(European Society for Medical Oncology) A study of 4,532 men in the Veneto region of Italy has found that those who were being treated for prostate cancer with androgen-deprivation therapies (ADT) were less likely to develop the coronavirus COVID-19 and, if they were infected, the disease was less severe. The study is published in Annals of Oncology.

(University of Tsukuba) Researchers from the University of Tsukuba have revealed that pectin, a carbohydrate found in plant cell walls, plays a vital part in the development of female reproductive tissues of rice plants. It was found that the presence of a gene involved in pectin modification increased plant fertility relative to a modified plant with the gene removed. These findings could have major implications in crop variety development and genetic modification.

(University of Oklahoma) OU Medicine recently received a $1.4 million grant from the National Institutes of Health to study one method of embryo transfer involved in IVF: cryopreserved (frozen) embryo transfer.

Mary de Groot
Jan 1, 2010; 23:18-25
From Research to Practice

Daren Anderson
Jan 1, 2007; 20:10-16
Feature Articles

Lawrence Fisher
Oct 1, 2004; 17:215-219
Articles

Last month, Prime Minister Andrew Holness announced the establishment of an Economic Recovery Task Force, chaired by Finance Minister Dr Nigel Clarke. The multisectoral task force, which is mandated to oversee Jamaica's economic recovery from...

A Manchester mother is pleading with the authorities to provide her with the results of COVID-19 tests done on her and her week-old baby. The woman claims that she has been in isolation in hospital since April 27, a day after she gave birth to...

Fundraising efforts, along with a generous donation from Beyond Meat, founded by Ethan Brown ’08, helps restaurant P.S. Kitchen, owned by April Tam Smith ’10 and Graham Smith ’21, provide meals to healthcare workers.

The kappa opioid receptor (KOR) is implicated in various neuropsychiatric disorders. We previously evaluated an agonist tracer, ¹¹C-GR103545, for PET imaging of KOR in humans. Although ¹¹C-GR103545 showed high brain uptake, good binding specificity, and selectivity to KOR, it displayed slow kinetics and relatively large test-retest variability (TRV) of distribution volume (V_T) estimates (15%). Therefore we set out to develop two novel KOR agonist radiotracers, ¹¹C-EKAP and ¹¹C-FEKAP, and in nonhuman primates, both tracers exhibited faster kinetics and comparable binding parameters to ¹¹C-GR103545. The aim of this study was to assess their kinetic and binding properties in humans. Methods: Six healthy subjects underwent 120-min test-retest PET scans with both ¹¹C-EKAP and ¹¹C-FEKAP. Metabolite-corrected arterial input functions were measured. Regional time-activity curves (TACs) were generated for 14 regions of interest. One- and two-tissue compartment models (1TC, 2TC) and the multilinear analysis-1 (MA1) method were applied to the regional TACs to calculate V_T. Time-stability of V_T values and test-retest reproducibility were evaluated. Levels of specific binding, as measured by the non-displaceable binding potential (BP_ND) for the three tracers (¹¹C-EKAP, ¹¹C-FEKAP and ¹¹C-GR103545), were compared using a graphical method. Results: For both tracers, regional TACs were fitted well with the 2TC model and MA1 method (t*=20min), but not with the 1TC model. Given unreliably estimated parameters in several fits with the 2TC model and a good match between V_T values from MA1 and 2TC, MA1 was chosen as the appropriate model for both tracers. Mean MA1 V_T values were highest for ¹¹C-GR103545, followed by ¹¹C-EKAP, then ¹¹C-FEKAP. Minimum scan time for stable V_T measurement was 90 and 110min for ¹¹C-EKAP and ¹¹C-FEKAP, respectively, compared with 140min for ¹¹C-GR103545. The mean absolute TRV in MA1 V_T estimates was 7% and 18% for ¹¹C-EKAP and ¹¹C-FEKAP, respectively. BP_ND levels were similar for ¹¹C-FEKAP and ¹¹C-GR103545, but ~25% lower for ¹¹C-EKAP. Conclusion: The two novel KOR agonist tracers showed faster tissue kinetics than ¹¹C-GR103545. Even with slightly lower BP_ND, ¹¹C-EKAP is judged to be a better tracer for imaging and quantification of KOR in humans, based on the shorter minimum scan time and excellent test-retest.

