Hypopituitarism in the elderly: a narrative review on clinical management of hypothalamic-pituitary-gonadal, hypothalamic-pituitary-thyroid and hypothalamic-pituitary-adrenal axes dysfunction.

Hypopituitarism is an uncommon and under-investigated endocrine disorder in old age since signs and symptoms are unspecific and, at least in part, can be attributed to the physiological effects of aging and related co-morbidities. Clinical presentation is often insidious being characterized by non-specific manifestations, such as weight gain, fatigue, low muscle strength, bradipsychism, hypotension or intolerance to cold. In these circumstances, hypopituitarism is a rarely life-threatening condition, but evolution may be more dramatic as a result of pituitary apoplexy, or when a serious condition of adrenal insufficiency suddenly occurs. Clinical presentation depends on the effects that each pituitary deficit can cause, and on their mutual relationship, but also, inevitably, it depends on the severity and duration of the deficit itself, as well as on the general condition of the patient. Indeed, indications and methods of hormone replacement therapy must include the need to normalize the endocrine profile without contributing to the worsening of intercurrent diseases, such as those of glucose and bone metabolism, and the cardiovascular system, or to the increasing cancer risk. Hormonal requirements of elderly patients are reduced compared to young adults, but a prompt diagnosis and appropriate treatment of pituitary deficiencies are strongly recommended, also in this age range.

Structural glance into a novel anti-staphylococcal peptide.

Novel antimicrobial peptides are valuable molecules for developing anti-infective drugs to counteract the contemporary spread of microbial drug-resistance. Here we focus on a novel peptide (RKWVWWRNR-NH2) derived from the fragment 107-115 of the human lysozyme that displays a 20-fold increase in anti-staphylococcal activity. The conformational analysis of this peptide and its interaction with model lipidic phases-as assayed by circular dichroism and fluorescence spectroscopy-show a noteworthy spectral change, which might be related to its anti-staphylococcal activity. The secondary structure of peptide [K(108)W(111)] 107-115 hLz was dramatically affected through a single substitution at position 111 (Ala by Trp). Therefore, this conformational change might improve the interaction of the novel peptide with the bacterial plasma membrane. These results highlight the role of peptide secondary structure and the distribution of polar/nonpolar residues for the effective interaction of this peptide with the bacterial plasma membrane, a key step for triggering its lethal effect. This knowledge may contribute to the rational design of a new generation of antimicrobial peptides with increased efficacy developed from natural sources by simple screening tools.

Fast itch relief in an experimental model for methylprednisolone aceponate topical corticosteroid activity, based on allergic contact eczema to nickel sulphate.

BACKGROUND: Topical corticosteroids (TC) consistently show effectiveness against itch, a paradigmatic symptom, in various eczemas. Rapid itch relief is a therapeutic goal. The early response of itch to TC has not been adequately studied. OBJECTIVES: To assess the effect on itch of a TC, methylprednisolone aceponate 0.1% ointment (MPA), in induced eczema in volunteers sensitized to nickel sulphate. METHODS: Sixteen volunteers with a late positive patch-test reaction to nickel sulphate entered the study. Eczema was treated once daily with » fingertip unit of MPA for 5 days. Pruritus intensity was assessed with a 10 cm visual analogue scale (VAS). Mean time to itch relief (TR ) defined as the time to reach a 30% decrease in the highest VAS value recorded was assessed, as well as TR-baseline, colorimetry and planimetric morphometry of the reaction. RESULTS: Mean TR was 1.0 days [standard deviation (SD) = 1.1] and mean TR -baseline was 1.6 days (SD = 1.4). Five volunteers reached 100% decrease from itch baseline-VAS in 2.0 ± 1.2 days, whereas a 75% decrease was obtained in 1.7 ± 1.6 days by 16 volunteers. A clinical improvement of patch-test reaction was apparent at day 11, although erythema was still present. CONCLUSION: We present a valid model to assess the efficacy and speed of action of TC treatment to alleviate pruritus and the signs of eczema. The fast effect of MPA against pruritus supports the appropriateness of treating allergic contact eczema with TC.

Systemic hypertension counteracts potential benefits of growth hormone replacement therapy on left ventricular remodeling in adults with growth hormone deficiency.

