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This article, published in the journal "Ultrasound in Obstetrics & Gynecology," discusses the use of transvaginal sonographic (TVS) sliding bladder sign as a diagnostic tool for predicting vesicouterine adhesions. The study conducted at Amsterdam UMC included patients scheduled for gynecologic laparoscopic surgery for a benign disorder. The results showed that the absence of sliding bladder on TVS had a high positive predictive value for any adhesions and a high sensitivity for severe adhesions. The presence of sliding bladder had a high negative predictive value for severe adhesions and a high specificity for any adhesions. The study concludes that the sliding bladder sign using TVS is a reliable tool for predicting vesicouterine adhesions and recommends its routine use in preoperative planning. [Extracted from the article]

Unlabelled: The prerequisite for liver transplantation as a therapeutic option for inherited metabolic diseases should be that the enzyme defect, being responsible for the major clinical (hepatic and/or extra-hepatic) abnormalities, is localised in the liver. Furthermore, no adequate dietary or pharmacological treatment should be available or such treatment should have an unacceptable influence on the quality of life. We report an infant, who developed end-stage liver disease with persistent lactic acidaemia in his first months of life. Analysis of the mitochondrial respiratory chain in liver tissue revealed a combined partial complex I and IV deficiency. No extra-hepatic involvement could be demonstrated by careful screening for multiple organ involvement, including analysis of the mitochondrial respiratory chain in muscle tissue and cultured skin fibroblasts. The boy received a reduced size liver graft at the age of 8 months. He recovered successfully. Almost 5 years after transplantation he is in good clinical condition. No clinical or biochemical signs of any organ dysfunction have been demonstrated. The considerations on which basis it was decided that there was no contra-indication to perform liver transplantation in this patient are discussed.Conclusion: The possibility of a mitochondrial respiratory chain deficiency should be considered in liver disease of unknown origin prior to liver transplantation. Liver transplantation is a therapeutic option in mitochondrial respiratory chain deficiency-based end-stage liver disease provided that extra-hepatic involvement is carefully excluded. [ABSTRACT FROM AUTHOR]

