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Abstract Cell migration through confining three dimensional (3D) topographies can lead to loss of nuclear envelope integrity, DNA damage, and genomic instability. Despite these detrimental phenomena, cells transiently exposed to confinement do not usually die. Whether this is also true for cells subjected to long‐term confinement remains unclear at present. To investigate this, photopatterning and microfluidics are employed to fabricate a high‐throughput device that circumvents limitations of previous cell confinement models and enables prolonged culture of single cells in microchannels with physiologically relevant length scales. The results of this study show that continuous exposure to tight confinement can trigger frequent nuclear envelope rupture events, which in turn promote P53 activation and cell apoptosis. Migrating cells eventually adapt to confinement and evade cell death by downregulating YAP activity. Reduced YAP activity, which is the consequence of confinement‐induced YAP1/2 translocation to the cytoplasm, suppresses the incidence of nuclear envelope rupture and abolishes P53‐mediated cell death. Cumulatively, this work establishes advanced, high‐throughput biomimetic models for better understanding cell behavior in health and disease, and underscores the critical role of topographical cues and mechanotransduction pathways in the regulation of cell life and death.

Seven physician organization think so, and they're joining forces to place universal coverage on the national agenda this election year. [ABSTRACT FROM AUTHOR]

As integrated organizations come apart, family physicians are finding a variety of ways to bail out. [ABSTRACT FROM AUTHOR]

Background: Globally, 20% of all newborns are born with low birth weight (LBW). There is, therefore, an urgent need to expedite the delivery of high-impact, evidenced-based, and low-cost interventions such as kangaroo mother care (KMC (defined as continuous skin-to-skin care) and exclusive breastfeeding for this vulnerable group., Methods: A multinational World Health Organization (WHO)-supported consortium created and tested the impact of locally-specific and globally-informed phases of KMC care on KMC uptake/scale-up across multiple sites. Here we report on the study of KMC predictors that is nested within Amhara's KMC implementation trial in Amhara, Ethiopia. We used multivariate logistic regression phases to identify diverse predictors of KMC, skin-to-skin contact, and exclusive breastfeeding at hospital discharge and day 28 of life., Results: We analysed data from 860 LBW newborns. At day 28, implementation period (adjusted odds ratio (aOR) = 3.2-5.0), hospital facility (aOR = 3.0-4.6), and having multiple births (aOR = 0.31) were the strongest predictors of effective KMC. Meanwhile, previous death of a newborn, type of health facility where delivery occurred, and previous LBW delivery were predictors of effective KMC at both time points. No single factor predicted KMC, skin-to-skin contact, and exclusive breastfeeding at all time points and across all implementation periods. Having multiple births was a negative predictor for skin-to-skin contact, while the implementation period and having older fathers (>29 years) were strong positive predictors for exclusive breastfeeding at both discharge and day 28. Mothers with a previous history of neonatal death and current skin-to-skin-care uptake strongly predicted exclusive breastfeeding uptake at both time points. At discharge, however, having a history of preterm birth and neonatal death strongly predicted exclusive breastfeeding uptake, while multiple current births, current very LBW newborns, and the use of standard binders decreased the likelihood of exclusive breastfeeding., Conclusions: To achieve the effective KMC coverage target of ≥80% in Ethiopia, KMC scale-up phases may have to consider the key predictors of KMC, EBF, and SSC to effectively target beneficiaries., Competing Interests: Disclosure of interest: The authors completed the ICMJE Disclosure of Interest Form (available upon request from the corresponding author) and disclose no relevant interests., (Copyright © 2024 by the Journal of Global Health. All rights reserved.)

Patients with chronic lymphocytic leukemia (CLL) respond well to initial treatment with the Bcell lymphoma 2 (BCL2) inhibitor venetoclax. Upon relapse, they often retain sensitivity to BCL2 targeting, but durability of response remains a concern. We hypothesize that targeting both BCL2 and B-cell lymphoma-extra large (BCLXL) will be a successful strategy to treat CLL, including for patients who relapse on venetoclax. To test this hypothesis, we conducted a pre-clinical investigation of LP-118, a highly potent inhibitor of BCL2 with moderate BCLXL inhibition to minimize platelet toxicity. This study demonstrated that LP-118 induces efficient BAK activation, cytochrome C release, and apoptosis in both venetoclax naïve and resistant CLL cells. Significantly, LP-118 is effective in cell lines expressing the BCL2 G101V mutation and in cells expressing BCLXL but lacking BCL2 dependence. Using an immunocompetent mouse model, Eμ-TCL1, LP-118 demonstrates low platelet toxicity, which hampered earlier BCLXL inhibitors. Finally, LP-118 in the RS4;11 and OSU-CLL xenograft models results in decreases in tumor burden and survival advantage, respectively. These results provide a mechanistic rationale for the evaluation of LP-118 for the treatment of venetoclax responsive and relapsed CLL.

