Lack Of Suppression Research Articles

12376 Comparison Of 1 Mg Versus 2 Mg Dexamethasone Suppression In Obesity

Abstract Disclosure: H. Babu: None. A. Nawaz: None. A.J. Spiro: None. T.D. Hoang: None. M.K. Shakir: None. The overnight 1 mg dexamethasone suppression test (DST) is widely used to screen for Cushing’s Syndrome (CS), especially due to its low incidence of false negative results. Serum cortisol concentrations <1.8 µg/dL suggests adequate HPA axis suppression and usually excludes CS. Concentrations >1.8 µg/dL should be verified with a second test. However, the lack of suppression on DST has been documented previously in 1.46% to 15% of obese patients without CS. Previous studies have suggested simultaneous measurements of serum cortisol, ACTH, and dexamethasone levels after DST to ensure adequate suppression. In this retrospective analysis, we compared the plasma levels of ACTH, dexamethasone, and cortisol levels after 1 mg and 2 mg DST in healthy obese (class III) subjects. The study involved 6 subjects (2 males, 4 females, age 37.5 ± 8.79 years, BMI 43.65 ± 3.12 (kg/m2) who were referred for evaluation of abnormal weight gain. Exclusion criteria for these subjects included diabetes mellitus, pregnancy, history of CS, psychiatric disorders, chronic liver disease, chronic renal failure, malabsorption disorders and nephrotic syndrome. The exclusion of CS was done by history and physical examination showing the lack of specific clinical features of CS. Additionally, none of the subjects were taking drugs that interfered with CYP3A4 or oral contraceptives within 3 months preceding the study. None of the participants reported alcohol consumption of more than 30 g per day. Screening tests for CS involved 1 mg, 2 mg DST, LNSC and 24-hour urine cortisol levels. Results: Following 1 mg DST in 5 subjects, the mean serum cortisol levels were 1.35 ± 0.13 mcg/dL and the mean serum dexamethasone levels, and ACTH levels were 282 ± 44 ng/dL and 5.92 ± 1.56 pg/mL, respectively. However, in one subject (BMI 43.5) the post-DST cortisol level was 2.96 mcg/dL with corresponding dexamethasone level of 138 ng/dL and ACTH level of 21 pg/mL. However, following 2 mg DST in all 6 subjects the serum cortisol levels were less than 1.8 mcg/dL (1.21± 0.22 mcg/dL) with ACTH levels (3.87 ± 0.70 pg/mL) and dexamethasone levels of 482 ± 80 ng/dL. The LNSC levels were normal in 4 subjects (0.010 ± 0.005 mcg/dL), whereas in 2 subjects these were minimally elevated. 24-hour urine cortisol levels were normal in 5 subjects (29.4 ± 3.74 mcg) and in one subject this was mildly elevated (67 mcg). Long term follow-up of all subjects confirmed normal cortisol status. Previous studies have demonstrated that routine CS screening of patients affected by severe obesity is not indicated. However, other investigations have shown CS may occur in a small percentage of severe obese patients. In conclusion, 2 mg DST is a preferred test in obese patients suspected to have CS although 1 mg DST generally can be used as an initial screening test. Additionally, serum dexamethasone and ACTH measurements may still be useful in patients who are suspected to have a false-positive DST. Presentation: 6/1/2024

Frequency of low-dose dexamethasone suppression test (LDDST) response patterns and their correlation with clinicopathologic signs in dogs suspected of having Cushing's syndrome: A retrospective study

A retrospective cross-sectional study was conducted to assess the frequency of low-dose dexamethasone suppression test (LDDST) patterns in canine patients that had clinicopathologic signs consistent with Cushing's syndrome (CS). Medical records for patients of interest (N = 128) were reviewed between January 2014 and December 2020 to analyse and classify LDDST results based upon the following patterns: lack of suppression, partial suppression, complete suppression, escape, or inverse. Complete suppression, lack of suppression, partial suppression, escape, and inverse patterns were identified in 39.1%, 31.2%, 14.1%, 10.1% and 5.5% of cases respectively. LDDST results were also evaluated with respect to clinical signs, serum alkaline phosphatase (ALP) activity, urine specific gravity (USG) and adrenal ultrasonographic findings. There was no association between LDDST patterns and clinical signs (p = 0.11), increased ALP (p = 0.32), USG (p = 0.33) or adrenal ultrasonographic findings (p = 0.19). In all dogs that demonstrated complete suppression or an inverse pattern, CS was excluded by the attending clinician. The diagnosis of CS was also excluded without further exploration in 23.1%, 7.5% and 5.6% of dogs that demonstrated an escape pattern, lack of suppression and partial suppression pattern, respectively. These results suggest that the clinical significance of LDDST patterns, particularly escape and inverse patterns, are misunderstood by some clinicians, leading them to prematurely exclude the diagnosis of CS.

