Endovascular solutions for symptomatic free-floating thrombus in thoracic aorta in rheumatoid arthritis patients: Two clinical cases.

OBJECTIVES: We present two clinical cases of association between symptomatic free-floating thrombus (FFT) in thoracic aorta and rheumatoid arthritis (RA). METHODS: In the first patient, we observed a recent onset of peripheral and visceral signs of embolization: after a first treatment with anticoagulation, our Aortic team scheduled the coverage of FFT (sited in zone 1 of the aortic arch) with an anatomical debranching of anonymous trunk and left carotid artery, a left carotid-subclavian bypass, and a TEVAR of the aortic arch with proximal landing in zone 0 of the arch. The second case was characterized by chest pain, left upper limb ischemia, and CTA evidence of an FFT in zone 3 of the aortic arch; we planned a chimney-TEVAR on the left subclavian artery and descending thoracic aorta (with proximal landing in zone 2 of the aortic arch) to exclude the FFT. RESULTS: No complications resulted and no new embolic episodes were registered. CONCLUSIONS: Evaluating the aorta is warranted in all patients with peripheral emboli of uncertain pathogenesis. In our opinion, the endovascular treatment of a symptomatic FFT could represent an effective and safe solution in a patient fit for endovascular surgery, but larger studies are required to define a personalized treatment strategy.

Substance P and neprilysin in chronic pancreatitis.

BACKGROUND/AIMS: We aimed to analyze substance P (SP) and neprilysin (NEP), the membrane metallopeptidase that degrades SP, in chronic pancreatitis (CP). METHODS: SP and NEP mRNA levels were analyzed by qRT-PCR in tissue samples from 30 patients with CP and 8 organ donors. In addition, SP serum levels were determined before and after surgery in the same patients, by means of a competitive ELISA assay. Genetic and epigenetic analyses of the NEP gene were also performed. RESULTS: SP mRNA expression levels were higher in CP tissues compared to controls (p = 0.0152), while NEP mRNA showed no significant differences between CP and healthy subjects (p = 0.2102). In CP patients, SP serum levels correlated with those in tissue, and after surgical resection SP serum levels were reduced compared to the preoperative values. Failure of NEP to overexpress in CP tissues was associated with significant miR-128a overexpression (p = 0.02), rather than with mutations in the NEP coding region or the presence of hypermethylation sites in the NEP promoter region. CONCLUSION: Tissue and serum levels of SP were increased in CP, while NEP levels remained unaltered. In an SP/NEP-mediated pathway, it would appear that NEP fails to provide adequate surveillance of SP levels. Failure of NEP to overexpress could be associated with miRNA regulation.

Effectiveness of neoadjuvant radiotherapy in the treatment of locally advanced rectal cancer: a single-center experience in 263 patients.

AIM: To determine the frequency of local recurrence (LR) and distant recurrence (DR) with 5-year survival analysis. METHODS: Patients with T3-T4 rectal cancer located within 10 cm from the anal verge. Radiotherapy protocol: 36 Gy, delivered in 12 daily doses of 3 Gy each for 5 days/week, followed by surgery after a 2-week break. RESULTS: 263 patients were recruited. Radiotherapy was well tolerated. None of the patients broke off treatment. Complete histological response was 3% and maximum radio-induced downstaging 31.4%. Overall complication rate was 25.8% and direct radio-induced complications 0.4%. Mean duration of treatment was 35.7 days. In 172 patients with a minimum follow-up of 5 years, the rate of LR was 6.0% and DR 24.4%. Five-year overall survival was 70.2%, overall specific survival 78.0%, disease-free survival 70.7%, LR-free specific survival 92.9%, and DR-free specific survival 73.5%. CONCLUSIONS: In our experience, local disease control was achieved in 94% of patients. Any changes in our treatment protocols will aim at improving results in terms of LR and DR. In view of the four-fold higher rate of DR as compared to LR, improvement of DR can be defined as the challenge for the future.

Endoscopic therapy for type B surgical biliary injury in a patient with short cystic duct.

