Non-pituitary growth hormone enables colon cell senescence evasion.

DNA damage-induced senescence is initially sustained by p53. Senescent cells produce a senescence-associated secretory phenotype (SASP) that impacts the aging microenvironment, often promoting cell transformation. Employing normal non-tumorous human colon cells (hNCC) derived from surgical biopsies and three-dimensional human intestinal organoids, we show that local non-pituitary growth hormone (npGH) induced in senescent cells is a SASP component acting to suppress p53. npGH autocrine/paracrine suppression of p53 results in senescence evasion and cell-cycle reentry, as evidenced by increased Ki67 and BrdU incorporation. Post-senescent cells exhibit activated epithelial-to-mesenchymal transition (EMT), and increased cell motility. Nu/J mice harboring GH-secreting HCT116 xenografts with resultant high GH levels and injected intrasplenic with post-senescent hNCC developed fourfold more metastases than did mice harboring control xenografts, suggesting that paracrine npGH enables post-senescent cell transformation. By contrast, senescent cells with suppressed npGH exhibit downregulated Ki67 and decreased soft agar colony formation. Mechanisms underlying these observations include npGH induction by the SASP chemokine CXCL1, which attracts immune effectors to eliminate senescent cells; GH, in turn, suppresses CXCL1, likely by inhibiting phospho-NFκB, resulting in SASP cytokine downregulation. Consistent with these findings, GH-receptor knockout mice exhibited increased colon phospho-NFκB and CXCL1, while GH excess decreased colon CXCL1. The results elucidate mechanisms for local hormonal regulation of microenvironmental changes in DNA-damaged non-tumorous epithelial cells and portray a heretofore unappreciated GH action favoring age-associated epithelial cell transformation.

WIP1 is a novel specific target for growth hormone action.

DNA damage repair (DDR) is mediated by phosphorylating effectors ATM kinase, CHK2, p53, and γH2AX. We showed earlier that GH suppresses DDR by suppressing pATM, resulting in DNA damage accumulation. Here, we show GH acting through GH receptor (GHR) inducing wild-type p53-inducible phosphatase 1 (WIP1), which dephosphorylated ATM and its effectors in normal human colon cells and three-dimensional human intestinal organoids. Mice bearing GH-secreting xenografts exhibited induced colon WIP1 with suppressed pATM and γH2AX. WIP1 was also induced in buffy coats derived from patients with elevated GH from somatotroph adenomas. In contrast, decreased colon WIP1 was observed in GHR-/- mice. WIP1 inhibition restored ATM phosphorylation and reversed GH-induced DNA damage. We elucidated a novel GH signaling pathway activating Src/AMPK to trigger HIPK2 nuclear-cytoplasmic relocation and suppressing WIP1 ubiquitination. Concordantly, blocking either AMPK or Src abolished GH-induced WIP1. We identify WIP1 as a specific target for GH-mediated epithelial DNA damage accumulation.

When do we need to suspect maturity onset diabetes of the young in patients with type 2 diabetes mellitus?

ABSTRACT Objetivo: Maturity onset diabetes of the young (MODY) patients have clinical heterogeneity as shown by many studies. Thus, often it is misdiagnosed to type 1 or type 2 diabetes(T2DM). The aim of this study is to evaluate MODY mutations in adult T2DM patients suspicious in terms of MODY, and to show clinical and laboratory differences between these two situations. Subjects and methods: In this study, we analyzed 72 type 2 diabetic patients and their relatives (35F/37M) who had been suspected for MODY and referred to genetic department for mutation analysis. The gene mutations for MODY have been assessed in the laboratory of Marmara University genetics. Totally 67 (32F/35M; median age 36.1) diabetic patients were analyzed for 7 MODY mutations. Twelve patients who have uncertain mutation (VUS) were excluded from study for further evaluation. MODY(+) (n:30) patients and T2DM patients (n:25) were compared for clinical and laboratory parameters. Results: In MODY(+) subjects, mutations in GCK (MODY 2) (n:12; 40%) were the most common followed by HNF4A (MODY 1) (n:4; 13.3%). Diabetes diagnosis age was younger in MODY(+) group but not statistically significant. Sixty-six percent of MODY(+) subjects had diabetes history at 3-consecutive generations in their family compared with 28% of T2DM patients statistically significant (p:0.006). Gender, BMI, C-peptide, HbA1c, lipid parameters, creatinine, GFR, microalbuminuria, vitamin D and calcium were not statistically different between the groups. Conclusion: According to present study results, MODY mutation positivity is most probable in young autoantibody (-) diabetic patients diagnosed before 30 years of age, who have first degree family history of diabetes.