Unlabelled: We studied the glucose-6-phosphatase (G6Pase) gene of 30 unrelated glycogen storage disease type Ia (GSD Ia) patients using single strand conformational polymorphism (SSCP) prior to automated sequencing of exons revealing an aberrant SSCP pattern. In all patients we could identify mutations on both alleles of the G6Pase gene, indicating that this method is a reliable procedure. A total of 14 different mutations were identified. R83C (16/60), 158delC (12/60), Q347X (7/60), R170X (6/60) and deltaF327 (4/60) were found most frequently. Nine other mutations accounted for the other 15 mutant alleles. Two DNA-based prenatal diagnoses were performed successfully. At present, 56 mutations in the G6Pase gene have been reported in 300 unrelated GSD Ia patients and an overview of these mutations is presented. Evidence for a clear genotype-phenotype correlation could be established neither from our data nor from those in the literature. With increased knowledge about the genetic basis of GSD Ia and GSD Ib and the high detection rate of mutations, it is our opinion that the diagnoses GSD Ia and GSD Ib can usually be based on clinical and biochemical abnormalities combined with mutation analysis instead of enzyme assays in liver tissue obtained by biopsy. A newly developed flowchart for the diagnosis of GSD I is presented.Conclusion: Increased knowledge of the genetic basis of glycogen storage disease type I provides a DNA-based diagnosis, prenatal DNA-based diagnosis in chorionic villus samples and carrier detection. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective Methods Results Conclusions Adhesions between the uterus, bladder and anterior abdominal wall are associated with clinical sequelae, including chronic pelvic pain and dyspareunia, and can also yield complications during surgery. The transvaginal sonographic (TVS) sliding bladder sign is a minimally invasive diagnostic tool to evaluate the presence of vesicouterine adhesions. This study aimed to determine the predictive value and intra‐ and interobserver variation of the TVS sliding bladder sign in the assessment of vesicouterine adhesions.This was a prospective observational double‐blind diagnostic accuracy study conducted at the Amsterdam University Medical Center. Patients scheduled for gynecological laparoscopic surgery for a benign disorder between January 2020 and December 2022 were included consecutively. All patients underwent preoperative TVS, including a dynamic sliding bladder sign examination in our outpatient clinic. Videoclips of the TVS scans were stored for offline assessment and used as an index test. The recordings of both TVS and laparoscopy were evaluated for diagnostic characteristics of vesicouterine adhesions by independent assessors, who were blinded to the clinical situation in addition to the laparoscopic findings when assessing recordings of TVS and vice versa. The presence of adhesions on laparoscopy was used as the reference standard. The positive predictive value (PPV), negative predictive value (NPV), specificity and sensitivity of the sliding bladder sign were calculated. In addition, inter‐ and intraobserver variability of the sliding bladder sign on TVS were assessed.Of 116 included women, 57 had a negative sliding bladder sign on TVS, while on laparoscopy, 51 women had mild and 28 had severe vesicouterine adhesions. A negative sliding bladder sign had a PPV of 94.7% (95% CI, 88.9–100%) for the presence of any vesicouterine adhesions, and a positive sliding bladder sign had a specificity of 91.9% (95% CI, 83.1–100%). For severe adhesions, the negative sliding bladder sign had a sensitivity of 89.3% (95% CI, 77.8–100%) and a positive sliding bladder sign had a NPV of 94.9% (95% CI, 89.3–100%). When using Cohen's kappa coefficient, inter‐ and intraobserver agreement between assessors was good.Sliding bladder sign evaluation using TVS is a reliable diagnostic tool for the prediction of vesicouterine adhesions on laparoscopy. A negative sliding bladder sign indicates the presence of vesicouterine adhesions, while a positive sliding bladder sign makes the presence of severe adhesions unlikely. Establishing vesicouterine adhesions by TVS may optimize preoperative planning, and can be used for future studies to evaluate the relationship between symptomatology and vesicouterine adhesions and, subsequently, the effect of adhesion‐prevention interventions. © 2024 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Background: Hypertensive disorders of pregnancy (HDP) are a primary cause of adverse maternal and neonatal outcomes worldwide. For women at risk of hypertensive complications, guidelines recommend frequent surveillance of blood pressure and signs of preeclampsia. Clinic visits range from every 2 weeks to several times a week. Given the wide ubiquity of smartphones and computers in most countries and a growing attention for self-management, digital technologies, including mobile health (mHealth), constitute a promising component of monitoring (self-measured) blood pressure during pregnancy. Currently, little is known about the experiences of women using such platforms and how mHealth can be aligned with their needs and preferences., Objective: The objectives were twofold: (1) to explore the experiences of Dutch women who had an increased risk of HDP with a blended care approach (mHealth combined with face-to-face care) for remote self-monitoring of blood pressure and preeclampsia symptoms and (2) to formulate recommendations for the use and integration of mHealth in clinical care., Methods: Alongside a prospective blended care study (SAFE@home study) that monitors pregnant women at increased risk of HPD with mHealth technology, a mixed methods study was conducted, including questionnaires (n=52) and interviews (n=11). Results were analyzed thematically., Results: Of the 4 themes, 2 themes were related to the technologies themselves (expectations, usability), and 2 themes were related to the interaction and use of mHealth (autonomy and responsibilities of patients, responsibilities of health care professionals). First, the digital platform met the expectations of patients, which contributed to user satisfaction. Second, the platform was considered user-friendly, and patients favored different moments and frequencies for measuring their blood pressure. Third, patient autonomy was mentioned in terms of increased insight about their own condition and being able to influence clinical decision making. Fourth, clinical expertise of health care professionals was considered essential to interpret the data, which translates to subsequent responsibilities for clinical management. Data from the questionnaires and interviews corresponded., Conclusions: Blended care using an mHealth tool to monitor blood pressure in pregnancy was positively evaluated by its users. Insights from participants led to 7 recommendations for designing and implementing similar interventions and to enhance future, morally sound use of digital technologies in clinical care., (©Karin Rolanda Jongsma, Josephus F M van den Heuvel, Jasmijn Rake, Annelien L Bredenoord, Mireille N Bekker. Originally published in JMIR mHealth and uHealth (http://mhealth.jmir.org), 04.08.2020.)