Objective: To compare time to construct completion and leak testing between hand-sewn and skin staple anastomoses and enterotomies in cats., Study Design: Ex vivo, randomized study., Animals: Fresh feline cadavers (n = 20)., Methods: Jejunal segments (8 cm) were harvested and tested on the same day as euthanasia. From each cadaver, one segment was randomly assigned to control (C), hand-sewn enterotomy (HSE), and skin staple enterotomy (SSE) groups, and two segments were randomly assigned to hand-sewn anastomosis (HSA) and skin staple anastomosis (SSA) groups. Construct completion time, initial leak pressure (ILP), and maximum intraluminal pressure were compared. Leakage location was reported., Results: Mean time (s) ± SD was longer (p < .001) for HSA (317.0 ± 50.9) than SSA (160.8 ± 13.1) and for HSE (172.0 ± 36.5) than SSE (20.3 ± 5.0). ILP (mean ± SD) for C (600.0 mmHg ±0.0) was higher (p < .001) than all constructs. ILP (mean ± SD) for SSA (124.2 mmHg ±83.7) was not different (p = .49) than HSA (86.1 ± 51.9), but HSE (200.3 ± 114.7) was higher (p < .001) than SSE (32.2 ± 39.7). Immediate leakage from the center of enterotomy closure was observed in 7/20 SSE., Conclusions: HSA construct completion took twice as long as SSA with no difference in intraluminal pressures. Although HSE construct completion took 8x as long as SSE, HSE had higher intraluminal pressures., Clinical Significance: In cats, SSA may be an alternative to HSA for intestinal anastomosis, but SSE is not recommended as an alternative to HSE for intestinal enterotomy closure., (© 2024 American College of Veterinary Surgeons.)

Purpose: B-cell lymphoma-extra-large (BCL-xL) regulates apoptosis and is an attractive anticancer therapeutic target. However, BCL-xL inhibition also kills mature platelets, hampering clinical development. Using an innovative prodrug strategy, we have developed pelcitoclax (APG-1252), a potent, dual BCL-2 and BCL-xL inhibitor. Aims of this study were to characterize the antitumor activity and safety of pelcitoclax and explore its underlying mechanisms of action (MOA)., Patients and Methods: Cell line-derived xenograft and patient-derived xenograft (PDX) models were tested to evaluate antitumor activity and elucidate MOA. Subjects (N = 50) with metastatic small-cell lung cancer and other solid tumors received intravenous pelcitoclax once or twice weekly. Primary outcome measures were safety and tolerability; preliminary efficacy (responses every 2 cycles per RECIST version 1.1) represented a secondary endpoint., Results: Pelcitoclax exhibited strong BAX/BAK‒dependent and caspase-mediated antiproliferative and apoptogenic activity in various cancer cell lines. Consistent with cell-based apoptogenic activity, pelcitoclax disrupted BCL-xL:BIM and BCL-xL:PUMA complexes in lung and gastric cancer PDX models. Levels of BCL-xL complexes correlated with tumor growth inhibition by pelcitoclax. Combined with taxanes, pelcitoclax enhanced antitumor activity by downregulating antiapoptotic protein myeloid cell leukemia-1 (MCL-1). Importantly, pelcitoclax was well tolerated and demonstrated preliminary therapeutic efficacy, with overall response and disease control rates of 6.5% and 30.4%, respectively. Most common treatment-related adverse events included transaminase elevations and reduced platelets that were less frequent with a once-weekly schedule., Conclusions: Our data demonstrate that pelcitoclax has antitumor activity and is well tolerated, supporting its further clinical development for human solid tumors, particularly combined with agents that downregulate MCL-1., (©2023 American Association for Cancer Research.)

