Gonadotropin-secreting and thyrotropin-secreting pituitary adenomas: A single-center experience

ABSTRACT Objective: Data regarding rare FPAs from India, a resource limited setting, are limited. We describe a case series of rare FPAs from a single center in western India. Materials and methods: This was a retrospective case record review of patients diagnosed between January 2010 and July 2022. The diagnosis was based on biochemical (inappropriately elevated serum FSH/LH) and pathologic (positive immunostaining for FSH/LH) features in patients with FGA, and elevated serum thyroid hormones and normal/elevated TSH in patients with TSHomas. Results: We identified 11 patients with a total of six FGAs (median age 43.5 years, five men, one FGA cosecreting TSH, median largest dimension 40 mm, range 33-60 mm) and six TSHomas (median age 34.5 years, four women, two TSHomas cosecreting GH, median largest dimension 42.5 mm, range 13-60 mm). Symptoms of sellar mass effects led to pituitary imaging in most patients with FGA. Patients with TSHomas had symptoms of excess hormone secretion (GH/TSH) or sellar mass effects. The TSHomas that cosecreted GH/FSH were larger than those secreting only TSH. Transsphenoidal resection was the most common first-line therapy but significant residual disease was frequent (3 out of 6 FGAs and 4 out of 5 TSHomas). Conclusion: This is the first and second case series of FGAs and TSHomas, respectively, from India. In this study, TSHomas presented at younger age, were larger and had low surgical cure rates.

Gonadotropin-secreting and thyrotropin-secreting pituitary adenomas: A single-center experience.

Objective: Data regarding rare FPAs from India, a resource limited setting, are limited. We describe a case series of rare FPAs from a single center in western India. Materials and methods: This was a retrospective case record review of patients diagnosed between January 2010 and July 2022. The diagnosis was based on biochemical(inappropriately elevated serum FSH/LH) and pathologic (positive immunostaining for FSH/LH) features in patients with FGA, and elevated serum thyroid hormones and normal/elevated TSH in patients with TSHomas. Results: We identified 11 patients with a total of six FGAs (median age 43.5 years, five men, one FGA cosecreting TSH, median largest dimension 40 mm, range 33-60 mm) and six TSHomas (median age 34.5 years, four women, two TSHomas cosecreting GH, median largest dimension 42.5 mm, range 13-60 mm). Symptoms of sellar mass effects led to pituitary imaging in most patients with FGA. Patients with TSHomas had symptoms of excess hormone secretion (GH/TSH) or sellar mass effects. The TSHomas that cosecreted GH/FSH were larger than those secreting only TSH. Transsphenoidal resection was the most common first-line therapy but significant residual disease was frequent (3 out of 6 FGAs and 4 out of 5 TSHomas). Conclusion: This is the first and second case series of FGAs and TSHomas, respectively, from India. In this study, TSHomas presented at younger age, were larger andhad low surgical cure rates.

Dual-phase computed tomography for localization of parathyroid lesions in children and adolescents with primary hyperparathyroidism.

BACKGROUND: Childhood and adolescent primary hyperparathyroidism (PHPT) is a rare disease caused by single adenomas in 65-94% of patients. In this patient group, there is no data on computed tomography (CT) for pre-operative parathyroid localization that may facilitate focused parathyroidectomy. METHODS: Two radiologists reviewed dual-phase (nonenhanced and arterial) CT images of twenty-three operated children and adolescents [20:single-gland disease(SGD), 3:multi-glandular disease(MGD)] with proven histopathological PHPT. Percentage arterial enhancement (PAE) was calculated as [100*{arterial-phase Hounsfield unit (HU)-nonenhanced phase HU}/nonenhanced HU] of the parathyroid lesion(s), thyroid, and lymph node. RESULTS: Dual-phase CT lateralized 100%, localized to the correct quadrant/site 85% SGD (including 3/3 ectopic), and identified 1/3 MGD. PAE (cutoff ≥ 112.3%) was sensitive (91.3%) and specific (99.5%) in distinguishing parathyroid lesions from local mimics (P<0.001). The average effective dose was 3.16±1.01mSv, comparable to the planar/single photon emission CT (SPECT) Technetium 99m(Tc)-sestamibi and choline positron emission tomography (PET)/CT scans. Solid-cystic morphology identified in 4 patients harboring pathogenic germline variants (3:CDC73, 1:CASR) may serve as a radiological clue to molecular diagnosis. Nineteen out of 20 (95%) patients with SGD who had undergone single gland resection based on pre-operative CT findings were in remission over a median follow-up of 18 months. CONCLUSION: As most children/adolescents with PHPT have SGD, dual-phase CT protocols which reduce the effective radiation dose with high localization sensitivity for single parathyroid lesions may be a sustainable pre-operative imaging modality in this patient group.

