Predicting postoperative hypocortisolism in patients with non-aldosterone-producing adrenocortical adenoma: a retrospective single-centre study.

BACKGROUND: Limited information exists on postoperative hypocortisolism and hypothalamus-pituitary-adrenal axis recovery in patients with adrenal incidentaloma following unilateral adrenalectomy. We evaluated frequency of postoperative hypocortisolism and predictors for recovery in non-aldosterone-producing adrenocortical adenoma patients after unilateral adrenalectomy. METHODS: A retrospective analysis of 32 adrenal incidentaloma patients originally included in the ITACA trial (NCT04127552) with confirmed non-aldosterone-producing adrenocortical adenoma undergoing unilateral adrenalectomy from September 2019 to April 2023 was conducted. Preoperative assessments included adrenal MRI, anthropometrics, evaluation of comorbidities, adrenal function assessed via ACTH, urinary free cortisol, and 1 mg dexamethasone suppression test. ACTH and serum cortisol or Short Synacthen test were performed within 6 days, 6 weeks, 6 months, and a year after surgery. RESULTS: Six days postoperative, 18.8% of patients had normal adrenal function. Among those with postoperative hypocortisolism, 53.8% recovered by 6 weeks. Patients with earlier adrenal recovery (6 weeks) had lower preoperative 1 mg dexamethasone suppression test (median 1 mg dexamethasone suppression test 76.2 [61.8-111.0] nmol/L vs 260.0 [113.0-288.5] nmol/L, p < 0.001). Univariate analysis showed preoperative 1 mg dexamethasone suppression test negatively related with baseline ACTH levels (r = - 0.376; p = 0.041) and negatively associated with the 6-week baseline (r = - 0.395, p = 0.034) and 30-min cortisol levels during Short Synacthen test (r = - 0.534, p = 0.023). Logistic regression analysis demonstrated preoperative 1 mg dexamethasone suppression test as the only biochemical predictor for 6-week adrenal recovery: ROC curve identified a 1 mg dexamethasone suppression test threshold of 131 nmol/L predicting 6-week recovery with 89.5% sensitivity and 72.7% specificity (AUC 0.87; 95% CI 66.9-98.7, p < 0.001). Other preoperative assessments (tumor size, ACTH levels and anthropometrics) were not associated with postoperative hypothalamus-pituitary-adrenal axis function, but the presence of diabetes was associated with a lower probability of recovery (OR = 24.55, p = 0.036). ACTH levels increased postoperatively in all patients but did not predict hypothalamus-pituitary-adrenal axis recovery. CONCLUSIONS: The preoperative 1 mg dexamethasone suppression test cortisol value and presence of diabetes are the only relevant predictor of hypothalamus-pituitary-adrenal axis recovery in patients with non-aldosterone- producing adrenocortical adenoma undergoing surgery, regardless other clinical and biochemical variables. Notably, pre- and postoperative ACTH levels did not predict hypothalamus-pituitary-adrenal axis recovery. These findings point towards the potential for saving resources by optimizing their allocation during follow-up assessments for patients with non-aldosterone-producing adrenocortical adenoma undergoing unilateral adrenalectomy.

Long-term results of arthroscopic repair of type II SLAP lesions in sports: assessment of return to pre-injury playing level and critical risk factors for complication.

PURPOSE: The management of isolated SLAP lesions is still debated especially in athletes. Aims of the study were: 1. to analyse our algorithm to treat SLAP lesions starting from the selection of patients for surgery and 2. to correlate the familiarity for diabetes and hypothyroid disorders with post-operative results. METHODS: Seventy-eight patients with isolated SLAP lesion were arthroscopically treated using knotless anchors and microfractures. All patients had a pre-operative and post-operative clinical examination according to Walch-Duplay, Constant, Rowe and Dash scores and interviewed for familiarity to diabetes and hypothyroid disorders. RESULTS: About 68.8% of patients solved pain with rehabilitation. About 29% of patients returned to the sports activities. About 32% of patients were no responder to physiotherapy and were arthroscopically treated. About 53.9% of patients responded excellent, 34.7% good, 3.8% medium and 7.6% poor results according to Walch-Duplay score. The Constant score increased from 64 to 95, the Rowe score from 48 to 96. The outcomes were significantly worse in patients with familiarity for diabetes. CONCLUSIONS: Microfractures and knotless anchor give long-term good results for the treatment of SLAP lesions in athletes. The familiarity for diabetes is an important risk factor that can lead to decreased outcomes.