Capillary microarchitectural changes in Cushing's syndrome.

PURPOSE: Macrovascular alterations are prominent in Cushing's syndrome (CS). Microvascular abnormalities are yet to be established. This cross-sectional observational study aimed to evaluate microvascular changes in nailfold capillaries and their association with disease status and carotid intima-media thickness (CIMT) as a marker of atherosclerosis. METHODS: A total of 70 patients with CS [46 (65.7%) ACTH-dependent pituitary adenoma and 24 (34.3%) adrenocortical adenomas] and 100 healthy controls were enrolled. The microvascular structure was evaluated using nailfold video-capillaroscopy (NVC). RESULTS: The median number of capillaries was less [10 mm (IQR: 2, min-max:7-14) vs. 11 mm (IQR: 2, min-max:9-19) (p < 0.001)], the median limb diameter and capillary width were wider in the CS group than in the controls (p = 0.016 and p = 0.002, respectively). Microhemorrhages within limited areas were more frequent in the CS group than in the controls (p = 0.046). Observed capillary changes were similar among the patients with CS with remission or active disease. CIMT levels were higher in the CS group than in the controls and similar in subjects with active disease and remission. Univariate logistic regression analyses revealed that the number of capillaries and capillary widths were associated with body mass index (BMI), the presence of type 2 diabetes mellitus, HbA1c, and CIMT. CONCLUSION: Morphologic alterations present similarly in nailfold capillaries in subjects with CS regardless of disease status, resembling changes in chronic atherosclerotic diseases. Microvascular changes in nailfold capillaries measured using NVC can be used as a marker in the assessment of cardiovascular risk in patients with CS.

Does concomitant prolactin measurement increase the accuracy of inferior petrosal sinus sampling?

INTRODUCTION: Prolactin (PRL) measurement during inferior petrosal sinus sampling (IPSS) can be helpful to improve the accuracy. We aimed to evaluate the effect of measuring PRL levels as a predictor for the accuracy of IPSS and evaluate its impact on the lateralization of adenomas. METHODS: In this retrospective cohort study, we reviewed 51 patients who had undergone IPSS for the investigation of ACTH-dependent hypercortisolism. RESULTS: Forty-nine patients had proven Cushing's disease (CD), one had EAS, and the remaining one patient had adrenal adenoma. Forty-seven patients had an above 2 ACTH IPS/P ratio at baseline, and all the post-corticotropin-releasing hormone (CRH) ACTH IPS/P ratios of patients with proven CD were above 3. In these two patients whose ACTH IPS/P ratio at baseline was below 2, PRL IPS/P ratios were above 1.8 in only the dominant side, which was considered secondary to a prolactin intersinus gradient due to the biological effects of the tumor. PRL-adjusted ACTH IPS/P ratios were > 1.3 in all patients with proven CD; it was 0.7 in the patient with EAS. Surgically confirmed positive lateralization was observed in 55.1% of patients with the ACTH gradient, but when PRL-adjusted ACTH IPS/IPS ratios were used in addition to the ACTH gradient, the ratio increased to 67.3%. CONCLUSION: Although PRL-adjusted ACTH IPS/P ratios can be helpful to improve the accuracy of results during IPSS procedures, a prolactin intersinus gradient towards the ACTH-dominant side in patients with CD may invalidate PRL as an indicator of pituitary venous outflow.

Corticomedullary Mixed Tumor of the Adrenal Gland with Apparent 18F-Fluorodeoxyglucose Activity But No 68GA-DOTATATE Uptake on Positron Emission Tomography/Computed Tomography.

Corticomedullary mixed tumor (CMT) is a single adrenal tumor mass composed histologically by an admixture of adrenal cortical and medullary cells. It is a rare condition, with approximately 20 cases reported to date. To our knowledge, the positron emission tomography (PET) imaging findings of this mostly benign tumor have not been reported in the literature. We present a case of CMT who was evaluated with both 18F-fluorodeoxyglucose (18F-FDG) and 68Ga-DOTATATE. The hypermetabolic tumor seen on 18F-FDG PET/computed tomography scan showed no abnormal uptake by 68Ga-DOTATATE.