Anatomical variations of the cystic duct are well-defined. The presence of short or absent cystic duct is unusual and represents a co-factor of biliary injury especially during laparoscopic cholecystectomy. Thus, its knowledge is important to avoid ductal injury in hepato-biliary surgery. We experienced the case of a 40-year-old woman with symptomatic cholelitiasis, who underwent to laparoscopic cholecystectomy. At surgery, an accidental bile duct lesion was carried, during Calot's triangle dissection, due the particular difficulties in dissecting an extremely short cystic duct found at the junction of the common hepatic duct and common bile duct. No vascular anomalies were present. The biliary leakage from the common bile duct was intraoperative identified and subsequentially treated by the endoscopic method. Laparoscopic cholecystectomy with sequential biliary endoprosthesis insertion was completed without conversion to open surgery. The endoscopic stenting was the definitive treatment for the leakage. No evidence of biliary stent complication was observed during the follow-up. This report documents a case of short cystic duct with particular emphasis to the biliary injury risk during the laparoscopic dissection of "unusual" Calot's triangle, and examines our mini-invasive therapeutic strategies in the management of bile leakage after laparoscopic cholecystectomy.

[Evaluating patients manual handling hazards in nursing personnel of a hospital]. / Patologie muscolo-scheletriche in operatori addetti alla movimentazione di pazienti in istituto di riposo per anziani.

Low back pain (LBP) and shoulder and arm disorders are common among workers exposed to risk due to manual weight lifting, and this health care problem is also very costly. We also know that nursing personnel exposed to manual patient handling activity report high number of work-related musculoskeletal disorders. The objective of our study was to evaluate the relationships between work and musculoskeletal disorders in personnel exposed to manual patient handling activity. 160 health care workers of an hospice exposed to patient handling were compared to a control group of 172 people not exposed to the handling risk. In our study we considered only subject with pathology already diagnosed, withdrawing people with disturbs but without clinical trials. The statistical evaluation using the chi2 test has not shown any meaning in the comparison between the two groups, we have calculated the Odds Ratio risk for discal hernia and protrusion finding a risk between low and modest (1.52). We think that the least prevalence of musculoskeletal disorders to the back in the group exposed to manual patient handling activity, could be explained partly with the "healthy worker" effect and partly with the workplace improvement. That is demonstrated also with the M.A.P.O. index scoring between 0 and 1.5 (negligible risk).

The ECM proteoglycan decorin links desmoplasia and inflammation in chronic pancreatitis.

BACKGROUND: Recurrent inflammation in chronic pancreatitis (CP) is not well understood. AIMS: To investigate whether decorin, an extracellular matrix (ECM) proteoglycan with macrophage modulating activity, is a pathogenic factor allowing diseased pancreatic stroma to sustain inflammation by affecting the cytokine profile of accumulating inflammatory cells. METHODS: Decorin was examined in 18 donors and 32 patients with CP by quantitative reverse transcription polymerase chain reaction (QRT-PCR), western blotting, and immunohistochemistry of pancreatic specimens. QRT-PCR was used to assess cytokine expression in donor peripheral blood mononuclear cells (PBMC), exposed or not to decorin in vitro, and to compare it with the cytokine profile of circulating and resident mononuclear cells (MNC) of patients with CP. RESULTS: In CP, desmoplasia is associated with overexpression of decorin in the growing ECM and enlarged pancreatic nerves. In culture, exposure of MNC to decorin stimulated expression of the MNC recruiting chemokine MCP-1. In biopsies, MNC infiltrates in decorin rich CP tissue showed a 300-fold upregulation of MCP-1 compared with decorin free peripheral blood, whereas no difference was found in basal MCP-1 expression in PBMC of patients versus donors. This effect was specific for MCP1-other inflammatory cytokines, such as interleukin 1beta and tumour necrosis factor alpha, were not affected. CONCLUSION: Decorin is a molecular marker of desmoplasia in CP, and excessive decorin may allow fibrotic masses to nourish and protract inflammation by deregulating the process of MNC accumulation and activation. These data provide a molecular basis for surgical resection of diseased tissue as a treatment option in CP.

Growth-associated protein-43 and protein gene-product 9.5 innervation in human pancreas: changes in chronic pancreatitis.

