Proteasome system dysregulation and treatment resistance mechanisms in major depressive disorder.

Several studies have demonstrated that allelic variants related to inflammation and the immune system may increase the risk for major depressive disorder (MDD) and reduce patient responsiveness to antidepressant treatment. Proteasomes are fundamental complexes that contribute to the regulation of T-cell function. Only one study has shown a putative role of proteasomal PSMA7, PSMD9 and PSMD13 genes in the susceptibility to an antidepressant response, and sparse data are available regarding the potential alterations in proteasome expression in psychiatric disorders such as MDD. The aim of this study was to clarify the role of these genes in the mechanisms underlying the response/resistance to MDD treatment. We performed a case-control association study on 621 MDD patients, of whom 390 were classified as treatment-resistant depression (TRD), and we collected peripheral blood cells and fibroblasts for mRNA expression analyses. The analyses showed that subjects carrying the homozygous GG genotype of PSMD13 rs3817629 had a twofold greater risk of developing TRD and exhibited a lower PSMD13 mRNA level in fibroblasts than subjects carrying the A allele. In addition, we found a positive association between PSMD9 rs1043307 and the presence of anxiety disorders in comorbidity with MDD, although this result was not significant following correction for multiple comparisons. In conclusion, by confirming the involvement of PSMD13 in the MDD treatment response, our data corroborate the hypothesis that the dysregulation of the complex responsible for the degradation of intracellular proteins and potentially controlling autoimmunity- and immune tolerance-related processes may be involved in several phenotypes, including the TRD.

The choice of surgical procedure for peritonitis due to colonic perforation.

OBJECTIVE: Because the choice of surgical procedure for colonic perforation is still matter of debate, we retrospectively studied peritonitis caused by spontaneous colonic perforation to assess predictors of mortality and the safety of primary resection and anastomosis. DESIGN: Case series. PATIENTS: We investigated one hundred thirty-six consecutive patients with peritonitis due to colonic perforation who were surgically treated in an emergency surgery department. Eighty-one patients underwent primary resection and anastomosis, thirty-three underwent the Hartmann procedure, and twenty-two had simple colostomy. The seriousness of peritonitis was assessed in terms of Hinchey stage, the Mannheim Peritonitis Index (MPI), and the acute physiology and chronic health evaluation (APACHE) II score. RESULTS: The overall mortality rate was 20%. The APACHE II scores and MPIs were lower for survivors than for nonsurvivors. The mortality rate was 6% for primary resection and anastomosis, 30% for the Hartmann procedure, and 59% for simple colostomy, but the severity scores were significantly lower in patients who underwent primary resection than those of patients who had the Hartmann procedure and colostomy, respectively. CONCLUSIONS: Since primary resection and anastomosis has been shown to be safe, we suggest that is is proper, even in the presence of peritonitis. In spite of this, we conclude that the surgical procedure does not influence outcome but that the mortality rate is related to the severity of peritonitis, accurately measured by APACHE II score and MPI.

Predictive factors for cholelithiasis complications.

BACKGROUND: Cholelithiasis is a benign disease that is very frequently encountered throughout the world. Its surgical mortality is usually minimal (0.1%), but the risk is considerably greater (2-10%) in patients developing complications particularly if they are elderly. The identification of possible predictive signs of complications is therefore crucial for the indication of preventive surgery. METHODS: The present study retrospectively examined 490 patients admitted to hospital because of complicated and uncomplicated cholelithiasis in order to establish the existence of previous (clinical or instrumental) symptoms that may be predictive of the course of the disease. The analysis of some variables (age, sex, pregnancy, diet, ethanol consumption, smoking, previous/concomitant diseases, and blood chemistry and instrumental test results) and the specific symptoms of cholelithiasis made it possible to identify two potential risk factors: an age of more than 60 years and the onset of biliary colic. RESULTS: The risk of developing complications is 3.2 times greater in patients aged more than 60 years than in those who are younger, and 3.3 times greater in symptomatic than in asymptomatic patients. Statistical analysis also revealed that the risk of complications is about ten times greater in patients with both risk factors than in those with neither. CONCLUSIONS: In conclusion, the indication for surgery must be considered absolute in symptomatic patients aged more than 60 years and relative to younger symptomatic patients.

