Public Funding for NonPublic Education: School Vouchers Initiatives

On June 27, 2002, in Zelman v. Simmons-Harris, the United States Supreme Court upheld Ohio\u27s school voucher initiative, authorizing government aid for students in failing Cleveland public schools to attend, upon independent parental choice, private and parochial schools. Similar education reform initiatives may face distinct challenges in the Commonwealth. Significantly, traditional legal interpretation of Virginia constitutional provisions has been more restrictive than those of federal constitutional provisions addressing government entanglement with religion. While carefully crafted voucher initiatives aiding sectarian private schools may pass muster under the U.S. Constitution, application of the Commonwealth\u27s constitutional requirements could warrant a different result

Public Funding for NonPublic Education: School Vouchers Initiatives

On June 27, 2002, in Zelman v. Simmons-Harris, the United States Supreme Court upheld Ohio\u27s school voucher initiative, authorizing government aid for students in failing Cleveland public schools to attend, upon independent parental choice, private and parochial schools. Similar education reform initiatives may face distinct challenges in the Commonwealth. Significantly, traditional legal interpretation of Virginia constitutional provisions has been more restrictive than those of federal constitutional provisions addressing government entanglement with religion. While carefully crafted voucher initiatives aiding sectarian private schools may pass muster under the U.S. Constitution, application of the Commonwealth\u27s constitutional requirements could warrant a different result

Pathological and Transcriptome Changes in the ReninAAV db/db uNx Model of Advanced Diabetic Kidney Disease Exhibit Features of Human Disease

The ReninAAV db/db uNx model of diabetic kidney disease (DKD) exhibits hallmarks of advanced human disease, including progressive elevations in albuminuria and serum creatinine, loss of glomerular filtration rate, and pathological changes. Microarray analysis of renal transcriptome changes were more similar to human DKD when compared to db/db eNOS−/− model. The model responds to treatment with arterial pressure lowering (lisinopril) or glycemic control (rosiglitazone) at early stages of disease. We hypothesized the ReninAAV db/db uNx model with advanced disease would have residual disease after treatment with lisinopril, rosiglitazone, or combination of both. To test this, ReninAAV db/db uNx mice with advanced disease were treated with lisinopril, rosiglitazone, or combination of both for 10 weeks. All treatment groups showed significant lowering of urinary albumin to creatinine ratio compared to baseline; however, only combination group exhibited lowering of serum creatinine. Treatment improved renal pathological scores compared to baseline values with residual disease evident in all treatment groups when compared to db/m controls. Gene expression analysis by TaqMan supported pathological changes with increased fibrotic and inflammatory markers. The results further validate this model of DKD in which residual disease is present when treated with agents to lower arterial pressure and glycemic control

Efficacy of ruxolitinib cream in vitiligo by patient characteristics and affected body areas: Descriptive subgroup analyses from a phase 2, randomized, double-blind trial

To the Editor: Vitiligo is a chronic autoimmune disease resulting in patches of depigmented skin and reduced quality of life. In a randomized, dose-ranging phase 2 study (NCT03099304) in 157 adult patients, the Janus kinase (JAK) 1/JAK2 inhibitor ruxolitinib cream produced substantial repigmentation of facial and total body vitiligo lesions after 24 weeks, with continued improvement through week 52, and was well tolerated.3 Here, we present treatment response subanalyses from the phase 2 trial

Mutations in epigenetic regulators including SETD2 are gained during relapse in pediatric acute lymphoblastic leukemia

Relapsed pediatric acute lymphoblastic leukemia (ALL) has high rates of treatment failure. Epigenetic regulators have been proposed as modulators of chemoresistance, here we sequence genes encoding epigenetic regulators in matched diagnosis-remission-relapse ALL samples. We find significant enrichment of mutations in epigenetic regulators at relapse with recurrent somatic mutations in SETD2, CREBBP, MSH6, KDM6A and MLL2, mutations in signaling factors are not enriched. Somatic alterations in SETD2, including frameshift and nonsense mutations, are present at 12% in a large de novo ALL patient cohort. We conclude that the enrichment of mutations in epigenetic regulators at relapse is consistent with a role in mediating therapy resistance

Desacetyl-α-melanocyte stimulating hormone and α-melanocyte stimulating hormone are required to regulate energy balance.