BACKGROUND: Systemic Hypertension (SH) is the main cause of left ventricular (LV) hypertrophy in the general population, but only scanty data are available on LV geometric remodeling (LVGR) in hypertensive patients with GH deficiency (GHD). AIM: We investigated hypertensive LVGR in adult-onset GHD patients, before (T0) and after 55±16 months (T1) of individualized GH replacement therapy (GHRT). SUBJECTS: Fifty-one patients, aged 45±15 yr, 29 women, were enrolled. Fifteen patients met criteria for SH (group A) whereas 36 were normotensive (group B). METHODS: An echocardiogram was performed on all patients, at least twice (at T0 and T1). LV geometric remodeling as a relationship between LV mass (LVM) index and relative wall thickness (RWT), LV volumes, and ejection fraction were measured. RESULTS: At T0, group A showed higher LV mass and LVM index values than group B; LV hypertrophy was found in 40% and 22% of patients, respectively (p=0.06). At T1, IGF-I levels had increased significantly in both groups. LV hypertrophy rate consistently increased in group A (from 40 to 60%, p<0.05), whereas slightly decreased in group B (from 22 to 19%, ns). Body surface area (p<0.001), age (p<0.05), and systolic blood pressure (p<0.05) were main determinants of LVM at multivariate analysis. CONCLUSIONS: Along with body surface area and age, SH was significantly related to abnormal LVGR (LV hypertrophy) in GHD patients. As a result, blood pressure management and caloric intake restrictions are deemed necessary for this subset of patients.

Cell proliferation parameters and apoptosis indices in pituitary macroadenomas.

BACKGROUND: Pituitary adenomas are usually well-differentiated tumors but may show locally aggressive behavior. AIM: To investigate the relationship between proliferation and apoptosis parameters and tumor recurrence in a series of 20 radically resected pituitary macroadenomas (11 functioning, 9 non-functioning). MATERIALS AND METHODS: Proliferative activity and DNA ploidy were analyzed by flow cytometry (FCM) on fresh surgical specimens. Immunohistochemistry for Ki-67/MIB-1 and for the anti-apoptotic protein Bcl-2 was performed on paraffin-embedded specimens from the same tumors. Tumor regrowth was evaluated by magnetic resonance imaging (MRI). RESULTS: Six adenomas recurred after surgery, regardless of hormonal hypersecretion. Pre-surgical tumor size was significantly higher in recurrent than in non-recurrent adenomas (p=0.003). Pre-surgical MRI demonstrated cavernous sinus (CS) invasiveness in all recurrent tumors, while none of the non-invasive adenomas recurred (p=0.042, by Fisher's exact test). The DNA content was aneuploid in 5/20 adenomas, one of which recurred. Cell percentages in the S (%SPF) and G2+M (%G2-M) phases and proliferative index (PI) (PI=%SPF+%G2-M) were significantly higher in aneuploid than in diploid adenomas (p<0.05), but no significant differences concerning all FCM parameters were observed between recurrent and non-recurrent adenomas. Similarly, MIB-1 did not show a significant difference of expression between recurrent and non-recurrent adenomas (p=0.33). Bcl-2 immunoreactivity was detected in 12/15 pituitary adenomas, involving 63±35% of tumor cells, regardless of tumor recurrence. CONCLUSIONS: In this group of radically resected pituitary macroadenomas, neuroradiological finding of CS invasiveness--but not FCM parameters nor MIB-1 and Bcl-2 expression--is useful for predicting tumor recurrence.

Mechanical and metabolic responses during a high-intensity circuit training workout in competitive runners.

AIM: This study aimed to assess the mechanical and metabolic responses of competitive runners throughout a high-intensity circuit training (HICT) workout, designed to improve explosive strength under acute metabolic fatigue. METHODS: Eight high-level endurance runners (age: 21.8±3.7 y; body mass: 61.5±5.7 kg; height: 175.2±5.2 cm; 1500-m record: 3 min 54±7 s) completed an incremental exhaustive running test to determine the maximum oxygen uptake (VO2max) and maximum aerobic speed (MAS). The athletes then performed on a track a HICT workout, consisting of two identical circuits interspersed by 5-min of passive recovery. Each circuit was constituted by six 30-s dynamic or explosive strength exercises, alternated to 200-m runs (1000-m for the final run) at 90-95% of MAS. During a hopping exercise included in the circuit, and during the 1000-m run, lower limb stiffness measures were obtained from contact and flight times using a method based on the spring-mass model. RESULTS: Hopping stiffness was significantly lower (P<0.05) in the second circuit (12.42±2.70 kN·m⁻¹) compared to the first one (13.76±2.10 kN·m⁻¹). Conversely, leg stiffness during running was similar (P>0.05) in the first and the second circuit (8.08±1.49 vs. 7.87±1.31 kN·m⁻¹), as well as vertical stiffness (33.56±5.25 vs. 32.16±5.45 kN·m⁻¹). The mean VO2 in the 1000-m run of the two circuits was 93.17±3.56% and 93.47±3.91% of VO2max, respectively. CONCLUSION: Despite the occurrence of acute neuromuscular fatigue throughout the workout, the runners avoided an impairment of their stiffness during running. Furthermore, the relatively high percentage of VO2max achieved indicates the HICT involves also stimuli for aerobic conditioning.