[Smooth-muscle-cell tumors of the gastroenteric tract. A review of cases]. / I tumori a cellule muscolari lisce del tratto gastroenterico. Revisione casistica.

Smooth muscle tumors of the gastrointestinal tract are difficult to evaluate and to stage. Twenty-four patients surgically treated during the last ten years have been evaluated using a TGM staging to identify the more rational criteria for the therapeutic choice. Six gastric leiomyomas, 1 ileal leiomyoma, 4 gastric leiomyosarcomas, 1 esophageal leiomyosarcoma, 4 ileal leiomyosarcomas, 2 rectal leiomyosarcomas and 6 gastric leiomyoblastomas were included. 62.5% of cases presented acute clinical features. Preoperative histological diagnosis was adequate in 29% of cases. We performed 7 excisions, 6 gastric subtotal resections, 3 total gastrectomies, 1 esophageal resection, 5 ileal resections, 2 rectal low anterior resection. Fourteen patients were staged I/II, 8 staged III and 2 staged IV. The overall median survival time was 27.5 months (56, 20 and 5 months concerning stage I/II, III and IV respectively; p < 0.01). In relation to T and G factors overall survival was statistically significant. TGM staging was highly significant to predict long-term survival. Radical surgical procedure was highly effective to guarantee long-term survival. Extended follow up is requested because recurrences after many years seem to be possible also with low histologic grade at first presentation.

[Hypertonic saline solutions in resuscitation in hemorrhagic shock. An experimental study]. / Le soluzioni saline ipertoniche nel recupero dallo shock emorragico. Studio sperimentale.

The aim of the study was to evaluate the use of hypertonic solutions in restoring intravascular volume in a model of hemorrhagic shock. Eighteen pigs underwent general anesthesia and were instrumented with a carotid catheter to record mean arterial pressure (MAP), a pulmonary artery catheter for pulmonary arterial pressure (MPAP) and cardiac output (CO) monitoring and an electromagnetic flowmeter around the abdominal supraceliac aorta for aortic flow measurement (Vaor). Oxygen delivery (DO2) and oxygen consumption (VO2) data were calculated by standard formulas. The animals were hemorrhaged to a MAP of 45 mmHg, held for 1 hour. They were resuscitated during the following hour until the aortic flow regained its basal value, using three different solutions: normotonic saline (NS = NaCl 0.9%), hypertonic saline (HS = NaCl 7.5%), hypertonic saline added with dextran (HSDX = NaCl 7.5% + 6% dextran 70). An hour of autologous blood transfusion and a two hours follow-up concluded the experiment. Volumes infused were remarkably lower administering HS (13.70 +/- 1.44 ml/kg) and HSDX (9.11 +/- 1.20 ml/kg) compared to NS (90.32 +/- 24.83 ml/kg). MAP, CO and DO2 values resulted significantly higher in the HSDX animals, with lower MPAP levels. During the two hours follow-up only the animals reinfused with HSDX maintained hemodynamic and oxygen transport values at normal levels. We conclude that the administration of hypertonic saline solutions during hemorrhagic shock allows the saving of infusion volumes, thus diminishing the occurrence of interstitial edema formation. The adding of dextran to the solution prolongs the hemodynamic effects.

Predictive value of a pathophysiological score in the surgical treatment of perforated diverticular disease.