Genotype-Phenotype Correlations in Asian Indian Children and Adolescents with Primary Hyperparathyroidism.

Childhood and adolescent primary hyperparathyroidism (PHPT) is a very rare disease. Data on its molecular genetics are scarce. We performed a retrospective analysis (January 2000-January 2021) to determine the deleterious germline variants and genotype-phenotype correlations in children and adolescents < 20 years diagnosed with PHPT from a single referral center. Clinical features, biochemistry, imaging, management, and genetics (clinical exome analyzed for 11 PHPT and 7 pancreatitis-associated genes, MLPA for CDC73) were recorded. Thirty-six patients (20 males; median age 17 years) were classified into those with familial and/or syndromic (F/S) or apparently sporadic (AS) presentation. Sixteen (44.4%) harbored pathogenic/likely pathogenic germline variants in PHPT-associated genes. The genetic yield in F/S group was 90% (MEN1:8/10; CDC73:1/10), and AS group was 26.9% (CDC73:4/26; CASR:3/26). F/S group had frequent asymptomatic presentation (60% vs none; P < 0.001), lower serum PTH (237.5 vs 1369.1 pg/mL; P = 0.001), and maximum parathyroid dimension (0.9 vs 2.2 cm; P = 0.01) than AS group. Among the AS group, renal involvement was higher in those with molecular diagnoses (71.4% vs 10.5%; P = 0.01). All those with novel CASR variants (including one homozygous) had hypercalciuria and histology-proven parathyroid adenoma/carcinoma. A missense CTRC VUS occurred in one patient with chronic pancreatitis. In summary, Asian Indian children and adolescents with PHPT have high genetic yield, even with apparently sporadic presentation. The phenotypic spectrum of CASR variants is expanded to include childhood/adolescent PHPT with hypercalciuria and single gland neoplasia. The proposed roles for renal involvement to predict molecular diagnosis among those with apparently sporadic presentation require further elucidation.

Percentage arterial enhancement on 2D CT in the diagnosis of primary hyperparathyroidism: A prospective validation study and potential pitfalls.

BACKGROUND: Parathyroid lesions are identified by subjective enhancement and washout patterns on computed tomography (CT). We have previously proposed "percentage arterial enhancement" (PAE) as an objective index and now aim to validate its performance prospectively. METHODS: Dual-phase CT was performed in 40 consecutive primary hyperparathyroidism patients. PAE was calculated as [{arterial phase Hounsfield unit (HU)-unenhanced phase HU}/unenhanced phase HU] × 100. PAE > 128.9% was considered parathyroid. RESULTS: PAE had 94.2% sensitivity, 100% positive predictive value (PPV) in lateralization, and sensitivity and PPV of 93.9% in quadrant localization of single-gland disease. PAE failed to identify two lesions: an intrathyroidal parathyroid carcinoma in the background of multinodular goiter and another lower enhancing cystic parathyroid adenoma. PAE had 60% sensitivity, and 100% PPV to identify multigland disease. The mean effective dose was 2.74 mSV. CONCLUSIONS: PAE is a specific CT index for parathyroid lesions with less radiation exposure. Areas of caution include intrathyroidal and cystic lesions.

Fecal microbiota transplantation in alcohol-associated acute-on-chronic liver failure: an open-label clinical trial.

BACKGROUND: Severe alcoholic hepatitis (SAH) presenting as acute-on-chronic liver failure (ACLF) carries a high short-term mortality. Alteration of gut microbiota is a crucial component implicated in its pathogenesis, whose modulation has been suggested as a potential therapeutic tool. We evaluated the safety of fecal microbiota transplantation (FMT) and its efficacy in improving short-term survival and clinical severity scores in patients with SAH-ACLF. METHODS: Thirty-three patients [13 in the FMT arm; 20 in the standard of care arm (SOC)] with SAH-ACLF were included in this open-label study. A single FMT session was administered as a freshly prepared stool suspension from pre-identified healthy family member stool donors through a nasojejunal tube. Patients were followed up on days 7, 28, and 90. RESULTS: Survival at 28 and 90 days was significantly better in the FMT arm (100% versus 60%, p = 0.01; 53.84% versus 25%, p = 0.02). Hepatic encephalopathy resolved in 100% versus 57.14% (FMT versus SOC, p = 0.11) patients, while ascites resolved in 100% versus 40% survivors (p = 0.04). Major adverse event rates, including spontaneous bacterial peritonitis and gastrointestinal bleeding, were similar in both groups (p = 0.77; p = 0.70). Median IL1beta decreased by 21.39% (IQR - 73.67 to 7.63) in the FMT group, whereas it increased in the SOC by 27.44% (IQR - 0.88 to 128.11) (p = 0.01). Percentage changes in bilirubin and ALT between baseline and day 7 emerged as predictors of 90-day mortality. CONCLUSION: FMT is safe, improves short-term and medium-term survival, and leads to improvement in clinical severity scores in patients with SAH-ACLF. CLINICAL TRIAL NUMBER: NCT03827772 available from http://clinicaltrials.gov/ct2/show/NCT03827772 CTRI Reference number: CTRI/2019/02/017538 dated 7 February 2019.