PMON98 High-dose dexamethasone suppression test in ACTH-dependent Cushing's syndrome: Lessons learned on the lack of cortisol suppression

Abstract Background The overnight 8-mg high-dose dexamethasone suppression test (HDDST) has been used to discern Cushing's disease from ectopic ACTH production. However, because of its reported low diagnostic accuracy, its use is limited to the assessment of ACTH-dependent Cushing's disease when combined with a corticotropin releasing hormone (CRH) or a desmopressin stimulation test. We evaluated a patient with Cushing's disease in whom the HDDST failed to identify the pituitary source. We point to limitations in test interpretation and highlight the need of future studies to enhance understanding of the clinical utility of this non-invasive test. Clinical Case A 42-year-old male presented with lower extremity cellulitis and hypertensive emergency. He reported increased abdominal girth, easy bruising, severe back pain and proximal muscle weakness and noted headache and blurred vision. Exam was pertinent for obesity (body mass index 31.5 kg/m2), moon facies, dorso-cervical hump and prominent abdominal striae. Lumbar and thoracic compression fractures were noted on imaging. The elevated 24-hour urinary free cortisol level (198 ug/dL; reference: 10-100 ug/24hr) and lack of suppression on the overnight 1-mg dexamethasone suppression test (morning cortisol 23.7 ug/dL) confirmed Cushing's syndrome; a high ACTH level of 92 pg/dL defined it as ACTH-dependent. The 8-mg HDDST resulted in only a 9.7% reduction of his baseline morning cortisol. The patient was not on any medications that enhanced dexamethasone clearance. Serum dexamethasone levels were measured to aid in test interpretation and, although a level was provided, reference values for the single overnight 8-mg dose of dexamethasone were lacking. A CRH stimulation test was performed and resulted in a 60% increase in ACTH levels from baseline, supporting the diagnosis of Cushing's disease. Additionally, a pituitary MRI revealed a suprasellar 2.5×1.5×1.3 cm mass. Due to ambiguity posed by the HDDST result, despite tumor size, neurosurgery requested inferior petrosal sinus sampling (IPSS). Prior to this procedure, the patient underwent an overnight 16-mg HDDST. While limited information remains on the diagnostic performance of this test, we observed that the baseline morning cortisol decreased by 53.9%. IPSS confirmed the diagnosis of Cushing's disease and pathology identified a corticotroph adenoma. Conclusion The diagnosis of Cushing's disease is complex and recommendations continue to evolve. Th role of the HDDST in combination with another dynamic test remains clinically relevant. It is important that when considering a HDDST, clinicians review medication history to exclude agents that may interfere with dexamethasone metabolism. Our case highlights the need of studies that determine an appropriate reference range for dexamethasone plasma levels after a single 8-mg overnight dose and that evaluate the diagnostic performance of the HDDST in this context. It also brings attention to the need of further elucidating the diagnostic utility of a higher dexamethasone dose in the evaluation of ACTH-dependent Cushing's syndrome. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

ODP621 Hypertension with Hypokalemia in Pregnancy? Think "Cushing's Syndrome"