Objective: To investigate the incidence, the severity, and the course of neutropenia, neutrophil dysfunction, and inflammatory bowel disease (IBD) in glycogen storage disease (GSD) type Ib., Method: As part of a collaborative European Study on GSD type I, a retrospective registry was established in 12 European countries that included all patients with GSD-I who were known at the centers and were born from 1960 to 1995. Of a total of 288 patients with GSD-I, 57 who had GSD-Ib form the basis of this study., Results: Neutropenia (defined as an absolute neutrophil count <1 x 10(9)/L) was found in 54 patients. In 64% of the patients neutropenia was documented before the age of 1 year, but in 18% of the patients neutropenia was first noted between the ages of 6 and 9 years. Neutropenia was persistent in 5 patients and intermittent without any clear cyclical course in 45. Neutrophil function was investigated in 18 patients with neutropenia and was abnormal in all. Perioral infections were reported in 37 patients, perianal infections in 27 patients, and protracted diarrhea in 23 patients. Findings on colonoscopy and radiologic studies in 10 of 20 patients suspected to have IBD were abnormal in all. All patients with IBD, perioral infections, and perianal infections had neutropenia., Conclusions: Intermittent severe neutropenia is frequently found in patients with GSD-Ib. The study also indicates that IBD in GSD-Ib is underdiagnosed; up to 77% of the patients studied had evidence of IBD, all of whom had neutropenia. IBD was not detected in those with normal neutrophil counts. These findings support the notion that neutropenia and/or neutrophil dysfunction in GSD-Ib and IBD are causally related.

SR233377 is a novel thioxanthenone analogue that demonstrated solid tumor selectivity in vitro with activity confirmed in vivo against several murine tumors including those of colon, pancreas, and mammary origin. Its primary preclinical dose-limiting toxicities included myelosuppression and neurological toxicity. The neurological toxicity was acute and could be ameliorated in mice when the drug was administered as a 1-h infusion instead of rapid i.v. injection. As a result of its preclinical efficacy profile, SR233377 entered Phase I clinical investigation. The compound was administered i.v. over 2 h on day 1 repeated every 28 days. The starting dose was 33 mg/m2 (one-tenth the mouse LD10). Escalations continued to 445 mg/m2 (six escalations), where dose-limiting toxicity was observed. At this dose, acute ventricular arrhythmias, including one patient with torsades de pointes and transient cardiac arrest, occurred. Because this toxicity might have been related to the plasma peak, the protocol was amended to a 24-h infusion beginning at 225 mg/m2. With this dose, prolongation of the corrected QT interval (QTc) over the pretreatment levels resulted. Because prolonged QTc is a known forerunner to acute ventricular arrhythmias, clinical development of SR233377 was stopped. However, preclinical antitumor and toxicity studies with analogues are underway with hopes of identifying a new clinical candidate with similar antitumor effects that is devoid of cardiac toxic effects.

We identified a novel mutation (867delA) in the glucose-6-phosphatase gene of two siblings with glycogen storage disease type Ia. Although both siblings share the same mutations, their phenotype regarding adult height and hepatomegaly differs. In glycogen storage disease type Ia, substantial heterogeneity in phenotype is observed. So far, no evidence for a clear genotype-phenotype correlation has been found. Hum Mutat 15:381, 2000., (Copyright 2000 Wiley-Liss, Inc.)