Resection is the preferred method of perforated diverticular disease treatment compared to conservative treatment. However, the immediate or deferred timing of bowel continuity restoration for advanced degrees of peritoneal contamination is debatable. This is a retrospective study designed to identify operative mortality predictors and guidelines for safe primary anastomosis. A pathophysiological score (acute physiology and chronic health evaluation, APACHE II) was applied to 135 consecutive patients who had undergone surgery for acute inflammatory complication of diverticular disease. A multivariate analysis was used to identify prognostic factors such as age, chronic diseases, neoplastic cancer, Acute Physiology Score (APS), Hinchey's classification and APACHE II scores. Seventy patients underwent primary resection and anastomosis, 35 underwent Hartmann's procedure and 15 conservative treatment. There was a significant correlation between operative mortality and increasing disease severity based on Hinchey's classification, APS and APACHE II scores. The multivariate analysis proved APACHE II scores to be the only prognostic factor of operative mortality. Both single and multivariate analysis of variance failed to identify a factor significantly associated with surgical and/or medical postoperative complications. APACHE II scores were the best predictor for operative mortality in patients with diverticular disease complications, but none of the classification criteria used was effective in predicting postoperative complication. Patients with phlegmonous sigmoiditis can be safely treated with primary resection and anastomosis. Conservative treatment should not be considered an effective method for diverticular disease. A prospective trial comparing resection with and without colostomy should be done for local and diffuse purulent peritonitis treatment. Hartmann's procedure is seen to be the only indicator for faecal peritonitis.

[Open treatment in acute severe pancreatitis]. / Trattamento aperto nella pancreatite acuta severa.

Technical procedures normally used for open packing in our Institute (ICU) are described. Results of this procedure, utilized in thirteen patients suffering from infected pancreatic necrosis and multiple organ failure are reported. The grade of pancreatitis severity has been studied in detail. At admission patients presented a mean Ranson score of 6 and the morphological alteration sec. Balthazar was D in six patients and E in seven. At least two organs were insufficient at the beginning of our observation and the mean number of insufficient organs was 4. The mean APACHE II score was 20. Necrosis was documented in all patients. They were all admitted to ICU and the mean time of treatment was 50 days. Daily debridement was performed and continuous lavage was later added to daily open review. Three patients died, one from local bleeding and two from respiratory insufficiency. No patient died of sepsis and no mortality was observed in the last six cases. According to the severity of Ranson score, APACHE II, the number of insufficient organs and TAC morphological alteration predicted mortality rate should have been 70-80%; on the contrary, it was 25%. In conclusion open packing seems to be the correct treatment for infected pancreatic necrosis, particularly when it is complicated by multiple organ dysfunction.

[One-stage curative treatment of neoplastic colonic obstruction: long-term results, comparison with elective surgery and therapeutic implications]. / Il trattamento curativo in un tempo dell'occlusione colica neoplastica: risultati a lungo termine, confronto con l'elezione e implicazioni terapeutiche.

Over a period of ten years (1980-1989) 528 patients with colon cancer were treated at one institution. One hundred seventy nine (33.9%) were obstructed (O) and underwent emergency surgery, while 349 received elective (E) treatment; of these 363 had one-stage curative treatment. Operative mortality was 10.3% (O) and 3.5% (E) respectively (p < .0.5). Three hundred forty three patients survived surgery and entered follow-up: 96 were O (M:F, 54:42) and 247 E (M:F, 119:128, p = N.S.). Their mean age was 69.5 and 64.4 (p < .001), respectively. Dukes' stage and histological grading were evenly distributed within the two groups, but sites of the primary were not (p < .001). During the follow-up local recurrence occurred in 40 patients (13 O, 27 E, p = N.S.) and metastatic disease in 78 (28 O, 50 E, p < .05, Life Table Analysis) including liver recurrence in 17 O and 30 E (p = .063). Five year crude survival (51%) was significantly worse in obstructed patients. Multivariate analysis showed that Dukes' stage and obstruction were the only prognostic factors of recurrent disease, while survival was affected by the same variables and age over 70. When recurrent disease was introduced in the model survival depended on Dukes' stage, site of the primary and age over 70 and the variable obstruction disappeared as prognostic factor. Right sided tumours showed a better and those at the splenic flexure a worse prognosis. Despite one-stage curative treatment obstruction carries a significantly higher risk of developing metastatic disease, suggesting that obstruction enhances cancer cell dissemination. These patients might benefit from per-operative intra-portal and post-operative systemic adjuvant chemotherapy.

