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Objective: To evaluate the clinical presentation, biochemical profile, and etiology of Cushing's syndrome (CS) in women stratified by age., Methods: Retrospective study of patients with CS, treated at Rabin Medical Center from 2000 to 2020, or Maccabi Healthcare Services in Israel from 2005 to 2017. Disease etiology, presentation and biochemical profile were compared according to age at diagnosis: ≤ 45, 46-64, or ≥ 65 years. Study was approved by the Ethics Review Boards of both facilities with waiver of consent., Results: The cohort included 142 women (mean age, 46.0 ± 15.1 years):81 (57.0%) with Cushing's disease (CD), and 61 (43.0%) with adrenal CS. Pituitary etiology was more common among women < 45 (70.6%), compared with patients ≥ 65 years (31.6%) (P < 0.05). Among CS patients, hypercortisolism was diagnosed in the context of screening after an adrenal incidentaloma detection in 15.0% of patients < 45 and 53.8% of ≥ 65 years (P < 0.001). Weight gain was evident in 57.4% of women < 45 (56.3% CD, 60.0% CS), and 15.8% of women ≥ 65 years (50% CD, 0% CS) (P = 0.011). Mean UFC levels were highest for women < 45 (3.8 × ULN) and lowest for ≥ 65 years (2.3 × ULN) (P < 0.001)., Conclusion: We have shown for the first time that women with CS ≥ 65 years of age more commonly have adrenal etiology. The initial presentation of CS also differs between age groups, where women < 45 years are likely to present with weight gain, while those ≥ 65 years are frequently diagnosed incidentally, when screening for hypercortisolism in the presence of an adrenal incidentaloma., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background : Reports on clinical and biochemical differences between adrenocorticotropic hormone (ACTH)-secreting pituitary microadenomas and macroadenomas are limited and inconsistent. Objective: Compare clinical and biochemical characteristics of patients with corticotroph microadenomas and macroadenomas and assess predictive factors for biochemical response to dynamic testing for Cushing's disease (CD) in a clinical trial and a systematic review. A second aim was to evaluate differences between macroadenomas with and without cavernous and sphenoid sinus invasion. Methods: Retrospective charts review of patients with CD, treated at Rabin Medical Center between 2000 and 2020 or at Maccabi Healthcare Services in Israel between 2005 and 2017. Clinical and biochemical factors were compared between patients with corticotroph microadenomas and macroadenomas. We have also performed a systematic review of all studies (PRISMA guidelines) comparing corticotroph microadenomas with macroadenomas up to 31 November 2021. Results : The cohort included 105 patients (82 women, 78%; mean age, 41.5 ± 14.5 years), including 80 microadenomas (mean size, 5.2 ± 2.2 mm) and 25 macroadenomas (mean size, 18.0 ± 7.7 mm). Other baseline characteristics were similar between groups. Most common presentation suggestive for hypercortisolemia among patients with both micro- and macroadenomas were weight gain (46.3% vs. 48.0%, p = NS) and Cushingoid features (27.5% vs. 20.0%, p = NS). Mean 24 h urinary free cortisol (5.2 ± 5.4 × ULN vs. 7.8 ± 8.7 × ULN) and serum cortisol following low-dose dexamethasone (372.0 ± 324.5 vs. 487.6 ± 329.8 nmol/L), though higher for macroadenomas, were not significant. Levels of ACTH were greater for macroadenomas (1.9 ± 1.2 × ULN vs. 1.3 ± 0.8 × ULN, respectively, p = 0.01). Rates of recurrent/persistent disease were similar, as were rates of post-operative adrenal insufficiency and duration of post-operative glucocorticoid replacement. Macroadenomas with sphenoid or cavernous sinus invasion were associated with higher ACTH, 24 h free urinary cortisol, and serum cortisol following low-dose dexamethasone, compared with suprasellar or intrasellar macroadenomas. Conclusions: While ACTH-secreting macroadenomas exhibit higher plasma ACTH than microadenomas, there was no association between tumor size with cortisol hypersecretion or clinical features of hypercortisolemia. Though overall rare, increased awareness is needed for patients with CD with tumor extension in the cavernous or sphenoid sinus, which displays increased biochemical burden, highlighting that extent/location of the adenoma may be more important than size per se. Our systematic review, the first on this topic, highlights differences and similarities with our study.