Despite recent advances in the therapy of diffuse large B-cell lymphoma (DLBCL), many patients are still not cured. Therefore, new therapeutic strategies are needed. The anti-apoptotic B-cell lymphoma 2 (BCL2) gene is commonly dysregulated in DLBCL due to various mechanisms such as chromosomal translocation t(14;18)(q32;q21) and copy number alterations; however, targeting BCL-2 with the selective inhibitor, venetoclax, led to response in only a minority of patients. Thus, we sought to identify a rational combination partner of venetoclax to improve its activity against DLBCL cells. Utilizing a functional assay, dynamic BH3 profiling, we found that the DNA hypomethylating agent decitabine increased mitochondrial apoptotic priming and BCL-2 dependence in DLBCL cells. RNA-sequencing analysis revealed that decitabine suppressed the pro-survival PI3K-AKT pathway and altered the mitochondria membrane composition in DLBCL cell lines. Additionally, it induced a DNA damage response and increased BAX and BAK activities. The combination of decitabine and venetoclax synergistically suppressed proliferation of DLBCL cells both in vitro and in vivo in a DLBCL cell line-derived xenograft mouse model. Our study suggests that decitabine plus venetoclax is a promising combination to explore clinically in DLBCL.

The B cell leukemia/lymphoma 2 (BCL-2) inhibitor venetoclax is effective in chronic lymphocytic leukemia (CLL); however, resistance may develop over time. Other lymphoid malignancies such as diffuse large B cell lymphoma (DLBCL) are frequently intrinsically resistant to venetoclax. Although genomic resistance mechanisms such as BCL2 mutations have been described, this probably only explains a subset of resistant cases. Using 2 complementary functional precision medicine techniques - BH3 profiling and high-throughput kinase activity mapping - we found that hyperphosphorylation of BCL-2 family proteins, including antiapoptotic myeloid leukemia 1 (MCL-1) and BCL-2 and proapoptotic BCL-2 agonist of cell death (BAD) and BCL-2 associated X, apoptosis regulator (BAX), underlies functional mechanisms of both intrinsic and acquired resistance to venetoclax in CLL and DLBCL. Additionally, we provide evidence that antiapoptotic BCL-2 family protein phosphorylation altered the apoptotic protein interactome, thereby changing the profile of functional dependence on these prosurvival proteins. Targeting BCL-2 family protein phosphorylation with phosphatase-activating drugs rewired these dependencies, thus restoring sensitivity to venetoclax in a panel of venetoclax-resistant lymphoid cell lines, a resistant mouse model, and in paired patient samples before venetoclax treatment and at the time of progression.

Purpose: This global phase I trial investigated the safety, efficacy, pharmacokinetics, and pharmacodynamics of lisaftoclax (APG-2575), a novel, orally active, potent selective B-cell lymphoma 2 (BCL-2) inhibitor, in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (R/R CLL/SLL) and other hematologic malignancies (HMs)., Patients and Methods: Maximum tolerated dose (MTD) and recommended phase II dose were evaluated. Outcome measures were safety and tolerability (primary) and pharmacokinetic variables and antitumor effects (secondary). Pharmacodynamics in patient tumor cells were explored., Results: Among 52 patients receiving lisaftoclax, MTD was not reached. Treatment-emergent adverse events (TEAEs) included diarrhea (48.1%), fatigue (34.6%), nausea (30.8%), anemia and thrombocytopenia (28.8% each), neutropenia (26.9%), constipation (25.0%), vomiting (23.1%), headache (21.2%), peripheral edema and hypokalemia (17.3% each), and arthralgia (15.4%). Grade ≥ 3 hematologic TEAEs included neutropenia (21.2%), thrombocytopenia (13.5%), and anemia (9.6%), none resulting in treatment discontinuation. Clinical pharmacokinetic and pharmacodynamic results demonstrated that lisaftoclax had a limited plasma residence and systemic exposure and elicited rapid clearance of malignant cells. With a median treatment of 15 (range, 6-43) cycles, 14 of 22 efficacy-evaluable patients with R/R CLL/SLL experienced partial responses, for an objective response rate of 63.6% and median time to response of 2 (range, 2-8) cycles., Conclusions: Lisaftoclax was well tolerated, with no evidence of tumor lysis syndrome. Dose-limiting toxicity was not reached at the highest dose level. Lisaftoclax has a unique pharmacokinetic profile compatible with a potentially more convenient daily (vs. weekly) dose ramp-up schedule and induced rapid clinical responses in patients with CLL/SLL, warranting continued clinical investigation., (©2023 American Association for Cancer Research.)