Abstract Introduction Pregnancy is uncommon in women with Cushing's syndrome (CS) as hypercortisolism and hyperandrogenism suppress gonadotropins leading to anovulatory cycles. Such pregnancies carry a higher rate of fetal morbidity and mortality. Therefore, it is of paramount importance to diagnose and treat CS in pregnancy. The diagnosis of CS in pregnancy is challenging due to the physiologic changes of the hypothalamic-pituitary-adrenal axis during pregnancy. We describe a case of CS in pregnancy that was a successfully treated with surgery. Case description An asymptomatic 39-year-old pregnant female patient with gestational hypertension was admitted to the hospital after she was found to have uncontrolled hypertension (while on 3 anti-hypertensive medications) and severe hypokalemia with potassium level of 2.8 mEq/L. She was 14 weeks pregnant at the time. She has a family history of primary aldosteronism in her father successfully treated with adrenalectomy at the age of 60. Her work up included blood work (done at 13: 42) which showed sodium level of 146 mEq/L, plasma aldosterone concentration of <1 ng/dL, plasma renin activity of 1.0 ng/mL/hr, total testosterone of 46 ng/dL, DHEA-S of 31 mcg/dL, plasma metanephrines <50 pg/mL, 24-hour urine metanephrines 70 ug, 24-hour urine normetanephrines 164 ug/24 hrs, ACTH 5 pg/mL, and cortisol 28.2 mcg/dl. MRI abdomen without contrast showed a 3.5×3.0×4.2 cm left adrenal nodule consistent with adenoma. Patient was diagnosed with non-ACTH dependent subclinical CS based on her elevated cortisol and low ACTH levels. She underwent left laparoscopic adrenalectomy and was discharged on oral hydrocortisone. Pathology showed adrenal cortical adenoma. Her blood pressure normalized shortly after surgery and her anti-hypertensive medications were stopped. Discussion Pregnancy is associated with multiple changes in the hypothalamic-pituitary-adrenal axis making diagnosis of CS in pregnancy challenging. Those changes include increased Cortisol binding globulin production leading to increased serum cortisol level and lack of suppression with Dexamethasone beside placental production of CRH and ACTH, all leading to increased salivary and urinary free cortisol levels, as well. This case of hypertension and hypokalemia in pregnancy presented a diagnostic dilemma. Furthermore, the clinical presentation was confounded by a family history of primary aldosteronism. However, the low serum ACTH level highly suggested the diagnosis of CS. Unfortunately, there are no pregnancy-specific guidelines for the diagnosis of CS. The dexamethasone suppression test is not recommended as it often yields false-positive results. The use of urinary free cortisol and late-night salivary cortisol is recommended, and the diagnosis is established when results are three to four times the upper limit of normal. ACTH levels <10 pg/ml are suggestive of adrenal CS. MRI without contrast can be used for imaging. To date, there have been over 260 reported cases of CS in pregnancy with more than half of them being. Presentation: No date and time listed

The Role of Glucocorticoid Receptor in the Pathophysiology of Pituitary Corticotroph Adenomas.

Adrenocorticotropic Hormone (ACTH)-secreting pituitary adenomas are rare tumors characterized by autonomous ACTH secretion with a consequent increase in circulating cortisol levels. The resulting clinical picture is called Cushing’s disease (CD), a severe condition burdened with high morbidity and mortality. Apart from increased cortisol levels, CD patients exhibit a partial resistance to the negative glucocorticoid (GC) feedback, which is of paramount clinical utility, as the lack of suppression after dexamethasone administration is one of the mainstays for the differential diagnosis of CD. Since the glucocorticoid receptor (GR) is the main regulator of negative feedback of the hypothalamic–pituitary–adrenal axis in normal conditions, its implication in the pathophysiology of ACTH-secreting pituitary tumors is highly plausible. In this paper, we review GR function and structure and the mechanisms of GC resistance in ACTH-secreting pituitary tumors and assess the effects of the available medical therapies targeting GR on tumor growth.

Low but not undetectable early postoperative nadir serum cortisol predicts sustained remission in Cushing's disease.

Transsphenoidal surgery (TSS) is the first-line treatment for Cushing's disease. The objectives of the study were to determine remission and recurrence rates after TSS for Cushing's disease, identify factors that predict these outcomes, and define the threshold for postoperative morning serum cortisol (MSeC) that most accurately predicts sustained remission. Records were retrospectively reviewed for consecutive adults undergoing TSS for Cushing's disease at a tertiary centre (1990-2019). Remission was defined as MSeC <138 nmol/L by 6 weeks postoperatively. Recurrence was defined as elevated 24-h urine free cortisol, lack of suppression after dexamethasone or elevated midnight salivary cortisol. In this study, 42 patients (age 47 ± 13 years, 83% female) were assessed with 55 ± 56 months of follow-up. Remission occurred after 77% of primary (n = 30) and 42% of revision operations (n = 12). After primary surgery, remission was associated with lower MSeC nadir (26 ± 36 nmol/L vs 347 ± 220 nmol/L, P < 0.01) and lower adrenocorticotropin nadir (2 ± 3 pmol/L vs 6 ± 3 pmol/L, P = 0.01). Sustained remission 5 years after surgery was predicted by MSeC <92 nmol/L within 2 weeks postoperatively (sensitivity 100% and specificity 100%). After revision surgery, remission was predicted by lower MSeC nadir (70 ± 45 nmol/L vs 408 ± 305 nmol/L, P = 0.03), smaller tumour diameter (3 ± 2 mm vs 15 ± 13 mm, P = 0.05) and absence of cavernous sinus invasion (0% vs 71%, P = 0.03). Recurrence after primary and revision surgery occurred in 17% and 20% of patients respectively. Lower postoperative MSeC nadir strongly predicted remission after both primary and revision surgery. Following primary surgery, an MSeC <92 nmol/L within 2 weeks predicted sustained remission at 5 years. MSeC nadir was the most important prognostic marker following TSS for Cushing's disease.