Deployment of the BNT162b2 mRNA Covid-19 Vaccine in Israel began in December 2020. This is a retrospective analysis of serological data, showing SARS-CoV-2 anti-S IgG kinetics in 116 Israeli health care workers receiving BNT162b2. Sero-conversion occurred in 14 days in all study participants, with IgG levels peaking approximately 30 days after initiation of the vaccination series. A statistically significant difference was observed in IgG levels between subjects younger than 50 years and older participants, although in all cases, IgG levels were well above the level considered reactive by the test's manufacturer. The importance of this difference needs to be studied further, but a potential difference in vaccine efficacy and vaccine effect length could possibly be present between these two groups., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Beyond their substantial protection of individual vaccinees, coronavirus disease 2019 (COVID-19) vaccines might reduce viral load in breakthrough infection and thereby further suppress onward transmission. In this analysis of a real-world dataset of positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test results after inoculation with the BNT162b2 messenger RNA vaccine, we found that the viral load was substantially reduced for infections occurring 12-37 d after the first dose of vaccine. These reduced viral loads hint at a potentially lower infectiousness, further contributing to vaccine effect on virus spread.

The diagnostic utility of different thresholds of elevated urinary fractionated metanephrine (UFM) for pheochromocytoma-paraganglioma (PPGL) was evaluated in 10 164 community-dwelling subjects (2012-2017). Levels were ≥1.5× the upper normal limit (UNL) in 276 subjects (2.7%) and ≥2×UNL in 138 (1.4%). PPGL was subsequently diagnosed in 59 (mean age 51.9 ± 14.3, 64% female); 58 (98.3%) with UFM ≥ 2×UNL. Positive predictive values (PPV) were 42% for UFM ≥ 2×UNL, 55% for UFM ≥ 2.5×UNL, and 69% for UFM ≥ 3×UNL. The main reason for PPGL screening (52.5%) was adrenal incidentaloma. Mean (median) metanephrine/normetanephrine levels were 6.7 ± 9×UNL (3 × UNL) and 6.1 ± 8.9×UNL (2.5 × UNL). Six patients (10.2%) had an extra-adrenal tumor (one malignant paraganglioma); one had bilateral pheochromocytoma. Only one patient presented with the "classic triad" (headache, palpitations, sweating). In conclusion, after excluding obvious reasons for false-positive results, thorough diagnostic assessment for PPGL is justified in all subjects with UFM ≥ ×2UNL. The PPV of milder UFM elevations is very low., (©2019 Wiley Periodicals, Inc.)

Purpose: The most common etiology of Cushing's syndrome (CS) is an ACTH-producing pituitary adenoma (pitCS), reported as 2-3 times more frequent than primary adrenal CS (adrCS). We aimed to analyze and compare features of patients with pitCS and adrCS., Methods: A retrospective file review of 196 consecutive patients (age 46.8 ± 15.6 years, 76% female) diagnosed with CS in 2000-2017 and followed for 5.2 ± 4.2 years; 109 (55.6%) had pitCS and 76 (38.8%) adrCS. Epidemiologic, clinical and biochemical factors were compared between and within the pitCS and adrCS groups., Results: The relative proportion of pitCS to adrCS (1.4) was lower than previously reported and gradually decreased during the study years to only 1.2 in 2012-2017. The most common reason for CS screening was weight-gain in the pitCS group (48.6%) and adrenal incidentaloma in the adrCS group (39.5%). The pitCS patients were diagnosed at younger age (42.5 ± 15.1 vs. 51.6 ± 15.1 years, p < 0.001) and had lower prevalence of hypertension (51.4 vs. 74%, p = 0.005). There was no between-group difference in severity of hypercortisoluria. Within the adrCS group, patients diagnosed after detection of an adrenal incidentaloma had milder hypercortisoluria than the remaining patients, presented with smaller adrenal lesions (35.9 ± 16.3 vs. 49.1 ± 33.7 cm, p = 0.04), and received post-adrenalectomy glucocorticoid treatment for shorter periods (13 ± 11.6 vs. 31 ± 40 months, p = 0.04)., Conclusions: The relative proportion of adrCS to pitCS is rising, probably because of an increasing detection of cortisol-secreting adrenal incidentalomas associated with milder hypercortisolism. There is no difference between pitCS and adrCS in the severity of hypercortisoluria, although significant clinical differences were found.