This study investigated ibrutinib plus obinutuzumab in relapsed/refractory CLL, evaluating tolerability of 3 sequencing regimens as well as overall safety and efficacy. Fifty-two patients were initially randomized 1:1:1 to receive either obinutuzumab 1 month before ibrutinib initiation, ibrutinib 1 month prior to obinutuzumab initiation, or to start both drugs concomitantly. Higher rates of infusion-related reactions were observed with the first sequence, and only the latter 2 cohorts were expanded. Grade 4 hematologic toxicity was uncommon, and notable all-grade non-hematologic toxicities included bruising (58%), hypertension (46%), arthralgia (38%), diarrhea (37%), transaminitis (35%), atrial fibrillation (21%), and serious infection (17%). Best overall response rate was 96% (including 40% CR and 56% PR). Best rates of undetectable minimal residual disease in peripheral blood and bone marrow were 27% and 19%, respectively. With a median follow-up of 41.5 months, four-year progression-free and overall survival rates are 74% and 93%, respectively. Correlative studies demonstrated that serum CCL4 and CXCL13 levels were associated with clinical response, and BH3 profiling revealed increased BCL-2 and BCL-xL dependence in CLL cells from patients on treatment. Overall, ibrutinib plus obinutuzumab was highly active, with a manageable safety profile, supporting further investigation of this type of approach in relapsed/refractory CLL., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Conventional therapies for patients with T-cell prolymphocytic leukemia (T-PLL), such as cytotoxic chemotherapy and alemtuzumab, have limited efficacy and considerable toxicity. Several novel agent classes have demonstrated preclinical activity in T-PLL, including inhibitors of the JAK/STAT and T-cell receptor pathways, as well as histone deacetylase (HDAC) inhibitors. Recently, the BCL-2 inhibitor venetoclax also showed some clinical activity in T-PLL. We sought to characterize functional apoptotic dependencies in T-PLL to identify a novel combination therapy in this disease. Twenty-four samples from patients with primary T-PLL were studied by using BH3 profiling, a functional assay to assess the propensity of a cell to undergo apoptosis (priming) and the relative dependence of a cell on different antiapoptotic proteins. Primary T-PLL cells had a relatively low level of priming for apoptosis and predominantly depended on BCL-2 and MCL-1 proteins for survival. Selective pharmacologic inhibition of BCL-2 or MCL-1 induced cell death in primary T-PLL cells. Targeting the JAK/STAT pathway with the JAK1/2 inhibitor ruxolitinib or HDAC with belinostat both independently increased dependence on BCL-2 but not MCL-1, thereby sensitizing T-PLL cells to venetoclax. Based on these results, we treated 2 patients with refractory T-PLL with a combination of venetoclax and ruxolitinib. We observed a deep response in JAK3-mutated T-PLL and a stabilization of the nonmutated disease. Our functional, precision-medicine-based approach identified inhibitors of HDAC and the JAK/STAT pathway as promising combination partners for venetoclax, warranting a clinical exploration of such combinations in T-PLL., (© 2021 by The American Society of Hematology.)

Introduction: Microglia is the resident tissue macrophages of the central nervous system. Prolonged microglial activation often occurs after traumatic brain injury and is associated with deteriorating neurocognitive outcomes. Resolution of microglial activation is associated with limited tissue loss and improved neurocognitive outcomes. Limiting the prolonged pro-inflammatory response and the associated secondary tissue injury provides the rationale and scientific premise for considering microglia as a therapeutic target., Areas Covered: In this review, we discuss markers of microglial activation, such as immunophenotype and microglial response to injury, including cytokine/chemokine release, free radical formation, morphology, phagocytosis, and metabolic shifts. We compare the origin and role in neuroinflammation of microglia and monocytes/macrophages. We review potential therapeutic targets to shift microglial polarization. Finally, we review the effect of cell therapy on microglia., Expert Opinion: Dysregulated microglial activation after neurologic injury, such as traumatic brain injury, can worsen tissue damage and functional outcomes. There are potential targets in microglia to attenuate this activation, such as proteins and molecules that regulate microglia polarization. Cellular therapeutics that limit, but do not eliminate, the inflammatory response have improved outcomes in animal models by reducing pro-inflammatory microglial activation via secondary signaling. These findings have been replicated in early phase clinical trials.

[Figure: see text].

Objectives: Written text contains verbal immediacy cues-word form or grammatical cues that indicate positive attitude or liking towards an object, action, or person. We asked if adults with moderate-severe traumatic brain injury (TBI) would respond to these cues, given evidence of TBI-related social communication impairments., Methods: Sixty-nine adults with TBI and 74 healthy comparison (HC) peers read pairs of sentences containing different types of immediacy cues (e.g., speaker A said "these Canadians" vs. B said "those Canadians.") and identified which speaker (A or B) had a more positive attitude towards the underlined entity (Task 1); and pairs of sentences comprised of a context sentence (e.g., Fred is asked, "Did you visit Joan and Sue?") and a statement sentence (Fred says, "I visited Sue and Joan.") and were asked to indicate how much Fred liked or disliked the underlined words (Task 2)., Results: HC group scores were significantly higher on Task 1, indicating more sensitivity to cues. On Task 2, TBI and HC group ratings differed across cue types and immediacy types, and the TBI group appeared to have less sensitivity to these cues., Conclusions: Findings suggest that TBI-related impairments may reduce sensitivity to subtle social cues in text.