Triple-negative breast cancer (TNBC) is characterized by poor response to therapy and low overall patient survival. Recently, Estrogen Receptor beta (ERβ) has been found to be expressed in a fraction of TNBCs where, because of its oncosuppressive actions on the genome, it represents a potential therapeutic target, provided a better understanding of its actions in these tumors becomes available. To this end, the cell lines Hs 578T, MDA-MB-468 and HCC1806, representing the claudin-low, basal-like 1 and 2 TNBC molecular subtypes respectively, were engineered to express ERβ under the control of a Tetracycline-inducible promoter and used to investigate the effects of this transcription factor on gene activity. The antiproliferative effects of ERβ in these cells were confirmed by multiple functional approaches, including transcriptome profiling and global mapping of receptor binding sites in the genome, that revealed direct negative regulation by ERβ of genes, encoding for key components of cellular pathways associated to TNBC aggressiveness representing novel therapeutic targets such as angiogenesis, invasion, metastasis and cholesterol biosynthesis. Supporting these results, interaction proteomics by immunoprecipitation coupled to nano LC-MS/MS mass spectrometry revealed ERβ association with several potential nuclear protein partners, including key components of regulatory complexes known to control chromatin remodeling, transcriptional and post-transcriptional gene regulation and RNA splicing. Among these, ERβ association with the Polycomb Repressor Complexes 1 and 2 (PRC1/2), known for their central role in gene regulation in cancer cells, was confirmed in all three TNBC subtypes investigated, suggesting its occurrence independently from the cellular context. These results demonstrate a significant impact of ERβ in TNBC genome activity mediated by its cooperation with regulatory multiprotein chromatin remodeling complexes, providing novel ground to devise new strategies for the treatment of these diseases based on ligands affecting the activity of this nuclear receptor or some of its protein partners.

Previous studies have shown that sphingosine kinase interacting protein (SKIP) inhibits sphingosine kinase (SK) function in fibroblasts. SK phosphorylates sphingosine producing the potent signaling molecule sphingosine-1-phosphate (S1P). SKIP gene (SPHKAP) expression is silenced by hypermethylation of its promoter in acute myeloid leukemia (AML). However, why SKIP activity is silenced in primary AML cells is unclear. Here, we investigated the consequences of SKIP down-regulation in AML primary cells and the effects of SKIP re-expression in leukemic cell lines. Using targeted ultra-HPLC-tandem MS (UPLC-MS/MS), we measured sphingolipids (including S1P and ceramides) in AML and control cells. Primary AML cells had significantly lower SK activity and intracellular S1P concentrations than control cells, and SKIP-transfected leukemia cell lines exhibited increased SK activity. These findings show that SKIP re-expression enhances SK activity in leukemia cells. Furthermore, other bioactive sphingolipids such as ceramide were also down-regulated in primary AML cells. Of note, SKIP re-expression in leukemia cells increased ceramide levels 2-fold, inactivated the key signaling protein extracellular signal-regulated kinase, and increased apoptosis following serum deprivation or chemotherapy. These results indicate that SKIP down-regulation in AML reduces SK activity and ceramide levels, an effect that ultimately inhibits apoptosis in leukemia cells. The findings of our study contrast with previous results indicating that SKIP inhibits SK function in fibroblasts and therefore challenge the notion that SKIP always inhibits SK activity.