[Comparison of mechanical and manual anastomoses in emergency gastric resection]. / Confronto fra anastomosi meccaniche e manuali nella resezione gastrica in urgenza.

Hundred and twenty-one patients underwent emergency subtotal gastrectomy for complications related to peptic ulcer (86) and malignant diseases (35). According to the type of anastomosis performed (manual or mechanical) patients were divided into two groups: 81 with hand-sutured anastomoses (double layer) and 40 with stapled anastomoses. The latter were more commonly used in the Roux-en-Y reconstruction and Billroth 1 gastrectomy. Median operating time (192' versus 190'), hospital stay (15.2 versus 13.5 days), postoperative complications (38% versus 32.5%) and anastomotic or duodenal stump leakage (7.4% versus 5%) showed no significant difference between groups. Therefore, in emergency subtotal gastrectomy mechanical anastomoses allow to obtain results comparable to the more used manual ones.

Outcome of large-bowel perforation in patients with colorectal cancer.

PURPOSE: Perforation of the colon is seldom associated with malignant disease. Operative mortality varies widely in published studies and little is known about patterns of failure and long-term outcome. An observational study was undertaken to assess the outcome of colorectal cancer complicated by perforation. METHOD: We reviewed a series of 83 consecutive patients treated during a 14-year period at one institution. RESULTS: Fifty-four (65 percent) patients had perforation of the tumor itself, and 29 (35 percent) had diastatic perforation proximal to an obstructing tumor. Twenty-six (31.5 percent) patients had metastatic disease at laparotomy. Primary resection of the diseased segment was performed in 47 (87 percent) patients with perforation of the tumor itself and in 21 (72.4 percent) patients with diastatic perforation proximal to an obstructing tumor. However, only 57 patients (39 (72.2 percent) with perforation of the tumor itself; 18 (62 percent) with diastatic perforation proximal to an obstructing tumor; P = not significant) were potentially cured. Operative mortality was 16.7 and 48.3 percent, respectively (P < 0.01) and correlated significantly with Hinchey's stage (P < 0.001) and advanced disease (P = 0.023). At a mean follow-up of 43 (median 31) months, 21 (46 percent) of the 46 potentially cured survivors were alive. The local recurrence rate was 22.9 percent in patients with perforation of the tumor itself and 18.2 percent in patients with diastatic perforation proximal to an obstructing tumor (P = not significant). Peritoneal seeding occurred in 17 and 0 percent (P = not significant); the mean disease-free interval was 33.9 and 49.9 months (P = not significant); and five-year cumulative disease-related survival probability was 0.51 and 0.90 (P = 0.049), respectively. CONCLUSIONS: Diastatic perforation proximal to an obstructing tumor is associated with higher operative mortality and better cancer-related survival than a tumor perforating through the bowel wall. Early diagnosis in diastatic perforation and aggressive management of sepsis associated with radical surgical resection is recommended.

Obstructing colonic cancer: failure and survival patterns over a ten-year follow-up after one-stage curative surgery.

BACKGROUND: Large-bowel cancers that present as obstructing lesions have a poor prognosis. However, little is known of the reasons for the dismal survival and of failure patterns after potentially curative treatment. METHOD: An observational study and multivariate analysis were conducted to identify determinants of survival and to compare recurrence patterns between obstructing and nonobstructing tumors after primary resection and anastomosis as curative treatment. RESULTS: Over a period of ten years (1980-1989), 528 patients with colonic cancer were treated at one institution. The cancer was obstructing in 179 cases and nonobstructing in 349. One-stage primary resection and anastomosis as curative treatment were performed in 107 obstructed and 256 nonobstructed patients. Three hundred thirty-six potentially cured survivors (94 in the former group and 242 in the latter) were followed for a median of 55 months. During follow-up, local recurrence occurred in 37 patients (12 obstructed (12.8 percent) and 25 nonobstructed (10.4 percent), P = 0.44) and metastatic disease in 68 (25 obstructed (27.6 percent) and 43 nonobstructed (17.8 percent), P = 0.029). Multivariate analysis of survival showed that age over 70 years, Dukes stage, histologic grade, and recurrence were the only prognostic factors. No statistically significant determinant turned out for local recurrence, whereas at multivariate analysis for metastatic and overall relapse, Dukes stage, positive nodes, and obstruction remained independent prognostic factors. CONCLUSIONS: After one-stage emergency curative treatment, patients presenting with obstructing tumors of the colon have a smaller survival probability than that of patients with nonobstructing lesions. Local recurrence pattern is similar between groups. Conversely, obstruction, along with pathologic stage and positive nodes, carries a significantly higher risk of metastatic tumor recurrence and death.