A highly active and broadly active thioxanthone has been identified: N-[[1-[[2-(Diethylamino)ethyl]amino]-7-methoxy-9-oxo-9H-thioxanthen++ +-4-yl] methylformamide (SR271425, BCN326862, WIN71425). In preclinical testing against a variety of subcutaneously growing solid tumors, the following %T/C and Log10 tumor cell kill (LK) values were obtained: Panc-03 T/C = 0, 5/5 cures; Colon-38 (adv. stage) T/C = 0, 3/5 cures, 4.9 LK; Mam-16/C T/C = 0, 3.5 LK; Mam-17/0 T/C = 0, 2.8 LK; Colon-26 T/C = 0, 1/5 cures, 3.2 LK; Colon-51 T/C = 0, 2.7 LK; Panc-02 T/C = 0, 3.1 LK; B16 Melanoma T/C = 13%, 4.0 LK; Squamous Lung-LC12 (adv. stage) T/C = 14%, 4.9 LK; BG-1 human ovarian T/C = 16%, 1.3 LK; WSU-Brl human breast T/C = 25%, 0.8 LK. The agent was modestly active against doxorubicin (Adr)-resistant solid tumors: Mam-17/AdrT/C =23%, 0.8 LK; and Mam-16/C/Adr T/C = 25%, 1.0 LK, but retained substantial activity against a taxol-resistant tumor: Mam-16/C/taxol T/C = 3%, 2.4 LK. SR271425 was highly active against IV implanted leukemias, L1210 6.3 LK and AML1498 5.3 LK. The agent was equally active both by the IV and oral routes of administration, although requiring approximately 30% higher dose by the oral route. Based on its preclinical antitumor profile, it may be appropriate to evaluate SR271425 in clinical trials.

Second messenger calcium responses to the neuropeptide neurotensin and its non-peptide antagonist SR 48692 were studied in relation to the proliferation of pancreatic cancer cells. Neurotensin caused a transient increase in intracellular calcium in two pancreatic lines, MIA PaCa-2 and PANC-1, with EC50 values of 4.6 and 11.4 nM and peak calcium concentrations of 190% and 470% of basal levels, respectively. SR 48692 inhibited these calcium changes with an IC50 (at 25 nM neurotensin) of 4.9 and 4.1 nM in MIA PaCa-2 and PANC-1 cells, respectively. In MIA PaCa-2 cells, SR 48692 may act as an inverse agonist as it depressed basal calcium. SR 48692 inhibited growth of both MIA PaCa-2 and PANC-1 cells. Only in MIA PaCa-2 cells did neurotensin overcome this inhibition or stimulate proliferation. The results imply that, in MIA PaCa-2 cells, the neurotensin antagonist SR 48692 inhibits growth in a neurotensin receptor-mediated fashion.

Deficient activity of glucose-6-phosphatase (G6Pase) causes glycogen storage disease type Ia (GSD Ia). We analysed the G6Pase gene of 16 GSD Ia patients using single strand conformation polymorphism (SSCP) analysis prior to automated sequencing of exon(s) revealing an aberrant SSCP pattern. In all GSD Ia patients we were able to identify mutations on both alleles of the G6Pase gene, indicating that this method is a reliable procedure to identify mutations. Four novel mutations (175delGG, R170X, G266V and V338F) were identified.

