The birth and rise of a craniopharyngioma: the radiological evolution of an incidental craniopharyngioma detected on serial MRI during medical treatment of a macroprolactinoma

This case demonstrates the rare coexistence of a prolactinoma with craniopharyngioma and documents its radiological growth. This case suggests that patients with pituitary neoplasms should be followed closely and although prolactinomas can often be managed medically, a coexistent other lesion may require surgery for histological assessment and to reduce mass effect

Vascular endothelial growth factor production and regulation in rodent and human pituitary tumor cells in vitro

Angiogenesis, the formation of a new blood supply, is an essential step in tumorigenesis. Although vascular endothelial growth factor (VEGF) is known to be a very potent angiogenic factor in most solid tumors, little is known about its production and regulation in pituitary adenomas. We have investigated basal and stimulated VEGF production by rodent pituitary tumor cells (mouse corticotrope AtT20, rat lactosomatotrope GH3, mouse gonadotrope alpha T3-1 and mouse folliculostellate TtT/GF cells), and by hormone-inactive (27), corticotrope (9), lactotrope (3) and somatotrope (21) human pituitary adenoma cell cultures. All 4 pituitary cell lines secreted VEGF, which in the case of AtT20, GH3 and TtT/GF cells was inhibited by approximately 50% by dexamethasone. TtT/GF cells were the most responsive to the different stimuli used since basal values were augmented by pituitary adenylate cyclase activating polypeptide-38 (PACAP-38), interleukin-6 (IL-6), transforming growth factor-cc (TGF-a), IGF-I and the somatostatin analogue ocreotide. However, in GH3, AtT20 and aT3-1 cells, basal VEGF levels where not enhanced with any of the stimuli tested. The majority of the human adenomas tested (92%) basally secreted measurable VEGF which was inhibited by dexamethasone in most cases (84%). VEGF levels were increased in hormone inactive adenomas, somatotrope tumors and prolactinomas by TGF-alpha, PACAP-38, and 17 beta -estradiol, respectively. In conclusion, pituitary tumor cells are capable of producing VEGF which may be involved in tumoral angiogenesis. Our results concerning the suppression of VEGF by dexamethasone suggest that glucocorticoids may have anti-angiogenic properties and therefore therapeutic relevance for the treatment of pituitary adenomas

Results of Gamma Knife Radiosurgery in Acromegaly

Objective. Single-session radiosurgery with Gamma Knife (GK) may be a potential adjuvant treatment in acromegaly. We analyzed the safety and efficacy of GK in patients who had previously received maximal surgical debulking at our hospital. Methods. The study was a retrospective analysis of hormonal, radiological, and ophthalmologic data collected in a predefined protocol from 1994 to 2009. The mean age at treatment was 42.3 years (range 22–67 yy). 103 acromegalic patients participated in the study. The median follow-up was 71 months (IQ range 43–107). All patients were treated with GK for residual or recurrent GH-secreting adenoma. Results. Sixty-three patients (61.2%) reached the main outcome of the study. The rate of remission was 58.3% at 5 years (95% CI 47.6–69.0%). Other 15 patients (14.6%) were in remission after GK while on treatment with somatostatin analogues. No serious side effects occurred after GK. Eight patients (7.8%) experienced a new deficit of pituitary function. New cases of hypogonadism, hypothyroidism, and hypoadrenalism occurred in 4 of 77 patients (5.2%), 3 of 95 patients (3.2%), and 6 of 100 patients at risk (6.0%), respectively. Conclusion. In a highly selected group of acromegalic patients, GK treatment had good efficacy and safety

Long-Term Use of Temozolomide as Safe and Effective Therapy for an Aggressive Corticotroph Adenoma in a Very Old Patient

Background: Temozolomide (TMZ) is safe and effective in the treatment of aggressive pituitary adenomas (PAs). However, the optimal duration of TMZ therapy is still unknown. Moreover, data about administration of TMZ in elderly (≥65 years) people to treat aggressive PAs are scarce. We report the case of the oldest female patient undergoing the longest TMZ protocol described so far to treat an aggressive, initially silent corticotroph PA. Case report: The patient initially underwent partial surgical removal of the PA. Subsequent treatment with cabergoline was applied, but it was unsuccessful in controlling the growth of the residual tumor. Pasireotide and external radiation also showed to be ineffective; therefore, treatment with TMZ was started at the standard dose of 200 mg/m2/day for 5 days every 4 weeks for a total of 47 cycles. At the time of treatment's beginning, the patient was 83 years old. Radiological follow-up documented a progressive, remarkable reduction of the adenoma and the last imaging, after 39 cycles of TMZ, showed an intrasellar lesion with large areas of cystic degeneration. The patient also developed adrenal deficiency managed with glucocorticoid replacement. No major side effects were observed throughout the treatment, with exception of nausea, well controlled with anti-emetic medication. TMZ therapy was discontinued after 47 cycles; hormonal and imaging follow-up investigations documented sustained functional and dimensional response. Conclusions: Our case supports the long-term use of TMZ, confirming its safety and efficacy also for elderly patients