[Introduction of the Couder manoeuvre and perineal injuries]. / Introduction de la manœuvre de Couder et évolution des lésions périnéales.

OBJECTIVE: To analyse the introduction of the Couder manoeuvre in our level 3 maternity unit shortly after its introduction in 2019. Then, to evaluate and compare the rate of perineal injuries between 2017, when the manoeuvre was not performed at all, and 2020. MATERIALS AND METHOD: A single-centre retrospective study of patients who delivered a singleton eutociously at term from 1 January to 31 December 2017 and 2020. RESULTS: In total, 2930 records were analysed. The Couder manoeuvre rate was 32.12% in 2020. A change in the distribution of perineal lesions was observed: the rate of intact perineum increased (P<0.001), while 2nd degree lesions decreased between 2017 and 2020 (P<0.05). The 1st degree perineum and obstetric anal sphincter injuries remained stable. The rate of episiotomy decreased significantly by almost a factor of 7. CONCLUSION: The practice of the Couder manoeuvre can be implemented fairly quickly after training of the actors with nearly a third of normal deliveries at term concerned one year after its introduction. This manoeuvre seems, in our practice, to have contributed to the reduction, as previously reported, of the rate of second degree perineal injuries.

High prevalence of coronary calcifications and increased risk for coronary heart disease in adults with growth hormone deficiency.

Assessment of coronary calcium deposits (CCD) by coronary computed tomography (CT) was recently introduced for evaluation of risk to develop events related to coronary heart disease (CHD). We investigated occurrence of CCD in 19 hypopituitary patients (patients), 34 healthy (H) subjects (H controls) and 36 patients with a similar rate of diabetes mellitus and hypertension (morbid, M), but without pituitary diseases (M controls). Patients were replaced with L-thyroxine, cortone acetate, sex hormones and/or desmopressin, but never with GH. Unenhanced coronary CT was performed by 16-row multislice scanner. Framingham score (FS) was calculated and CCD were measured by Agatston score (AS) in all subjects. AS>10 indicates increased CHD risk. CCD and AS >10 were detected in 50% and 33% of patients, respectively. Prevalence of CCD and mean AS were higher in patients than in H and M controls. In patients, AS was negatively dependent on IGF-I levels (p<0.01) and IGF-I SD (p<0.05), and AS >10 was associated with occurrence of hypertension (p<0.02) and hyperinsulinism (p<0.05). Men and women showed the same prevalence of AS >10 (25 vs 31%). FS and AS correlated significantly (rs=0.33, p<0.001), but CCD were detected also in 3/11 patients with low FS. In conclusion, 58% of patients were at CHD risk on the basis of increased FS and/or AS, above all if they were hypertensive and/or showed hyperinsulinism. CCD were detected also in patients with low FS. CHD risk is higher in women. Risk of CCD is increased in patients with low IGF-I levels.

Effects of budesonide on P38 MAPK activation, apoptosis and IL-8 secretion, induced by TNF-alpha and Haemophilus influenzae in human bronchial epithelial cells.