Purpose: Tirapazamine (3-amino-1,2,4-benzotriazine 1,4-dioxide; SR 4233) is a bioreductive agent that exhibits relatively selective cytotoxicity towards cells under hypoxic conditions and can enhance the antitumor activity of many standard oncolytics. In the present study we examined the interaction between tirapazamine in vivo with paclitaxel and paraplatin in two- and three-way combination studies using the MV-522 human lung carcinoma xenograft model., Methods: Agents were administered as a single i.p. bolus, with tirapazamine being given 3 h prior to paclitaxel, paraplatin, or their combination. Tumor growth inhibition (TGI), final tumor weights, partial and complete responses, and time to tumor doubling were determined after drug administration., Results: Tirapazamine as a single agent was ineffective against this human lung tumor model. A substantial increase in TGI was seen in animals treated with the triple-agent regimen (tirapazamine-paclitaxel-paraplatin) compared to animals treated with double-agent regimens that did not include tirapazamine. The addition of tirapazamine to paclitaxel-paraplatin therapy resulted in a 50% complete response rate; there were no complete responses seen when only the paclitaxel-paraplatin combination was administered. Time to tumor doubling was also significantly improved with the addition of tirapazamine to the paclitaxel and paraplatin combinations. Tirapazamine did not increase the toxicity of paclitaxel, paraplatin, or their combinations as judged by its minimal impact on body weight and the fact that no toxic deaths were observed with tirapazamine-containing regimens., Conclusions: These results are important since recent studies have suggested that the combination of paclitaxel and paraplatin may be particularly active in patients with advanced stage non-small-cell lung cancer. Since tirapazamine can significantly improve efficacy, but does not appear to enhance the toxicity of paclitaxel and paraplatin, its evaluation in future clinical trials in combination with paclitaxel-paraplatin-based therapy appears warranted.

Thioxanthones are aromatic hydrocarbons with cytotoxic activity against several tumor models. Potential mechanisms of action may include DNA intercalation, inhibition of nucleic acid biosynthesis, and topoisomerase inhibition, as well as formation of intracellular DNA single strand breaks. Such a broad spectrum of expected antitumor activity makes this class of compounds particularly interesting and worth pursuing in clinical studies. SW 33377 (Win 33377, SR 233377) was so promising in vitro that it was taken into Phase I clinical trials for further evaluation. The compound had undesirable cardiac effects, so new analogs were sought that would have similar antitumor effects without the undesirable side effects. In the present study, two new analogs SW 68210 (WIN 68210), and SW 71425 (WIN 71425) are compared to the antiproliferative action of SW 33377 against a variety of freshly explanted human tumor specimens using an in vitro soft agar cloning system. All compounds were more effective with continuous exposure than 1 hour exposure and a concentration-response effect was evident with all compounds. SW 68210 with continuous exposure showed similar activity to SW 33377 at all concentrations. SW 71425 with continuous exposure was less effective at the lower concentrations but was nearly as effective at 10 microg/ml as the other two compounds and was highly effective at 50 microg/ml. At the 10 microg/ml concentration all compounds were similarly effective against breast, colon, non-small cell lung, and ovarian tumors. The two new analogs, SW 68210 and SW 71425 have activity similar to SW 33377 and are both likely candidates for further development.

Two new thioxanthenones, 183577 and 232759, have rekindled interest in the development of representatives from this class of structures as useful anticancer agents. Although the mechanism of action is unknown, both compounds demonstrated a similar spectrum of solid tumor selectivity. 232759 was selected for clinical development because it showed no hepatotoxicity in preliminary studies, whereas 183577 showed hepatotoxicity but only at the maximum tolerated dose (MTD). The limiting toxicity for the clinical candidate was myelosuppression in preliminary studies. Plasma and tissue drug levels, as well as protein binding, were studied in mice using optimal administration times at the MTD for each drug (for 183577, this was a 4-h infusion at 1350 mg/m2 and for 232759, it was a 5-min injection at 240 mg/m2), as well as at one-half the MTD for the clinical candidate. The drugs were 96-100% bound by plasma proteins. The peak drug concentrations, half-life, and area under the concentration-time curve in plasma for 183577 were 3483 ng/ml, 465 min, and 2018 microgram/ml. min, respectively. The peak drug concentration, half-life, and area under the concentration-time curve in plasma for 232759 were 5257 ng/ml, 44 min, and 276 microgram/ml. min, respectively, at the MTD and 2810 ng/ml, 40 min, and 110 microgram/ml. min at one-half the MTD. In all instances of simultaneous measurements, drug concentrations were equal or higher in tissues than they were in plasma. Unlike the plasma and kidney concentrations of 183577, the liver concentrations did not show a declining trend over the 8-h observation period. Declines in plasma, liver, kidney, and tumor levels of 232759 were detected over the 8-h observation period. The sustained high 183577 concentration in liver is believed to be responsible for its prolonged half-life and hepatotoxicity. Evidence for metabolism of the parent drugs was based on the finding of additional peaks on the high-pressure liquid chromatography tracings. Future studies will focus on identification and antitumor studies of these presumed metabolites in hopes of a better understanding of the solid tumor activity profiles and toxic effects of these compounds.