Fungal Solubilisation and Subsequent Microbial Methanation of Coal Processing Wastes.

Large quantities of rejects from coal processing plants are currently disposed of as waste piles or in ponds and rivers, resulting in environmental concerns including pollution of rivers, and ground and surface water contamination. This work investigates for the first time, a two-stage microbial process for converting coal processing wastes (coal rejects) to methane, involving (1) fungal solubilisation of coal rejects and (2) microbial methanation of the solubilised products. Phanerochaete chrysosporium, Trichoderma viride and Neurospora discreta were screened for their ability to solubilise coal rejects. N. discreta was found to be the most suitable candidate based on the extent of bio-solubilisation, laccase activity and reversed-phase high-performance liquid chromatography (RP-HPLC) analysis. Bio-methanation of fungal-solubilised coal rejects was carried out in mesophilic anaerobic reactors with no additional carbon source, using inoculum from an anaerobic food digester. Coal rejects solubilised by N. discreta produced 3- to 6-fold higher methane compared to rejects solubilised by the other two fungi. No methane was produced from untreated coal rejects, demonstrating the importance of the fungal solubilisation stage. A total of 3.7 mmol of methane was generated per gram of carbon in 15 days from N. discreta-solubilised coal rejects. This process offers a timely, environment-friendly, and sustainable solution for the treatment of coal rejects and the generation of value-added products such as methane and volatile fatty acids.

Difference in keratinase activity of dermatophytes at different environmental conditions is an attribute of adaptation to parasitism.

Dermatophytes are a group of morphologically and physiologically related moulds, which cause well-defined infection called dermatophytosis. The enzymatic ability of fungi to decompose keratin has long been interpreted as a key innovation in the evolution of animal dermatology. In the present study, keratinase activity profile among Trichophyton mentagrophytes, Trichophyton rubrum, Microsporum canis and Microsporum gypseum isolated on keratin substrates such as human hair, human nail and chicken feather at variable environmental conditions of temperature, pH and metal ions was elucidated. All the above-mentioned fungal strains were isolated from soil using To-KA-Va baiting technique and keratinolytic activity was measured spectrophotometrically. In the temperature range of 30-40 °C and slightly alkaline pH (7.0-8.0), Trichophyton produced the highest activity of keratinase. It can be presumed that high enzyme production of Trichophyton species at normal body temperature range and pH could be an attribute for obligate anthropization in some dermatophytes.

The Werner syndrome helicase is a cofactor for HIV-1 long terminal repeat transactivation and retroviral replication.

The Werner syndrome helicase (WRN) participates in DNA replication, double strand break repair, telomere maintenance, and p53 activation. Mutations of wrn cause Werner syndrome (WS), an autosomal recessive premature aging disorder associated with cancer predisposition, atherosclerosis, and other aging related symptoms. Here, we report that WRN is a novel cofactor for HIV-1 replication. Immortalized human WRN(-/-) WS fibroblasts, lacking a functional wrn gene, are impaired for basal and Tat-activated HIV-1 transcription. Overexpression of wild-type WRN transactivates the HIV-1 long terminal repeat (LTR) in the absence of Tat, and WRN cooperates with Tat to promote high-level LTR transactivation. Ectopic WRN induces HIV-1 p24(Gag) production and retroviral replication in HIV-1-infected H9(HIV-1IIIB) lymphocytes. A dominant-negative helicase-minus mutant, WRN(K577M), inhibits LTR transactivation and HIV-1 replication. Inhibition of endogenous WRN, through co-expression of WRN(K577M), diminishes recruitment of p300/CREB-binding protein-associated factor (PCAF) and positive transcription elongation factor b (P-TEFb) to Tat/transactivation response-RNA complexes, and immortalized WRN(-/-) WS fibroblasts exhibit comparable defects in recruitment of PCAF and P-TEFb to the HIV-1 LTR. Our results demonstrate that WRN is a novel cellular cofactor for HIV-1 replication and suggest that the WRN helicase participates in the recruitment of PCAF/P-TEFb-containing transcription complexes. WRN may be a plausible target for antiretroviral therapy.