Elevated Pre-injection Basal Luteinizing Hormone Concentrations are Common in Girls Treated for Central Precocious Puberty

Objective:A consensus on how to monitor girls with central precocious puberty (CPP) during gonadotropin-releasing hormone agonist (GnRHa) treatment is lacking. Increased, unstimulated basal luteinizing hormone (LH) concentrations have been suggested to indicate lack of suppression. The aim was to evaluate pre-injection basal LH concentrations during GnRHa (leuprorelin 3.75 mg) treatment every four weeks in girls with CPP.Methods:Medical records were reviewed for girls with CPP treated at a single center from 2014-2019. Clinical characteristics and laboratory findings during treatment were systematically recorded.Results:A total of 587 GnRHa pre-injection basal LH concentrations were analyzed in 74 girls. Basal LH was pubertal (≥0.3 IU/L) in 53.5% of blood samples and 87.8% of all girls had a pubertal basal LH concentration at least once. A GnRH test (n=29) was repeated in 23 girls due to suspicion of clinical progression, elevated basal LH or recordable estradiol concentrations. None had a stimulated LH >3.1 IU/L. The predictability of treatment suppression (specificity) of basal LH concentrations was 12.0% when compared to repeated GnRH stimulation tests. Despite shortening the GnRHa injection interval to three weeks, basal LH concentrations remained pubertal in 85.7% girls. A significant reduction in height standard deviation score (p<0.001) and bone age advance (p<0.001) was observed during treatment.Conclusion:Pre-injection basal LH remains at pubertal concentrations during treatment with leuprorelin 3.75 mg in girls with CPP. Clinical monitoring of pubertal progression is preferable to routine basal LH concentrations. Repeat GnRH stimulation testing should be regarded as the gold standard.

Patterns of the low-dose dexamethasone suppression test in canine hyperadrenocorticism revisited.

BackgroundThe low‐dose dexamethasone suppression test (LDDT) is considered an accurate screening and valuable differentiation test in dogs with suspected hyperadrenocorticism (HAC). A recent study showed that the different response patterns not only provide complementary information about etiology, but also the probability of HAC in these patients.ObjectivesWe aimed to determine the diagnostic test performance of LDDT response patterns in a population of dogs from an animal hospital.MethodsThe electronic database was retrospectively searched for dogs suspected of HAC that were given an LDDT. Dogs with acute non‐adrenal illnesses during the test were excluded. Response patterns were classified as complete suppression, lack of suppression, partial suppression, escape, inverse, and increasing patterns. Cortisol concentrations ≥ 27.59 nmol/L (≥1 µg/dL) 8 hours after dexamethasone administration were considered positive results irrespective of the patterns observed. Calculations included likelihood ratios (LRs) and predictive values (PVs).ResultsHAC and non‐adrenal illness were diagnosed in 115 (54%) and 62 (46%) dogs, respectively. The positive (+) LRs (95% CI) for the lack of suppression, partial suppression, escape, and an inverse pattern to diagnose HAC were infinite, 8.09 (2‐32.72), 3.23 (0.75‐14), and 0.2 (0.06‐0.73), respectively.ConclusionsThe study confirms that the “lack of suppression” pattern strongly supports a diagnosis of HAC. It shows that the “partial suppression” pattern moderately increases, and the “inverse” pattern decreases the likelihood of HAC. The fact that the study found no association between the “escape” pattern and a diagnosis of HAC, does not support its integration into decision making.