Inhibition by methylprednisolone of leukocyte-induced pulmonary damage.

BACKGROUND AND METHODS: The purpose of this study was twofold: the development of a chronic model of leukocyte-mediated pulmonary injury and the evaluation of the protective effects of methylprednisolone. Rabbits were inoculated ip with zymosan. Blood gases and circulating leukocytes were evaluated. Survivors were killed on day 10 for microscopic studies and for the evaluation of lung lipid peroxidation through the by-product malondialdehyde. RESULTS: Intraperitoneal zymosan resulted in a marked decrease of Pao2 and circulating leukocytes, and increased cellularity of alveolar septa, interstitial edema, and increased lung malondialdehyde. Pulmonary damage was partially prevented when methylprednisolone was administered before zymosan inoculation, but not when methylprednisolone was given 24 hr later. CONCLUSIONS: The authors conclude that a local nonseptic inflammatory stimulus may provoke remote changes to the lungs and that methylprednisolone may counteract the process only if it is administered before or very early after the onset of inflammation.

Follow-up in colorectal cancer patients: a cost-benefit analysis.

BACKGROUND: No conclusive evidence exists concerning the effectiveness of follow-up programs after curative surgery for colorectal cancer, and presently cost-benefit analyses have not indicated that follow-up strategies increase survival or quality of life. METHODS: Five hundred five patients who survived curative surgery for stage I-III colorectal adenocarcinoma were closely followed for at least 4 years. RESULTS: One hundred forty-one (28%) patients had recurrence. Of these, 32 underwent one or more surgical procedures for cure, whereas 109 could only benefit from palliation. Eighteen were cured. The mean survival of all recurrent cases was 44.4 months. Of those operated on with curative intent, the mean survival was 69.3 months compared with 37.1 months in those operated on with palliative intent. Of those 18 patients who were cured by reoperative surgery, the average survival was 81.4 months. The overall follow-up cost was $1,914,900 (U.S.) for the 505 patients; $13,580 (U.S.) for each recurrence, $59,841 (U.S.) for each case treated for cure, and $136,779 (U.S.) for those effectively cured. CONCLUSIONS: Careful postoperative monitoring is expensive yet effective when one considers that one-quarter of the detected recurrences were suitable for potentially curative second surgery; however, only 3.6% of the original group were effectively cured. Follow-up programs should be tailored according to the stage and site of the primary to reduce costs.

Comparison of rhinomanometry, symptom score, and inflammatory cell counts in assessing the nasal late-phase reaction to allergen challenge.

Inspiratory nasal resistance, symptom score, and influx of inflammatory cells into the nose were evaluated before and after a nasal challenge in 15 patients with grass pollen rhinitis and in six nonallergic control subjects, to study the nasal late-phase reaction and its relationship with nasal cytology. All patients had an immediate positive reaction to specific nasal challenge. In seven allergic subjects we observed a later inspiratory nasal resistance increase, but only two had a significant late symptom score. Inflammatory cells increased by 8 hours in all the patients; the higher the cell influx, the higher the symptom score. Close correlations were found between the inspiratory nasal resistance increase, nasal obstruction at hours 8 and 24, and all cell counts. In control challenges there were no significant increases of symptom score or inspiratory nasal resistance either during the challenge or in the next 24 hours. A weakly significant increase was found only for neutrophil counts at 8 hours. These results indicate that an inflammatory reaction constantly occurs after a specific nasal challenge; its extent is closely related to inspiratory nasal resistance and to the intensity of nasal obstruction. Moreover, our data outline the pivotal role played by eosinophils and basophils in the genesis of an allergic late-phase reaction in the nose.