Background: National data on iodine status in Israel are lacking. Reliance on iodine-depleted desalinated water, the absence of a salt iodization program, and reports of increased use of thyroid medication in Israel suggest that the population's iodine intake is likely inadequate. The aims of this study were therefore to determine the iodine status of Israeli school-age children (SAC) and pregnant women (PW) in a nationally representative sample obtained by a novel approach of using pre-discard urinalysis samples collected from a centralized national laboratory., Methods: Spot urine samples from 1023 SAC and 1074 PW, representing all regions and major sectors in Israel, were collected during 2016 at the Maccabi Healthcare Services central laboratory. Urinary iodine concentration (UIC) was measured, and the results were analyzed by trimester, sex, region, and sector., Results: SAC were iodine deficient, with a median (interquartile range [IQR]) UIC of 83 μg/L (52-127 μg/L); 62% of SAC UICs were below the World Health Organization adequacy range for SAC (100-199 μg/L). PW were also iodine deficient, with a median (IQR) UIC of 61 μg/L (36-97 μg/L); 85% of PW UICs were below the adequacy range for PW (150-249 μg/L). For both SAC and PW, the median UIC was below the World Health Organization's adequacy range across all sectors, sexes, and districts. Among SAC, the median (IQR) UIC was lower among females (75 μg/L; 48-119 μg/L) than males (92 μg/L; 59-133 μg/L; p < 0.05). Median UIC values of PW correlated significantly with the median UIC for SAC by sub-district (R 2  = 0.3, p < 0.05)., Conclusions: Urine sampling via a centralized national laboratory was efficient and cost-saving. Iodine deficiency in Israeli SAC and PW is a serious public-health concern. A national program of salt iodization and iodine supplementation of PW should be urgently considered.

Objective: To investigate the incidence of Cushing's syndrome (CS) in patients with significant hypercortisoluria and the performance of urinary free cortisol (UFC) screening., Design: Retrospective file review., Methods: The computerized database of a publicly funded health maintenance organization (HMO) in Israel was searched for all patients who underwent 24-h UFC testing in 2005-2014 with a result of more than twice the upper limit of normal (ULN). The patients' medical files were reviewed for a subsequent diagnosis of CS by an expert endocrinologist. Findings were evaluated for patterns in CS diagnosis and UFC testing over time., Results: Of 41 183 individuals tested, 510 (1.2%) had UFC >2× ULN (214 >3× ULN). Eighty-five (16.7%) individuals were diagnosed with CS (63 female and mean age 47.2 ± 15.1 years), mainly Cushing's disease (55.3%) or adrenal Cushing's syndrome (37.6%). The number of UFC tests increased steadily, from 1804 in 2005 to 6464 in 2014; yet, the resultant detection rate of CS remained generally stable. The calculated incidence of CS in the general HMO-insured population based only on the patients identified in the present cohort was 4.5 new cases/million/year (median 4.9/million/year, range 1.7-5.9/million/year), which was also relatively stable. The most common reason for referral for UFC screening was obesity. Of the 148 patients before bariatric surgery with UFC >2× ULN, 2 were diagnosed with CS., Conclusions: The incidence of CS is higher than previously suggested. The consistently increasing number of UFC tests being performed has not been accompanied by a similar increase in CS detection rate. The expected yield of routine UFC testing before bariatric surgery is low., (© 2017 European Society of Endocrinology.)