Accumulating evidence suggests that brown adipose tissue (BAT) is a potential therapeutic target for managing obesity and related diseases. PGAM family member 5, mitochondrial serine/threonine protein phosphatase (PGAM5), is a protein phosphatase that resides in the mitochondria and regulates many biological processes, including cell death, mitophagy, and immune responses. Because BAT is a mitochondria-rich tissue, we have hypothesized that PGAM5 has a physiological function in BAT. We previously reported that PGAM5-knockout (KO) mice are resistant to severe metabolic stress. Importantly, lipid accumulation is suppressed in PGAM5-KO BAT, even under unstressed conditions, raising the possibility that PGAM5 deficiency stimulates lipid consumption. However, the mechanism underlying this observation is undetermined. Here, using an array of biochemical approaches, including quantitative RT-PCR, immunoblotting, and oxygen consumption assays, we show that PGAM5 negatively regulates energy expenditure in brown adipocytes. We found that PGAM5-KO brown adipocytes have an enhanced oxygen consumption rate and increased expression of uncoupling protein 1 (UCP1), a protein that increases energy consumption in the mitochondria. Mechanistically, we found that PGAM5 phosphatase activity and intramembrane cleavage are required for suppression of UCP1 activity. Furthermore, utilizing a genome-wide siRNA screen in HeLa cells to search for regulators of PGAM5 cleavage, we identified a set of candidate genes, including phosphatidylserine decarboxylase (PISD), which catalyzes the formation of phosphatidylethanolamine at the mitochondrial membrane. Taken together, these results indicate that PGAM5 suppresses mitochondrial energy expenditure by down-regulating UCP1 expression in brown adipocytes and that its phosphatase activity and intramembrane cleavage are required for UCP1 suppression.

Plasma lipoprotein (a) [Lp(a)] levels are largely determined by variation in the LPA gene, which codes for apo(a). Genome-wide association studies (GWASs) have identified nonsynonymous variants in LPA that associate with low Lp(a) levels, although their effect on apo(a) function is unknown. We investigated two such variants, R990Q and R1771C, which were present in four null Lp(a) individuals, for structural and functional effects. Sequence alignments showed the R990 and R1771 residues to be highly conserved and homologous to each other and to residues associated with plasminogen deficiency. Structural modeling showed both residues to make several polar contacts with neighboring residues that would be ablated on substitution. Recombinant expression of the WT and R1771C apo(a) in liver and kidney cells showed an abundance of an immature form for both apo(a) proteins. A mature form of apo(a) was only seen with the WT protein. Imaging of the recombinant apo(a) proteins in conjunction with markers of the secretory pathway indicated a poor transit of R1771C into the Golgi. Furthermore, the R1771C mutant displayed a glycosylation pattern consistent with ER, but not Golgi, glycosylation. We conclude that R1771 and the equivalent R990 residue facilitate correct folding of the apo(a) kringle structure and mutations at these positions prevent the proper folding required for full maturation and secretion. To our knowledge, this is the first example of nonsynonymous variants in LPA being causative of a null Lp(a) phenotype.

Using the NCR form of a surrogate pair as an input string to the UNICODE function does not convert the string to the appropriate display character.

Hypo-vascularised diabetic non-healing wounds are due to reduced number and impaired physiology of endogenous endothelial progenitor cell (EPC) population that, limits their recruitment and mobilization at the wound site. To enrich the EPC repertoire from non-endothelial precursors, abundantly available mesenchymal stromal cells (MSCs) were reprogrammed into induced-endothelial cells (iECs). We identified cell signaling molecular targets by meta-analysis of microarray datasets. BMP-2 induction leads to the expression of inhibitory Smad 6/7-dependent negative transcriptional regulation of ID1, rendering the latter's reduced binding to TWIST1 during transdifferentiation of WJ-MSC into iEC. TWIST1, in turn, regulates endothelial genes transcription, positively of pro-angiogenic-KDR and negatively, in part, of anti-angiogenic-SFRP4. Twist1 reprogramming enhanced the endothelial lineage commitment of WJ-MSC, increased the vasculogenic potential of reprogrammed EC (rEC). Transplantation of stable TWIST1-rECs into full-thickness type 1 and 2 diabetic-splinted wound healing murine model enhanced the microcirculatory blood flow and accelerated the wound tissue regeneration. An increased or decreased co-localization of GFP with KDR/SFRP4 and CD31 in the regenerated diabetic wound bed with TWIST1 overexpression or silencing (piLenti-TWIST1-shRNA-GFP), respectively further confirmed improved neovascularization. This study depicted the reprogramming of WJ-MSCs into rECs using unique transcription factors, TWIST1 for an efficacious cell transplantation therapy to induce neovascularization–mediated diabetic wound tissue regeneration.