Bone marrow derived multipotent mesenchymal stem cells (MSCs) have the potential to differentiate into bone, cartilage, fat, and muscle cells and are being investigated for their utility in cell-based therapies. Stem cell transplantation therapy represents a novel and innovative approach with the promise to restore function to diseased or damaged heart muscle. Transplanted MSCs are expected to engraft, differentiate, and remodel in response to the surrounding cardiac microenvironment significantly changing the therapeutic approach for heart disease. Quantum Dots (QDs) offer an alternative to organic dyes and fluorescent proteins to label and track cells in vitro and in vivo. Here, we describe in vitro QD labeling of MSCs, MSC integration in a cardiomyocyte co-culture microenvironment, and a fluorescent recovery after photobleaching (FRAP) technique to assess functional cell-cell communication. FRAP techniques establish an optical record of dynamic cellular interactions with high spatial and temporal resolution and can be used to successfully evaluate dynamic changes in cellular coupling in multicellular preparations.

Verbal play, or the playful manipulation of elements of language, is a pervasive component of social interaction, serving important interpersonal functions. We analyzed verbal play in the interactional discourse of ten healthy younger pairs and ten healthy older pairs as they completed a collaborative referencing task. A total of 1,893 verbal play episodes were coded. While there were no group differences in verbal play frequency, age-related differences in the quality and function of these episodes emerged. While older participants engaged in more complex, extended, and reciprocal episodes that supported the social nature of communicative interactions (e.g., teasing), younger participants were more likely to engage in verbal play episodes for the purpose of successful task completion. Despite these age-related variations in the deployment of verbal play, verbal play is a robust interactional discourse resource in healthy aging, highlighting an element of human cognition that does not appear to decline with age.

A new instrument is presented for investigating interactions between individual colloidal particles, emulsion droplets, foam bubbles, and other particle-particle or particle-surface interactions. Measurement capabilities are demonstrated by measuring interfacial tension, coalescence time for emulsion droplets, adhesion between giant multilamellar vesicles, and adhesion between model food emulsion particles. The magnitude of the interaction force that can be measured or imposed, ranges from 1 nN to 1 mN for particles ranging in size from 10 μm to 1 mm in diameter.

Mesenchymal stem cells (MSCs) are multipotent cells with the potential to differentiate into bone, -cartilage, adipose, and muscle cells. Adult derived MSCs are being actively investigated because of their potential to be utilized for therapeutic cell-based transplantation. Methods to track MSCs in vivo are -limited, preventing long-term functional studies of transplanted cells. Quantum Dots (QDs) offer an alternative to organic dyes and fluorescent proteins to label and track cells in vitro and in vivo. Nanoparticles are resistant to chemical and metabolic degradation, demonstrating long-term photostability. Here, we describe the technique to label MSCs with QDs and demonstrate intracellular QD distribution in the labeled MSCs with laser scanning confocal fluorescent microscopy.

HIV-infected infants and young children are at high risk of serious illness and death. Morbidity and mortality can be greatly reduced through early infant diagnosis (EID) of HIV and timely initiation of antiretroviral therapy (ART). Despite global efforts to scale-up of EID and infant ART, uptake of these services in resource poor, high HIV burden countries remain low. We conducted a qualitative study of 59 HIV-infected women to identify and explore barriers women face in accessing HIV testing and care for their infants. To capture different perspectives, we included mothers whose infants were known positive (n=9) or known negative (n=14), mothers of infants with unknown HIV status (n=13), and pregnant HIV-infected women (n=20). Five important themes emerged: lack of knowledge regarding EID and infant ART, the perception of health care workers as authority figures, fear of disclosure of own and/or child's HIV status, lack of psychosocial support, and intent to shorten the life of the child. A complex array of cultural, economic, and psychosocial factors creates barriers for HIV-infected women to participate in early infant HIV testing and care programs. For optimal impact of EID and infant ART, reasons for poor uptake should be better understood and addressed in a culturally sensitive manner.

