Advances in the treatment of prolactinomas

Prolactinomas account for approximately 40% of all pituitary adenomas and are an important cause of hypogonadism and infertility. The ultimate goal of therapy for prolactinomas is restoration or achievement of eugonadism through the normalization of hyperprolactinemia and control of tumor mass. Medical therapy with dopamine agonists is highly effective in the majority of cases and represents the mainstay of therapy. Recent data indicating successful withdrawal of these agents in a subset of patients challenge the previously held concept that medical therapy is a lifelong requirement. Complicated situations, such as those encountered in resistance to dopamine agonists, pregnancy, and giant or malignant prolactinomas, may require multimodal therapy involving surgery, radiotherapy, or both. Progress in elucidating the mechanisms underlying the pathogenesis of prolactinomas may enable future development of novel molecular therapies for treatment-resistant cases. This review provides a critical analysis of the efficacy and safety of the various modes of therapy available for the treatment of patients with prolactinomas with an emphasis on challenging situations, a discussion of the data regarding withdrawal of medical therapy, and a foreshadowing of novel approaches to therapy that may become available in the future.     

Complete weaning off immunosuppression in HCV liver transplant recipients is feasible and favourably impacts on the progression of disease recurrence

BACKGROUND/AIMS: HCV-related disease recurrence progresses rapidly after liver transplantation. We hypothesised that withdrawal of immunosuppression might favourably impact on disease progression. METHODS: Weaning off immunosuppression was attempted in 34 HCV-RNA positive patients (mean age 62+/-6.4 years) transplanted 63.5+/-20.1 months earlier, under cyclosporine A monotherapy. Patients were followed for 3 years including yearly protocol liver biopsies. Primary endpoints were feasibility of weaning off immunosuppression and its impact on disease progression. Secondary endpoint was to identify predictors of an immunosuppression-free state and fibrosis progression. RESULTS: Complete and permanent immunosuppression withdrawal was achieved in 8 patients (23.4%), whereas 14 (41.2%) developed rejection within eight months despite an initial response and 12 (35.2%) rejected during tapering. After a mean follow-up 45.5+/-5.8 months weaned patients showed stabilisation/improvement of histological fibrosis (P<0.01), lower necro-inflammation (P<0.02) and improved liver function (P<0.05) compared to weaning-intolerants. Multiple logistic regression identified low blood cyclosporine A trough levels during the first post-transplant week (P=0.004) and initial steroid-free immunosuppression (P<0.008) as independent predictors of sustained weaning. Achievement of immunosoppression freedom (P=0.02) and baseline staging score (P<0.0001) were independently associated with stabilisation/improvement of histological fibrosis. CONCLUSIONS: Reconstitution of immune-competence in the host improves the natural history of HCV recurrence in the graft.     

Suitability of <Emphasis Type="Italic">Daphnia similis</Emphasis> as an alternative organism in ecotoxicological tests: implications for metal toxicity

The acute toxicity of metals to Daphnia similis was determined and compared to other daphnid species to evaluate the suitability of this organism in ecotoxicology bioassays. To verify the performance D. similis in toxicity tests, we also investigated the effect of Pseudokirchneriella subcapitata at 1 × 10⁵ and 1 × 10⁶ cells ml⁻¹ on Cd and Cr acute toxicity to the cladoceran. Daphnid neonates were exposed to a range of chromium and cadmium concentrations in the absence and presence of the algal cells. Metal speciation calculations using MINEQL⁺ showed that total dissolved metal concentrations in zooplankton culture corresponded to 96.2% free Cd and 100% free Cr concentrations. Initial total dissolved metal concentrations were used for 48 h-LC₅₀ determination. LC₅₀ for D. similis was 5.15 × 10⁻⁷ mol l⁻¹ dissolved Cd without algal cells, whereas with 1 × 10⁵ cells ml⁻¹, it was significantly higher (7.15 × 10⁻⁷ mol l⁻¹ dissolved Cd). For Cr, the 48 h-LC₅₀ value of 9.17 × 10⁻⁷ mol l⁻¹ obtained for the cladoceran in tests with 1 × 10⁶ cells ml⁻¹ of P. subcapitata was also significantly higher than that obtained in tests without algal cells (5.28 × 10⁻⁷ mol l⁻¹ dissolved Cr). The presence of algal cells reduced the toxicity of metals to D. similis, as observed in other studies that investigated the effects of food on metal toxicity to standard cladocerans. Comparing our results to those of literature, we observed that D. similis is as sensitive to metals as other standardized Daphnia species and may serve as a potential test species in ecotoxicological evaluations.     