Hip fracture in hospitalized medical patients

BACKGROUND: The aim of the present study is to analyze the incidence of hip fracture as a complication of admissions to internal medicine units in Spain. METHODS: We analyzed the clinical data of 2,134,363 adults who had been admitted to internal medicine wards. The main outcome was a diagnosis of hip fracture during hospitalization. Outcome measures included rates of in-hospital fractures, length of stay and cost. RESULTS: A total of 1127 (0.057%) admittances were coded with an in-hospital hip fracture. In hospital mortality rate was 27.9% vs 9.4%; p < 0.001, and the mean length of stay was significantly longer for patients with a hip fracture (20.7 days vs 9.8 days; p < 0.001). Cost were higher in hip-fracture patients (6927€ per hospitalization vs 3730€ in non fracture patients). Risk factors related to fracture were: increasing age by 10 years increments (OR 2.32 95% CI 2.11-2.56), female gender (OR 1.22 95% CI 1.08-1.37), admission from nursing home (OR 1.65 95% CI 1.27-2.12), dementia (1.55 OR 95% CI1.30-1.84), malnutrition (OR 2.50 95% CI 1.88-3.32), delirium (OR 1.57 95% CI 1.16-2.14), and anemia (OR 1.30 95%CI 1.12-1.49). CONCLUSIONS: In-hospital hip fracture notably increased mortality during hospitalization, doubling the mean length of stay and mean cost of admission. These are reasons enough to stress the importance of designing and applying multidisciplinary plans focused on reducing the incidence of hip fractures in hospitalized patients

Calreticulin mutations affect its chaperone function and perturb the glycoproteome

Calreticulin (CALR) is an endoplasmic reticulum (ER)-retained chaperone that assists glycoproteins in obtaining their structure. CALR mutations occur in patients with myeloproliferative neoplasms (MPNs), and the ER retention of CALR mutants (CALR MUT) is reduced due to a lacking KDEL sequence. Here, we investigate the impact of CALR mutations on protein structure and protein levels in MPNs by subjecting primary patient samples and CALR-mutated cell lines to limited proteolysis-coupled mass spectrometry (LiP-MS). Especially glycoproteins are differentially expressed and undergo profound structural alterations in granulocytes and cell lines with homozygous, but not with heterozygous, CALR mutations. Furthermore, homozygous CALR mutations and loss of CALR equally perturb glycoprotein integrity, suggesting that loss-of-function attributes of mutated CALR chaperones (CALR MUT) lead to glycoprotein maturation defects. Finally, by investigating the misfolding of the CALR glycoprotein client myeloperoxidase (MPO), we provide molecular proof of protein misfolding in the presence of homozygous CALR mutations. Keywords: CP: Cancer; CP: Molecular biology; calreticulin; chaperone; glycoprotein; limited proteolysis-coupled mass spectrometry; myeloperoxidase; myeloproliferative neoplasm; protein folding; proteome

A conformational switch controlling the toxicity of the prion protein

Prion infections cause conformational changes of the cellular prion protein (PrPC) and lead to progressive neurological impairment. Here we show that toxic, prion-mimetic ligands induce an intramolecular R208-H140 hydrogen bond (‘H-latch’), altering the flexibility of the α2–α3 and β2–α2 loops of PrPC. Expression of a PrP2Cys mutant mimicking the H-latch was constitutively toxic, whereas a PrPR207A mutant unable to form the H-latch conferred resistance to prion infection. High-affinity ligands that prevented H-latch induction repressed prion-related neurodegeneration in organotypic cerebellar cultures. We then selected phage-displayed ligands binding wild-type PrPC, but not PrP2Cys. These binders depopulated H-latched conformers and conferred protection against prion toxicity. Finally, brain-specific expression of an antibody rationally designed to prevent H-latch formation prolonged the life of prion-infected mice despite unhampered prion propagation, confirming that the H-latch is an important reporter of prion neurotoxicity