Serum osteoprotegerin levels, endothelial function and carotid intima-media thickness in type 2 diabetic patients.

OBJECTIVES: Osteoprotegerin (OPG), a well-known protein that inhibits osteoclast formation and activity, might also be a potential marker for identifying patients with high cardiovascular risk. This study aimed to compare OPG levels, FMD, and CIMT measurements in subjects with vs. without diabetes and investigate the association of serum osteoprotegerin level with the early atherosclerotic markers, endothelial function, and carotid intima-media thickness (CIMT) in patients with type 2 diabetes mellitus (DM2). METHODS: Forty-nine patients with DM2 (F/M: 26/23, 49.3 ± 10.0 years) and 45 healthy volunteers (F/M: 26/19, 48.3 ± 7.5 years) were included in this cross-sectional study. Serum OPG levels were measured by solid-phase enzyme-linked immunosorbent assay (ELISA). Fasting plasma glucose (FPG) and HbA1c levels were measured. CIMT was measured by B-mode ultrasound, and endothelial function was evaluated via flow-mediated dilation (FMD) of the brachial artery with Doppler ultrasonography. RESULTS: Serum OPG levels were significantly higher in patients with DM2 (617.0 ± 111.0 pg/mL) compared to controls (481.0 ± 96.0 pg/mL, p < 0.001). While CIMT in diabetic patients (0.65 + 0.13 mm) was higher than controls (0.54 ± 0.10 mm, p = 0.009), FMD measurement was lower in DM2 group (4.2% ± 3.1 mm vs. 7.6% ± 4.1 mm, p = 0.01). Univariate analysis showed that OPG was associated with the presence of diabetes (OR: 6.999, p = 0.001, R2: 15.1%) and hypertension (OR = 6.925, p = 0.001, R2: 13.2%). There was no relationship between OPG levels and CIMT or FMD. CONCLUSION: Osteoprotegerin and CIMT levels were increased, and FMD measurements were decreased in patients with DM2. No association between CIMT, FMD, and OPG measurements was observed. The presence of DM and hypertension were associated with circulating OPG levels.

Determinants of remission in a case series of medullary thyroid carcinoma

Background/aim: We aimed to present the clinical results of patients with medullary carcinoma under follow-up in our center and to determine parameters affecting remission and lymph node metastases. Material and methods: A retrospective analysis was performed of the medical records of 27 patients with MTC who were followed up between 2004 and 2020. Results: The mean age at diagnosis was 47.7 ± 14 years. The mean follow-up was 7.29 ± 4.9 years. Metastatic neck lymphadenopathy was detected in eight (29.6%) patients; none had distant metastasis at the time of diagnosis. The median tumor diameter was 1.50 (range: 0.4­6) cm. The median postoperative calcitonin level was 3.3 (range, 0.5­871) ng/L. Relapse occurred in 2 (range, 1­14) years after the first surgery in three (11.1%) patients. In the last visit, 7 (25.9%) patients had a structural incomplete response, and three (11.1%) patients had a biochemical incomplete response. Seventeen (59.3%) patients were in remission, no patients died of MTC or any other cause. Elevated postoperative calcitonin level was a significant prognostic parameter for remission (p = 0.12) and lymph node metastasis (p < 0.001). Conclusion: Elevated postoperative calcitonin level and perithyroid soft tissue invasion were significant prognostic parameters for remission and lymph node metastasis. Postoperative calcitonin level and calcitonin doubling time should be considered for prognostic and survival risk assessments.

The Fabrication of Poly(Σ-caprolactone)-Poly(ethylene oxide) Sandwich Type Nanofibers Containing Sericin-Capped Silver Nanoparticles as an Antibacterial Wound Dressing.

