Autoimmune Disorders Associated With Surgical Remission of Cushing's Disease : A Cohort Study.

BACKGROUND: Glucocorticoids suppress inflammation. Autoimmune disease may occur after remission of Cushing's disease (CD). However, the development of autoimmune disease in this context is not well described. OBJECTIVE: To determine 1) the incidence of autoimmune disease in patients with CD after surgical remission compared with patients with nonfunctioning pituitary adenomas (NFPAs) and 2) the clinical presentation of and risk factors for development of autoimmune disease in CD after remission. DESIGN: Retrospective matched cohort analysis. SETTING: Academic medical center/pituitary center. PATIENTS: Patients with CD with surgical remission and surgically treated NFPA. MEASUREMENTS: Cumulative incidence of new-onset autoimmune disease at 3 years after surgery. Assessment for hypercortisolemia included late-night salivary cortisol levels, 24-hour urine free cortisol (UFC) ratio (UFC value divided by the upper limit of the normal range for the assay), and dexamethasone suppression tests. RESULTS: Cumulative incidence of new-onset autoimmune disease at 3 years after surgery was higher in patients with CD (10.4% [95% CI, 5.7% to 15.1%]) than in those with NFPAs (1.6% [CI, 0% to 4.6%]) (hazard ratio, 7.80 [CI, 2.88 to 21.10]). Patients with CD showed higher prevalence of postoperative adrenal insufficiency (93.8% vs. 16.5%) and lower postoperative nadir serum cortisol levels (63.8 vs. 282.3 nmol/L) than patients with NFPAs. Compared with patients with CD without autoimmune disease, those who developed autoimmune disease had a lower preoperative 24-hour UFC ratio (2.7 vs. 6.3) and a higher prevalence of family history of autoimmune disease (41.2% vs. 20.9%). LIMITATION: The small sample of patients with autoimmune disease limited identification of independent risk factors. CONCLUSION: Patients achieving surgical remission of CD have higher incidence of autoimmune disease than age- and sex-matched patients with NFPAs. Family history of autoimmune disease is a potential risk factor. Adrenal insufficiency may be a trigger. PRIMARY FUNDING SOURCE: Recordati Rare Diseases Inc.

Rice florigens control a common set of genes at the shoot apical meristem including the F-BOX BROADER TILLER ANGLE 1 that regulates tiller angle and spikelet development.

Rice flowering is triggered by transcriptional reprogramming at the shoot apical meristem (SAM) mediated by florigenic proteins produced in leaves in response to changes in photoperiod. Florigens are more rapidly expressed under short days (SDs) compared to long days (LDs) and include the HEADING DATE 3a (Hd3a) and RICE FLOWERING LOCUS T1 (RFT1) phosphatidylethanolamine binding proteins. Hd3a and RFT1 are largely redundant at converting the SAM into an inflorescence, but whether they activate the same target genes and convey all photoperiodic information that modifies gene expression at the SAM is currently unclear. We uncoupled the contribution of Hd3a and RFT1 to transcriptome reprogramming at the SAM by RNA sequencing of dexamethasone-inducible over-expressors of single florigens and wild-type plants exposed to photoperiodic induction. Fifteen highly differentially expressed genes common to Hd3a, RFT1, and SDs were retrieved, 10 of which still uncharacterized. Detailed functional studies on some candidates revealed a role for LOC_Os04g13150 in determining tiller angle and spikelet development and the gene was renamed BROADER TILLER ANGLE 1 (BRT1). We identified a core set of genes controlled by florigen-mediated photoperiodic induction and defined the function of a novel florigen target controlling tiller angle and spikelet development.

Levothyroxine for a high-normal TSH in unexplained infertility.

