Uncovering elevated tau TPP motif phosphorylation in the brain of Alzheimer's disease patients.

INTRODUCTION: A wide array of post-translational modifications of the tau protein occurs in Alzheimer's disease (AD) and they are critical to pathogenesis and biomarker development. Several promising tau markers, pT181, pT217, and pT231, rely on increased phosphorylation within a common molecular motif threonine-proline-proline (TPP). METHODS: We validated new and existing antibodies against pT217, pT231, pT175, and pT181, then combined immunohistochemistry (IHC) and immunoassays (ELISA) to broadly examine the phosphorylation of the tau TPP motif in AD brains. RESULTS: The tau burden, as examined by IHC and ELISA, correlates to Braak stages across all TPP sites. Moreover, we observed regional variability across four TPP motif phosphorylation sites in multiple brains of sporadic AD patients. DISCUSSION: We conclude that there is an elevation of TPP tau phosphorylation in AD brains as disease advances. The regional variability of pTPP tau suggests that examining different phosphorylation sites is essential for a comprehensive assessment of tau pathology.

Trabecular bone score and bone mineral density as indices of skeletal fragility in endogenous Cushing's syndrome.

OBJECTIVE: Endogenous Cushing's syndrome (CS) is a known cause of secondary osteoporosis. Vertebral fractures (VFs) in endogenous CS may occur despite normal bone mineral density (BMD). Trabecular bone score (TBS) is a relatively new, non-invasive technique to assess bone microarchitecture. The objective of our study was to analyse the BMD and bone microarchitecture using TBS in endogenous CS and compare it with a group of age and sex-matched healthy controls, and also analyse the factors predicting BMD and TBS. DESIGN: Cross-sectional study of cases and controls. PATIENTS AND MEASUREMENTS: We included 40 female patients with overt endogenous CS, out of which 32 were adrenocorticotropic hormone (ACTH)-dependent CS and 8 were ACTH-independent. We also included 40 healthy, female controls. Both patients and controls were subjected to an assessment of biochemical parameters and BMD and TBS. RESULTS: Patients with endogenous CS had significantly lower BMD at the lumbar spine, femoral neck, and total hip and significantly lower TBS than healthy controls (all p < .001), while no significant difference was noted in the distal radius BMD (p = .055). In endogenous CS, a large proportion of patients, n = 13 (32.5%) had normal BMD for age (BMD Z-score ≥ -2.0) with low TBS (L1 -L4 TBS ≤ 1.34). TBS correlated negatively with HbA1c (p = .006), and positively with serum T4 (p = .027). CONCLUSION: TBS should be considered an important complementary tool in addition to BMD for the routine assessment of skeletal health in CS.

High prevalence and a long delay in the diagnosis of primary aldosteronism among patients with young-onset hypertension.

BACKGROUND: Despite being the most common cause of secondary hypertension, prevalence of primary aldosteronism (PA) among patients with young-onset hypertension (YH - age of hypertension onset <40 years) remains poorly studied. OBJECTIVE: We assessed the prevalence of PA in patients with YH referred for evaluation of secondary hypertension. DESIGN AND PATIENTS: In this prospective, cross-sectional study, 202 patients with YH, visiting endocrine and cardiology clinics of All India Institute of Medical Sciences, India, were evaluated. MEASUREMENTS: Primary aldosteronism was screened by measuring plasma aldosterone concentration (PAC) and direct renin concentration (DRC) and calculating aldosterone-to-renin ratio (ARR), followed by confirmatory saline infusion test (SIT) according to Endocrine Society Guideline. Those confirmed with post-SIT PAC >5 ng/dl underwent adrenal computed tomography (CT), followed by adrenal venous sampling (AVS). RESULTS: Of 202 YH patients, 38 (18.8%) screened positive, and PA was confirmed in 36 (17.8%). The mean age was 43.9 ± 10.9 years, and median duration of hypertension was 10.5 (3.5-18) years. The prevalence of PA increased with grade of hypertension (8.1% in grade 1 to 37.1% in grade 3), number of antihypertensive medications (2.5% in those taking ≤1 to 50% in those taking ≥4 medications) and severity of hypokalaemia (0% in potassium >5 to 85.7% in potassium <3.5 mmol/L). The prevalence of PA by age of hypertension onset was highest in age group 30-39 years (31.3%). CONCLUSIONS: There is a high prevalence and a long delay in diagnosis of PA among patients with YH, and YH should be considered as a separate high-risk category in PA screening algorithm.