Predictors of malignancy in high-risk indeterminate (TIR3B) cytopathology thyroid nodules.

PURPOSE: The classification of indeterminate cytopathology at thyroid fine-needle-aspiration (FNA) has been updated to reduce the number of unnecessary surgery; the 2014 Italian classification introduced the low-risk (TIR3A) and high-risk (TIR3B) subcategories. Aim of this study was to identify the ultrasonographic (US), clinical and cytological predictors of malignancy among TIR3B nodules from a single institution. METHODS: A prospective observational study including 1844 patients who underwent thyroid FNA from June 2014 to January 2019. Ultrasonographic, clinical and cytological features were recorded. All TIR3B diagnoses were referred to surgery. According to final histology, patients were divided into thyroid cancer (TC) or benign nodules. Chi-square test, or Fisher exact test when appropriate, were used to compare groups and logistic regression analyses were used to determine independent predictors of malignancy. RESULTS: Of 1844 FNAs, 96 (5.2%) were TIR3B. Histology report was available in 65. Among them, 25 (38.5%) were TC. Predictors of TC were nodule size < 20 mm [Odds Ratio (OR) = 5.88, 95% CI 1.91-18.11, p = 0.002], absence or weak intralesional flow [OR = 0.3, 95% CI 0.09-0.77, p = 0.015], microcalcifications [OR = 6.5, 95% CI 1.90-21.93, p = 0.003] at US; nuclear inclusions [OR = 25.3, 95% CI 1.34-476.07, p = 0.031] and chromatin clearing [OR = 3.7, 95% CI 1.27-10.99, p = 0.017] at cytopathology. Patients aged < 55 years had a significantly higher risk of TC [OR = 9.7, 95% CI 2.79-34.07, p < 0.001]. In multivariate analysis, age < 55 and nodule size < 20 mm resulted as independent risk factors. CONCLUSIONS: Patients < 55 years receiving a diagnosis TIR3B on nodules < 20 mm, with microcalcifications, showing specific nuclear atypia at cytopathology are more likely to have TC. Combining US, cytological and clinical features could help determining which patients with a TIR3B diagnosis should be referred to surgery.

Solution and gas phase evidence of anion binding through the secondary bonding interactions of a bidentate bis-antimony(iii) anion receptor.

The solution and gas phase halide binding to a bis-antimony(iii) anion receptor was studied. This new class of anion receptors utilizes the strong Sb-centered secondary bonding interactions (SBIs) that are formed opposite to the polar Sb-O primary bond. 1H NMR titration data were fitted statistically to binding models and solution-phase binding energetics were extracted, while the formation of anion-to-receptor complexes was observed using ESI-MS. Density functional theory calculations suggest that their affinity towards binding halide anions is mitigated by the strong explicit solvation effect in DMSO, which gives insights into future designs that circumvent direct solvent binding and are anticipated to yield tighter and perhaps more selectivity in anion binding.

Growth hormone, prolactin, and sexuality.

GH and PRL, although not considered as 'classi cal' sexual hormones, could play a role in the endocrine control of sexual function both in men and women. Physiologically, PRL seems to be involved in the central control of sexual behavior and activity, by modulating mainly the effects of dopaminergic and serotoninergic systems on sexual function. Indeed, circulating PRL levels increase after orgasm and may potentially play a role in the acute regulation of further sexual arousal following orgasm both in men and women. On the other hand, either short-term or long-term PRL in crease can modulate central nervous system areas involved in the control of sexual function and, peripherally, can directly influence mechanisms of penile erection in men, and presently only as an hypothesis, mechanisms related to the sexual response of genitalia in women. Furthermore, chronic hyperprolactinemia is classically associated with hypogonadotropic hypogonadism and sexual dysfunction in both sexes. Successful treatment of chronic hyperprolactinemia generally restores normal sexual function both in men and women although this effect is not only related to relapse of gonadal function. Hypoprolactinemia is recently recognised as a possible risk factor of arteriogenic erectile dysfunction while a possible role on female sexual function is not known. The physiological role of GH on sexual function is not fully elucidated. GH is an important regulator of hypothalamus-pituitary-gonadal axis and seems to participate in the regulation of the sexual response of genitalia in men, and potentially also in women. Sexual function in men and women with GH deficiency (GHD) and GH excess, particularly in acromegaly, is scantily studied and GH- or IGF-I-dependent effects are difficult to quantify. Nevertheless, a decrease of desire and arousability both in men and women, together with an impairment of erectile function in men, have been described both in patients with GHD and acromegaly, although it is not clear whether they are dependent directly on the hormone defect or excess or they are consequence of the hypogonadism or the different clinical complications or the physical disfigurement and psychological imbalance, which are associated with the diseases, and are potentially affecting sexual function. Data on beneficial effects of GH replacement therapy and specific surgical or pharmacological approach for acromegaly are far to be fully elucidated although restoring normal GH/IGF-I levels have been associated to improvement of sexual function.