Mobilization of hematopoietic stem/progenitor cells (HSPCs) from the bone marrow (BM) is impaired in diabetes. Excess oncostatin M (OSM) produced by M1 macrophages in the diabetic BM signals through p66Shc to induce Cxcl12 in stromal cells and retain HSPCs. BM adipocytes are another source of CXCL12 that blunts mobilization. We tested a strategy of pharmacologic macrophage reprogramming to rescue HSPC mobilization. In vitro, PPAR- activation with pioglitazone switched macrophages from M1 to M2, reduced Osm expression, and prevented transcellular induction of Cxcl12. In diabetic mice, pioglitazone treatment downregulated Osm, p66Shc and Cxcl12 in the hematopoietic BM, restored the effects of granulocyte-colony stimulation factor (G-CSF), and partially rescued HSPC mobilization, but it increased BM adipocytes. Osm deletion recapitulated the effects of pioglitazone on adipogenesis, which was p66Shc-independent, and double knockout of Osm and p66Shc completely rescued HSPC mobilization. In the absence of OSM, BM adipocytes produced less CXCL12, being arguably devoid of HSPC-retaining activity, whereas pioglitazone failed to downregulate Cxcl12 in BM adipocytes. In diabetic patients under pioglitazone therapy, HSPC mobilization after G-CSF was partially rescued. In summary, pioglitazone reprogrammed BM macrophages and suppressed OSM signaling, but sustained Cxcl12 expression by BM adipocytes could limit full recovery of HSPC mobilization.

Accumulating evidence suggests that brown adipose tissue (BAT) is a potential therapeutic target for managing obesity and related diseases. PGAM family member 5, mitochondrial serine/threonine protein phosphatase (PGAM5), is a protein phosphatase that resides in the mitochondria and regulates many biological processes, including cell death, mitophagy, and immune responses. Because BAT is a mitochondria-rich tissue, we have hypothesized that PGAM5 has a physiological function in BAT. We previously reported that PGAM5-knockout (KO) mice are resistant to severe metabolic stress. Importantly, lipid accumulation is suppressed in PGAM5-KO BAT, even under unstressed conditions, raising the possibility that PGAM5 deficiency stimulates lipid consumption. However, the mechanism underlying this observation is undetermined. Here, using an array of biochemical approaches, including quantitative RT-PCR, immunoblotting, and oxygen consumption assays, we show that PGAM5 negatively regulates energy expenditure in brown adipocytes. We found that PGAM5-KO brown adipocytes have an enhanced oxygen consumption rate and increased expression of uncoupling protein 1 (UCP1), a protein that increases energy consumption in the mitochondria. Mechanistically, we found that PGAM5 phosphatase activity and intramembrane cleavage are required for suppression of UCP1 activity. Furthermore, utilizing a genome-wide siRNA screen in HeLa cells to search for regulators of PGAM5 cleavage, we identified a set of candidate genes, including phosphatidylserine decarboxylase (PISD), which catalyzes the formation of phosphatidylethanolamine at the mitochondrial membrane. Taken together, these results indicate that PGAM5 suppresses mitochondrial energy expenditure by down-regulating UCP1 expression in brown adipocytes and that its phosphatase activity and intramembrane cleavage are required for UCP1 suppression.

Women with endometriosis have significantly higher rates of depression than women in the general population. That’s according to psychiatrist Dr Kristen Robinson-Barrett. It’s the end of endometriosis month, so Flair spoke to the expert to explore...

Jackie Applebee is a GP in Tower Hamlets in London, and is concerned that the way the GP funding formula is working doesn't take account of the earlier health needs of people in deprived areas. For more about the Tower Hamlets Save Our Surgery campaign, visit their facebook page https://www.facebook.com/SaveOurGPsurgeries BMJ Voices is a...

Oversimplification and lack of evidence stigmatise people with mental illness and impede prevention efforts, says Simon Wessley, professor of psychiatry at King's College London, in an editorial published on thebmj.com. Read the full editorial: http://www.bmj.com/content/354/bmj.i4869

Patients who are depressed and prescribed antidepressants may report weight gain, but there has been limited research into the association between the two. However new observational research published on bmj.com aims to identify that association. Rafael Gafoor, a psychiatrist and researcher at Kings College London, and one of the authors of that...