Absence of cerebrospinal fluid oligoclonal bands is associated with delayed disability progression in relapsing-remitting MS patients treated with interferon-beta

To determine whether combined studies of Mini-Mental State Examination (MMSE) and brain single photon emission CT (SPECT) would provide more useful means of differentiating between dementia with Lewy bodies (DLB) and Alzheimer's disease (AD), we studied 36 patients with probable DLB and 96 patients with probable AD. DLB patients had significantly better performance on word recall, but more impaired attention and copying than AD patients. We confirmed that a weighted score derived by Ala et al. [Ala, T.A., Hughes, L.F., Kyrouac, G.A., Ghobrial, M.W., Elble, R.J. The Mini-Mental State exam may help in the differentiation of dementia with Lewy bodies and Alzheimer' disease. Int J Geriatr Psychiatry 2002;17:503–9]: (Attention − 5/3 · Memory + 5 · Construction), was helpful in discriminating between DLB and AD. SPECT study revealed that medial occipital perfusion significantly decreased in DLB patients than AD patients. Combined studies of MMSE and brain SPECT achieved a high discrimination between DLB and AD with a sensitivity of 81% and a specificity of 85%, suggesting that there is a useful and practical approach to differentiate DLB from AD. Our findings will need to be substantiated in an independent and prospective study sample.     

De novo AML patients with favourable–intermediate karyotype may benefit from the addition of low-dose gemtuzumab ozogamicin (GO) to fludarabine, Ara-C and idarubicin (FLAI): a contribution to the reopened “GO question”

We report the final results of a prospective trial testing the combination of fludarabine, Ara-C and idarubicin (FLAI) followed by low-dose gemtuzumab ozogamicin (FLAI-GO) in 85 patients aged 60 years or more with CD33+ acute myeloid leukaemia (AML). Median age was 68 years (60–82); karyotype was unfavourable in 21 patients (24 %), intermediate in 63 (74 %) and favourable in 1 (2 %). There were five therapy-related deaths. Of the 80 evaluable patients, 47 achieved complete response (CR) (58 %); CR rates were 65 and 32 % in good-intermediate/poor karyotype patients, respectively. Median length of CR was 7 months (3–76). The cumulative incidence of relapse was 84 % with an actuarial survival of 50.3 % at 1 year and 14.4 % at 2 years. The study control population is an unselected consecutive historic cohort of 104 patients treated with the FLAI regimen, who were matched for age and prognostic factors. CR rates after FLAI-GO and FLAI were comparable. However, patients with de novo AML and intermediate–favourable karyotype receiving GO had a significantly lower risk of relapse at 2 years as compared to patients not receiving GO (n?=?77) (40 vs 80 %, p?=?0.01) and significantly better disease-free survival (p?=?0.018) and overall survival (p?=?0.022).     

Effect of weight loss on sympatho-vagal balance in subjects with grade-3 obesity: restrictive surgery versus hypocaloric diet

Few and mostly uncontrolled studies indicate that weight loss improves heart rate variability (HRV) in grade-3 obesity. The aim of this study was to compare in grade-3 obesity surgery and hypocaloric diet on clinical and metabolic variables and on autonomic indices of HRV. Twenty-four subjects (body mass index, BMI 45.5 ± 9.13 kg/m²) underwent surgery (n = 12, gastric banding, LAGB) or received hypocaloric diet (n = 12, 1,000–1,200 kg/day). Clinical [BMI, systolic blood pressure (SBP) and diastolic blood pressure (DBP), heart rate] and metabolic variables [glucose, cholesterol, HDL- and LDL-cholesterol, triglycerides, AST and ALT transaminases] and 24-h Holter electrocardiographic-derived HRV parameters [R–R interval, standard deviation of R–R intervals (SDNN); low/high-frequency (LF/HF) ratio, and QT interval] were measured at baseline and after 6 months. The two groups were identical at baseline. BMI (?7.5 ± 3.57 kg/m², mean ± SD), glucose (?24.1 ± 26.77 mg/dL), SBP (?16.7 ± 22.19 mmHg) and DBP (?6.2 ± 8.56 mmHg) decreased in LAGB subjects (p < 0.05) and remained unchanged in controls. At 6 months, SDNN increased in LAGB subjects (+25.0 ± 37.19 ms, p < 0.05) and LF/HF ratio diminished (2.9 ± 1.84 vs. 4.9 ± 2.78; p = 0.01), with no change in controls; LF (daytime) and HF (24 h and daytime) increased in LAGB subjects, with no change in controls. Decrease in BMI correlated with SBP and DBP decrease (p < 0.05), and DBP decrease correlated with HR decrease (p < 0.05) and QT shortening (p < 0.05). Weight loss is associated with improvement of glucose metabolism, of blood pressure, and with changes in time and frequency domain parameters of HRV; all these changes indicate recovery of a more physiological autonomic control, with increase in parasympathetic and reduction in sympathetic indices of HRV.     

