurons. Moreover, we demonstrated that a ceramide analogue with an aromatic ring in the sphingoid moiety is recognized as a substrate by glucosylceramide synthase, which suggests that the observed biological effects are mediated by activation of the ceramide analogue via glucosylation. Introduction of a methyl, pentyl, fluoro, or methoxy substituent in the para position of the phenyl ring in the sphingoid moiety yielded partly active compounds. Likewise, substitution of the benzene ring for a thienyl group did not abolish the ability to reverse the inhibition of accelerated axonal growth by FB(1). Both D-erythro- and L-threo-ceramide analogues, having an allylic fluorine substituent, partly reversed the FB(1) inhibition.

Polymer-assisted solution-phase synthesis of 2'-amido-2'-deoxyadenosine derivatives targeted at the NAD(+)-binding sites of parasite enzymes.

A polymer-assisted solution-phase (PASP) synthesis of lead structure analogues ready for biological testing without the demand for chromatographic purification is described. Carboxylic acids are coupled to the Kenner or Ellman safety catch linker, respectively, activated by methylation or cyanomethylation and subsequently transferred to the 2'-amino group of the 2'-amino-2'-deoxyadenosine scaffold (5). The chemoselective attack of weakly nucleophilic amino groups on the N-alkylated N-acyl sulfonamide linker allows for the synthesis of amides 6 in high yields without the need for protection of primary and secondary hydroxyl functions. Thus, the use of 4-sulfamylbenzoylaminomethyl polystyrene is reported for the construction of chemoselective polymer-supported acylating reagents instead of its known use as linker in solid-phase peptide or organic synthesis. This approach is demonstrated to be well suited to obtain 2'-amido-2'-deoxyadenosine derivatives 6 in parallel format. Biological evaluation of all compounds reported revealed no improvement over known lead structures.

Synthesis and apoptogenic activity of fluorinated ceramide and dihydroceramide analogues.

Short-chain 3-fluoro-(dihydro)ceramide analogues are synthesized from L-serine using diethylaminosulfur trifluoride (DAST) as fluorinating agent. The apoptogenic activity of these compounds was measured in three different cell lines and compared with their hydroxylated counterparts.