We describe two pediatric patients who developed autoimmune hypothyroidism 2 years after unrelated allogeneic hematopoietic stem cell transplantation. The causes of post-transplantation autoimmune ...hypothyroidism are probably multiple. In these two patients, the presence of chronic graft-versus-host disease may be the most significant contributing factor.
Coastal Ecosystem Values, Threats, and Decline Coastal wetlands, such as seagrass beds, mangrove wetlands, salt marshes, macroalgal, and seaweed beds, shellfish reefs, tidal freshwater wetlands, and ...coral reefs, are remarkable features of tropical and temperate coastlines. ...these systems are subject to what may be called “a triple whammy” of increasing industrialization and urbanization, an increased loss of biological and physical resources (fish, water, energy, space), and a decreased resilience to the consequences of a warming climate and sea level rise (Elliott et al., 2016). Trans-Disciplinary Teams Looking forward into the next decade, coastal habitat restoration will truly require a trans-disciplinary approach with skills drawn from engineering, modeling, ecology, chemistry, hydrology, social sciences including economics, financial, and project planning, governance, and integrated land, and sea spatial planning and management. Coastal ecosystems are at least as complex as terrestrial ecosystems, although arguably more dynamic, with the added gravity of the “triple whammy”—future development expansion that further alters shoreline ecosystems, loss of biodiversity and environmental conditions (e.g., water quality), and changing climate which alters sea level in many complex ways.
Abstract Purpose In previous studies of fungal keratitis (FK) from temperate countries, yeasts were the predominant isolates with ocular surface disease (OSD) being the leading risk factor. Since the ...2005-6 outbreak of contact lens (CL) associated Fusarium keratitis, there may have been a rise in CL associated filamentary FK in the United Kingdom. This retrospective case series investigated the patterns of FK from 2007 to 2014. We compared these to 1994-2006 data from the same hospital. Design Retrospective observational study Methods All cases of FK presenting to Moorfields Eye Hospital between 2007 and 2014 were identified. The definition of FK was either a fungal organism isolated by culture or fungal structures identified by light microscopy (LM) of scrape material, histopathology, or in-vivo corneal confocal microscopy (IVCM). Main outcome measure was the cases of FK per year. Results 112 patients had confirmed FK. Median age was 47.2 years. Between 2007 and 2014, there was an increase in annual numbers of FK (Poisson regression, p=0.0001). FK was confirmed using various modalities: 79 (70.5%) had positive cultures, 16 (14.3%) by LM, and 61 (54.5%) by IVCM. 78 (69.6%) were diagnosed with filamentary fungus alone, 28 (25%) with yeast alone and 6 (5.4%) with mixed filamentary and yeast infections. This represents an increase in the proportion of filamentary fungal infections from the pre-2007 data. Filamentary fungal and yeast infections were associated CL use and OSD respectively. Conclusions The number of FK has increased. This increase is due to CL associated filamentary FK. Clinicians should be aware of these changes, which warrant epidemiological investigations to identify modifiable risk factors.
Epidermal growth factor receptor (EGFR) is frequently overexpressed in metastatic triple-negative breast cancer (mTNBC). One strategy for overcoming resistance to EGFR inhibition is concomitant ...inhibition of downstream signaling. The antidiabetic drug metformin inhibits both MAPK and PI3K/mTOR pathway signaling. We evaluated the combination of erlotinib and metformin in a phase 1 study of patients with mTNBC.
Patients with mTNBC who had received at least one prior line of therapy for metastatic disease were eligible. Erlotinib dose was fixed at 150 mg daily. Metformin dose escalation was planned according to a 3 + 3 design. Dose-limiting toxicities (DLT) were assessed during the first 5 weeks of therapy. The primary objective was to determine the maximum tolerated dose of metformin with fixed-dose erlotinib. Secondary endpoints were response rate, stable disease rate, and progression-free survival.
Eight patients were enrolled. The median number of prior therapies for metastatic disease was 2.5 (range, 1-6). No DLT events were reported during the DLT assessment period. Most adverse events were grade 1/2. Grade 3 diarrhea despite maximum supportive care required dose reduction of metformin in one patient. Grade 3 rash led to study withdrawal in one patient. No grade 4 adverse events were reported. The best observed response was stable disease in 2 patients (25%). Median progression-free survival was 60 days (range, 36-61 days).
Erlotinib and metformin were well tolerated in a population of pretreated mTNBC patients but did not demonstrate efficacy in this population.
A 21-month-old girl with hemoglobin Bart's hydrops received bone marrow transplantation (BMT) from a matched sibling. No major BMT-related complications developed. Hemoglobin levels remained greater ...than 10 gm/dl for 20 months without blood transfusion support despite the presence of residual host hemopoietic cells from 2 months after BMT. We suggest consideration of this therapeutic option for surviving patients. (J Pediatr 1998;132:1039-42.)
Altered neural dynamics in the medial prefrontal cortex (mPFC) and hippocampus may contribute to cognitive impairments in the complex chromosomal disorder Down syndrome (DS). Here, we demonstrate ...non-overlapping behavioral differences associated with distinct abnormalities in hippocampal and mPFC electrophysiology during a canonical spatial working memory task in three partially trisomic mouse models of DS (Dp1Tyb, Dp10Yey, and Dp17Yey) that together cover all regions of homology with human chromosome 21 (Hsa21). Dp1Tyb mice show slower decision-making (unrelated to the gene dose of DYRK1A, which has been implicated in DS cognitive dysfunction) and altered theta dynamics (reduced frequency, increased hippocampal-mPFC coherence, and increased modulation of hippocampal high gamma); Dp10Yey mice show impaired alternation performance and reduced theta modulation of hippocampal low gamma; and Dp17Yey mice are not significantly different from the wild type. These results link specific hippocampal and mPFC circuit dysfunctions to cognitive deficits in DS models and, importantly, map them to discrete regions of Hsa21.