In this study, antibacterial, synthetic poly(Σ-caprolactone)-poly(ethylene oxide) (PCL-PEO) multilayer nanofibers were produced by an electrospinning method. The material was synthesized in 3 layers. The upper-lower protective layers were produced by PCL nanofibers and the intermediate layer was produced from PEO nanofiber containing sericin-capped silver nanoparticles (S-AgNPs). The electrospinning conditions in which nano-sized, smooth, bead-free fibers were obtained was determined to be an applied voltage of 20 kV, a flow rate of 8 µL/min and a distance between the collector and the needle tip of 22 cm for the PCL layer (dissolved at a 12% g/mL concentration in a chloroform:methanol (3:2) solvent mixture) layer. For the S-AgNPs doped PEO layer (dissolved at a 3.5% g/mL concentration in water), the corresponding conditions were determined to be 20 kV, 15 µL/min and 20 cm. To characterize the three-layer material that consisted of PCL and S-AgNPs doped PEO layers, FTIR and SEM analyses were performed, and the water retention capacity, in situ degradability and antibacterial activity of the material was investigated. According to SEM analysis, the fibers obtained were found to be nano-sized, smooth and bead-free and the average size of the nanofibers forming the PCL layer was 687 nm while the average size of the fibers forming the PEO layer was 98 nm. Antibacterial activity tests were performed using gram-positive (Staphylococcus aureus ATCC 6538) and gram-negative (Escherichia coli ATCC 25922) bacteria and the resulting biomaterial was found to have antimicrobial effect on both gram-negative and gram-positive bacteria. It was determined that the 3-layer material obtained in this study can be used as a wound dressing.

Preoperative plasmapheresis in patients with Graves' disease intolerant to antithyroid drugs.

Antithyroid drugs (ATDs) are the mainstay of treatment for Graves' disease with possible detrimental adverse effects. Surgery or radioactive iodine (RAI) ablation is the second choice among the treatment options in cases of non-remission. Normalization of serum thyroid hormone levels as much as possible is required before surgery or RAI to prevent thyrotoxic crisis in patients with uncontrolled Graves' disease. In recent decades, therapeutic plasma exchange (TPE) has been used in the treatment of thyroid storm, drug-induced hepatotoxicity and agranulocytosis, or patients with hyperthyroidism scheduled for emergency surgery. TPE is an effective method to reduce serum FT3, FT4, and TRAB levels in severe hyperthyroid conditions. Although TPE-related complications are rare, the risk of bleeding needs to be taken into consideration in patients who were scheduled for surgery within 24 h after TPE. In terms of reducing intraoperative bleeding, patients can be referred to surgery 24-48 h after TPE, or fresh frozen plasma transfusion can be the preferred treatment for emergency cases.

Efficacy and Safety of Stereotactic Radiotherapy in Cushing's Disease: A Single Center Experience.

OBJECTIVE: To determine the efficacy and safety of stereotactic radiotherapy (RT) in patients with Cushing's disease (CD). METHODS: The study included 38 patients [31 patients who received gamma knife radiosurgery (GKS) and 7 patients who received cyberknife hypofractionated RT (HFRT)] with CD. Hormonal remission was considered if the patient had suppressed cortisol levels after low dose dexamethasone, normal 24-hour urinary free cortisol (UFC), and lack or regression of clinical features. RESULTS: Biochemical control after RT was observed in 52.6% of the patients with CD and median time to hormonal remission was 15 months. Tumor size control was obtained in all of the patients. There was no significant relationship between remission rate and laboratory, radiological and pathological variables except for preoperative UFC. Remission rate was higher in patients with lower preoperative UFC. Time to remission increased in parallel to postoperative cortisol and 1mg DST level. Although medical therapy before RT did not affect the rate of- and time to remission, medical therapy after RT prolonged the time to hormonal remission. CONCLUSION: In this current single center experience, postoperative cortisol and 1mg DST levels were found as the determinants of time to remission. Although medical therapy before RT did not affect the rate of- and time to remission, medical therapy after RT prolonged the time to biochemical control . This latter finding might suggest a radioprotective effect of cortisol lowering medication use on peri-RT period.

Primary hypophysitis: Experience of a Single Tertiary Center.