Is Palinopsia in Migraineurs a Phenomenon of Impaired Habituation of Visual Cortical Neurons?

Palinopsia in migraine has been reported recently, which may be due to the dysexcitability of visual cortical neurons. In this cross-sectional study, we report the correlation of neuronal dysexcitability with palinopsia using pattern shift visual evoked potential (PSVEP) in 91 migraineurs and 25 healthy controls. The presence of palinopsia was evaluated using a novel objective method, and revealed more frequent palinopsia in the migraineurs compared to the controls (53 of 91 [58.2%] vs 3 of 25 [12%]; P < .001). Five consecutive blocks of PSVEP were recorded for the evaluation of sensitization and impaired habituation. Amplitudes of N75 and P100 in block 1 were considered for sensitization. Impaired habituation of N75 and P100 was considered if any amplitudes in blocks 2 to 5 were higher than block 1. Impaired habituation was more frequent in migraineurs compared with the controls, and was more marked in wave N75 (81.3% vs 32%; P < .001) than wave P100 (63.7% vs 44%; P = .12). Impaired habituations of wave N75 (81.7% vs 58.9%; P = .008) and wave P100 (71.7% vs 46.4%; P = .008) were more frequent in those with palinopsia compared with those without. There was a lack of suppression of P100 amplitude in block 3 in the palinopsia group compared to the controls. The duration of palinopsia correlated with the extent of impaired habituation of N75. It can be concluded that the impaired habituation of PSVEP waveforms is a biomarker of palinopsia in migraine.

Induction of apoptosis and role of paclitaxel-loaded hyaluronic acid-crosslinked nanoparticles in the regulation of AKT and RhoA

Cancer is a complex multifactorial disease and leading causes of death worldwide. Despite the development of many anticancer drugs, there is a reduced survival rate due to severe side effects. The nontargeted approach of convention drugs is one of the leading players in context to toxicity. Hyaluronan is a versatile bio-polymer and ligand of the receptor (CD44) on cancer cells. The MCF-7 and HT-29 cancer cell lines treated with hyaluronic acid-paclitaxel (HA-PTX) showed the distinguishing morphological features of apoptosis. Flow cytometric analysis showed that HA-PTX induces apoptosis as a significant mode of cell death. The activation level of tumor suppressor protein (p53) increased after PTX treatment in MCF-7, but no changes observed in HT-29 might be due to hereditary mutations. The lack of suppression in AKT and Rho A protein suggest the use of possible inhibitors in future studies which might could play a role in increasing the sensitivity of drug towards mutated cells line and reducing the possibilities for cancer cell survival, migration, and metastasis.

Tramadol Induced Hypoglycemia Masquerading as a Seizure Disorder

Background: Common causes of hypoglycemia include hypoglycemic agents including exogenous insulin and insulin secretagogues, increased endogenous insulin, decline in circulating cortisol, human growth hormone and enzymes required for glucose production as well as hepatic and renal dysfunction. Case presentation: Patient presented to emergency room with re-current seizures treated with Levetricatem and Topiramate for 10 years with increased frequency of 2-3/week during last 6 months. During ER visits to different hospitals for these episodes, plasma glucose, 1.5-1.8 mM/L and undetectable levels of insulin, C peptide, proinsulin, Insulin antibodies eliminated hyperinsulinemia due to insulinoma, insulin secretagogues as well as exogenous insulin as a cause of hypoglycemia. Normal HGH, ACTH and cortisol responses at onset of hypoglycemia excluded hypopituitarism with HGH and/or ACTH deficiency and primary adrenal insufficiency. Large tumor secreting IGF2 was eliminated by CT scans of chest and abdomen. Hepatic and renal disease as a cause of hypoglycemia were excluded as well by documentation of normal laboratory tests. Tramadol use in high daily dose confirmed by elevated urine levels and total remission of hypoglycemia and seizures following withdrawal of tramadol resulted in documenting this unique presentation of tramadol induced hypoglycemia. We believe lack of suppression of IGF2 in presence of hypoglycemia may indicate role of Tramadol in stimulating production or decreasing metabolism or clearance of IGF2 responsible for onset and perpetuation of hypoglycemia. Conclusion: A unique presentation of Tramadol induced hypoglycemia masquerading as a seizure disorder probably caused by IGF2 dysregulation.