Superoxide dismutating molecules rescue the toxic effects of PINK1 and parkin loss.

Reactive oxygen species exert important functions in regulating several cellular signalling pathways. However, an excessive accumulation of reactive oxygen species can perturb the redox homeostasis leading to oxidative stress, a condition which has been associated to many neurodegenerative disorders. Accordingly, alterations in the redox state of cells and mitochondrial homeostasis are established hallmarks in both familial and sporadic Parkinson's disease cases. PINK1 and Parkin are two genes which account for a large fraction of autosomal recessive early-onset forms of Parkinson's disease and are now firmly associated to both mitochondria and redox homeostasis. In this study we explored the hypothesis that superoxide anions participate in the generation of the Parkin and PINK1 associated phenotypic effect by testing the capacity of endogenous and exogenous superoxide dismutating molecules to rescue the toxic effects induced by loss of PINK1 or Parkin, in both cellular and fly models. Our results demonstrate the positive effect of an increased level of superoxide dismutase proteins on the pathological phenotypes, both in vitro and in vivo. A more pronounced effectiveness for mitochondrial SOD2 activity points to the superoxide radicals generated in the mitochondrial matrix as the prime suspect in the definition of the observed phenotypes. Moreover, we also demonstrate the efficacy of a SOD-mimetic compound, M40403, to partially ameliorate PINK1/Parkin phenotypes in vitro and in vivo. These results support the further exploration of SOD-mimetic compounds as a therapeutic strategy against Parkinson's disease.

A Curious Case of Severe Recurrent Hypocalcemia.

Hypocalcemia, characterized by low blood calcium levels, can range from asymptomatic to life-threatening. Common causes include hypoparathyroidism and vitamin D deficiency (VDD). Pseudohypoparathyroidism is a rare metabolic disorder marked by resistance to parathyroid hormone (PTH). This report details a young female presenting with severe hypocalcemia, hyperphosphatemia, and elevated PTH levels. She also had an associated VDD, which complicated the clinical picture. Despite receiving intravenous calcium and oral supplementation, she required extended treatment and readmission. Genetic testing revealed a variant in the CACNA1S gene. Her condition eventually stabilized with a strict, adjusted treatment regimen. This case underscores the importance of a systematic diagnostic approach, prolonged intravenous calcium therapy, and close monitoring. Pseudohypoparathyroidism represents a rare cause of severe hypocalcemia, emphasizing the need for close monitoring and regular follow-up to achieve improved outcomes.

Risk of incident gout following exposure to recombinant zoster vaccine in US adults aged ≥50 years.

OBJECTIVE: To assess whether recombinant zoster vaccine (RZV) is associated with an increased risk of new-onset gout among US adults aged ≥50 years. METHODS: We conducted a real-world, retrospective safety study with a self-controlled risk interval (SCRI) design using administrative claims data. We included health plan members aged ≥50 years with RZV exposure, followed by incident gout within 60 days. Days 1-30 following RZV exposure were considered the risk window (RW), and days 31-60 were considered the control window (CW). We estimated the risk ratio (RR) of gout in the RW versus CW, using a conditional Poisson model. The primary analysis estimated the risk of incident gout following any RZV dose. Sensitivity analyses evaluated dose 1- and dose 2-specific risks, risk among patients compliant with recommended dose spacing of 60-183 days, adjustment for seasonality, and restriction to the pre-COVID-19 era (before December 1, 2019). RESULTS: A total of 461,323 individuals received ≥1 RZV dose; we included 302 individuals (mean age 72.5 years; 66 % male) with evidence of new-onset gout within 60 days in SCRI analyses. A total of 153 (50.7 %) individuals had gout events in the RW and 149 (49.3 %) in the CW (RR 1.03; 95 % confidence interval 0.81, 1.29). All sensitivity analyses had consistent results, with no association of RZV with incident gout. CONCLUSION: In a population of US adults aged ≥50 years, there was no statistically significant increase in the risk of gout during the 30 days immediately after RZV exposure, compared with a subsequent 30-day CW.