Objective: Primary hyperparathyroidism (PHPT) during pregnancy may pose considerable risks to mother and fetus. This study examined pregnancy outcomes in women with gestational PHPT in relation to clinical and laboratory parameters., Design: This study was designed as a retrospective case series., Methods: The study group included 74 women aged 20-40 years who were diagnosed with PHPT after a finding of serum calcium ≥ 10.5 mg/dL on routine screening at a health maintenance organization (2005-2013) and who became pregnant during the time of hypercalcemia (124 pregnancies). Clinical and laboratory data were collected from the files. Pregnancy outcomes were compared with 175 normocalcemic pregnant women (431 pregnancies) tested during the same period., Results: The cohort represented 0.03% of all women of reproductive age tested for serum calcium during the study period. Abortion occurred in 12 of 124 pregnancies (9.7%), and other complications occurred in 19 (15.3%) with no statistically significant differences from controls. Hypercalcemia was first detected during pregnancy in 14 of 74 women (18.9%) and before pregnancy (mean, 33.4 ± 29 mo) in 60. Serum calcium was measured antenatally in 57 of 124 pregnancies (46%); the mean level was 10.7 ± 0.6 mg/dL (median, 10.6 mg/dL). Measurement of the serum PTH level (with consequent diagnosis of PHPT) was performed during the first studied pregnancy in 17 of 74 women (23%), before pregnancy (mean, 37.8 ± 25.5 mo; median, 34 mo) in 23 (31.1%), and after delivery (mean, 54.7 ± 45.7 mo; median, 35 mo) in 34 (45.9%). Forty-three women (58.1%) underwent parathyroidectomy, six during pregnancy, without maternal or fetal complications. No difference was found in abortion or any pregnancy-related complication between patients who subsequently underwent parathyroidectomy and those who did not. No significant correlation was found between calcium level during pregnancy and pregnancy outcomes., Conclusions: Serum calcium levels are usually only mildly elevated during pregnancy in women with PHPT. A significant proportion of cases go undiagnosed. Mild hypercalcemia in gestational PHPT is generally not associated with an increased risk of obstetrical complications.

Objective: Hypothyroidism during pregnancy has been associated with adverse obstetrical outcomes. Most studies have focused on subjects with a mild or subclinical disorder. The aims of the present study were to determine the relative rate of severe thyroid dysfunction among pregnant women with hypothyroidism, identify related factors and analyse the impact on pregnancy outcomes., Design: A retrospective case series design was employed., Methods: The study group included 101 pregnant women (103 pregnancies) with an antenatal serum TSH level >20.0 mIU/l identified from the 2009-2010 computerised database of a health maintenance organisation. Data were collected from the medical records. Pregnancy outcomes were compared with those of a control group of 205 euthyroid pregnant women during the same period., Results: The study group accounted for 1.04% of all insured pregnant women with recorded hypothyroidism during the study period. Most cases had an autoimmune aetiology. All women were treated with levothyroxine (L-T₄) during pregnancy. Maximum serum TSH level measured was 20.11-150 mIU/l (median 32.95 mIU/l) and median serum TSH level 0.36-75.17 mIU/l (median 7.44 mIU/l). The mean duration of hypothyroidism during pregnancy was 21.2 ± 13.2 weeks (median 18.5 weeks); in 36 cases (34.9%), all TSH levels during pregnancy were elevated. Adverse pregnancy outcomes included abortions in 7.8% of the cases, premature deliveries in 2.9% and other complications in 14.6%, with no statistically significant differences from the control group. Median serum TSH level during pregnancy was positively correlated with the rate of abortions+premature deliveries and rate of all pregnancy-related complications (P<0.05)., Conclusions: Abortions and premature deliveries occur infrequently in women with severe hypothyroidism. Intense follow-up and L-T₄ treatment may improve pregnancy outcomes even when target TSH levels are not reached.

Purpose: Amino acid esters containing tertiary or quaternary nitrogen heterocycles were synthesized for dexanabinol (1) and evaluated as water-soluble prodrugs or congeners., Methods: Syntheses were performed by conventional methods; stability studies in water, blood (rat, dog, human) and assay-media were performed by HPLC; NMDA receptor binding was determined by [3H] MK-801 displacement; neuroprotection and neurotoxicity studies were performed in cortical cell cultures., Results: 7-morpholino and N-methylpiperazino acetates and butyrates and the respective N-methylmorpholinium and piperazinium iodides as well as a 3'-N-methyl morpholino butyrate and the corresponding N-methyl quaternary type derivative were synthesized. All compounds were relatively soluble in water or 10% aqueous ethanol. The examined derivatives were stable in water and generally less stable in blood and assay media. Quaternary derivatives of dexanabinol were found to hydrolyze faster. All examined compounds inhibited NMDA receptor and protected neurons against NMDA induced toxicity. Neuroprotection (with one exception) is however attributed to the parent 1 released by hydrolysis during the assay., Conclusions: Some of the examined derivatives could be further evaluated as prodrugs on congeners of 1.