Virologic outcomes in early antiretroviral treatment: HPTN 052

Introduction: The HIV Prevention Trials Network (HPTN) 052 trial demonstrated that early antiretroviral therapy (ART) prevented 93% of HIV transmission events in serodiscordant couples. Some linked infections were observed shortly after ART initiation or after virologic failure.Objective: To evaluate factors associated with time to viral suppression and virologic failure in participants who initiated ART in HPTN 052.Methods: 1566 participants who had a viral load (VL) > 400 copies/mL at enrollment were included in the analyses. This included 832 in the early ART arm (CD4 350–550 cells/mm3 at ART initiation) and 734 in the delayed ART arm (204 with a CD4 < 250 cells/mm3 at ART initiation; 530 with any CD4 at ART initiation). Viral suppression was defined as two consecutive VLs ≤ 400 copies/mL after ART initiation; virologic failure was defined as two consecutive VLs > 1000 copies/mL > 24 weeks after ART initiation.Results: Overall, 93% of participants achieved viral suppression by 12 months. The annual incidence of virologic failure was 3.6%. Virologic outcomes were similar in the two study arms. Longer time to viral suppression was associated with younger age, higher VL at ART initiation, and region (Africa vs. Asia). Virologic failure was strongly associated with younger age, lower educational level, and lack of suppression by three months; lower VL and higher CD4 at ART initiation were also associated with virologic failure.Conclusions: Several clinical and demographic factors were identified that were associated with longer time to viral suppression and virologic failure. Recognition of these factors may help optimize ART for HIV treatment and prevention.

Differentiation of Osteoporotic and Neoplastic Vertebral Fractures by Chemical Shift {In-Phase and Out-of Phase} Magnetic Resonance Imaging and Diffusion Weighted Sequence

In elderly population neoplastic wedging of the spine may be an early manifestation of underlying malignancy and differentiating benign wedging due to underlying osteoporosis from malignant wedging has been an important and sought after goal of imaging. Other challenging clinical case scenario is the occurrence of benign osteoporotic vertebral collapse in a patient already known to have underlying malignancy .Although magnetic resonance imaging (MRI) is a sensitive method for assessing bone marrow, it lacks specificity. The problem is that abnormal signal intensity in benign compression fractures on conventional MR imaging can be similar to that seen in vertebrae with underlying malignancy. Although certain morphologic signs may be helpful for assessing the cause of the fracture yet these lack specificity. The presence of both fat and water in normal marrow results in suppression of signal intensity on the opposed-phase images. In benign osteoporotic collapse, no marrow replacement has occurred, thus the existence of normal marrow fat should result in suppression of signal intensity on the opposed-phase images; while in malignant collapse the normal fat-containing marrow is replaced with tumoral process which should result in lack of suppression on the opposed phase images. Diffusion-weighted sequences are sensitive to molecular motion because random motion of water molecules in gradient fields produces phase dispersion and, therefore, signal attenuation. The current review will focus on the advent of both modalities and the value to order them in proper clinical setting.

Maternal emotion socialization differentially predicts third-grade children's emotion regulation and lability.

Numerous parental emotion socialization factors have been implicated as direct and indirect contributors to the development of children's emotional competence. To date, however, no study has combined parents' emotion-related beliefs, behaviors, and regulation strategies in one model to assess their cumulative-as well as unique-contributions to children's emotion regulation. We considered the 2 components that have recently been distinguished: emotion regulation and emotional lability. We predicted that mothers' beliefs about the value of and contempt for children's emotions, mothers' supportive and nonsupportive reactions to their children's emotions, as well as mothers' use of cognitive reappraisal and suppression of their own emotions would each contribute unique variance to their children's emotion regulation and lability, as assessed by children's teachers. The study sample consisted of an ethnically and socioeconomically diverse group of 165 mothers and their third-grade children. Different patterns emerged for regulation and lability: Controlling for family income, child gender, and ethnicity, only mothers' lack of suppression as a regulatory strategy predicted greater emotion regulation in children, whereas mothers' valuing of children's emotions, mothers' lack of contempt for children's emotions, mothers' use of cognitive reappraisal to reinterpret events, and mothers' lack of emotional suppression predicted less lability in children. These findings support the divergence of emotion regulation and lability as constructs and indicate that, during middle childhood, children's lability may be substantially and uniquely affected by multiple forms of parental socialization.