Growth hormone, prolactin, and sexuality.

GH and PRL, although not considered as 'classical' sexual hormones, could play a role in the endocrine control of sexual function both in men and women. Physiologically, PRL seems to be involved in the central control of sexual behavior and activity, by modulating mainly the effects of dopaminergic and serotoninergic systems on sexual function. Indeed, circulating PRL levels increase after orgasm and may potentially play a role in the acute regulation of further sexual arousal following orgasm both in men and women. On the other hand, either short-term or long-term PRL increase can modulate central nervous system areas involved in the control of sexual function and, peripherally, can directly influence mechanisms of penile erection in men, and presently only as an hypothesis, mechanisms related to the sexual response of genitalia in women. Furthermore, chronic hyperprolactinemia is classically associated with hypogonadotropic hypogonadism and sexual dysfunction in both sexes. Successful treatment of chronic hyperprolactinemia generally restores normal sexual function both in men and women although this effect is not only related to relapse of gonadal function. Hypoprolactinemia is recently recognised as a possible risk factor of arteriogenic erectile dysfunction while a possible role on female sexual function is not known. The physiological role of GH on sexual function is not fully elucidated. GH is an important regulator of hypothalamuspituitary- gonadal axis and seems to participate in the regulation of the sexual response of genitalia in men, and potentially also in women. Sexual function in men and women with GH deficiency (GHD) and GH excess, particularly in acromegaly, is scantily studied and GH- or IGF-I-dependent effects are difficult to quantify. Nevertheless, a decrease of desire and arousability both in men and women, together with an impairment of erectile function in men, have been described both in patients with GHD and acromegaly, although it is not clear whether they are dependent directly on the hormone defect or excess or they are consequence of the hypogonadism or the different clinical complications or the physical disfigurement and psychological imbalance, which are associated with the diseases, and are potentially affecting sexual function. Data on beneficial effects of GH replacement therapy and specific surgical or pharmacological approach for acromegaly are far to be fully elucidated although restoring normal GH/IGF-I levels have been associated to improvement of sexual function.

Articulating spacers in elderly patients affected by periprosthetic knee infection: clinical findings and outcome.

OBJECTIVE: Although the two-stage technique is a validated strategy in periprosthetic joint infections, there is a lack of data on the patients' clinical outcomes after the spacer placement. This study aims at evaluating the quality of life, joint function, and pain in patients over 70 years affected by periprosthetic joint infection treated with a two-stage exchange using metal on polyethylene spacers. PATIENTS AND METHODS: We conducted a follow-up study to evaluate the quality of life and functionality of consecutive patients over 70 years treated for PJI at our institution using a validated assessment set including the Western Ontario and Mac Master University (WOMAC) score, Knee Society Score (KSS), numerical rating scale (NRS). Knee Range of Movement (ROM) before and after the surgery was also analyzed. RESULTS: Forty-five patients with a mean age of 76 ± 5.3 years were included. Coagulase-negative staphylococci were the most isolated microorganisms. In the preoperative study group, the WOMAC score was 48.4 ± 18.9, and the KSS objective and functional scores were 37.6 ± 17.3 and 27.6 ± 22.3, respectively. NRS was 7.3 ± 1.8. After three months of follow-up, we found better results than preoperative clinical evaluation. We retrieved similar results comparing our post-operative PROMS (WOMAC and KSS scores) with published thresholds for treatment success two months after primary total knee arthroplasty. The infection eradication rate was 87%. CONCLUSIONS: The two-stage technique confirmed its efficacy in the treatment of PJI. Patients over 70 years who had undergone the first stage of the two-stage technique for PJI showed a good quality of life and knee function.