Growth-associated protein-43, an established marker of neuronal plasticity during development and in injury, was used to characterize innervation in the normal human pancreas and changes in chronic alcohol-induced pancreatitis by using light microscopic immunocytochemistry and computer-assisted image analysis. Immunostaining for the pan-neuronal marker protein gene-product 9.5 served as a reference for the characterization of total innervation in both groups. In normal human pancreas, strong protein gene-product 9.5 immunostaining revealed all nerve fibres in nerve trunks, all neuronal cell bodies and the entire parenchymal innervation. In contrast, growth-associated protein-43 immunoreactivity was restricted to a few nerve fibres in interlobular nerve trunks and to fine varicose nerve fibres supplying the parenchyma, blood vessels, pancreatic ducts and intrinsic ganglia. In cell bodies of intrinsic neurons, growth-associated protein-43 immunoreactivity was absent or extremely faint. In chronic pancreatitis, the protein gene-product 9.5 innervation exhibited region-specific changes. In areas with reduced parenchyma, the protein gene-product 9.5 innervation was sparse. In fibrotic regions, which are characteristic for advanced stages of chronic pancreatitis, enlarged nerve trunks showing neuroma-like formations were heavily stained for protein gene-product 9.5. In fibrotic tissue, protein gene-product 9.5-containing nerve fibres were extremely rare. The growth-associated protein-43 innervation in chronic pancreatitis was characterized by a dramatic increase, which was most pronounced in the enlarged nerve trunks. Such nerve trunks were frequently surrounded by infiltrates of immune cells, which in some cases formed follicle-like structures. Digital image analysis of adjacent sections and double fluorescence immunocytochemistry revealed that growth-associated protein-43 immunoreactivity was present in the vast majority of protein gene-product 9.5-immunoreactive nerve fibres. In contrast to the normal pancreas, a major subpopulation of intrinsic neurons immunostained for growth-associated protein-43. The expression of growth-associated protein-43 in the terminal fields of pancreatic nerve suggests that the innervation of the normal human pancreas undergoes continual and toposelective remodelling. The increase in the density of growth-associated protein-43 immunoreactive nerve fibres in enlarged nerve trunks paralleled by augmented expression of growth-associated protein-43 in intrinsic neurons and reduced parenchymal growth-associated protein-43-immunoreactive innervation underline the dramatic plasticity of pancreatic innervation in chronic pancreatitis.(ABSTRACT TRUNCATED AT 400 WORDS)

[Carcinoma of the male breast. Our experience]. / Il carcinoma della mammella maschile. Nostra esperienza.

A case series of 5 male patients afflicted with breast carcinoma is reported. The Authors describe symptomatology, diagnostic iter, principles of surgical treatment and results. Underlined is the wider surgical demolition in male breast cancer in comparison with females, even if natural history and biological conduct are comparable. This is because in male breast carcinoma the local and remote infiltration is more rapid than female for the less development of breast gland. Finally, indications for radiochemotherapy are comparable to female breast cancer.

Mechanisms of pain in chronic pancreatitis.

Pain is a leading symptom in chronic pancreatitis (CP) and often its management necessitates surgical intervention. Nevertheless the presence of different hypotheses, the pathophysiology of pain is not understood, thus the indications for therapy remain controversial. Increased pressure within the ductal system and/or the parenchyma has been suggested to be one of the causes of pain. This controversial theory has been substantiated by the demonstration of a relationship between intrapancreatic pressure and intensity of pain. On the other hand, recent studies have shown the inflammatory involvement of intrapancreatic nerve fibres in a so called "neuroimmune interaction". In fact, infiltration of inflammatory cells around the nerves together with an increase in the number of nerve fibres in the fibrotic pancreatic tissue have been proposed as a possible cause of pain in chronic pancreatitis. Moreover, immunohistological studies have shown that the amount of neurotransmitters, such as substance P and calcitonin gene related peptide, is increased in afferent pancreatic nerves and a close interrelationship between pain and immune cell infiltration of the nerves has been reported in CP. In addition to these hypothesis, extrapancreatic causes such as common bile duct obstruction and duodenal stenosis are discussed. This article review points to the different pathogenic mechanisms of pancreatic pain in CP.

Clock gene expression levels and relationship with clinical and pathological features in colorectal cancer patients.