OBJECTIVE: Unexplained infertility affects nearly one-third of infertile couples. Women with unexplained infertility are more likely to have a high-normal thyroid-stimulating hormone level (TSH: 2.5-5 mIU/L) compared to women with severe male factor infertility. Practice guidelines vary on whether treatment should be initiated for TSH levels >2.5 mIU/L in women attempting conception because the effects of treating a high-normal TSH level with levothyroxine are not known. We evaluated conception and live birth rates in women with unexplained infertility and high-normal TSH levels. DESIGN, PATIENTS AND MEASUREMENTS: Retrospective study including 96 women evaluated for unexplained infertility at a large academic medical centre between 1 January 2000 and 30 June 2017 with high-normal TSH (TSH: 2.5-5 mIU/L and within the normal range of the assay) who were prescribed (n = 31) or not prescribed (n = 65) levothyroxine. Conception and live birth rates were assessed. RESULTS: The conception rate in the levothyroxine group was 100% compared to 90% in the untreated group (p = .086 unadjusted; p < .05 adjusted for age; p = .370 adjusted for TSH; p = .287 adjusted for age and TSH). The live birth rate was lower in the levothyroxine group (63%) compared to the untreated group (84%) (p = .05 unadjusted; p = .094 adjusted for age; p = .035 adjusted for TSH; p = .057 adjusted for age and TSH). CONCLUSIONS: Women with unexplained infertility and high-normal TSH levels treated with levothyroxine had a higher rate of conception but lower live birth rate compared to untreated women, with the limitation of a small sample size. These findings assert the need for prospective, randomized studies to determine whether treatment with levothyroxine in women with unexplained infertility and high-normal TSH is beneficial.

Incidence of postoperative hyponatremia after endoscopic endonasal pituitary transposition for skull base pathologies.

PURPOSE: Pituitary transposition is a novel surgical approach to access the retroinfundibular space and interpeduncular cistern. Few studies have evaluated post-surgical outcomes, including incidence of hyponatremia, following pituitary transposition. METHODS: This is a retrospective study including 72 patients who underwent endoscopic endonasal surgery involving pituitary transposition for non-pituitary derived tumors over a decade at the University of Pittsburgh Medical Center. Anterior pituitary deficiencies and replacement therapy, tumor pathology and pre-operative serum sodium (Na) were recorded. Na was assessed at postoperative day 1, 3, 5, 7, and 10. Anatomical/surgical parameters included sellar height, sellar access angle to approach the tumor, and cranial extension of the tumor above the sellar floor (B) compared to the height of the gland (A) (B/A). T-test (normally distributed variables) and Wilcoxon rank-sum test (not-normally distributed) were applied for mean comparison. Logistic regression analyzed correlations between anatomical/surgical parameters and postoperative hyponatremia. RESULTS: 55.6% of patients developed post-operative transient hyponatremia. Two patients (5%) developed severe hyponatremia (sodium level < 120 mmol/L). Eleven (15.3%) patients required desmopressin replacement immediately post-operatively, and 2 other patients needed desmopressin after discharge and after sodium nadir developed. Hyponatremia was inversely associated with sellar access angle (p = 0.02) and the tumor cranial extension above the sellar floor showing a trend towards significance (p = 0.09). CONCLUSION: More than half of patients who had pituitary transposition developed transient hyponatremia. Hyponatremia was more common in those with narrower sellar access angle and smaller cranial extension of the tumor above the sellar floor. Anatomical/surgical parameters may allow risk-stratification for post-operative hyponatremia following pituitary transposition.

The anabolic applications of androgens in older adults with functional limitations.

Aging is associated with a progressive decrease in skeletal muscle mass, strength and power and impairment of physical function. Serum testosterone concentrations in men decrease with advancing age due to defects at all levels of the hypothalamic-pituitary-testicular axis. Testosterone administration increases skeletal muscle mass, strength and power in older men with low or low normal testosterone levels, but the effects on performance-based measures of physical function have been inconsistent. Adequately powered randomized trials are needed to determine the long-term safety and efficacy of testosterone in improving physical function and quality of life in older adults with functional limitations.

Antagonistic Transcription Factor Complexes Modulate the Floral Transition in Rice.