We present monozygotic twins discordant for the autosomal dominant disorder neurofibromatosis type 1 (NF1). The affected twin was diagnosed with NF1 at age 12, based upon accepted clinical criteria for the disorder. Both twins were re-examined at ages 35 and 57, at which times the unaffected twin continued to show no clinical manifestations of NF1. Short tandem repeat marker (STR) genotyping at 10 loci on chromosome 17 and 10 additional loci dispersed across the genome revealed identical genotypes for the twins, confirming their monozygosity. The affected twin has three children, two of whom also have NF1, while the unaffected twin has two children, both unaffected. Using lymphoblastoid, fibroblast, and buccal cell samples collected from both twins and from other family members in three generations, we discovered a pathogenic nonsense mutation in exon 40 of the NF1 gene. This mutation was found in all cell samples from the affected twin and her affected daughter, and in lymphoblastoid and buccal cells but not fibroblasts from the unaffected twin. We also found a novel non-synonymous change in exon 16 of the NF1 gene that was transmitted from the unaffected mother to both twins and co-segregated with the pathogenic mutation in the ensuing generation. All cells from the twins were heterozygous for this apparent exon 16 polymorphism and for single nucleotide polymorphisms (SNPs) within 2.5 kb flanking the site of the exon 40 nonsense mutation. This suggests that the NF1 gene of the unaffected twin differed in the respective lymphoblastoid cells and fibroblasts only at the mutation site itself, making post-zygotic mutation leading to mosaicism the most likely mechanism of phenotypic discordance. Although the unaffected twin is a mosaic, the distribution of the mutant allele among different cells and tissues appears to be insufficient to cause overt clinical manifestations of NF1., ((c) 2010 Wiley-Liss, Inc.)

Background: Mesenchymal stem cells (MSCs) are multipotent cells with the potential to differentiate into bone, cartilage, fat and muscle cells and are being investigated for their utility in cell-based transplantation therapy. Yet, adequate methods to track transplanted MSCs in vivo are limited, precluding functional studies. Quantum Dots (QDs) offer an alternative to organic dyes and fluorescent proteins to label and track cells in vitro and in vivo. These nanoparticles are resistant to chemical and metabolic degradation, demonstrating long term photostability. Here, we investigate the cytotoxic effects of in vitro QD labeling on MSC proliferation and differentiation and use as a cell label in a cardiomyocyte co-culture., Results: A dose-response to QDs in rat bone marrow MSCs was assessed in Control (no-QDs), Low concentration (LC, 5 nmol/L) and High concentration (HC, 20 nmol/L) groups. QD yield and retention, MSC survival, proinflammatory cytokines, proliferation and DNA damage were evaluated in MSCs, 24 -120 hrs post QD labeling. In addition, functional integration of QD labeled MSCs in an in vitro cardiomyocyte co-culture was assessed. A dose-dependent effect was measured with increased yield in HC vs. LC labeled MSCs (93 +/- 3% vs. 50% +/- 15%, p < 0.05), with a larger number of QD aggregates per cell in HC vs. LC MSCs at each time point (p < 0.05). At 24 hrs >90% of QD labeled cells were viable in all groups, however, at 120 hrs increased apoptosis was measured in HC vs. Control MSCs (7.2% +/- 2.7% vs. 0.5% +/- 0.4%, p < 0.05). MCP-1 and IL-6 levels doubled in HC MSCs when measured 24 hrs after QD labeling. No change in MSC proliferation or DNA damage was observed in QD labeled MSCs at 24, 72 and 120 hrs post labeling. Finally, in a cardiomyocyte co-culture QD labeled MSCs were easy to locate and formed functional cell-to-cell couplings, assessed by dye diffusion., Conclusion: Fluorescent QDs label MSC effectively in an in vitro co-culture model. QDs are easy to use, show a high yield and survival rate with minimal cytotoxic effects. Dose-dependent effects suggest limiting MSC QD exposure.

Background: Cellular cardiomyoplasty is emerging as a potentially novel therapeutic option for heart failure and typically involves direct intramyocardial injection of donor cells into a beating heart. Yet, limited rates of cell engraftment remain an obstacle to be overcome before cell therapy is fully recognized. Mechanical and biological mechanisms may account for observed donor cell loss. This study examines acute mechanical loss during intramyocardial injections in beating and arrested hearts., Materials and Methods: A porcine cardiopulmonary bypass model was used. Animals underwent either beating (n = 5) or arrested (n = 5) intramyocardial injections into the left ventricle. Fluorescent microspheres were used in lieu of cells because they are biologically inert. Thirty minutes after delivery, animals were euthanized. Microspheres in cardiac and peripheral tissues were quantified using flow cytometry., Results: Approximately 10% of microspheres were retained within the site of injection in both groups. There was no statistical difference between microsphere retention rates in either the beating or the arrested heart group. Microspheres were found in peripheral organs, pericardial fluid, and the delivery device., Conclusions: The majority of microspheres injected intramyocardially are lost in both beating and arrested hearts. Cardiac standstill does not enhance microsphere retention. Possible mechanisms include leakage from the injection site and washout via the cardiac venous/lymphatic system. Delivery strategy will need to be modified if more cells are to be retained within the target organ.