The clock gene machinery controls cellular metabolism, proliferation, and key functions, such as DNA damage recognition and repair. Dysfunction of the circadian clock is involved in tumorigenesis, and altered expression of some clock genes has been found in cancer patients. The aim of this study was to evaluate the expression levels of core clock genes in colorectal cancer (CRC). Quantitative real-time polymerase chain reaction (qPCR) was used to examine ARNTL1, CLOCK, PER1, PER2, PER3, CRY1, CRY2, Timeless (TIM), TIPIN, and CSNK1? expression levels in the tumor tissue and matched apparently healthy mucosa of CRC patients. In the tumor tissue of CRC patients, compared to their matched healthy mucosa, expression levels of ARNTL1 (p=.002), PER1 (p=.002), PER2 (p=.011), PER3 (p=.003), and CRY2 (p=.012) were lower, whereas the expression level of TIM (p=.044) was higher. No significant difference was observed in the expression levels of CLOCK (p=.778), CRY1 (p=.600), CSNK1 (p=.903), and TIPIN (p=.136). As to the clinical and pathological features, a significant association was found between low CRY1 expression levels in tumor mucosa and age (p=.026), and female sex (p=.005), whereas high CRY1 expression levels in tumor mucosa were associated with cancer location in the distal colon (p?=?.015). Moreover, high TIM mRNA levels in the tumor mucosa were prevalent whenever proximal lymph nodes were involved (p= .013) and associated with TNM stages III-IV (p=.005) and microsatellite instability (p=.015). Significantly poorer survival rates were evidenced for CRC patients with lower expression in the tumor tissue of PER1 (p=.010), PER3 (p= .010), and CSNKIE (p=.024). In conclusion, abnormal expression levels of core clock genes in CRC tissue may be related to the process of tumorigenesis and exert an influence on host/tumor interactions.

Vanilloids in pancreatic cancer: potential for chemotherapy and pain management.

BACKGROUND: Success of chemotherapy and alleviation of pain are frequently less than optimal in pancreatic cancer patients, leading to increasing interest in new pharmacological substances, such as vanilloids. Our study addressed the question of whether vanilloids influence pancreatic cancer cell growth, and if vanilloids could be used for pain treatment via the vanilloid 1 receptor (VR1) in pancreatic cancer patients. METHODS: In vitro, the effect of resiniferatoxin (vanilloid analogue) on apoptosis and cell growth in pancreatic cancer cells--either alone, combined with 5-fluorouracil (5-FU), or combined with gemcitabine--was determined by annexin V staining, FACS analysis, and MTT assay, respectively. VR1 expression was evaluated on RNA and protein level by quantitative polymerase chain reaction and immunohistochemistry in human pancreatic cancer and chronic pancreatitis. Patient characteristics--especially pain levels--were registered in a prospective database and correlated with VR1 expression. RESULTS: Resiniferatoxin induced apoptosis by targeting mitochondrial respiration and decreased cell growth in pancreatic cancer cells without showing synergistic effects with 5-FU or gemcitabine. Expression of VR1 was significantly upregulated in human pancreatic cancer and chronic pancreatitis. VR1 expression was related to the intensity of pain reported by cancer patients but not to the intensity of pain reported by patients with chronic pancreatitis. CONCLUSIONS: Resiniferatoxin induced apoptosis in pancreatic cancer cells indicates that vanilloids may be useful in the treatment of human pancreatic cancer. Furthermore, vanilloid might be a novel and effective treatment option for neurogenic pain in patients with pancreatic cancer.

Is increased pancreatic pressure related to pain in chronic pancreatitis?

In this study, we investigated the relationship between pain and pancreatic pressure in patients with chronic pancreatitis (CP). We studied 12 patients with CP undergoing surgery and five controls with cancer of the pancreatic tail. CP was staged on the basis of morphological (ERP) and functional (serum-pancreolauryl test) criteria. Patients kept daily records of the intensity of pain on a linear analog scale. Intraoperatively, pressure within the pancreas was assessed by the introduction of a fine needle into the pancreatic parenchyma connected to a pressure transducer. In controls, pressure was determined in macroscopically normal tissue in the head of the pancreas. Pancreatic pressure was significantly higher in CP than in controls (29.9 +/- 3.1 vs 7.2 +/- 1.1 mmHg, p < 0.001). No relationship was found between the pain score and the pancreatic pressure. Pressure was positively correlated with ductal changes (r = 0.831; p < 0.001), but not with exocrine function of the pancreas. Postoperatively, pancreatic pressure fell by 15.3% in four patients with CP in whom pressure assessment was repeated after surgical decompression. We conclude that pancreatic parenchyma pressure is not closely related to pain in CP.