No correlation between response and survival in patients with multiple myeloma treated with vincristine, melphalan, cyclophosphamide, and prednisone.

A vincristine, melphalan, cyclophosphamide, and prednisone (VMCP) multi-drug regimen was used in 85 previously untreated patients with multiple myeloma (MM) (symptomatic Durie Stages II and III) until they became refractory. The prognostic significance of various pretreatment characteristics was evaluated in terms of therapeutic response (according to Southwest Oncology Group [SWOG] and Chronic Leukemia-Myeloma Task Force [TF] criteria) and survival. Therapeutic responses, obtained in 31.2% (SWOG) and 68.7% (TF) of patients, had a significant inverse correlation with myeloma cell mass, serum calcium, and bone status. Median survival time of Stage II and Stage III patients was 39 and 34 months, respectively. Serum B2 microglobulin greater than or equal to 6 micrograms/ml was the only variable correlating unfavorably with survival duration after multi-variate analysis (increased risk = 2.79), although therapeutic response as a time-dependent variable had no effect on survival. These data suggest no correlation between response and survival, partially because of inadequate response assessment criteria and partially because no existing treatment is curative (although current therapeutic approaches may prevent death from complications).

Cholelithiasis in cirrhosis: analysis of 500 cases.

The prevalence of cholelithiasis (gallstones or previous cholecystectomy) was evaluated in a series of 500 cirrhotic patients from Northern Italy (329 males and 171 females, mean age 58 +/- 11 (SD) yr and 61 +/- 10 yr, respectively). Cirrhosis was related to chronic alcohol abuse in 180 cases, non-A non-B (NANB) hepatitis in 160, hepatitis B virus (HBV) in 94 (including 38 with concomitant alcohol abuse), idiopathic hemochromatosis in 44, and miscellaneous causes in the remaining 22 (including 15 with primary biliary cirrhosis). One hundred and sixteen patients (23.2%) had gallstones, and 31 others (6.2%) had previously undergone cholecystectomy, with an overall prevalence of cholelithiasis of 29.4%. The frequency was similar in both sexes (91/329 males, 27.7% vs. 56/171 females, 32.7%; p = NS), showed a slight increase with age, and differed significantly according to etiology (p less than 0.05), with the highest prevalence in the miscellaneous group and the alcoholics (36.4% and 33.3%, respectively). No significant difference was found in the prevalence of cholelithiasis according to Child's A, B, or C class.

Mesenteric and renal oxygen transport during hemorrhage and reperfusion: evaluation of optimal goals for resuscitation.

BACKGROUND: Changes in flow to the gut and the kidney during hemorrhage and resuscitation contribute to organ dysfunction and outcome. We evaluated regional and splanchnic oxygen (O2) flow distribution and calculated oxygen supply distribution during hemorrhage and reperfusion and compared them with global measures. METHODS: Seven anesthetized pigs were instrumented to evaluate global hemodynamics, visceral blood flow, and oxygen transport. Tonometric pH probes were positioned in the stomach and jejunum. Animals were bled to 45 mm Hg for 1 hour. Crystalloids and blood were infused during the following 2 hours to normalize blood pressure, heart rate, urine output, and hemo- globin. RESULTS: During hemorrhage, mesenteric flow and O2 consumption were significantly decreased, whereas systemic consumption remained normal. Renal flow was reduced, but renal O2 consumption remained normal. After resuscitation, despite normal hemodynamics, neither systemic, mesenteric, nor renal O2 delivery returned to baseline. Lactate remained significantly increased. Arterial pH, base excess, and gastric and jejunal pH were all decreased. CONCLUSION: During hemorrhage, the gut is more prone than other regions to O2 consumption supply dependency. After resuscitation, standard clinical parameters do not detect residual O2 debt. Lactate, arterial pH, base excess, and intramucosal gut pH are all markers of residual tissue hypoperfusion.