Plants measure day or night lengths to coordinate specific developmental changes with a favorable season. In rice (Oryza sativa), the reproductive phase is initiated by exposure to short days when expression of HEADING DATE 3a (Hd3a) and RICE FLOWERING LOCUS T 1 (RFT1) is induced in leaves. The cognate proteins are components of the florigenic signal and move systemically through the phloem to reach the shoot apical meristem (SAM). In the SAM, they form a transcriptional activation complex with the bZIP transcription factor OsFD1 to start panicle development. Here, we show that Hd3a and RFT1 can form transcriptional activation or repression complexes also in leaves and feed back to regulate their own transcription. Activation complexes depend on OsFD1 to promote flowering. However, additional bZIPs, including Hd3a BINDING REPRESSOR FACTOR1 (HBF1) and HBF2, form repressor complexes that reduce Hd3a and RFT1 expression to delay flowering. We propose that Hd3a and RFT1 are also active locally in leaves to fine-tune photoperiodic flowering responses.

Medical comorbidities and endocrine dysfunction in low-weight females with avoidant/restrictive food intake disorder compared to anorexia nervosa and healthy controls.

OBJECTIVE: To improve our understanding of medical complications and endocrine alterations in patients with low-weight avoidant/restrictive food intake disorder (ARFID) and how they may differ from those in anorexia nervosa (AN) and healthy controls (HC). METHOD: We performed an exploratory cross-sectional study comparing low-weight females with ARFID (n = 20) with females with AN (n = 42) and HC (n = 49) with no history of an eating disorder. RESULTS: We found substantial overlap in medical comorbidities and endocrine features in ARFID and AN, but with earlier onset of aberrant eating behaviors in ARFID. We also observed distinct medical and endocrine alterations in ARFID compared to AN, such as a greater prevalence of asthma, a lower number of menses missed in the preceding 9 months, higher total T3 levels, and lower total T4 : total T3 ratio; these differences persisted after adjusting for age and might reflect differences in pathophysiology, acuity of weight fluctuations, and/or nutritional composition of food consumed. CONCLUSION: These results highlight the need for prompt diagnosis and intensive therapeutic intervention from disease onset in ARFID.

Transcriptional and Post-transcriptional Mechanisms Limit Heading Date 1 (Hd1) Function to Adapt Rice to High Latitudes.

Rice flowering is controlled by changes in the photoperiod that promote the transition to the reproductive phase as days become shorter. Natural genetic variation for flowering time has been largely documented and has been instrumental to define the genetics of the photoperiodic pathway, as well as providing valuable material for artificial selection of varieties better adapted to local environments. We mined genetic variation in a collection of rice varieties highly adapted to European regions and isolated distinct variants of the long day repressor HEADING DATE 1 (Hd1) that perturb its expression or protein function. Specific variants allowed us to define novel features of the photoperiodic flowering pathway. We demonstrate that a histone fold domain scaffold formed by GRAIN YIELD, PLANT HEIGHT AND HEADING DATE 8 (Ghd8) and several NF-YC subunits can accommodate distinct proteins, including Hd1 and PSEUDO RESPONSE REGULATOR 37 (PRR37), and that the resulting OsNF-Y complex containing Hd1 can bind a specific sequence in the promoter of HEADING DATE 3A (Hd3a). Artificial selection has locally favored an Hd1 variant unable to assemble in such heterotrimeric complex. The causal polymorphism was defined as a single conserved lysine in the CCT domain of the Hd1 protein. Our results indicate how genetic variation can be stratified and explored at multiple levels, and how its description can contribute to the molecular understanding of basic developmental processes.

Hd3a, RFT1 and Ehd1 integrate photoperiodic and drought stress signals to delay the floral transition in rice.