Changes of protein gene product 9.5 (PGP 9.5) immunoreactive nerves in inflamed appendix.

The existence of chronic appendicitis is controversial. In this prospective study, we investigated possible changes in the innervation of the appendix under different pathological conditions and correlated histological findings with clinical observation. Thirty appendectomy specimens and 14 appendices obtained from organ donors or patients who underwent right hemicolectomy were immediately fixed in Bouin's solution and processed for immunocytochemistry using an antiserum directed against the panneuronal marker protein gene product 9.5 (PGP 9.5). The density of PGP 9.5 immunostaining was evaluated by digitized morphometry. Significant differences in the density of the PGP 9.5-immunoreactive area were detected in the mucosal layer. In the nonacute appendicitis group, PGP 9.5 was increased (10.99 +/- 3.15%) as compared to acute appendicitis (3.89 +/- 1.77%) and controls (4.98 +/- 1.25%). The significant increase of PGP 9.5 in nonacute appendicitis may suggest axonal sprouting leading to hyperinnervation of the mucosa. This may be a neuronal factor in the pathophysiology of the disease and pain symptoms.

Neuroimmune appendicitis.

BACKGROUND: 15-25% of appendices removed from patients with suspected appendicitis appear normal on histological examination. The cause of pain in such patients is unknown. Since the content of neuropeptides seems to be altered in chronic inflammation, we investigated possible changes in peptidergic innervation for substance P (SP), vasoactive intestinal peptide (VIP), and growth-associated protein-43 (GAP-43). METHODS: Appendices classified as showing acute appendicitis, non-acute appendicitis (clinical signs of acute appendicitis, but histologically not inflamed), or normal were processed for SP, VIP, and GAP-43 immunocytochemistry. The density of SP immunostaining was assessed by digitised morphometry. FINDINGS: 31 appendix specimens were studied (16 acute, 15 non-acute). 16 specimens were used as controls. Expression of GAP-43 was increased in the non-acute appendices. We observed larger amounts of SP-immunoreactive and VIP-immunoreactive nerves in the mucosal layer of the appendix in patients with non-acute appendicitis than in controls and patients with acute appendicitis (mean % area SP-immunoreactive 0.0496 [SD 0.0113] non-acute, 0.0221 [0.0049] acute, 0.0229 [0.0068] controls). In addition, a close spatial relation between SP-immunoreactive and VIP-immunoreactive nerve fibres and lymphoid cells was detected in the outer zone of lymph follicles. INTERPRETATION: Neuroproliferation in the appendix, in association with an increase in neurotransmitters SP and VIP, may be involved in the pathophysiology of acute right abdominal pain in the absence of an acute inflammation of the appendix. Our data, together with increasing knowledge about the way in which the nervous system and immune cells interact, suggest that neuroimmune appendicitis is a distinct pathological entity.

Chronic pancreatitis: the perspective of pain generation by neuroimmune interaction.

Chronic pancreatitis (CP) is an inflammatory, often painful, disease of the exocrine pancreas which leads to exocrine insufficiency. The pathophysiology of pain in CP is incompletely understood. Several hypotheses have been advanced, including pancreatic and extrapancreatic causes. Here, the different pain hypotheses are discussed and evidence is presented that neuroimmune interactions are significant in the pathogenesis of pain generation and inflammation in CP. A better understanding of the complex cellular and molecular mechanisms of neuroimmune interactions should offer possibilities for innovative therapy and long term disease prevention.

Beneficial effects of Batimastat (BB-94), a matrix metalloproteinase inhibitor, in rat experimental colitis.