Historically, many new anticancer agents were first detected in a prescreen; usually consisting of a molecular/biochemical target or a cellular cytotoxicity assay. The agent then progressed to in vivo evaluation against transplanted human or mouse tumors. If the investigator had a large drug supply and ample resources, multiple tests were possible, with variations in tumor models, tumor and drug routes, dose-decrements, dose-schedules, number of groups, etc. However, in most large programs involving several hundred in vivo tests yearly, resource limitations and drug supply limitations have usually dictated a single trial. Under such restrictive conditions, we have implemented a flexible in vivo testing protocol. With this strategy, the tumor model is dictated by in vitro cellular sensitivity; drug route by water solubility (with water soluble agents injected intravenously); dosage decrement by drug supply, dose-schedule by toxicities encountered, etc. In this flexible design, many treatment parameters can be changed during the course of treatment (e.g., dose and schedule). The discovery of two active agents are presented (Cryptophycin-1, and Thioxanthone BCN 183577). Both were discovered by the intravenous route of administration. Both would have been missed if they were tested intraperitoneally, the usual drug route used in discovery protocols. It is also likely that they would have been missed with an easy to execute fixed protocol design, even if injected i.v.

We have examined the DNA cleavage site specificity of human type II DNA topoisomerase in the presence of each of five novel quinolone derivatives. Each quinolone derivative inhibited the human enzyme, inducing double-strand breaks with a four-base stagger. Break sites generated in response to each derivative had a predominance of C in the 3'-terminal position. Consensus sequences derived for cleavage sites induced by each derivative were strikingly similar, not only at the 3'-terminal position, but also at additional positions on either side of the broken phosphodiester bond. Analysis of these consensus sequences yielded information about possible interactions of specific substituents on the quinolone derivatives with DNA and/or topoisomerase. Comparison of the quinolone-based consensus sequences with those derived for cleavage sites generated by the human type II topoisomerase in the presence of either m-AMSA or VM-26, or in the absence of drug, provided compelling evidence that DNA cleavage sites include two domains: one which interacts with drug and a second, larger domain which interacts with topoisomerase.

1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-ox o-3-quinolinecarboxylic acid (1), a previously reported potent inhibitor of bacterial DNA gyrase, was found to be interactive with mammalian topoisomerase II (topo II). In a DNA-cleavage assay using topo II isolated from HeLa cells, 1 exhibited an EC50 value of 7.6 microM (VP-16; EC50 = 0.81 microM). A series of analogues modified at the 1-, 2-, 3-, 5-, and 7-positions of 1 were subsequently made and assessed for topo II inhibition. Compound 1 was considerably more potent than derivatives where the 1-substituent was alkyl, aryl, or H, or when N-c-C3H5 was replaced with S. The descarboxyl (i.e., 3-H) analogue had potency comparable to that of 1; when both these compounds were substituted at the 2-position with methyl or phenyl, an interesting relationship between activity and the conformation of the carboxyl group emerged. Upon replacement of the 5-H of 1 with NH2 or F, sustained potency was seen. No enhancement of activity was evident upon replacing the 7-substituent of 1 with other pyridinyl groups, 4-methyl-1-piperazinyl, or pyrrolidinyl groups; however, the 7-(4-hydroxyphenyl) analogue (CP-115,953) was 6-fold more potent than 1. The topo II inhibitory properties of 1 translated to modest in vitro cytotoxicity and in vivo activity versus P388.