PURPOSE: The authors review the clinical outcomes of patients with primary hypophysitis (PH). METHODS: Patients with PH who were followed up between 2007 and 2018 at our clinic were evaluated. Clinical, endocrinologic, pathologic, radiologic findings and treatment modalities were assessed. RESULTS: Seventeen patients with PH were assessed. The median follow-up was 24 (range, 6-84) months. Histologic confirmation was available in 8 patients (6 lymphocytic hypophysitis, 1 lymphocytic-granulomatous hypophysitis, 1 xanthomatous hypophysitis). None of the cases were diagnosed after pregnancy. Two patients had an autoimmune disease. The most commonly seen symptom was headache. The most common anterior pituitary deficiencies were hypocortisolemia and hypothyroidism. The radiologic findings of the patients at the time of diagnosis revealed various results including space-occupying lesion (41.2%), loss of posterior hypophysis bright spot (47.1%), pituitary stalk thickening (41.2%), uniform contrast enhancement (17.6%), partially empty sella (11.8%), optic chiasm compression (11.8%). The most frequent initial treatment modality was observation. Ten patients who were followed up conservatively had no endocrinologic deterioration; additional treatment was not needed in 8 of these 10 patients. The second most frequent initial treatment modality was pituitary surgery. Five patients received steroid treatment. We found serious adverse effects during steroid treatment in 3 of 5 (60%) patients; unilateral avascular necrosis of the femoral head (n=2), diabetes mellitus(n=1). CONCLUSION: Correctly diagnosing PH and giving appropriate treatment is challenging. It is unclear whether active treatment with steroids improves clinical outcomes. The serious adverse effects of steroids are also taken into account. Observation, surgery and/or radiotherapy can be appropriate treatment modalities for selected patients.

Skin Autofluorescence and Carotid Intima-Media Thickness Evaluation Following Bariatric Surgery in Patients with Severe Obesity.

PURPOSE: Advanced glycation end product (AGE) is a marker of metabolic memory. Accumulated AGEs in skin collagen measured with skin autofluorescence (SAF) was found to be associated with subclinical atherosclerosis. We aimed to evaluate SAF and carotid intima-media thickness (CIMT) and its association with clinical and biochemical parameters in severely obese patients before and after bariatric surgery. MATERIALS AND METHODS: In this observational study, 432 morbid obese patients evaluated before and after 6 and 12 months of bariatric surgery for metabolic and anthropometric parameters, CIMT and SAF. SAF was assessed in the forearm with an AGE Reader. RESULTS: SAF measurements were higher in diabetic (2.04 ± 0.52 AU) obese patients compared to non-diabetic (1.78 ± 0.40 AU) obese patients (p < 0.0001). Although bariatric surgery-induced weight loss resulted in a decrease in CIMT in the 6th and 12th months compared to baseline, weight loss and metabolic improvements were not associated with a parallel decrease in SAF measurements. SAF measurements were positively correlated with body mass index (r 0.527, p < 0.0001), HbA1c (r 0.362, p < 0.0001), and CIMT (r 0.319, p < 0.0001). Multivariate analysis showed the presence of diabetes (but not BMI, age, and sex) was independently associated with SAF (R2 = 7.62%), and the presence of diabetes, low-density cholesterol, and systolic blood pressure were independently associated with CIMT measurements (R2 = 21.7%). CONCLUSION: Bariatric surgery-induced weight loss and metabolic improvement were found to be associated with improvement in CIMT, while skin AGE accumulation was not regressed in the first year of surgery.

Seven cases of parathyroid carcinoma and review of the literature.

Parathyroid cancer is a rare malignancy and an uncommon cause of hyperparathyroidism. In the present study, we present seven cases of parathyroid carcinoma. The female ratio was 5/7 (71.4%). Median age at diagnosis was 47 years, and median follow-up duration was 60 months (IQR 29-75). Mean calcium level at diagnosis was 12.7 mg/dL (range, 11.3-13.9), and mean parathormone level was 1115 ng/L (IQR 287-1470). Two patients (28.5%) had a palpable neck mass. Coexisting brown tumor was present in three patients (42.8%), and nephrolithiasis was found in one patient (14.2). Average tumor size was 29 mm (IQR 28-40). Capsular and vascular invasion were detected in six patients (85.7%), intrathyroidal spread was observed in two patients (28.5%), and soft tissue invasion was seen in three patients (42.8%). Parathyroid adenoma was present in one patient and parathyroid gland hyperplasia in another patient. Adjuvant radiotherapy was given to four patients (57.1%). There was no metastatic disease or death. At the last visit, two patients had increased parathormone levels and no additional focus could be detected in either. Patients with markedly elevated parathormone and calcium levels and a palpable larger mass on the neck should be evaluated for parathyroid cancer. En bloc resection is the mainstay treatment. Despite contradictory results, adjuvant radiotherapy to the neck may help to reduce the risk of local recurrence in patients with microscopic residual parathyroid carcinoma.