Plants show a high degree of developmental plasticity in response to external cues, including day length and environmental stress. Water scarcity in particular can interfere with photoperiodic flowering, resulting in the acceleration of the switch to reproductive growth in several species, a process called drought escape. However, other strategies are possible and drought stress can also delay flowering, albeit the underlying mechanisms have never been addressed at the molecular level. We investigated these interactions in rice, a short day species in which drought stress delays flowering. A protocol that allows the synchronization of drought with the floral transition was set up to profile the transcriptome of leaves subjected to stress under distinct photoperiods. We identified clusters of genes that responded to drought differently depending on day length. Exposure to drought stress under floral-inductive photoperiods strongly reduced transcription of EARLY HEADING DATE 1 (Ehd1), HEADING DATE 3a (Hd3a) and RICE FLOWERING LOCUS T 1 (RFT1), primary integrators of day length signals, providing a molecular connection between stress and the photoperiodic pathway. However, phenotypic and transcriptional analyses suggested that OsGIGANTEA (OsGI) does not integrate drought and photoperiodic signals as in Arabidopsis, highlighting molecular differences between long and short day model species.

Loss of floral repressor function adapts rice to higher latitudes in Europe.

The capacity to discriminate variations in day length allows plants to align flowering with the most favourable season of the year. This capacity has been altered by artificial selection when cultivated varieties became adapted to environments different from those of initial domestication. Rice flowering is promoted by short days when HEADING DATE 1 (Hd1) and EARLY HEADING DATE 1 (Ehd1) induce the expression of florigenic proteins encoded by HEADING DATE 3a (Hd3a) and RICE FLOWERING LOCUS T 1 (RFT1). Repressors of flowering antagonize such induction under long days, maintaining vegetative growth and delaying flowering. To what extent artificial selection of long day repressor loci has contributed to expand rice cultivation to Europe is currently unclear. This study demonstrates that European varieties activate both Hd3a and RFT1 expression regardless of day length and their induction is caused by loss-of-function mutations at major long day floral repressors. However, their contribution to flowering time control varies between locations. Pyramiding of mutations is frequently observed in European germplasm, but single mutations are sufficient to adapt rice to flower at higher latitudes. Expression of Ehd1 is increased in varieties showing reduced or null Hd1 expression under natural long days, as well as in single hd1 mutants in isogenic backgrounds. These data indicate that loss of repressor genes has been a key strategy to expand rice cultivation to Europe, and that Ehd1 is a central node integrating floral repressive signals.

An integrative model of the control of ovule primordia formation.

Upon hormonal signaling, ovules develop as lateral organs from the placenta. Ovule numbers ultimately determine the number of seeds that develop, and thereby contribute to the final seed yield in crop plants. We demonstrate here that CUP-SHAPED COTYLEDON 1 (CUC1), CUC2 and AINTEGUMENTA (ANT) have additive effects on ovule primordia formation. We show that expression of the CUC1 and CUC2 genes is required to redundantly regulate expression of PINFORMED1 (PIN1), which in turn is required for ovule primordia formation. Furthermore, our results suggest that the auxin response factor MONOPTEROS (MP/ARF5) may directly bind ANT, CUC1 and CUC2 and promote their transcription. Based on our findings, we propose an integrative model to describe the molecular mechanisms of the early stages of ovule development.

Weight regain after total meal replacement very low-calorie diet program with and with-out anti-obesity medications.

Background: Very low-calorie diets (VLCDs) employing total meal replacement (TMR) offer substantial short-term weight loss. Concurrently, anti-obesity medications (AOMs) have shown promise as adjunctive treatments when combined with VLCDs. Aims: This study aimed to investigate the impact of adjuvant AOMs on weight loss and weight regain within a comprehensive lifestyle program. Methods: This is a retrospective study of patients with obesity enrolled in VLCD/TMR programs,  specifically the OPTIFAST program. Results: Data from 206 patients (68% women, mean age 52.39 ± 13.05 years, BMI 41.71 ± 7.04 kg/m2) were analyzed. Of these, 139 received no AOM (AOM-), while 67 received AOMs (AOM+). Total body weight loss percentages (TWL%) at 6 and 18 months were -17.87% ± 7.02 and -12.10% ± 11.56, respectively. There was no significant difference in 6-month weight loss between the AOM groups. However, the AOM + group exhibited lower weight regain (3.29 kg ± 10.19 vs. 7.61 kg ± 11.96; p = 0.006) and weight regain percentage (WR%) (31.5% ± 68.7 vs. 52.16% ± 64.4; p = 0.04) compared with the AOM- group. Conclusion: The findings highlighted the potential of AOMs and VLCD/TMR as effective strategies for long-term weight management in individuals with obesity.