No Evidence of an Association between Helicobacter pylori Infection and Raynaud Phenomenon

Background: Raynaud phenomenon (RP) is a vasospastic condition that manifests itself as cold-induced ischemic attacks of the fingers with skin color changes. It may be classified as primary (PRP) or secondary (SRP), if associated to other diseases, mainly connective-tissue diseases. Recently, the association between PRP and Helicobacter pylori infection has been reported. The aims of this study were to evaluate the prevalence of gastric H. pylori infection in a large group of patients affected by PRP and SRP and to assess whether it was more evident in patients with more recent onset of RP. Methods: Ninety-eight consecutive patients (93 F and 5 M), referring to our videocapillaroscopic service for the diagnosis of vascular and connective-tissue diseases, were evaluated. Forty-nine of them were affected by PRP and 49 by SRP. Patients were classified as having PRP on the basis of normal serological and immunological findings, normal videocapillaroscopic examination and exclusion of other conditions inducing RP. H. pylori infection was diagnosed by ¹³C-urea breath test (UBT). Two groups of 49 age-and sex-matched controls, respectively, were also evaluated. Results: Patients with SRP resulted significantly older than those with PRP (P &lt; 0.006). UBT was found positive in 22/49 patients with PRP (45%) and in 29/49 patients with SRP (59%). The positivity of the respective control groups was 36% and 53% (P = NS). There was no higher prevalence of H. pylori infection in patients with RP lasting for less than 4 years. Conclusions: The results do not confirm the previously reported high prevalence of H. pylori infection in patients with PRP. A high association was not even found between the presence of the microorganism and SRP. There was no difference in the prevalence of H. pylori infection among the subgroups with more recent onset of both PRP and SRP.     

Adhesive properties of platelets from different animal species

The use of large animals (e.g., pig and sheep) in human medicine, and the need to develop new therapeutic strategies for domestic animal diseases related to platelet disorders, require better characterization of the physiology of animal platelets. In this study, the ability of platelets from buffaloes, horses, pigs and sheep to adhere to immobilized autologous fibrinogen was compared with that of human platelets. Blood samples were collected from the jugular vein of six healthy subjects of each species and platelet-rich plasma (PRP) was obtained by centrifugation. Platelets, isolated by further centrifugation of PRP, were washed by gel-filtration on Sepharose-2B, counted and added to the wells of 96-well plates pre-coated with autologous fibrinogen. After different times of incubation, non-adherent platelets were removed, and the number of adherent platelets was assessed by measuring endogenous acid phosphatase activity. Horse platelets showed the strongest ability to adhere to autologous immobilized fibrinogen, being 1.7-, 3.1- and 2.3-fold more active than human, buffalo and porcine platelets, respectively. Sheep platelets were unable to adhere to autologous immobilized fibrinogen. Platelet activation by adenosine 5-diphosphate (ADP) increased both human and animal platelet adhesive response. ADP-stimulated sheep platelets were able to adhere to autologous immobilized fibrinogen, albeit to a lesser extent than platelets from the other animal species. The observed interspecies variability in adhesive properties of platelets may reflect structural differences, or differences in the availability of the fibrinogen receptor (glycoprotein IIb/IIIa) on the platelet surface.     

Met-enkephalin and preproenkephalin mRNA changes in the striatum of the nicotine abstinence mouse

We studied the changes of met-enkephalin (Met-Enk) content and preproenkephalin (PPE) mRNA in the striatum in a mouse model of nicotine abstinence. Nicotine, 2 mg/kg, s.c., was administered four times daily for 14 days and Met-Enk and PPE mRNA evaluated at various times (4-96 h) following drug discontinuation. Met-Enk, assayed by radioimmunoassay, was increased in the ventral (nucleus accumbens) but not dorsal (putamen/caudate) striatum, while PPE mRNA, assayed in whole striatum by Northern blotting was elevated. Both changes were seen early during withdrawal and lasted over 72 h. In situ hybridization revealed enhanced signal in the dorsal striatum, mostly laterally, and smaller increases in the rostral pole, core and shell of the nucleus accumbens. These observations indicate that during nicotine withdrawal, striatal enkephalinergic neurons undergo adaptative responses, which might contribute to the abstinence behavioral syndrome.     

Modulation of the inflammatory response in rats chronically treated with the antidepressant agomelatine

Growing evidence suggests that the activation of the inflammatory/immune system contributes to depression pathogenesis, a hypothesis that might hold strong clinical implication. Indeed more than 30% of depressed patients fail to achieve remission, which poses the necessity to identify systems that may represent novel targets for medications. Accordingly, goal of this study was to evaluate the ability of the antidepressant agomelatine to modulate specific components of the immune response in the rat brain following an inflammatory challenge with lipopolysaccharide (LPS). To this aim, adult male rats were chronically treated with agomelatine before being acutely challenged with LPS 16 h after the last drug administration. Rats were sacrificed 2, 6, or 24 h after the challenge and several components of the inflammatory response have been investigated by using real-time PCR or ELISA. We found that agomelatine significantly reduced the LPS-induced up-regulation of the pro-inflammatory cytokines interleukin-1β and interleukin-6 in the rat brain as well as at peripheral level. At central level, these effects are associated to the inhibition of NF-κB translocation as well as to alterations of mechanisms responsible for microglia activation. In addition, we found that agomelatine was also able to alter the expression of enzymes related to the kynurenine pathway that are thought to represent important mediators to inflammation-related depression. These data disclose novel properties that may contribute to the therapeutic effect of agomelatine providing evidence for a crucial role of specific components of the immune/inflammatory system in the antidepressant response and thereby in depression etiopathology.