Assessment of 1 mg Dexamethasone Suppression Test in Patients with Obesity Before Bariatric Surgery.

PURPOSE: This study aims to examine the prevalence of Cushing's syndrome (CS) in class 3 obese patients before bariatric surgery. MATERIALS AND METHODS: The data of 1037 class 3 obese patients admitted to the endocrinology outpatient clinic for endocrinological evaluation before bariatric surgery between 2012 and 2019were reviewed retrospectively. One milligram dexamethasone suppression test (DST) was used for the evaluation of hypercortisolism in all cases and cutoff accepted as 1.8 µg/dL. RESULTS: The mean body mass index (BMI) was 48 ± 8.9 kg/m2 and age was 42 ± 10 years with female preponderance (F/M: 799/238] being observed in this cohort. Insufficient cortisol suppression was found in 40 patients; confirmed hypercortisolemia was detected in 8 patients. The prevalence of pathologic DST was 3.85% and 0.77% in confirmed hypercortisolism. The specificity for 1-mg DST with the cutoff 1.8 µg/dL was calculated as 96.8%. CONCLUSION: Hypercortisolism prevalence was found to be low, and 1 mg DST is a sufficient test for the screening of CS in class 3 obese patients evaluated before bariatric surgery.

Preoperative plasmapheresis experience in Graves' disease patients with anti-thyroid drug-induced hepatotoxicity.

Hepatotoxicity is a rare but serious side effect of antithyroid drug (ATI) therapy in Graves' disease patients. Cessation of ATI drug is needed in most of the patients if liver enzymes highly elevated or in case of agranulocytosis. Permanent therapy, surgery or radioactive iodine ablation are the treatment choices to ensure euthyroidism in active Graves' disease patients. Therapeutic plasma exchange (TPE) can be an option to ensure euthyroidism, especially in patients scheduled for urgent surgery. In the present study, we present consecutive five cases of methimazole related severe hepatotoxicity that underwent TPE before thyroid surgery. The median number of apheresis sessions was 3 (range: 2-5). Free triiodothyronine (FT3) 65-83 %, free thyroxine (FT4) 22-66 %, thyrotropin receptor antibodies (TRAB) 55-96 % decreases were observed. All patients underwent total thyroidectomy. TPE is an effective method to reduce serum FT3, FT4, TRAB levels in the short term to provide better thyroid hormone status before urgent surgery in ATI induced toxic hepatitis patients.

Germline mutations of aryl hydrocarbon receptor-interacting protein (AIP) gene and somatostatin receptor 1-5 and AIP immunostaining in patients with sporadic acromegaly with poor versus good response to somatostatin analogues.

OBJECTIVE: To determine aryl hydrocarbon interacting protein (AIP) gene variations and AIP and somatostatin receptor (SSTR) 1-5 immunostaining in patients with apparently sporadic acromegaly with poor versus good response to somatostatin analogues (SRLs). METHODS: A total of 94 patients (66 with poor and 28 with good response to SRLs) were screened for the AIP gene variations using Sanger sequencing. Immunostaining was performed in 60 tumors. RESULTS: Several variations, albeit some with undetermined significance, were detected, especially in poor responder patients. The prevalence of AIP mutation was 2.1% in the whole group and 1.5% in patients with poor response to SRLs. AIP, SSTR2A, and SSTR2B immunostainings were decreased in patients with poor response (p < 0.05 for all), and other SSTRs did not differ between the groups (p > 0.05 for all). Patients with low AIP had decreased levels of SSTR2A and SSTR3 (p < 0.05 for all). AIP and SSTR2A immunostainings were positively correlated to the treatment response and age at diagnosis was negatively correlated (p < 0.05 for all). In poor responder patients with high SSTR2A immunostaining, SSTR2B immunostaining and preoperative tumor size were positively and negatively correlated, respectively, to SRL response (p < 0.05 for all). CONCLUSIONS: Lack of response to SRLs does not necessarily increase the risk of harboring AIP mutations. The finding of decreased AIP, SSTR2A, and SSTR2B immunostaining in patients with poor response to SRLs and decreased SSTR2A and SSTR3 level in those with low AIP immunostaining suggests a possible interaction between AIP and some SSTR subtypes that might alter SRL sensitivity.