Intranasal Oxytocin for Obesity.

BACKGROUND: Accumulating preclinical and preliminary translational evidence shows that the hypothalamic peptide oxytocin reduces food intake, increases energy expenditure, and promotes weight loss. It is currently unknown whether oxytocin administration is effective in treating human obesity. METHODS: In this randomized, double-blind, placebo-controlled trial, we randomly assigned adults with obesity 1:1 (stratified by sex and obesity class) to receive intranasal oxytocin (24 IU) or placebo four times daily for 8 weeks. The primary end point was change in body weight (kg) from baseline to week 8. Key secondary end points included change in body composition (total fat mass [g], abdominal visceral adipose tissue [cm2], and liver fat fraction [proportion; range, 0 to 1; higher values indicate a higher proportion of fat]), and resting energy expenditure (kcal/day; adjusted for lean mass) from baseline to week 8 and caloric intake (kcal) at an experimental test meal from baseline to week 6. RESULTS: Sixty-one participants (54% women; mean age ± standard deviation, 33.6 ± 6.2 years; body-mass index [the weight in kilograms divided by the square of the height in meters], 36.9 ± 4.9) were randomly assigned. There was no difference in body weight change from baseline to week 8 between oxytocin and placebo groups (0.20 vs. 0.26 kg; P=0.934). Oxytocin (vs. placebo) was not associated with beneficial effects on body composition or resting energy expenditure from baseline to week 8 (total fat: difference [95% confidence interval], 196.0 g [-1036 to 1428]; visceral fat: 3.1 cm2 [-11.0 to 17.2]; liver fat: -0.01 [-0.03 to 0.01]; resting energy expenditure: -64.0 kcal/day [-129.3 to 1.4]). Oxytocin compared with placebo was associated with reduced caloric intake at the test meal (-31.4 vs. 120.6 kcal; difference [95% confidence interval], -152.0 kcal [-302.3 to -1.7]). There were no serious adverse events. Incidence and severity of adverse events did not differ between groups. CONCLUSIONS: In this randomized, placebo-controlled trial in adults with obesity, intranasal oxytocin administered four times daily for 8 weeks did not reduce body weight. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; ClinicalTrials.gov number, NCT03043053.).

VERDANDI is a direct target of the MADS domain ovule identity complex and affects embryo sac differentiation in Arabidopsis.

In Arabidopsis thaliana, the three MADS box genes SEEDSTICK (STK), SHATTERPROOF1 (SHP1), and SHP2 redundantly regulate ovule development. Protein interaction studies have shown that a multimeric complex composed of the ovule identity proteins together with the SEPALLATA MADS domain proteins is necessary to determine ovule identity. Despite the extensive knowledge that has become available about these MADS domain transcription factors, little is known regarding the genes that they regulate. Here, we show that STK, SHP1, and SHP2 redundantly regulate VERDANDI (VDD), a putative transcription factor that belongs to the plant-specific B3 superfamily. The vdd mutant shows defects during the fertilization process resulting in semisterility. Analysis of the vdd mutant female gametophytes indicates that antipodal and synergid cell identity and/or differentiation are affected. Our results provide insights into the pathways regulated by the ovule identity factors and the role of the downstream target gene VDD in female gametophyte development.

Early Onset GH Excess: Somatotroph Adenoma in a Young Adult.