Elevated Troponin I as a Marker for Unfavorable Outcomes in Acute Ischemic Stroke.

OBJECTIVE: To assess if elevated cardiac troponin I (cTnI) serves as a sign of unfavorable functional outcomes in ischemic stroke. METHODS: In this single-center prospective cohort study, 100 consecutive patients admitted with acute ischemic stroke (normal troponin I group n = 52, raised troponin I group n = 48) were included. Hospital mortality was documented in both groups; the remaining patients were followed up to 90 days. Then two groups were compared in terms of unfavorable short-term outcomes (Modified Rankin Scale > 3) and mortality. Multivariate logistic regression was conducted to determine the predictive value of elevated cTnI. The Kaplan-Meier curve was drawn and compared to determine the difference in survival between the two groups. To find out the most probable cut-off level for an unfavorable outcome, a receiver operating characteristic (ROC) analysis was conducted. RESULT:  A higher frequency of coronary artery disease (p=0.030), higher National Institutes of Health Stroke Scale (NIHSS) (p=0.008) score, and lower Glasgow Coma Scale (GCS) (p=0.002) was observed in raised troponin I group. Even after the exclusion of confounding elevated troponin I was found to be an independent predictor of unfavorable outcomes (adjusted odds ratio, OR 8.25 {95% confidence interval, CI: 2.65-25.75}; p<0.001). The patients with raised troponin I had a significantly lower rate of survival after 90 days (p=0.022). The elevated troponin I was observed to have a significantly high accuracy (p<0.001; area under curve, AUC: 0.768 {moderate accuracy}, 95% CI: 0 .676 to 0.861) in predicting unfavorable outcomes. CONCLUSION: Elevated cTnI is independently associated with unfavorable short-term outcomes. It is also associated with a lower rate of survival.

The spectrum of manifestations of primary hyperparathyroidism in children and adolescents.

INTRODUCTION: Primary hyperparathyroidism (PHPT) is a rare disease in children and adolescents. Early recognition of this disease is important to prevent significant morbidity and mortality. MATERIAL AND METHODS: We included 10 consecutive patients with PHPT aged 14 to 19 years of age and followed-up prospectively upto one year after parathyroidectomy. RESULTS: Our cohort included 6 females and 4 males. The mean age of the patients was 16.7 ±1.8 years. The symptoms at presentation were musculoskeletal pain (90%), bone deformity (50%), fracture (30%), proximal myopathy (40%), renal stones (50%), reflux symptoms (40%), and pancreatitis (30%). The mean serum calcium was 3.1 ±0.5 mmol/l, mean serum inorganic phosphorus was 0.9 ±0.3 mmol/l and median serum alkaline phosphatase (ALP) was 1911.5 IU/l (IQR: 522.7-5702.3). The median serum intact parathyroid hormone was 133.5 pmol/l (IQR: 69.5 -178.7) while serum 25(OH)D was 47.7 nmol/l (IQR: 23.7-72.7). Hypercalciuria was observed in 7 patients. Hungry bone syndrome was observed in 4 (40%) patients after surgery. Typical parathyroid adenoma was found in 9 (90%) patients while one patient had atypical adenoma with high mitotic index. After one year of surgery, all patients had significant improvement in clinical and biochemical parameters with persistence of residual bone deformities. CONCLUSIONS: Our study showed the spectrum of manifestations of PHPT in children and adolescents and outcomes of parathyroidectomy till one year. Long-term follow-up studies with bigger cohorts are required to understand the true nature of the disease in children and adolescents.

Adrenocortical adenoma manifesting as Cushing's syndrome and pseudo-precocious puberty in a toddler.