Advice from a Medical Expert through the Internet on Queries about AIDS and Hepatitis: Analysis of a Pilot Experiment

BACKGROUND: Advice from a medical expert on concerns and queries expressed anonymously through the Internet by patients and later posted on the Web, offers a new type of patient–doctor relationship. The aim of the current study was to perform a descriptive analysis of questions about AIDS and hepatitis made to an infectious disease expert and sent through the Internet to a consumer-oriented Web site in the Spanish language. METHODS AND FINDINGS: Questions were e-mailed and the questions and answers were posted anonymously in the “expert-advice” section of a Web site focused on AIDS and hepatitis. We performed a descriptive study and a temporal analysis of the questions received in the first 12 months after the launch of the site. A total of 899 questions were received from December 2003 to November 2004, with a marked linear growth pattern. Questions originated in Spain in 68% of cases and 32% came from Latin America (the Caribbean, Central America, and South America). Eighty percent of the senders were male. Most of the questions concerned HIV infection (79%) with many fewer on hepatitis (17%) . The highest numbers of questions were submitted just after the weekend (37% of questions were made on Mondays and Tuesdays). Risk factors for contracting HIV infection were the most frequent concern (69%), followed by the window period for detection (12.6%), laboratory results (5.9%), symptoms (4.7%), diagnosis (2.7%), and treatment (2.2%). CONCLUSIONS: Our results confirm a great demand for this type of “ask-the-expert” Internet service, at least for AIDS and hepatitis. Factors such as anonymity, free access, and immediate answers have been key factors in its success

A spatio-temporally constrained gene regulatory network directed by PBX1/2 acquires limb patterning specificity via HAND2.

A lingering question in developmental biology has centered on how transcription factors with widespread distribution in vertebrate embryos can perform tissue-specific functions. Here, using the murine hindlimb as a model, we investigate the elusive mechanisms whereby PBX TALE homeoproteins, viewed primarily as HOX cofactors, attain context-specific developmental roles despite ubiquitous presence in the embryo. We first demonstrate that mesenchymal-specific loss of PBX1/2 or the transcriptional regulator HAND2 generates similar limb phenotypes. By combining tissue-specific and temporally controlled mutagenesis with multi-omics approaches, we reconstruct a gene regulatory network (GRN) at organismal-level resolution that is collaboratively directed by PBX1/2 and HAND2 interactions in subsets of posterior hindlimb mesenchymal cells. Genome-wide profiling of PBX1 binding across multiple embryonic tissues further reveals that HAND2 interacts with subsets of PBX-bound regions to regulate limb-specific GRNs. Our research elucidates fundamental principles by which promiscuous transcription factors cooperate with cofactors that display domain-restricted localization to instruct tissue-specific developmental programs

An Arrayed Genome-Wide Perturbation Screen Identifies the Ribonucleoprotein hnRNP K As Rate-Limiting for Prion Propagation

A defining characteristic of mammalian prions is their capacity for self-sustained propagation. Theoretical considerations and experimental evidence suggest that prion propagation is modulated by cell-autonomous and non-autonomous modifiers. Using a novel quantitative phospholipase protection assay (QUIPPER) for high-throughput prion measurements, we performed an arrayed genome-wide RNA interference (RNAi) screen aimed at detecting modifiers of prion propagation. We exposed prion-infected cells in high-density microplates to 35’364 ternary pools of 52’746 siRNAs targeting 17’582 genes representing the mouse protein-coding transcriptome. We identified 1191 modulators of prion propagation. While 1151 of these modified the expression of both the pathological prion protein, PrP$^{Sc}$, and its cellular counterpart PrP$^{C}$, 40 genes affected selectively PrP$^{Sc}$. Of the latter, 20 genes augmented prion production when suppressed. A prominent limiter of prion propagation was the heterogeneous nuclear ribonucleoprotein Hnrnpk. Psammaplysene A (PSA), which binds Hnrnpk, reduced prion levels in cultured cells and protected them from cytotoxicity. PSA also reduced prion levels in infected cerebellar organotypic slices and alleviated locomotor deficits in prion-infected Drosophila melanogaster expressing ovine PrP$^{C}$. Hence, genome-wide QUIPPER-based perturbations can discover actionable cellular pathways involved in prion propagation. Finally, the unexpected identification of a prioncontrolling ribonucleoprotein suggests a role for RNA in the generation of infectious prions