OBJECTIVE: Regulation of energy balance depends on pro-opiomelanocortin (POMC)-derived peptides and melanocortin-4 receptor (MC4R). Alpha-melanocyte stimulating hormone (α-MSH) is the predicted natural POMC-derived peptide that regulates energy balance. Desacetyl-α-MSH, the precursor for α-MSH, is present in brain and blood. Desacetyl-α-MSH is considered to be unimportant for regulating energy balance despite being more potent (compared with α-MSH) at activating the appetite-regulating MC4R in vitro. Thus, the physiological role for desacetyl-α-MSH is still unclear. METHODS: We created a novel mouse model to determine whether desacetyl-α-MSH plays a role in regulating energy balance. We engineered a knock in targeted QKQR mutation in the POMC protein cleavage site that blocks the production of both desacetyl-α-MSH and α-MSH from adrenocorticotropin (ACTH1-39). RESULTS: The mutant ACTH1-39 (ACTHQKQR) functions similar to native ACTH1-39 (ACTHKKRR) at the melanocortin 2 receptor (MC2R) in vivo and MC4R in vitro. Male and female homozygous mutant ACTH1-39 (Pomctm1/tm1) mice develop the characteristic melanocortin obesity phenotype. Replacement of either desacetyl-α-MSH or α-MSH over 14 days into Pomctm1/tm1 mouse brain significantly reverses excess body weight and fat mass gained compared to wild type (WT) (Pomcwt/wt) mice. Here, we identify both desacetyl-α-MSH and α-MSH peptides as regulators of energy balance and highlight a previously unappreciated physiological role for desacetyl-α-MSH. CONCLUSIONS: Based on these data we propose that there is potential to exploit the naturally occurring POMC-derived peptides to treat obesity but this relies on first understanding the specific function(s) for desacetyl-α-MSH and α-MSH

Tissue-resident, extravascular Ly6c- monocytes are critical for inflammation in the synovium

Monocytes are abundant immune cells that infiltrate inflamed organs. However, the majority of monocyte studies focus on circulating cells, rather than those in tissue. Here, we identify and characterize an intravascular synovial monocyte population resembling circulating non-classical monocytes and an extravascular tissue-resident monocyte-lineage cell (TR-MC) population distinct in surface marker and transcriptional profile from circulating monocytes, dendritic cells, and tissue macrophages that are conserved in rheumatoid arthritis (RA) patients. TR-MCs are independent of NR4A1 and CCR2, long lived, and embryonically derived. TR-MCs undergo increased proliferation and reverse diapedesis dependent on LFA1 in response to arthrogenic stimuli and are required for the development of RA-like disease. Moreover, pathways that are activated in TR-MCs at the peak of arthritis overlap with those that are downregulated in LFA1-/- TR-MCs. These findings show a facet of mononuclear cell biology that could be imperative to understanding tissue-resident myeloid cell function in RA.</p

Teprotumumab for Thyroid-Associated Ophthalmopathy

BACKGROUND: Thyroid-associated ophthalmopathy, a condition commonly associated with Graves' disease, remains inadequately treated. Current medical therapies, which primarily consist of glucocorticoids, have limited efficacy and present safety concerns. Inhibition of the insulin-like growth factor I receptor (IGF-IR) is a new therapeutic strategy to attenuate the underlying autoimmune pathogenesis of ophthalmopathy. METHODS: We conducted a multicenter, double-masked, randomized, placebo-controlled trial to determine the efficacy and safety of teprotumumab, a human monoclonal antibody inhibitor of IGF-IR, in patients with active, moderate-to-severe ophthalmopathy. A total of 88 patients were randomly assigned to receive placebo or active drug administered intravenously once every 3 weeks for a total of eight infusions. The primary end point was the response in the study eye. This response was defined as a reduction of 2 points or more in the Clinical Activity Score (scores range from 0 to 7, with a score of ≥3 indicating active thyroid-associated ophthalmopathy) and a reduction of 2 mm or more in proptosis at week 24. Secondary end points, measured as continuous variables, included proptosis, the Clinical Activity Score, and results on the Graves' ophthalmopathy-specific quality-of-life questionnaire. Adverse events were assessed. RESULTS: In the intention-to-treat population, 29 of 42 patients who received teprotumumab (69%), as compared with 9 of 45 patients who received placebo (20%), had a response at week 24 (P&lt;0.001). Therapeutic effects were rapid; at week 6, a total of 18 of 42 patients in the teprotumumab group (43%) and 2 of 45 patients in the placebo group (4%) had a response (P&lt;0.001). Differences between the groups increased at subsequent time points. The only drug-related adverse event was hyperglycemia in patients with diabetes; this event was controlled by adjusting medication for diabetes. CONCLUSIONS: In patients with active ophthalmopathy, teprotumumab was more effective than placebo in reducing proptosis and the Clinical Activity Score. (Funded by River Vision Development and others; ClinicalTrials.gov number, NCT01868997 .)

Large-scale GWAS reveals insights into the genetic architecture of same-sex sexual behavior.

Twin and family studies have shown that same-sex sexual behavior is partly genetically influenced, but previous searches for specific genes involved have been underpowered. We performed a genome-wide association study (GWAS) on 477,522 individuals, revealing five loci significantly associated with same-sex sexual behavior. In aggregate, all tested genetic variants accounted for 8 to 25% of variation in same-sex sexual behavior, only partially overlapped between males and females, and do not allow meaningful prediction of an individual's sexual behavior. Comparing these GWAS results with those for the proportion of same-sex to total number of sexual partners among nonheterosexuals suggests that there is no single continuum from opposite-sex to same-sex sexual behavior. Overall, our findings provide insights into the genetics underlying same-sex sexual behavior and underscore the complexity of sexuality