Cushing's syndrome is a rare disease in the paediatric age group. Adrenocortical carcinomas (ACC) constitute the most common cause of Cushing's syndrome between 1 and 5 years of age. Often, adrenocortical carcinomas co-secrete other hormones such as androgens (testosterone), deoxy-corticosterone (DOCA), or 17-hydroxy-progesterone [17(OH)P] in addition to cortisol. This may manifest with symptoms and signs of precocious puberty along with Cushing's syndrome. It is rare for a benign adrenocortical adenoma to co-secrete androgens and other hormones in addition to cortisol. Differentiation between adenoma and carcinoma is difficult in all aspects: clinical, radiological, and histopathological. Here, we describe the case of a 2.5-year-old male child who presented with Cushing's syndrome and virilization. Although we suspected ACC clinically, the radiological and histopathological findings were suggestive of benign adrenocortical adenoma. Our case represents the diagnostic challenge that exists in paediatric adrenocortical tumours.

Atypical parathyroid adenoma: Severe manifestations in an adolescent girl.

INTRODUCTION: Primary hyperparathyroidism (PHPT) is a disease that is usually diagnosed in an asymptomatic state during routine biochemical screening. It generally manifests as a sporadic disease in post-menopausal women. However, in India and developing countries, we continue to see severe skeletal and renal manifestations of the disease. CASE REPORT: Herein, we describe the case of a 16-year-old adolescent girl who presented with severe manifestations of primary hyperparathyroidism. Biochemically, she had severe parathyroid hormone (PTH)-dependent hypercalcaemia with hypophosphataemia and vitamin D deficiency (serum total Ca - 18.5 mg/dl [8.5-10.5 mg/dl], serum PO4 - 1.9 mg/dl [2.5-4.5 mg/dl], serum ALP - 2015 IU/l [80-240 IU/l], serum 25[OH]D - 19.1 ng/ml [30-100 ng/ml] and serum iPTH > 5000 pg/ml [15-65 pg/ml]). Pre-operatively, she required management with saline diuresis, bisphosphonate, and calcitonin. After surgery, the patient had severe hungry bone syndrome (serum Ca - 4.1 mg/dl, serum PO4 - 2.1 mg/dl, serum ALP > 10,000 IU/l) that required treatment with calcium infusions for almost 3 months. Although the clinical and biochemical picture was suggestive of parathyroid carcinoma, histopathology revealed atypical parathyroid adenoma with low proliferative index. Atypical parathyroid adenoma is a term applied to a neoplasm with 'worrisome' features but not fulfilling the 'absolute histopathological criteria of malignancy'. CONCLUSIONS: Atypical parathyroid adenoma, a rare cause of PHPT, may be associated with severe manifestations. Although malignancy was not discerned in the immediate post-operative period, we plan to continue long-term follow-up of the patient to look for any signs of recurrence or development of parathyroid carcinoma.

Motherhood and Endocrinology Training: Diary of a Female Resident.

Motherhood is tough and life-changing for every woman and even more so for females doing residency training. Pregnancy in itself was challenging and took a physical and mental toll on the body. Long and demanding work-hours with unrealistic expectations from oneself added to severe stress. If pregnancy part was difficult, then juggling the responsibilities of a child as well maintaining work-life balance was like walking the tight-rope with insecurities and self-doubts creeping in at several occasions. It required a great deal of motivation to carry on. It was the support of my 'village,' which made me finally achieve things that seemed impossible in the beginning.

Endocrine causes of heart failure: A clinical primer for cardiologists.

Heart failure (HF) may be a presenting manifestation of a few endocrine disorders and should be considered in evaluation of heart failure causes. This clinically oriented review is an attempt to highlight the protean manifestations of heart failure in endocrine diseases which could present either as acute or chronic heart failure. Acute heart failure manifests as hypertensive crisis, Takotsubo syndrome, or as tachy/brady cardiomyopathies. Chronic heart failure could masquerade with features of hyperdynamic heart failure, or hypertrophic, restrictive or dilated cardiomyopathy. Rarely constrictive features or resistant heart failure could be the presenting feature. Isolated presentation as pulmonary hypertension and right heart failure are also documented. Good history-taking and physical examination with targeted investigations will help in the timely management for reversing the pathophysiology to a significant extent by appropriated management.

Spontaneous Remission of Acromegaly After Pituitary Apoplexy in a Middle-Aged Male.