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•Study of behavior and EEG in three partially trisomic mouse models of Down syndrome (DS)•These mutant mice show non-overlapping differences in spatial working memory function•Behavioral changes segregate with distinct EEG abnormalities in the hippocampus and mPFC•This links cognitive deficits to specific changes in hippocampal and mPFC circuit dynamics
Chang et al. examine three partially trisomic mouse models of Down syndrome that together cover all regions of homology with human chromosome 21. They identify non-overlapping differences in spatial working memory function associated with distinct abnormalities in hippocampal and medial prefrontal electrophysiology.
The study of the noncovalent interaction now defined as a halogen bond (X-bond) has become one of the fastest growing areas in experimental and theoretical chemistryits applications as a design tool ...are highly extensive. The significance of the interaction in biology has only recently been recognized, but has now become important in medicinal chemistry. We had previously derived a set of empirical potential energy functions to model the structure–energy relationships for bromines in biomolecular X-bonds (BXBs). Here, we have extended this force field for BXBs (ffBXB) to the halogens (Cl, Br, and I) that are commonly seen to form stable X-bonds. The ffBXB calculated energies show a remarkable one-to-one linear relationship to explicit BXB energies determined from an experimental DNA junction system, thereby validating the approach and the model. The resulting parameters allow us to interpret the stabilizing effects of BXBs in terms of well-defined physical properties of the halogen atoms, including their size, shape, and charge, showing periodic trends that are predictable along the Group VII column of elements. Consequently, we have established the ffBXB as an accurate computational tool that can be applied, for example, for the design of new therapeutic compounds against clinically important targets and new biomolecular-based materials.
While previous reviews found a positive association between pre-existing cancer diagnosis and COVID-19-related death, most early studies did not distinguish long-term cancer survivors from those ...recently diagnosed/treated, nor adjust for important confounders including age. We aimed to consolidate higher-quality evidence on risk of COVID-19-related death for people with recent/active cancer (compared to people without) in the pre-COVID-19-vaccination period. We searched the WHO COVID-19 Global Research Database (20 December 2021), and Medline and Embase (10 May 2023). We included studies adjusting for age and sex, and providing details of cancer status. Risk-of-bias assessment was based on the Newcastle-Ottawa Scale. Pooled adjusted odds or risk ratios (aORs, aRRs) or hazard ratios (aHRs) and 95% confidence intervals (95% CIs) were calculated using generic inverse-variance random-effects models. Random-effects meta-regressions were used to assess associations between effect estimates and time since cancer diagnosis/treatment. Of 23 773 unique title/abstract records, 39 studies were eligible for inclusion (2 low, 17 moderate, 20 high risk of bias). Risk of COVID-19-related death was higher for people with active or recently diagnosed/treated cancer (general population: aOR = 1.48, 95% CI: 1.36-1.61, I
= 0; people with COVID-19: aOR = 1.58, 95% CI: 1.41-1.77, I
= 0.58; inpatients with COVID-19: aOR = 1.66, 95% CI: 1.34-2.06, I
= 0.98). Risks were more elevated for lung (general population: aOR = 3.4, 95% CI: 2.4-4.7) and hematological cancers (general population: aOR = 2.13, 95% CI: 1.68-2.68, I
= 0.43), and for metastatic cancers. Meta-regression suggested risk of COVID-19-related death decreased with time since diagnosis/treatment, for example, for any/solid cancers, fitted aOR = 1.55 (95% CI: 1.37-1.75) at 1 year and aOR = 0.98 (95% CI: 0.80-1.20) at 5 years post-cancer diagnosis/treatment. In conclusion, before COVID-19-vaccination, risk of COVID-19-related death was higher for people with recent cancer, with risk depending on cancer type and time since diagnosis/treatment.
Abstract 4663
Delayed immune reconstitution is a major cause of transplant-related mortality in allogeneic stem cell transplant setting. Reactivation of herpes viruses is a common post-transplant ...complication. In this study, we evaluate the recovery of cell-mediated immunity (CMI) to various herpes viruses by measuring lymphoproliferative response (LPR) to specific recall antigens.
Cell-mediated immunity was evaluated by the in-vitro lymphoproliferative response of peripheral blood mononuclear cells (PBMC) to specific purified HSV, VZV, CMV, EBV, HHV-6, 7, 8 antigens. Results were expressed as stimulation index (SI). SI≥a3 was regarded as positive lymphoproliferative response (LPR). Serial measurements were made at before transplant, and monthly during the initial 6 months post-transplant then quarterly till 12 months post-transplant.
From 2001-2004, 36 patients (M=19; F=17) with median age 10.5 years old were recruited. Hematological malignancies accounted for 58.3% of cases. Most transplants were from matched siblings (MSD) with peripheral blood stem cells (PBSC) as the source of stem cells. Altogether 50% of subjects showed positive LPR to HSV, CMV and VZV antigens at 2-4 months post-transplant; A significant upsurge of LPR were observed at 4-6 months post-transplant. However, no positive LPR to HSV, HHV-6,7 and 8 antigens were observed. The antibody status of donor and recipient for HSV, CMV and VZV were associated with the timing of recovery of CMI. Donor choice and stem cell source were important determinants of eventual LPR at day 100 post-transplant.
More than half of transplant recipients developed satisfactory LPR to HSV, CMV and VZV at 2-4 months after transplant. Pre-transplant serostatus of donor and recipient, donor choice and stem cell are important determinants of LPR to herpes viruses.
No relevant conflicts of interest to declare.
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