BACKGROUND AND AIMS: Matrix metalloproteinases (MMPs) represent a group of enzymes that regulate cell-matrix composition playing a major role in the inflammatory response. In the present study we evaluated the ability of the MMP inhibitor Batimastat (BB-94) to modify the course of experimental colitis induced in the rat by trinitrobenzensulfonic acid (TNB). METHODS: Colitis was induced in 40 rats by intracolonic administration of TNB. Animals were divided into four groups of ten rats each: group 1 received only intracolonic TNB, group 2 received TNB+5 mg/kg intraperitoneal BB-94, group 3 TNB+10 mg/kg BB-94 and group 4 TNB+20 mg/kg BB-94. The MMP inhibitor was administered 30 min before induction of colitis and twice daily until death. Ten rats receiving only intracolonic 0.9% saline served as controls. Animals were killed after seven days; segments of colon were removed and used for histological score of inflammation and myeloperoxidase (MPO) activity. RESULTS: Rats receiving only intracolonic 0.9% saline showed no evidence of colitis. The inflammation score was 0.9, MPO activity 0.235 U/mg. Group 1 (TNB-treated rats) exhibited a high inflammation score (12.4) and MPO activity (0.715 U/mg). Conversely, BB-94-treated rats showed, compared to the TNB group, a significantly lower inflammation score and MPO activity in a dose-dependent fashion. Group 2: inflammatory score 10.1, MPO activity 0.474 (p < 0.05 vs. TNB); group 3: inflammatory score 8.3, MPO activity 0.287 (p < 0.01 vs. TNB); group 4: inflammatory score 5.0, MPO activity 0.256 (p < 0.01 vs. TNB). CONCLUSIONS: Treatment with BB-94 has dose-dependent beneficial effects on the inflammatory alterations in rat experimental colitis. Thus, the inhibition of MMPs may represent a novel therapeutic approach for treatment of intestinal inflammation.

Immune cell infiltration and growth-associated protein 43 expression correlate with pain in chronic pancreatitis.

BACKGROUND & AIMS: Changes in innervation pattern and neuropeptide content have been shown in chronic pancreatitis (CP), including increased neuronal expression of growth-associated protein 43 (GAP-43). We used GAP-43 as an established marker of neuronal plasticity and correlated histological findings with pain scores of patients with CP. METHODS: In tissue samples from 29 patients with CP, the parenchyma-fibrosis ratio, degree of perineural immune cell infiltration, and neuronal GAP-43 immunoreactivity were determined by digitized morphometry and correlated with individual pain scores. RESULTS: In CP, GAP-43 was significantly increased in pancreatic nerve fibers and intrinsic neurons. GAP-43 expression correlated with individual pain scores. The infiltration of pancreatic nerves by immune cells was significantly correlated with the intensity of pain. Pain scores correlated neither with the degree of pancreatic fibrosis nor with the duration of the disease. CONCLUSIONS: The results suggest that infiltration of pancreatic nerves by immune cells and neuronal plasticity are pathogenic factors for the generation of pain, whereas the degree of pancreatic fibrosis has no major impact on pain in CP.

Nerve growth factor and Trk high affinity receptor (TrkA) gene expression in inflammatory bowel disease.

BACKGROUND: Nerve growth factor (NGF), a target derived factor for survival and maintenance of peripheral and central neurones, has been implicated in several chronic inflammatory processes. AIMS: To analyse the concomitant presence of NGF and its high affinity receptor TrkA in patients undergoing surgery for Crohn's disease (CD) and ulcerative colitis (UC). PATIENTS: CD tissues were obtained from 33 patients and UC tissue samples from 12 patients undergoing surgery. Normal intestinal tissue samples were obtained from 30 individuals through an organ donor programme. METHODS: Expression of NGF and TrkA was studied by northern blot analysis. Using in situ hybridisation and immunohistochemistry, the respective mRNA moieties and proteins were localised. Western blot analysis was used to confirm the specificity of NGF and TrkA antibodies. RESULTS: In CD, NGF mRNA was increased in 60% (2.4-fold; p<0.01) and TrkA mRNA in 54% (1.3-fold; p<0.05) of samples. In UC, NGF mRNA expression was enhanced in 58% (2.4-fold; p<0.01) and TrkA mRNA expression in 50% (1.5-fold; p<0.05) of samples. In situ hybridisation showed that NGF and TrkA mRNA were often concomitantly present in polymorphonuclear-like cells of the lamina propria, in mast cells, and in a few ganglia of Auerbach's plexus and Meissner's plexus. Immunohistochemistry revealed that lamina propria cells and inflammatory cells (mainly mast cells) were NGF and TrkA immunopositive. NGF was also present in Meissner's plexus (especially in CD) and TrkA in enteric glia surrounding intestinal ganglia. CONCLUSIONS: The concomitant enhanced expression of NGF and its receptor suggests activation of this pathway in chronic inflammation in CD and UC. The presence of NGF and TrkA in both neural and non-neural structures in CD and UC supports the hypothesis that neuroimmune interactions occur and are activated in both disorders.