A human T-cell lymphotropic virus type 1 enhancer of Myc transforming potential stabilizes Myc-TIP60 transcriptional interactions.

The human T-cell lymphotropic virus type 1 (HTLV-1) infects and transforms CD4+ lymphocytes and causes adult T-cell leukemia/lymphoma (ATLL), an aggressive lymphoproliferative disease that is often fatal. Here, we demonstrate that the HTLV-1 pX splice-variant p30II markedly enhances the transforming potential of Myc and transcriptionally activates the human cyclin D2 promoter, dependent upon its conserved Myc-responsive E-box enhancer elements, which are associated with increased S-phase entry and multinucleation. Enhancement of c-Myc transforming activity by HTLV-1 p30II is dependent upon the transcriptional coactivators, transforming transcriptional activator protein/p434 and TIP60, and it requires TIP60 histone acetyltransferase (HAT) activity and correlates with the stabilization of HTLV-1 p30II/Myc-TIP60 chromatin-remodeling complexes. The p30II oncoprotein colocalizes and coimmunoprecipitates with Myc-TIP60 complexes in cultured HTLV-1-infected ATLL patient lymphocytes. Amino acid residues 99 to 154 within HTLV-1 p30II interact with the TIP60 HAT, and p30II transcriptionally activates numerous cellular genes in a TIP60-dependent or TIP60-independent manner, as determined by microarray gene expression analyses. Importantly, these results suggest that p30II functions as a novel retroviral modulator of Myc-TIP60-transforming interactions that may contribute to adult T-cell leukemogenesis.

HIV-1 Tat interactions with p300 and PCAF transcriptional coactivators inhibit histone acetylation and neurotrophin signaling through CREB.

The human immunodeficiency virus type-1 (HIV-1) infects microglia, macrophages, and astrocytes in the central nervous system (CNS) and may cause severe neurological diseases, such as AIDS-related dementias or progressive encephalopathies, as a result of CNS inflammation and neurotrophin signaling defects associated with expression of viral antigens and HIV-1 replication in the brain. The HIV Tat protein can be endocytosed by surrounding uninfected cells; interacts with transcriptional coactivators/acetyltransferases, p300/CREB-binding protein, and p300/CREB-binding protein-associated factor (PCAF); and induces neuronal apoptosis. Since nerve growth factor (NGF) receptor and brain-derived neurotrophic factor receptor signaling through CREB requires p300 and PCAF histone acetyltransferases, we sought to determine whether HIV-1 Tat coactivator interactions interfere with neurotrophin receptor signaling in neuronal cells. Here, we demonstrate that Tat-coactivator interactions inhibit NGF- and brain-derived neurotrophic factor-responsive CRE trans-activation and neurotrophin protection against apoptosis in PC12 and IMR-32 neuroblastoma cells. Purified recombinant Tat or Tat-derived synthetic peptides, spanning p300- and PCAF-binding sequences, inhibit histone H3/H4 acetylation in vitro. A Tat mutant, TatK28A/K50A, defective for binding p300 and PCAF, neither repressed NGF-responsive CRE transactivation nor inhibited histone acetylation. HIV-1 Tat interacts in PCAF complexes in post-mortem CNS tissues from donor neuro-AIDS patients, as determined by fluorescence resonance energy transfer immunoconfocal microscopy. Importantly, these findings suggest that HIV-1 Tat-coactivator interactions may contribute to neurotrophin signaling impairments and neuronal apoptosis associated with HIV-1 infections of the CNS.

Nerve growth factor receptor signaling induces histone acetyltransferase domain-dependent nuclear translocation of p300/CREB-binding protein-associated factor and hGCN5 acetyltransferases.

The transcriptional coactivators, p300/CREB-binding protein-associated factor (PCAF) and hGCN5, are recruited to chromatin-remodeling complexes on enhancers of various gene promoters in response to growth factor stimulation. However, the molecular mechanisms by which surface receptor signals modulate the assembly of nuclear transcription complexes are not fully understood. Here we report that nerve growth factor receptor signaling induces nuclear translocation of PCAF and hGCN5 dependent upon the phosphorylation of Ser and Thr residues within their histone acetyltransferase domains, which requires activation of PI3K, Rsk2(pp90), and MSK-1. Neurotrophin stimulation induces p53(K320) acetylation by PCAF and transcriptionally activates p53-responsive enhancer elements within the p21(WAF/CIP1) promoter associated with G(1)/S arrest during neuronal differentiation. Most importantly, these findings represent the first evidence for signal-dependent nuclear translocation of PCAF and hGCN5 acetyltransferases and allude to a novel mechanism for ligand/receptor modulation of nuclear chromatin-remodeling complexes in neurons.