Similar programmed death ligand 1 (PD-L1) expression profile in patients with mild COPD and lung cancer.

Programmed Death Ligand 1 (PD-L1) is crucial in regulating the immunological tolerance in non-small cell lung cancer (NSCLC). Alveolar macrophage (AM)-derived PD-L1 binds to its receptor, PD-1, on surveilling lymphocytes, leading to lymphocyte exhaustion. Increased PD-L1 expression is associated with cigarette smoke (CS)-exposure. However, the PD-L1 role in CS-associated lung diseases associated with NSCLC, such as chronic obstructive pulmonary disease (COPD), is still unclear. In two different cohorts of ever smokers with COPD or NSCLC, and ever and never smoker controls, we evaluated PD-L1 expression: (1) via cutting-edge digital spatial proteomic and transcriptomic profiling (Geomx) of formalin-fixed paraffin-embedded (FFPE) lung tissue sections (n = 19); and (2) via triple immunofluorescence staining of bronchoalveolar lavage (BAL) AMs (n = 83). PD-L1 mRNA expression was also quantified in BAL AMs exposed to CS extract. PD-L1 expression was increased in the bronchiolar wall, parenchyma, and vascular wall from mild-moderate (GOLD 1-2) COPD patients compared to severe-very severe (GOLD 3-4) COPD patients and controls. Within all the COPD patients, PD-L1 protein expression was associated with upregulation of genes involved in tumor progression and downregulation of oncosuppressive genes, and strongly directly correlated with the FEV1% predicted, indicating higher PD-L1 expression in the milder vs. more severe COPD stages. In bronchioles, PD-L1 levels were strongly directly correlated with the number of functionally active AMs. In BAL, we confirmed that AMs from patients with both GOLD 1-2 COPD and NSCLC had the highest and similar, PD-L1 expression levels versus all the other groups, independently from active cigarette smoking. Intriguingly, AMs from patients with more severe COPD had reduced AM PD-L1 expression compared to patients with mild COPD. Acute CS extract stimulation increased PD-L1 mRNA expression only in never-and not in ever-smoker AMs. Lungs from patients with mild COPD and NSCLC are characterized by a similar strong PD-L1 expression signature in bronchioles and functionally active AMs compared to patients with severe COPD and controls. Active smoking does not affect PD-L1 levels. These observations represent a new resource in understanding the innate immune mechanisms underlying the link between COPD and lung cancer onset and progression and pave the way to future studies focused on the mechanisms by which CS promotes tumorigenesis and COPD.

Illness awareness in terminal cancer patients: an Italian study.

The amount and quality of information and awareness in cancer patients' is a topic frequently debated, but few studies have focussed on terminal patients. This is the objective of the present study that involved two different palliative home-care units in Italy, which recruited 550 terminal cancer patients. Data from patients and their caregivers was prospectively collected with special attention to information patients were provided with when their cancer was diagnosed and patients' awareness of their current health condition. In the case of the information, 67.0% of patients reported they were previously informed about their diagnosis, but only 58.0% seemed to be aware of their terminal condition. The comparison between the caregivers opinions about the level of information provided to the patients and their present awareness and what the patients really know about their own disease shows a high degree of correspondence. Some variables such as age and education level of patients were associated with patient's awareness.

Use of short implants for functional restoration of the mandible after giant cell tumor removal. Case report.

The giant cell tumor of the jaws is a rare benign lesion, it has a slow and progressive evolution and it is locally aggressive. Its etiopathogenesis is unknown, it is most common in the mandible and it is often asymptomatic but pain arises from palpation of the area. Diagnosis is made by radiological and histological examination and surgical treatment is necessary. The clinical case of a 28-year-old man affected by a giant cell tumor of the mandible with an aggressive clinical and radiographical behaviour is reported. The patient showed a jaw swelling covered by hyperemic fibro-mucous tissue from tooth 4.6 to 3.4, absence of cortical bone and mobility of teeth. He also reported lip anesthesia. The giant cell tumor diagnosis was made with orthopantomography (OPT), computed tomography (CT) and needle biopsy. The lesion was surgically removed and histological examination confirmed the diagnosis. In spite of the wide loss of bony substance after surgery, the patient was provided with an implant supported fixed prosthesis without previous bone graft. In this case short implants allowed the prosthetic rehabilitation of a mandible with severe ''resorption'' due to surgical removal of a tumor. Implants were placed in the residual bone volume and successfully used to support a fixed prosthesis. The final result is optimal as is the quality of life of the young patient.