Background: Pituitary apoplexy results from hemorrhage, infarction, or hemorrhagic infarction within a pituitary tumor. Subclinical or clinical apoplexy is not uncommon in acromegaly, owing to the large size of the tumor at initial detection. Growth hormone excess in acromegaly often persists following surgery. However, in rare instances, pituitary apoplexy may present a spontaneous cure to growth hormone excess. Case Report: A 40-year-old male presented with holocranial headache for the past 16 years that had worsened in severity during the prior year. Two months before presentation, he experienced a severe headache that he described as the worst headache of his life. The patient had prominent acromegaloid features that he ignored, as they seemed to cause no harm. The patient had no signs of clinically active disease. Magnetic resonance imaging of the brain revealed a pituitary macroadenoma with evidence of hemorrhage. Serum insulin-like growth factor 1 and oral glucose-suppressed serum growth hormone levels were normal, suggestive of inactive or silent disease. Pituitary apoplexy causing spontaneous remission of acromegaly was diagnosed, and close follow-up was planned for the evolution of hypopituitarism. Conclusion: This case highlights a rare presentation of acromegaly in which an episode of symptomatic pituitary apoplexy revealed the diagnosis of pituitary adenoma and led to the cure of growth hormone hypersecretion.

Renal Tubular Acidosis Manifesting as Severe Metabolic Bone Disease.

Renal tubular acidosis (RTA) is a condition characterized by normal anion gap metabolic acidosis. Type 1 and type 2 RTA are the most common, and are caused by defective secretion of hydrogen ions and impaired absorption of bicarbonate, respectively. Long-standing uncorrected acidosis can lead to metabolic bone disease (MBD). Rickets and osteomalacia remain the commonest manifestations of uncorrected RTA. In addition, there can be a myriad of other skeletal manifestations like fractures, pseudofractures, secondary osteoporosis and even sclerotic bone disease. The postulated mechanism for bone involvement includes acidosis-mediated exaggerated osteoclastic bone resorption. Other contributory factors include abnormal renal handling of phosphate leading to hypophosphataemia in proximal RTA, and impaired vitamin D metabolism and action. In distal RTA, hypercalciuria and secondary hyperparathyroidism may play a key role for bone involvement. Recognizing the disease in its early course is important to prevent permanent sequelae of skeletal involvement. Most of these patients may, in fact, undergo orthopaedic interventions without primary correction of acidosis. We describe five cases who presented with MBD in varied forms. While evaluating the aetiology of MBD, they were diagnosed with RTA. Subsequently, we attempted to analyse the causes of RTA. Although the common causes were ruled out, genetic aetiology could not be ascertained due to resource constraints. RTA remains an important differential diagnosis of MBD. More awareness is required to diagnose the disease early and to treat it adequately. Our case series is an attempt to provide the clinical, biochemical and skeletal spectrum of RTA. In addition, we have attempted to provide algorithms for the approach and evaluation of RTA along with their varied causes.

46, XY complete gonadal dysgenesis with pubertal virilisation due to dysgerminoma/gonadoblastoma.

Complete gonadal dysgenesis (CGD) or Swyer syndrome is characterised by sexual infantilism in a phenotypic female with 46, XY karyotype. Patients with gonadal dysgenesis and Y-chromosome material are at a high risk of developing gonadoblastoma and dysgerminoma. A 16-year-old girl presented with progressive virilisation, poor breast development and primary amenorrhea. On evaluation, she was found to have male-range serum testosterone, large abdominopelvic mass lesion, elevated germ cell tumour markers and 46, XY karyotype. She underwent surgical excision of left gonadal mass and right streak gonad, histopathology of which revealed dysgerminoma and gonadoblastoma, respectively. A diagnosis of virilising germ cell tumour arising in the setting of 46, XY CGD was, therefore, made. This case highlights a rare presentation of 46, XY CGD and the need to consider early prophylactic gonadectomy in patients affected with this rare condition. The presence of dysgerminoma/gonadoblastoma should be suspected if a hitherto phenotypic female with CGD undergoes virilisation.

A FLASH OF HOPE: Eye Movement Desensitization and Reprocessing (EMDR) Therapy.