Purpose: Glycinate ester-type water soluble derivatives of dexanabinol (HU-211) (1) a non-psychotropic cannabinoid with potential use in the treatment of brain damage were synthesized and evaluated as prodrugs or congeners., Methods: Conventional procedures were used for the synthesis of the novel derivatives. Stability studies in water and blood (rat, dog, human) were performed by HPLC; NMDA receptor binding was determined by radio ligand [3H] MK-801-displacement; the neuroprotection and neurotoxicity studies were performed in cortical cell cultures., Results: Glycinate (3), dimethyl- and diethylamine (5, 6), trimethyl- and triethyl- ammonium (7, 8) acetates of 1 were synthesized. All compounds were relatively soluble and stable in water. The quaternary ammonium salt-type derivatives rapidly hydrolyzed to the parent drug in various types of blood including human. In vitro activity studies indicated that the novel derivatives possess NMDA receptor binding properties. The neuroprotecting properties manifested by some of the new derivatives were associated with very low neuronal cell toxicity and are credited to parent compound released by hydrolysis during the experiments rather than to intrinsic activity., Conclusions: Compounds 7 and 8 are promising water-soluble pro-drug candidates for 1; the glycinate ester 3 might be used as an active analog.

45Ca accumulation was studied autoradiographically as a marker for lethally injured brain tissue following closed head injury (CHI), and applied to an investigation of the neuroprotective effect of the non-psychoactive cannabinoid (+)-(3S,4S)-7-hydroxy-D-6 tetrahydro-cannabinol 1,1-dimethylheptyl (HU-211). Amassment of 45Ca in rat brain was examined 24 or 72 h after induction of CHI in the left hemisphere by a weight-drop device. Concentration of 45Ca within 15 different brain regions was assessed by relative optical density. There was increased 45Ca accumulation in the hemisphere ipsilateral to the side of the insult as compared with the contralateral hemisphere. The highest density of radioactive labeling was found in the anterior cortex and in the frontal parts of the parietal cortex, with accumulation expanding as a function of time post injury. On the third day following trauma the amount of accumulated 45Ca was higher than that at 24 h after CHI, with more distant 45Ca-accumulating structures involved: the ventral posterolateral nucleus of the thalamus and the substantia nigra. Histological examination revealed necrotic tissue in the regions accumulating 45Ca. HU-211, a stereoselective inhibitor of the N-methyl-D-aspartate (NMDA) receptor, was injected immediately after induction of trauma. One day after trauma, HU-211 had significantly decreased both the volume of the 45Ca accumulating zone and the concentration of the amassed radioisotope. In the HU-211 treated rats a considerable reduction in radioactive labeling was also found 72 h after trauma. The ability of HU-211 to decrease 45Ca accumulation after head trauma is probably due to its ability to attenuate Ca2+ fluxes through the NMDA receptor-mediated calcium channels and to reduce the depolarization evoked Ca2+ fluxes. On the basis of our results, HU-211 seems to be a promising therapeutic agent for head trauma in humans.

The non-psychotropic cannabinoid (+)-(3S,4S)-7-hydroxy-delta 6- tetrahydrocannabinol 1,1-dimethylheptyl (HU-211), a stereoselective inhibitor of the N-methyl-D-aspartate (NMDA) receptor, protects primary cultures of rat forebrain against NMDA receptor-mediated neurotoxicity. Cell mortality produced by exposure for 10 min to NMDA or glutamate was reduced to approximately 18 or 27%, respectively, by application of 50 microM HU-211 for 10-15 min during or after exposure of cultures to excitatory amino acid. This effect of HU-211 was dependent on its concentration (EC50 = 8.7 +/- 4 microM). HU-211 also reduced the toxicity induced by brief exposure (10 min) to kinase or quisqualate, though less effectively. HU-211 may therefore prove useful as a non-psychoactive drug that protects against neurotoxicity mediated by the NMDA receptor.