Reversible and irreversible changes in nucleosome structure along the c-fos and c-myc oncogenes following inhibition of transcription.

A new affinity chromatographic procedure for the separation of transcriptionally active nucleosomes has been used to study the changes that take place in chromatin structure along the c-fos and c-myc genes when RNA synthesis is inhibited. Mercury-affinity chromatography separates the sulfhydryl-reactive nucleosomes of transcriptionally active genes from the compactly beaded, non-reactive nucleosomes of transcriptionally inert DNA sequences. The new procedure also discriminates between nucleosomes that have "unfolded" to reveal the previously shielded SH groups of histone H3 and nucleosomes that bind to the mercury column because of their association with thiol-containing non-histone proteins located in the transcription unit. Both classes of Hg-bound nucleosomes contain the c-fos and c-myc sequences, but only when they are being transcribed. We compared the effects of alpha-amanitin and actinomycin D on the transcription of c-fos and c-myc with the effects of each inhibitor on the distribution of the corresponding oncogenic DNA sequences in the chromatographically separated nucleosome fractions. It was found that the inhibition of RNA polymerase II by alpha-amanitin (added at the peaks of c-fos or c-myc expression in serum-stimulated BALB/c 3T3 cells) resulted in a rapid loss of affinity of the oncogene-containing nucleosomes for the mercury column. There was no corresponding effect on the mercury-binding properties of nucleosomes containing 28 S ribosomal gene sequences, which continue to be transcribed by amanitin-resistant RNA polymerase I. Therefore, the binding of the c-fos and c-myc nucleosomes to the mercury column seems to depend upon reversible structural changes associated with their transcription. Surprisingly, there was no corresponding loss of affinity of the c-fos and c-myc nucleosomes for the mercury column when actinomycin D was employed to inhibit RNA synthesis, despite the fact that transcription of both genes had been arrested abruptly. Measurements of [3H]actinomycin D binding show its preferential intercalation into the transcriptionally active nucleosomes. We suggest that the intercalation of actinomycin D into the DNA of active nucleosomes can lock the transcription complex into an "unfolded" but potentially active configuration. This was confirmed by run-off transcription assays showing a restoration of c-fos and c-myc RNA synthesis when actinomycin D was displaced by proflavine.

Glutathione, ascorbic acid and antioxidant enzymes in the tumor tissue and blood of patients with oral squamous cell carcinoma.

BACKGROUND: Oral squamous cell carcinoma is one of the most common cancers in the world. Reactive oxygen species are postulated to be involved in neoplastic transformation. The antioxidant defence system limits cell injury induced by reactive oxygen species. Oxidative stress occurs when there is an imbalance between the production of reactive oxygen species and a cell's oxidant capacity or when there is a decrease in this capacity. This stress may cause mutagenesis, cytotoxicity and changes in gene expression that initiate or promote carcinogenesis. OBJECTIVES: The present study was conducted to investigate whether tumor tissue and blood of patients with oral squamous cell carcinoma have altered antioxidants levels. METHODS: Levels of antioxidants such as reduced glutathione (GSH) and ascorbic acid (AA) and the activities of antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GPx), glutatione reductase (GR), were estimated in the tumor tissue and blood of 18 oral squamous cell carcinoma patients and in 20 healthy subjects as control. RESULTS: Significantly increased levels of GSH, GPx, GR and AA and significantly decreased activity of SOD were observed in tumor tissue (p < 0.001) and in tumor-free tissue of oral cancer patients as compared with healthy subjects. In contrast, decrease in antioxidants (GSH, GPx, GR and AA p < 0.001, SOD p < 0.05 respectively) was observed in the blood of oral cancer patients, as compared with healthy subjects. CONCLUSION: The low levels of antioxidants in the blood of oral cancer patients may be due to their increased utilization to scavenge lipid peroxides as well as their sequestration by tumor cells. The enhanced antioxidant capacities in tumor tissues can make them less susceptible to oxidative stress, conferring a selective growth advantage on tumor cells. These finding suggest that normalization of the levels of these antioxidants might be used to reduce oral tumor malignancy.