Factors influencing antiretroviral adherence for 42 HIV-positive children were elicited from primary caregivers, and the perspectives of families and clinicians regarding success with adherence were compared. Interviews in preferred language (Spanish or English), chart reviews, and visual analogue scales (VAS) were used. Adherence was high by traditional markers of prescriptions filled (100%), doses reported taken (97%), and appointments kept (88%). Clinicians estimated slightly but not significantly lower adherence than did families using the VAS. Sixty-four percent of families reported barriers to adherence, and 30% reported strategies that differ from those in the general adherence literature. Adherence strategies devised by families depended heavily on family support and resolution of disclosure issues in the household.

Aim: To determine whether an optimal site of injection exists for herniography., Materials and Methods: This was a prospective, randomized study of 93 consecutive patients who were referred for herniography over a period of 9 months. Patients underwent either a left iliac fossa (LIF) or midline puncture. Parameters assessed included initial adequate needle placement, complications, pain scores and body mass index (BMI). The groups were compared using Chi-squared test for categorical data, Student's t-test for continuous data and the Mann-WhitneyU-test for skewed data, withP < 0.05 considered statistically significant, Results: Four complications were encountered (4%), and these were equally distributed between the two groups. Adequate initial positioning of the needle was similar in both groups. The volume of local anaesthetic used was correlated with discomfort using a pain scale: a volume of >6 ml resulted in significantly more pain. More frequent initial adequate needle placement was observed in thin patients (BMI < 45 kg/m(2)) with experienced operators. Conversely, increased body mass index resulted in more difficult needle placement., Conclusion: Herniography is a safe procedure with few complications. There was no significant difference comparing the midline and LIF approaches.Nadkarni, S.et al. (2001). Clinical Radiology56, 389-392., (Copyright 2001 The Royal College of Radiologists.)

A prospective analysis of the radiological findings and final diagnoses of 342 patients discussed at joint surgical/radiological conferences over a seven-month period was undertaken in an attempt to define the role of the radiologist in the clinical management of surgical patients. Although the diagnosis had already been correctly made on clinical or radiological grounds in 38% (130/342) of patients presented at the X-ray conferences, careful review of the films resulted in an immediate firm diagnosis in a further 9% (31/342), or promoted further radiological investigations which were responsible for an eventual definitive diagnosis in 20% of the remainder (32/169). The input of the radiologist in selecting the most appropriate additional investigation was particularly valuable in the management of more complex clinical problems.

This study was undertaken to determine whether the omission of a low-residue diet in the days leading up to barium enema resulted in poorer bowel preparation. 300 patients were randomized prospectively into one of two groups. One group followed a low-residue diet for the 3 days leading up to the study, the other continued their usual diet. Both groups had two doses of "Picolax" the day before the study. 17 patients did not attend, and a further two patients were excluded, leaving 281 patients for prospective study. The subsequent investigation was assessed blind by a consultant radiologist and graded for faecal residue, mucosal coating and diagnostic quality. No statistically significant difference was found between the two groups for amount of faecal residue (p < 0.25), mucosal coating (p < 0.25) or diagnostic quality (p < 0.5). We conclude, therefore, that a preliminary low-residue diet is unnecessary in the preparation of patients for barium enema. Patients should continue with their usual diet up to the day prior to the test and then have standard purgative preparation.

The study was undertaken to identify the presenting features of intestinal endometriosis and to evaluate its investigation and surgical management. Twenty-six cases of intestinal endometriosis were identified during a fourteen year period. The commonest site of occurrence was the rectosigmoid region (11 cases) followed by the appendix (9 cases), and ileocaecal region (6 cases). Abdominal pain was the main presenting feature in 20 cases, with associated nausea and vomiting in 12 cases and altered bowel habit in ten. Other presenting features included rectal bleeding, abdominal bloating and tenesmus. Endometriosis was not suspected preoperatively in any of the patients without a past history of this condition. Accurate preoperative diagnosis proved very difficult, with only laparoscopy providing definite evidence of intestinal endometriosis prior to formal surgery. Colonic resections were performed in 12 cases, small bowel resection in six cases and appendicectomy in nine cases, together with resection of adjacent adherent structures. This series illustrates the difficulty of establishing an accurate preoperative diagnosis, and the propensity of intestinal endometriosis to mimic other gastrointestinal diseases, particularly carcinoma and inflammatory bowel disease.