The effects of the synthetic non-psychoactive cannabinoid (+)-(3S,4S)-7-hydroxy-delta 6-tetrahydrocannabinol 1,1-dimethylheptyl (HU-211) on the activity of the N-methyl-D-aspartate (NMDA) receptor/ion channel were examined. HU-211 non-competitively blocks the increase in binding of [3H]N-[1-(2-thienyl)-cyclohexyl]piperidine ([3H]TCP) induced by the polyamines spermine and spermidine or by glutamate and glycine. HU-211 does not, however, affect the direct binding of [3H]glycine and [3H]glutamate to their binding sites on the NMDA receptor, which suggests that the effects of HU-211 are not mediated via the binding sites of glutamate-, glycine- and phencyclidine-like drugs or of polyamines. HU-211 can also block 45Ca2+ uptake through the NMDA-receptor/ion channel in primary cell cultures of rat forebrain. All of the above inhibitory effects of HU-211 on the NMDA-receptor/ion channel activity are stereospecific, since the (-)(3R,4R) enantiomer (HU-210) is ineffective.

The kinetic and equilibrium binding of various tritiated phencyclidine (PCP)-like drugs to the N-methyl-D-aspartate (NMDA) receptor of rat brain cortex were analyzed and compared. The tested drugs showed the following rank order of affinity toward the receptor: [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imi ne maleate ([3H]MK-801) greater than [3H]-N-[1-(2-thienyl)cyclohexyl]piperidine ([3H]TCP greater than [3H]-N[1-(3-aminophenyl)cyclohexyl]piperidine ([3H]NH2PCP) greater than [3H]phencyclidine ([3H]PCP) greater than [3H]-N[1-(3-azidophenyl)cyclohexyl]piperidine ([3H]AZ-PCP) greater than [3H]-N-[1-(3-nitrophenyl)cyclohexyl]piperidine ([3H]NO2PCP) (Kd = 3, 10, 24, 35, 100 and 2500 nM, respectively). All of the labeled ligands were found to associate with and dissociate from the receptor; both processes occurred at relatively slow rates in the absence of added glutamate and its allosteric effector glycine (basal binding) but were markedly accelerated upon their addition. For each drug, the basal association rate was similar to the basal dissociation rate. However, the basal rates differed markedly among the different drugs tested, and their apparent time constants characterizing the first-order process of basal ligand binding (kb) correlated inversely with their equilibrium binding constants (KD). The recorded kb values (10(-3) min-1) were 2.3, 5.1, 12.4, 44 and 79 for [3H]MK-801, [3H]TCP, [3H]NH2PCP, [3H]PCP and [3H]AZ-PCP, respectively. The glutamate- and glycine-induced dissociation rates (characterized by the apparent time constant k-1) differed among the ligands and also correlated inversely with their KD values. Their induced association rates, however, were similar.(ABSTRACT TRUNCATED AT 250 WORDS)

Binding of the labeled anticonvulsant drug [3H]dibenzocycloalkenimine [(3H]MK-801 to the N-methyl-D-aspartate (NMDA) receptor and its dissociation from the receptor at 25 degrees C are slow processes, both of which follow first order kinetics (t1/2 approximately equal to 70 and 180 min, respectively). Both reactions are markedly accelerated by glutamate and glycine (t1/2 approximately equal to 5-8 and 4 min, respectively), which allow bimolecular association kinetics of the labeled drug with the receptors whereas equilibrium binding of [3H]MK-801 (Kd 2-4 nM) is hardly affected by glutamate and glycine. The data suggest that MK-801 acts as a steric blocker of the NMDA receptor channel. The competitive antagonist D-(-)-2-amino-5-phosphovaleric acid (AP-5) freezes the receptor in a state which precludes either binding of [3H]MK-801 to the receptor channel or its dissociation from it. These findings have therapeutic implications.