Autophagy regulates hepatocyte identity and epithelial-to-mesenchymal and mesenchymal-to-epithelial transitions promoting Snail degradation.

Epithelial-to-mesenchymal transition (EMT) and the reverse process mesenchymal-to-epithelial transition (MET) are events involved in development, wound healing and stem cell behaviour and contribute pathologically to cancer progression. The identification of the molecular mechanisms underlying these phenotypic conversions in hepatocytes are fundamental to design specific therapeutic strategies aimed at optimising liver repair. The role of autophagy in EMT/MET processes of hepatocytes was investigated in liver-specific autophagy-deficient mice (Alb-Cre;ATG7(fl/fl)) and using the nontumorigenic immortalised hepatocytes cell line MMH. Autophagy deficiency in vivo reduces epithelial markers' expression and increases the levels of mesenchymal markers. These alterations are associated with an increased protein level of the EMT master regulator Snail, without transcriptional induction. Interestingly, we found that autophagy degrades Snail in a p62/SQSTM1 (Sequestosome-1)-dependent manner. Moreover, accordingly to a pro-epithelial function, we observed that autophagy stimulation strongly affects EMT progression, whereas it is necessary for MET. Finally, we found that the EMT induced by TGFß affects the autophagy flux, indicating that these processes regulate each other. Overall, we found that autophagy regulates the phenotype plasticity of hepatocytes promoting their epithelial identity through the inhibition of the mesenchymal programme.

Involvement of adenosine A2A receptors in the induction of c-fos expression by clozapine and haloperidol.

Acute administration of the atypical antipsychotic clozapine induced a regional pattern of c-fos expression characterized by an increase in Fos-like-immunoreactivity (FLI) in the prefrontal and prelimbic/infralimbic cortices, nucleus accumbens, and lateral septum and a weak activation of FLI in the striatum. Haloperidol, similarly to clozapine, increased FLI in the nucleus accumbens and lateral septum, but it did not induce FLI in prefrontal and prelimbic/infralimbic cortices. Moreover, haloperidol increased FLI in the striatum. To gain insight into the mechanism by which clozapine and haloperidol induced FLI in these brain structures, we evaluated whether blockade of adenosine A2A receptors could influence these effects. The selective and high-affinity A2A receptor antagonist SCH 58261 (5 mg/kg) completely abolished FLI induced by clozapine (20 mg/kg) in all subdivisions of the nucleus accumbens (rostral pole, shell and core) and striatum, but did not affect the number of Fos-like positive neurons in the prefrontal, prelimbic/infralimbic cortices, and lateral septum. SCH 58261 (5 mg/kg) reduced FLI induced by haloperidol (0.1 mg/kg) in the striatum, lateral septum, and all nucleus accumbens subdivisions. In contrast, FLI induced by 0.5 mg/kg of haloperidol in the shell and core of the nucleus accumbens was not affected by SCH 58261. The results show that adenosine A2A receptors participate in the induction of FLI by clozapine and haloperidol and support the concept that A2A receptors are involved in the mediation of antipsychotic effects.

Positive and negative interactions in the behavioural expression of D1 and D2 receptor stimulation in a model of Parkinsonism: role of priming.

Previous exposure to a dopaminergic agonist (priming) strongly potentiates contralateral turning behaviour in response to D1 and D2 agonists in unilaterally 6-hydroxydopamine-lesioned rats. In order to study the influence of priming on the behavioural interaction of D1 and D2 receptors, we examined the effect of selective D1 and D2 receptor blockade on the contralateral turning induced by the mixed D2/D2 agonist apomorphine in drug-naive and primed 6-hydroxydopamine-lesioned rats. In drug-naive rats, apomorphine induced a dose-related, apparently monophasic rotation curve. Administration of selective D1 (SCH 23390) or D2 (raclopride) antagonists abolished the contralateral turning induced by 0.1 mg/kg of apomorphine and partially inhibited that induced by 0.5 mg/kg. In primed rats low doses of apomorphine (0.05 mg/kg) induced an apparently monophasic contralateral turning which was reduced by D1 receptor blockade and completely abolished by D2 receptor blockade; a higher dose of apomorphine (0.1 mg/kg) instead elicited a biphasic (two-peak) pattern of rotation. After this dose of the agonist, blockade of D1 or D2 receptors abolished the second peak of rotation but, while D1 blockade reduced the total number of turns, D2 blockade failed to do so. Quantitative analysis of the interaction between D1 and D2 receptors in the overall turning effect, as well as in the time-course of turning behaviour, indicates that D1 and D2 receptors interact not only positively but also negatively. After higher doses of apomorphine, both negative and positive interactions take place sequentially during the time-course of apomorphine action and provide a clue for explaining the two-peak pattern of rotation observed after apomorphine in rats previously exposed to the drug.