Suppressive effects on motion discrimination induced by transient flankers are reduced by perceptual learning.

We investigated spatial suppression of a drifting Gabor target of 0.5 c/° induced by adjacent and iso-oriented stationary Gabors (flankers) whose spatial frequency differed by ±1 and ±2 octaves to that of the drifting target. Stimuli (target and flankers) were presented for 33 ms. Results showed greater spatial suppression when the spatial frequency of the stationary but transient flanking Gabors was either equal or 1-2 octaves lower than when it was 1-2 octaves higher than the target's spatial frequency. This asymmetry was evident only for the drifting target, but not for the stationary target. In addition, we investigated whether perceptual learning (PL) reduced the spatial suppression induced by the flankers. We found that PL increased contrast sensitivity for the target, but only when it was reduced by the lateral masking flankers, and its effect did not transfer to an isolated drifting target of equal or higher spatial frequency. These results suggest that PL selectively affects suppressive interactions rather than contrast gain. We suggest that the suppressive effect of low spatial frequency flankers and the lack of suppression with high spatial frequency flankers may reflect two complementary phenomena: camouflage by the transient flankers (i.e., context) and breaking of camouflage by form-motion segmentation. Camouflage may result because both target and flankers activate the motion (magnocellular) system. Breaking of camouflage instead may occur when target and flankers' spatial frequency are more suitable for quasi-independent activation of the form system (by the flankers) and the motion system (by the target).

B cell resistance to Fas-mediated apoptosis contributes to their ineffective control by regulatory T cells in rheumatoid arthritis

ObjectiveTo investigate whether regulatory T cells (Treg) can control B cell function in rheumatoid arthritis (RA) and if not to explore the basis for this defect.MethodsSuppression of B cell responses...

Immunologic profiles of red blood cells using in vitro models of transfusion

BackgroundTransfusion of packed red blood cells (RBCs) produces a myriad of immunologic derangements, from suppressive to stimulatory. Proliferation of human T cells is suppressed in vitro after exposure to processed red blood cells (PRBCs). We hypothesized that this effect would be mitigated by using fresh RBCs. We also hypothesized that this suppressive effect was a generalized effect on lymphocyte proliferation and would be observed in both CD4+ and CD8+ T-cell subpopulations as well as B cells. Materials and methodsWe isolated human T cells from donor peripheral blood mononuclear cells and exposed them to either blood bank PRBCs or fresh RBCs from volunteer donors and stimulated them with anti-CD3/anti-CD28. Human B cells were stimulated with lipopolysaccharide and exposed to PRBCs or fresh RBCs. We measured proliferation of B cells by thymidine incorporation assays. We also treated RBCs with citrate-phosphate-dextrose (CPD) at different time points before culture them with stimulated T cells to determine the role of this common RBC storage solution in lymphocyte proliferation. ResultsIn vitro proliferation of CD4+ and CD8+ T cells was suppressed by blood bank RBCs. This suppression is eliminated when fresh RBCs were used. The B cells showed inhibition of proliferation when exposed to similar conditions, which appeared to be consistent over serial dilutions. Fresh RBCs exposed to CPD did not appear suppressive in the first 6 h after exposure. ConclusionsT-cell and B-cell proliferation inhibition by blood banked RBCs suggests a generalized effect of RBCs on cellular proliferation. The lack of suppression by fresh RBCs further suggests that something involved in blood banking alters RBC properties such that they attain a suppressive phenotype. One such blood banking component, CPD, does not appear to affect this suppressive phenotype within the first 6 h.