For the next few months Talk Evidence is going to focus on the new corona virus pandemic. There is an enormous amount of uncertainty about the disease, what the symptoms are, fatality rate, treatment options, things we shouldn't be doing. We're going to try to get away from the headlines and talk about what we need to know - to hopefully give...

David E. Cummings
Aug 1, 2001; 50:1714-1719
Rapid Publications

As the global battle against the deadly COVID-19 disease wages on, with each country’s government, healthcare industry, and general public playing its part in defeating this new and relatively unknown enemy, two seemingly unlikely foot soldiers...

The signal peptide of preproinsulin is a major source for HLA class I autoantigen epitopes implicated in CD8 T cell (CTL)–mediated β-cell destruction in type 1 diabetes (T1D). Among them, the 10-mer epitope located at the C-terminal end of the signal peptide was found to be the most prevalent in patients with recent-onset T1D. While the combined action of signal peptide peptidase and endoplasmic reticulum (ER) aminopeptidase 1 (ERAP1) is required for processing of the signal peptide, the mechanisms controlling signal peptide trimming and the contribution of the T1D inflammatory milieu on these mechanisms are unknown. Here, we show in human β-cells that ER stress regulates ERAP1 gene expression at posttranscriptional level via the IRE1α/miR-17-5p axis and demonstrate that inhibition of the IRE1α activity impairs processing of preproinsulin signal peptide antigen and its recognition by specific autoreactive CTLs during inflammation. These results underscore the impact of ER stress in the increased visibility of β-cells to the immune system and position the IRE1α/miR-17 pathway as a central component in β-cell destruction processes and as a potential target for the treatment of autoimmune T1D.

3 March 2020

To the extent that perceptions of a crisis in liberal democracy in Europe can be confirmed, this paper investigates the nature of the problem and its causes, and asks what part, if any, digital technology plays in it.

OBJECTIVE

To assess the contemporaneous prevalence of diabetic peripheral neuropathy (DPN) in people with type 1 diabetes (T1D) in Scotland and study its cross-sectional association with risk factors and other diabetic complications.

Korey K. Hood
Jun 1, 2006; 29:1389-1389
BR Epidemiology/Health Services/Psychosocial Research

While much attention has been given to the move by U.S. Citizenship and Immigration Services to raise its application fees—including an 83 percent hike to apply for U.S. citizenship—the policy changes embedded in the proposed rule have been less scrutinized. The changes, including the elimination of most fee waivers for lower-income applicants, would likely reduce the number and shift the profile of those getting a green card or other immigration status.

The ADA is calling for nominations for two seats to represent the Association in the Dental Quality Alliance.

The House of Representatives passed a new coronavirus relief bill April 23 that calls for additional funding for federal loan programs to help businesses nationwide, including dental practices, recover from the economic fallout of the pandemic.

A 29 years old female presented to us in the metabolic clinic of the University of Port Harcourt Teaching Hospital (UPTH) on account of a week history of easy fatigability, weakness, and lower extremity muscle cramps associated with numbness and tingling sensation in the peri-oral area, fingers and toes. Two weeks prior to the onset of her presenting symptoms, she had visited a local pharmaceutical shop on account of a distressing epigastric discomfort and was subsequently placed on daily oral omeprazole 20mg daily for a month by a pharmacist. She had been on the omeprazole medication for two weeks before her present symptoms manifested. Her past medical history was not suggestive of hypoparathyroidism nor pancreatitis. She was married with three children and has an uneventful family, social and obstetric histories. On examination, she was a healthy well-oriented young female with positive Trousseau’s, Chvostek’s and epigastric tenderness signs. Further Laboratory evaluation revealed she had low plasma magnesium, low plasma albumin-corrected calcium, and low serum parathyroid hormone levels, while other laboratory parameters were essentially normal. A diagnosis of omeprazole-induced electrolyte disorders (hypomagnesaemia and hypocalcaemia) associated with hypoparathyroidism was made following the review of her clinical examination and laboratory findings. She was subsequently managed with oral magnesium supplements following the withdrawal of the omeprazole medication (replaced with oral ranitidine), monitored weekly, and full recovery was achieved after three weeks.

The role of motherhood is complex and profound. Psychology and development experts agree — the role of the mother is critical to child development, for better or worse. This role...