Blockade of muscarinic receptors potentiates D1 dependent turning behavior and c-fos expression in 6-hydroxydopamine-lesioned rats but does not influence D2 mediated responses.

In rats with a unilateral 6-hydroxydopamine lesion of the dopaminergic nigrostriatal pathway, blockade of muscarinic receptors by scopolamine potentiates the contralateral turning induced by selective dopaminergic D1 agonists (SKF 38393, A 68930), but does not influence the contralateral turning induced by the D2 agonist LY 171555. Studies on the expression of the early gene c-fos as reflected by the immunohistochemical demonstration of the Fos protein, show that administration of scopolamine (5 mg/kg, i.p.) potentiates c-fos expression elicited by SKF 38393 (1.5 mg/kg, s.c.) in the caudate-putamen of the lesioned side. The results indicate that cholinergic transmission is differentially involved in the behavioral expression of D1 versus D2 receptor stimulation in a denervated condition and suggest that blockade of central cholinergic transmission might be useful in improving the antiparkinsonian efficacy of D1 receptor agonists.

Stimulation of dopamine transmission in the dorsal caudate nucleus by pargyline as demonstrated by dopamine and acetylcholine microdialysis and Fos immunohistochemistry.

The effect of pargyline on dopamine neurotransmission was investigated by trans-striatal microdialysis combined with Fos immunohistochemistry. Pargyline, 75 mg/kg i.p., increased dopamine and acetylcholine output while drastically decreased dopamine deaminated metabolites. Administration of pargyline resulted in the appearance of Fos-positive nuclei distributed along a gradient around the dialysis probe. Pretreatment with the D1 antagonist SCH 23390 potentiated the effect of pargyline on dopamine output while preventing that on acetylcholine output and on Fos formation. Similarly, lack of calcium in the perfusion medium abolished the effect of pargyline on dopamine and acetylcholine output and on Fos formation. In rats not implanted with dialysis probes pargyline administration resulted in only rare Fos-positive nuclei in the dorsal caudate. The present study indicates that pargyline stimulates dopamine transmission in the dorsal caudate in the area around the dialysis probe but not distant from the fibre or in unimplanted rats. This effect appears to reflect an interaction between the drug-induced changes and those locally elicited by the probe.

Crohn disease: susceptibility and disease heterogeneity revealed by HLA genotyping.

Predisposition to Crohn disease (CD) seems to be genetically determined but, though several reports on the matter, the association between HLA antigens and the disease is still controversial. PCR-SSP high resolution typing in 107 CD patients, and in subgroups selected according to clinical features, showed a positive association with the rare haplotype DRB1*07, DQB1*0303 both in the overall patients (p = 0.002; pc = ns) and in the subgroup of nonfistulized patients (p = 0.0008; pc = 0.032). Moreover, the protective role of the haplotype DRB1*03, DQB1*0201 (p = 0.029) was confirmed also in Italian patients, whereas no strong association with HLA class I alleles has been found. In addition, variability of the HLA alleles frequency in CD subgroups was observed, supporting the hypothesis of a genetic heterogeneity of the disease and suggesting that HLA alleles distribution in selected groups may allow to identify patients with probably different prognosis or associated complications.

Nimesulide and diclofenac in the control of cancer-related pain. Comparison between oral and rectal administration.

64 patients with pain associated with advanced cancer were treated with either nimesulide or diclofenac as initial analgesia. Patients were randomly allocated to 1 of 4 treatment groups: oral nimesulide 300 mg/day; oral diclofenac 150 mg/day; rectal nimesulide 400 mg/day; and rectal diclofenac 200 mg/day. After 1 week of treatment, both drugs provided an adequate degree of pain relief and allowed an increase in sleep duration. There were no significant differences in efficacy between the drugs or routes of administration. Fewer side effects were observed with nimesulide, giving this agent a better therapeutic index than the reference compound.