Clinical, radiological and pathological findings in 31 patients with xanthogranulomatous cholecystitis have been reviewed. The spectrum of presentation was similar to that of cholelithiasis but fewer patients had biliary colic (17 per cent) and there were more complications (32 per cent). Four patients had a biliary fistula and four a perforated gallbladder with abscess formation. Patients characteristically had gallstones. Appearances often mimicked carcinoma of the gallbladder at ultrasonography and/or laparotomy, with xanthogranulomatous tissue extending to adjacent structures. Xanthogranulomatous cholecystitis and carcinoma of the gallbladder coexisted in three patients. The possibility should be considered that an 'inoperable tumour' of the gallbladder may in fact be xanthogranulomatous cholecystitis, a benign condition that frozen-section biopsy may confirm.

It has previously been suggested that a single dose of magnesium citrate produces adequate cleansing of the bowel for barium enema examination. To determine whether such a regimen has any advantage over the widely used two doses of Picolax, a prospective randomized blinded trial was performed with over 100 patients allocated to each of the bowel preparation regimens. Radiographs were assessed for quality of mucosal coating, faecal residue and overall quality of bowel preparation. Patient compliance was good with both regimens. Normal daily activities were inconvenienced significantly more by the Picolax (P < 0.001), whereas the magnesium citrate (Citramag) caused more interruption of sleep (P < 0.01). Mucosal coating was similar with both regimens. There was more faecal residue and poorer overall bowel preparation with Citramag (P < 0.001), although diagnostic accuracy was only infrequently felt to be compromised as a result. Citramag may offer an alternative to Picolax in patients where minimal disruption to daily activities is desirable and where the detection of polyps is not critical.

Spigelian and epigastric hernias can cause diagnostic problems as they often present in elderly, obese patients with few specific symptoms or signs. Early diagnosis is important as both groups of hernia have a high rate of bowel strangulation. The combined value of ultrasound and tangential radiographs in the diagnosis of these hernias is presented along with a review of the literature.

Patients presenting with a right iliac fossa (RIF) mass are a diagnostic problem. The objective of this study was to assess the role of ultrasound (US) in their investigation. A prospective series of 50 patients presenting with a clinically suspected RIF mass was examined by US and the finding correlated with the final diagnosis. There was a positive finding in 34 patients (68%). Ultrasound correctly identified the organ of origin in 33 (97%) and was able to guide the patients' further management. In 12 cases no abnormality was found in the RIF, of which 11 had no positive findings at follow-up and one was shown to have an unrelated abnormality at laparotomy. In four cases the findings were due to normal variants. Ultrasound is the imaging modality of first choice in patients presenting with a RIF mass.

The incidence and presentation of upper tract tumours were studied in 180 patients who had previously undergone cystectomy for transitional cell carcinoma of the bladder. Intravenous urography was performed routinely 3 months after cystectomy, 1 year later and at 3-yearly intervals thereafter. Ten patients developed upper tract tumours; 1 presented with loin pain and the remainder with haematuria. Six patients underwent nephroureterectomy and 5 of them lived for at least 4 years; 4 were inoperable and only 1 survived longer than 6 months. In this series, all patients with upper tract tumours presented with symptoms and routine intravenous urography failed to detect any asymptomatic lesions. Routine radiological assessment of the upper tracts to detect tumours is not justified following cystectomy.

A case of recurrent liposarcoma of the oesophagus is presented. The clinical and radiological findings are discussed. Our case displays the characteristic features and behaviour of a common sarcoma arising in a rare site.

Results of the dexamethasone suppression test (DST) in 30 alcoholic patients tested on day 5 and again on day 25 after their last drink are presented. Nineteen patients (63%) failed to suppress cortisol on day 5; three (11%) failed to suppress cortisol on day 25. Depressive symptoms, measured by the Beck Depression Inventory, were significantly correlated with DST results; the lifetime diagnosis of depressive illness was not. The authors conclude that the DST is not useful in detecting primary affective disorders during the early phase of withdrawal from alcohol.

Four patients are described in whom recurrent large pleural effusions developed secondary to asymptomatic pancreatic disease. The diagnosis was made by measuring the amylase content of the pleural fluid. Endoscopic retrograde cholangiopancreatography (ERCP) and computed tomography (CT) were useful in demonstrating pancreatico-pleural fistulae. Two patients underwent laparotomy and distal pancreatectomy. One recovered spontaneously after ERCP appeared to relieve an obstruction of the pancreatic duct and the other recovered after a period of parenteral nutrition. We suggest that pleural fluid amylase content should be measured in any case of exudative pleural effusion of unknown aetiology.