Non-typeable Haemophilus influenzae (NTHi) is one of the most frequently involved pathogens in bacterial exacerbations of chronic obstructive pulmonary disease (COPD). In the airways, the main tissue target of NTHi is bronchial epithelium, where this pathogen can further amplify the inflammatory and structural changes induced by proinflammatory cytokines such as tumour necrosis factor-alpha (TNF-alpha). Therefore, the aim of this study is to investigate, in primary cultures of human bronchial epithelial cells, the effects of NTHi on signal transduction pathways, apoptotic events and chemokine production activated by TNF-alpha. Moreover, we also evaluated the effects exerted on such cellular and molecular phenomena by a corticosteroid drug. p38 mitogen-activated protein kinase (MAPK) phosphorylation was analyzed by Western blotting, using an anti-phospho-p38 MAPK monoclonal antibody. Apoptosis was assayed by active caspase-3 expression. Interleukin-8 (IL-8/CXCL8) was detected in cell-free culture supernatants by ELISA. TNF-alpha induced a significant increase in p38 MAPK phosphorylation. NTHi was able to potentiate the stimulatory actions of TNF-alpha on caspase-3 expression and, to a lesser extent, on IL-8 secretion. These effects were significantly (P less than 0.01) inhibited by a pharmacological pre-treatment with budesonide. These results suggest that TNF-alpha is able to stimulate, via activation of p38 MAPK signalling pathway, IL-8 release and airway epithelial cell apoptosis; the latter effect can be markedly potentiated by NTHi. Furthermore, budesonide can be very effective in preventing, through inhibition of p38 MAPK phosphorylation, both structural and proinflammatory changes elicited in bronchial epithelium by TNF-alpha and NTHi.

[99mTc-MAA peritoneal scintigraphy in pleuroperitoneal comunication in peritoneal dialysis patients]. / Gammagrafía peritoneal con 99mTc-MAA en las comunicaciones pleuroperitoneales en pacientes en diálisis peritoneal.

Peritoneal dialysis is a fully-contrasted alternative for the treatment of end-stage renal disease although it is not exempt of complications. Peritonitis and exit-site infections are among the most frequent complications found. Pleural effusion secondary to pleuroperitoneal communication (PPC) is a serious and uncommon complication in these patients. We present the case of a 50-year old man diagnosed of end-stage renal disease undergoing treatment with peritoneal dialysis who presented progressive dyspnea and right pleural effusion. The peritoneal scintigraphy with (99m)Tc-MAA makes it possible to confirm communication of intraperitoneal dialysis fluid to the pleural cavity.

Non-functioning pituitary adenomas infrequently harbor G-protein gene mutations.

BACKGROUND: Mutations of the genes encoding the alpha subunit of the stimulatory G protein (Gs) and of the inhibiting Gi2 protein (GNAS1 and GNAI2 genes, respectively) have been described in various endocrine neoplasias, including pituitary tumors. AIM: To search for mutations of GNAS1 and GNAI2 in a continuous series of non-functioning pituitary adenoma (NFPA) patients neurosurgically treated. SUBJECTS AND METHODS: The surgical samples of 22 patients who have been defined and characterized on a clinical, biochemical, histological, and immunohistochemical point of view have been processed for investigating the presence of the above mutations by PCR amplification of the hot spots exons 8 and 9 of GNAS1, and exons 5 and 6 of GNAI2, followed by direct sequencing. Moreover, the promoter region of GNAI2, in order to assess the prevalence of single nucleotide polymorphisms (SNP), was investigated in the same series. RESULTS: A CGT>TGT mutation at codon 201 of GNAS1 gene in a single case of NFPA was found, but no mutation of GNAI2A was demonstrated. CONCLUSIONS: This finding suggests and confirms that G-protein mutations are rare and not crucial in NFPA development. Additionally, we found a silent SNP at codon 318 in the promoter of the Gi2alpha gene in one out of the 22 NFPA.

[Utility of myocardial perfusion SPECT for evaluation of patients from Chest Pain Unit]. / Análisis y utilidad de la tomografía de emisión de fotón único de perfusión miocárdica en la evaluación de pacientes de la Unidad de dolor torácico.

UNLABELLED: The Chest Pain Units (CPU) are currently the best solution to improve management of patients with acute chest pain in the Emergency Room thanks to the use of reliable ischemia diagnostic detection tests and early treatment. OBJECTIVE: To assess the value of myocardial perfusion SPECT (MPS) in the CPU in order to treat acute coronary syndromes (ACS) early and discharge patients with low risk of coronary artery disease (CAD) who can be treated as outpatients. MATERIAL AND METHODS: We studied 629 patients from January 2003 to September 2005 with acute chest pain suggestive of angina, normal cardiac enzymes and normal or non-diagnostic ECG who had been referred to Nuclear Medicine for evaluation with a stress test for ischemia: 32 p treadmill stress testing and 597 p MPS (525 p exercise-rest and 72 p pharmacologic stress test). We compared the results with catheterization and clinical follow up for a 6-months period, evaluating new coronary events. RESULTS: 76 % of MPS were normal and 24 % pathological. Only 1.5 % of the patients with normal MPS had CAD or coronary events in the follow-up, increasing to 35.2 % in patients with ischemia. A total of 45 catheterizations were performed, showing CAD 27 (24 with pathological MPS). A total of 2.6 % of the patients had coronary events during follow-up, 75 % of whom had pathological MPS. CONCLUSION: The MPS improves diagnosis of ACS in the CPU, with a very low number of new coronary events at 6 months of the follow-up and permits safe discharge of these patients.