In his starting section, "Path", Macfarlane admits that not all walkers are benign or appealing. While I think he is a little hard on Morris Dancers and people who walk in sandals (p. 23) he does mention that trampers can have more sinister motives than mere enjoyment of nature and movement. He mentions people who walk because they are delusional or racist.

He also discusses two writers who walked to stave off depression -  19th-century walker George Borrow and poet Edward Thomas, who was killed in World War I. Borrow, who rode around on a black Arab stallion when at home, walked over not only England but also France, Spain, Portugal, Russia, and Morocco. He knew twelve languages and was acquainted with another forty. The activity of walking exposed him to new people and allowed him to exercise his mind as he exercised his body.

Edward Thomas and his poetry had the most influence over Macfarlane. The author admits that Thomas is the guiding spirit of his book (p. 24) and his first walk in The Old Ways is one that Thomas took a hundred years earlier. Macfarlane says that while Thomas

"was drawn to the romantic figure of the self-confident solitary walker, he was more interestingly alert to how we are scattered, as well as affirmed, by the places through which we move" (p. 25).

Thomas appears throughout The Old Ways, and Macfarlane gradually tells the story of Thomas's life in the "Ghost" section of the book. Thomas suffered badly from depression and moved frequently in the hopes that his new house would help him battle it; walking was a similar way to stave it off.

Interestingly enough, American poet Robert Frost knew Thomas. The famous Frost poem, "The Road Not Taken", was inspired by a walk that Frost and Thomas took together. When Frost sent Thomas a draft of the poem, Thomas decided that it was a sign that he should enlist in the British army. He was later killed in France in 1917.

WASHINGTON — Latinos and immigrants are at least twice as likely to lack health insurance coverage as the overall population in three central Kansas City metro counties, a new Migration Policy Institute (MPI) study reveals. In fact, they are four times as likely to be uninsured in Johnson County, Kansas. 

OBJECTIVE

This study aimed to reveal the associations between the risk of new-onset type 2 diabetes and the duration of antidepressant use and the antidepressant dose, and between antidepressant use after diabetes onset and clinical outcomes.

In a time of critical shortages of U.S. health-care workers during the COVID-19 pandemic, retired doctors are being called back to work and medical students are graduating on a fast track. There is another important pool that could be tapped: Immigrants and refugees who have college degrees in health fields but are working in low-skilled jobs or out of work. MPI estimates 263,000 immigrants are experiencing skill underutilization and could be a valuable resource.

Paul Ciechanowski
Apr 1, 2011; 29:43-49
Feature Articles

Depression is one of the most common mental health issues in the United States. In fact, according to the National Institutes of Mental Health, 1 in 14 Americans experienced an episode of major depression in the last year alone. Given the circumstances surrounding the current COVID-19 coronavirus pandemic, many in the mental health community predict that the number will be even higher this year because these circumstances are creating a “perfect storm” of depression risks. The widespread prevalence of depression has a lot of implications for our lives, even if we don’t personally have depression ourselves. Many of us will have loved ones, such as a romantic partner, who develops depression at some point. In these situations, it’s common for people to wonder how they can help their partner most effectively. So what should they do?

There are six areas of key work ahead, write John P. Bailey and Frederick M. Hess.

There are six areas of key work ahead, write John P. Bailey and Frederick M. Hess.

"A special challenge of hard rock exploration is to identify targets of interest within complex geological settings. Interpretation of the geology can be made from direct geological observations and knowledge of the area, and from 2D or 3D seismic surveys. These interpretations can be developed into 3D geological models that provide the basis for predictions as to likely targets for drilling and/or mining. To verify these predictions we need to simulate 3D seismic wave propagation in the proposed geological models and compare the simulation results to seismic survey data. To achieve this we convert geological surfaces created in an interpretation software package into discretised block models representing the different lithostratigraphic units, and segment these into discrete volumes to which appropriate density and seismic velocity values are assigned. This approach allows us to scale models appropriately for desired wave propagation parameters and to go from local to global geological models and vice versa. Then we use these digital models with forward modelling codes to undertake numerous 3D acoustic wave simulations. Simulations are performed with single shot and with exploding reflector (located on extracted geological surface) configurations" -- Summary.

Self-help techniques.