GH-secreting pituitary adenomas can cause gigantism or acromegaly, determined by onset before or after epiphyseal fusion of the distal ends of the radius and ulna. Overlapping phenotypes can occur when the condition presents peripubertally. Gigantism is associated with identifiable hereditary causes and genetic mutations in almost 50% of cases; genetic testing should be considered in patients with gigantism and early-onset acromegaly, especially (but not only) when pituitary tumors have aggressive features and/or are refractory to standard treatments. Here, we present a case of a young adult with a giant somatotroph adenoma resistant to multiple treatment modalities and negative for mutations in AIP, which encodes aryl hydrocarbon receptor-interacting protein.

Hypothalamic and Pituitary Dysfunction After Extensive Brain Surgery: There Is Thirst for More Knowledge.

Craniopharyngiomas are tumors originating from the infundibular stalk, extending to the parasellar and suprasellar region, thereby conferring multiple risks of this region. In particular, hypothalamic and pituitary damage related to its natural history as well as treatment effects of craniopharyngiomas substantially affect life expectancy and quality of life. Here, we describe an adult patient presenting with polyuria, memory, and visual field impairment secondary to concurrent craniopharyngioma and intraventricular glioma. He was treated with surgical resection with postoperative course notable for hypothalamic-pituitary dysfunction, including central hypothyroidism, central adrenal insufficiency, arginine vasopressin deficiency (AVP-D, formerly diabetes insipidus) with loss of sense of thirst, and hypothalamic hypothermia. The adipsia, combined with memory dysfunction, challenged the management of constant fluctuations in his sodium (129-168 mEq/L), with ultimate treatment through vasopressin repletion, fixed fluid intake, strict urine output monitoring, and close counseling of the patient and his caregiver. This case exemplifies the complexity of the endocrine care of patients with craniopharyngiomas and highlights the need for step-wise algorithms in the treatment of hypothalamic deficiencies such as adipsia.

Diabetes Mellitus Type 1 Presenting in the Setting of Diabetic Ketoacidosis and Acute SARS-CoV-2 Infection in Pregnancy.

Background/Objective: Diabetic ketoacidosis (DKA) during pregnancy is an obstetric emergency associated with a higher rate of maternofetal morbidity and mortality. Pregnancy itself is a ketosis-prone state and several unique mechanisms predispose to the development of insulin resistance, which can be further exacerbated by acute stressors such as infection. Thus, pregnant patients who additionally contract COVID-19 may be at an even higher risk of development of DKA. Case Report: A 32-year-old patient, with no prior history of impaired glucose tolerance, presented at 27 weeks of gestation with a 3-day history of shortness of breath, congestion, loss of taste and smell, polyuria, and polydipsia. Biochemical evaluation was consistent with DKA. Subsequently, she was diagnosed with acute SARS-CoV-2 infection. Treatment included intravenous hydration, electrolyte replacement, and insulin infusion. Postpartum phenotypic evaluation confirmed autoimmune diabetes (positive GAD-65 and zinc T8 antibodies) with residual ß-cell function. Six months postpartum, glycemic control remains at goal with basal- bolus insulin regimen. Discussion: This case describes the peculiar ability of SARS-CoV-2 infection to potentially rouse autoimmunity and how COVID-19 and DKA in pregnancy can be particularly challenging given the risk of significant maternal and fetal morbidity and mortality. Conclusion: Prompt diagnosis and evaluation of DKA in pregnancy as well as a higher level of suspicion is needed in the setting of SARS-CoV-2 infection. Additionally, this case depicts the need for closely monitoring the postpartum period for patients at risk of autoimmune disease, which may have been blunted in pregnancy.

Accurate measurement of total and free testosterone levels for the diagnosis of androgen disorders.

The circulating concentrations of total and free testosterone vary substantially in people over time due to biologic factors as well as due to measurement variation. Accurate measurement of total and free testosterone is essential for making the diagnosis of androgen disorders. Total testosterone should ideally be measured in a fasting state in the morning using a reliable assay, such as liquid chromatography tandem mass spectrometry, in a laboratory that is certified by an accuracy-based benchmark. Free testosterone levels should be measured in men in whom alterations in binding protein concentrations are suspected or in whom total testosterone levels are only slightly above or slightly below the lower limit of the normal male range for testosterone.