Atypical Hypertrophic Osteoarthropathy as a Presenting Complaint in a Non-Smoker

A 70-year-old non-smoker initially presented to accident and emergency with a painful left foot. This was an atypical presentation of hypertrophic osteoarthropathy (HPOA) secondary to grade 4 adenocarcinoma of the lung , highlighting the importance of routine chest x-ray in clinical assessment of atypical bone pain . Diagnosis was made using an isotope bone scan, the most sensitive method for detecting HPOA . The tumour and HPOA symptoms responded well to the first line chemotherapy regimen of cisplatin and pemetrexed. This supports the current understanding that treatment of the primary lung lesion will treat HPOA. The mechanism of this action is hypothesised to be by reduction of endogenous growth factor production, either by reduction in cell numbers producing the factor or direct inhibition of factor production: VEGF is emerging as the predominant growth factor causing HPOA. We believe the mechanism of cisplatin action on HPOA symptoms may be two fold; firstly, by direct reduction in VEGF secreting tumour bulk and secondly, by reduction of VEGF transcription. After disease progression of the lung tumours and recurrence of HPOA symptoms the patient received second line docetaxel. HPOA symptoms were unchanged but the chemotherapy stabilised the tumours. This lack of effect on HPOA symptoms may be due to a lack of tumour reduction or more speculatively the lack of suppression of VEGF transcription. HPOA symptoms were significantly improved when the patient was started on octreotide and current studies suggest that VEGF inhibition may be the mechanism of octretotide ’ s effect. doi: http://dx.doi.org/10.4021/jmc1057w

Drosophila TRPML Is Required for TORC1 Activation

Loss-of-function mutations in TRPML1 (transient receptor potential mucolipin 1) cause the lysosomal storage disorder, mucolipidosis type IV (MLIV). Here, we report that flies lacking the TRPML1 homolog displayed incomplete autophagy and reduced viability during the pupal period--a phase when animals rely on autophagy for nutrients. We show that TRPML was required for fusion of amphisomes with lysosomes, and its absence led to accumulation of vesicles of significantly larger volume and higher luminal Ca(2+). We also found that trpml(1) mutant cells showed decreased TORC1 (target of rapamycin complex 1) signaling and a concomitant upregulation of autophagy induction. Both of these defects in the mutants were reversed by genetically activating TORC1 or by feeding the larvae a high-protein diet. The high-protein diet also reduced the pupal lethality and the increased volume of acidic vesicles. Conversely, further inhibition of TORC1 activity by rapamycin exacerbated the mutant phenotypes. Finally, TORC1 exerted reciprocal control on TRPML function. A high-protein diet caused cortical localization of TRPML, and this effect was blocked by rapamycin. Our findings delineate the interrelationship between the TRPML and TORC1 pathways and raise the intriguing possibility that a high-protein diet might reduce the severity of MLIV.

Cochleopathy in Egyptian adolescents with Type 1 diabetes mellitus

BackgroundDiabetic neuropathy is recognized as the most common clinical picture of nervous system disorders caused by diabetes mellitus (DM). Although peripheral and autonomic nervous system involvements are frequently encountered, data about the incidence of central diabetic neuropathies is limited. ObjectiveOur study aimed to detect early asymptomatic auditory impairment whether at the level of outer hair cells (OHCs), inner hair cells (IHCs) and or olivo-cochlear bundle and the relationship between these abnormalities and other variables such as diabetes duration, degree of the metabolic control, or presence of microvascular complications. Subjects and methodsSeventy five adolescents with Type 1 DM and thirty three healthy controls participated in the study. Duration of DM, glycated hemoglobin (HbA1c) levels, microvascular complications were analyzed. All underwent basic audiological assessment to ensure normal hearing and normal middle ear function. Other tests comprised: transiently evoked otoacoustic emissions (TEOAEs) testing OHCs, TEOAEs with contralateral suppression (testing the integrity of olivo-cochlear bundle) and threshold equalizing noise (TEN) testing IHCs as evidenced by dead regions within the cochlea. ResultsEarly asymptomatic OHCs involvement as reflected by partial pass in 33.3% of cases with diminished suppression as compared to 9.1% control group. Eleven patients (7.33%) showed positive TEN Test reflecting resistance of IHCs to hyperglycemic injury. Diabetic patients had significantly higher amplitude on TEOAEs with noise suppression when compared to controls (P=0.002). The mean difference in amplitude of TEOAEs before and after suppression was significantly higher in diabetics with microvascular complications when compared to diabetic children without complications at all frequencies (P<0.001 for all).Duration of diabetes and microvascular complications (nephropathy, peripheral and autonomic neuropathy) were not correlated with the lack of suppression except for retinopathy (P=0.02). In contrast, poor metabolic control was associated with poor suppression (r=−0.443, P=0.001). ConclusionsCochleopathy can be detected in a relatively high proportion of subjects with Type 1 diabetes in spite of a normal audiometric hearing threshold. It should be considered as early manifestation of diabetic neuropathy which is related to the degree of metabolic control and retinopathy independent of other microvascular complications.