Differential regulation of membrane associated-growth hormone binding protein (MA-GHBP) and growth hormone receptor (GHR) expression by growth hormone (GH) in mouse liver.

Growth hormone (GH) binding to GH receptor (GHR) is the initial step that leads to the physiological functions of the hormone. Proteolytical cleavage of the GHR in humans and rabbits and alternative processing of the GHR transcript in rodents generates circulating growth hormone binding protein (GHBP). Moreover, other GHR truncated forms that result from alternative processing of the GHR mRNA transcript have been described. These GHR short forms are inserted in the plasma membrane but they are unable to transduce the signal. In rodents, membrane associated-GHBP (MA-GHBP), which accounts for a significant proportion of liver GH binding capacity, represents the main GHR short form found in membranes, and may therefore function as a negative form of the receptor. In the present study, GHR and MA-GHBP content in liver were analyzed using mutant and transgenic mice expressing different concentrations of growth hormone to evaluate the correlation between GH levels, body weight (BW), GHR and MA-GHBP expression. It was found that GH deficiency was associated with diminished BW, GHR and MA-GHBP expression, while increased GH concentration led to increased BW, GHR and MA-GHBP expression, but MA-GHBP upregulation was more pronounced than the observed increase in GHR expression. Since GHR and MA-GHBP both contribute to liver GH binding capacity, GH-induced enrichment of the dominant negative form would represent a compensatory mechanism triggered by high levels of the hormone. This attempt to attenuate the effects of supraphysiological concentrations of GH may be critical to reduce or prevent their plausible damaging effects on the organism.

[Iatrogenic lung microembolism detected by 18FDG PET/CT]. / Microembolia pulmonar iatrogénica detectada mediante 18F-FDG PET/TC.

We present the cases of two oncology patients: a male with Hodgkin's disease after completion of chemotherapy, and a woman recently diagnosed of melanoma, who underwent positron emission tomography/computed tomography (PET/CT) with 18F-FDG for therapeutic monitoring and initial staging, respectively. In both cases, hypermetabolic foci of 18F-FDG in lung parenchyma were found, without morphologic abnormalities in CT. These findings would have been consistent with lung pathology in the absence of any anatomic correlation. Combined PET/CT interpretation was of lung microembolisms probably originated at the injection site.

[Renal angiomyolipoma and fever: assessment with isotopic renogram and 67Ga scintigraphy]. / Angiomiolipoma renal y fiebre: valoración mediante renograma isotópico y gammagrafía con 67Ga.

A 26 year-old woman with tuberous sclerosis who came to the Emergency Department with high fever, bilious vomit, right hemiabdomen pain and syncope during 2 weeks. Laboratory analyses show hemoglobin 6.7 g/dl, creatinine 1.5 mg/dl and leukocytes 30,000. Abdominal CT is performed because of suspicion of active bleeding in right hemiabdomen, following rupture of right angiomyolipoma, treated by selective arterial embolization. She was referred to the Nuclear Medicine Department to perform a 67Gallium scintigraphy for the detection of infection, and static and dynamic renal scintigraphy for evaluation of the renal morphology and function.

Intervening in the ß-barrel structure of lipid binding proteins: consequences on folding, ligand-binding and aggregation propensity.

Natural ß-folds manage to fold up successfully. By contrast, attempts to dissect fragments or peptides from well folded ß-sheet proteins have met with insurmountable difficulties. Here we briefly review selected successful cases of intervention on the well-known scaffold of intestinal fatty acid binding protein (IFABP). Lessons from these examples might set guidelines along the design of proteins belonging to this class. Impact of modifications on topology, binding and aggregation is highlighted. With the aid of abridged variants of IFABP we focus on key structural features responsible for the assembly into oligomeric forms or aggregates.