DEPARTMENT EDITORS Julie P. Gentile, MD Professor and Chair, Department of Psychiatry, Wright State University, Boonshoft School of Medicine, Dayton, Ohio Allison E. Cowan, MD Associate Professor, Department of Psychiatry, Wright State University, Boonshoft School of Medicine, Dayton, Ohio EDITORS' NOTE The patient cases presented in Psychotherapy Rounds are composite cases written to illustrate certain diagnostic characteristics and to instruct on treatment techniques. The composite cases are not real patients in treatment. Any resemblance to a real patient is purely coincidental. ABSTRACT Eye movement desensitization and reprocessing (EMDR) is a specific treatment modality that utilizes bilateral stimulation to help individuals who have experienced trauma. This stimulation can occur in a variety of forms, including left-right eye movements, tapping on the knees, headphones, or handheld buzzers, known as tappers. This type of psychotherapy allows the individuals to redefine their self-assessment and responses to a given traumatic event in eight defined steps. While EMDR is relatively new type of psychotherapy, existing literature has demonstrated positive results using this form of therapy when treating patients with post-traumatic stress disorder (PTSD) by utilizing eye movements to detract from negative conceptualizations as a response to a specific trigger, while reaffirming positive self-assessments. Research indicates that EMDR could be a promising treatment for mental health issues other than PTSD, including bipolar disorder, substance use disorders, and depressive disorders. In this article, the eight fundamental processes of EMDR are illustrated through a composite case vignette and examined alongside relevant research regarding its efficacy in treating PTSD.

Performance of High School Students in a Laparoscopic Training Program.

BACKGROUND AND OBJECTIVES: We hypothesized that high school students can be subjected to the same laparoscopic surgical training curriculum used by surgeons and successfully complete it. The goal of this study was to evaluate the appropriateness of early training in minimally invasive surgical techniques. METHODS: Thirteen high school students, ages 15-18, participated in the validated Top Gun Surgeon Laparoscopic Skills and Suturing program. The students performed 3 preparatory drills 10 times each. The students' scores were then compared to a database of 393 surgeons. Performance graphs were prepared to allow comparison of skills acquisition between the 2 training groups. RESULTS: All 13 students successfully completed the tasks. The Students' performance (expressed as time/percentile range/average percentile) for each task were as follows: rope pass 101.8 seconds/3.8-47.1/11.8; bean drop 149.5 seconds/18.7-96.0/59.4; triangle transfer 303.2 seconds/1.3-16.0/5.8. The students started each drill with slower times, but their average improvement (decreased time to complete tasks) was more rapid than that of the surgeons between the first and second trials for each drill (-83 seconds vs -25 seconds, -120 seconds vs -53 seconds, -100 seconds vs -60 seconds). Average student times compared to average surgeon times during the last trials measured were not significantly different in the triangle transfer and rope pass drills (P = .40 and .18, respectively). Students' times were significantly faster than surgeons' in the last measured trial of the bean drop (P = .039). CONCLUSIONS: Despite the small sample size, this investigation suggests that high school students can successfully complete skill-building programs in minimally invasive surgery. Further study is needed to evaluate the appropriateness of starting surgical training of future residents at an earlier stage of their careers.

SRSF1-dependent nuclear export inhibition of C9ORF72 repeat transcripts prevents neurodegeneration and associated motor deficits.

Hexanucleotide repeat expansions in the C9ORF72 gene are the commonest known genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Expression of repeat transcripts and dipeptide repeat proteins trigger multiple mechanisms of neurotoxicity. How repeat transcripts get exported from the nucleus is unknown. Here, we show that depletion of the nuclear export adaptor SRSF1 prevents neurodegeneration and locomotor deficits in a Drosophila model of C9ORF72-related disease. This intervention suppresses cell death of patient-derived motor neuron and astrocytic-mediated neurotoxicity in co-culture assays. We further demonstrate that either depleting SRSF1 or preventing its interaction with NXF1 specifically inhibits the nuclear export of pathological C9ORF72 transcripts, the production of dipeptide-repeat proteins and alleviates neurotoxicity in Drosophila, patient-derived neurons and neuronal cell models. Taken together, we show that repeat RNA-sequestration of SRSF1 triggers the NXF1-dependent nuclear export of C9ORF72 transcripts retaining expanded hexanucleotide repeats and reveal a novel promising therapeutic target for neuroprotection.