Association between operative approach and complications in patients undergoing Hartmann's reversal.

BACKGROUND: Complications following reversal of Hartmann's procedure are common, with morbidity rates of up to 50 per cent, and a mortality rate as high as 10 per cent. This is based on case series with heterogeneous data collection and analysis. This study determined risk factors for complications following Hartmann's reversal. METHODS: Patients who underwent elective open and laparoscopic Hartmann's reversal were identified from the American College of Surgeons National Surgical Quality Improvement Program database (2005-2010). The programme collects patient demographics, preoperative medical history, clinical findings and laboratory investigations. Postdischarge data were obtained by a certified reviewer. Complications were categorized as major, septic or incisional. Risk-adjusted 30-day outcomes were assessed by univariable and multivariable analyses, adjusting for patient characteristics, co-morbidity and operative approach. RESULTS: During the study period 7996 patients had a Hartmann's procedure and 2567 cases of Hartmann's reversal were identified, including 336 laparoscopic procedures (13·1 per cent). Major, septic and incisional complication rates were 13·3, 8·5 and 15·7 per cent respectively, with a mortality rate of 0·5 per cent. A laparoscopic approach was found to be independently associated with fewer major (odds ratio (OR) 0·53, 95 per cent confidence interval 0·34 to 0·81), septic (OR 0·48, 0·27 to 0·83) and incisional (OR 0·54, 0·37 to 0·80) complications. A history of chronic obstructive pulmonary disease (OR 1·78-2·00), steroid use (OR 1·75), body mass index at least 30 kg/m² (OR 1·48), diabetes (OR 1·40), smoking (OR 1·33-1·40), American Society of Anesthesiologists fitness grade III and IV (OR 1·46-1·48) and prolonged operating time (OR 1·02) were other factors associated with complications. CONCLUSION: A laparoscopic approach to Hartmann's reversal was associated with fewer complications than open surgery in this highly selected group of patients.

Cyanidin reduces preadipocyte differentiation and relative ChREBP expression.

Adipogenesis is a continuous process even in adult adipose tissue for the presence of preadipocytes that, when subjected to appropriate stimuli can proliferate and differentiate. ChREBP, the essential transcription factor for lipogenesis, is expressed in all tissues, but mainly in lipogenic organs. In this study, we focused on ChREBP expression during preadipocytes differentiation. Since it was found that cyanidin-3 reduces body weight in mice even in the presence of a high-fat diet, by decreasing levels of blood glucose and by improving insulin sensitivity, we studied the effect of this substance on adipogenic differentiation. For this purpose we used preadipocytes obtained from subcutaneous and visceral human adipose explant tissue, characterized and stimulated to differentiate in selective media. On cytofluorimetric analysis these cells showed mesenchymal markers (CD29, CD90, CD44), whereas they were negative for hematopoietic markers (CD45, CD10, CD117,CD31). ChREBP expression levels were quantified by immunoelectron-microscopy and western blotting analysis. In this report we show that ChREBP is expressed in preadipocytes (both nuclear and cytoplasmic compartments); the cytoplasmic level of ChREBP increased by 50 percent on day seven of differentiation into mature adipocytes. Cyanidin reduced differentiation by 20 percent (as evaluated by red oil O staining) and the expression of ChREBP. In addition, cyanidin-treated cells showed abnormal morphology, a square shape with irregular size, probably due to the fact that cyanidin may interfere with the extracellular matrix. These findings suggest that dietary cyanidin, may have inhibitory effects on adipogenesis.

[Low rectal cancer: therapeutic options and clinical experience of a single center]. / Il carcinoma del retto basso: possibilità terapeutiche ed esperienza clinica di un singolo centro.

INTRODUCTION: Currently the therapeutic gold standard for medium and low rectal tumours is the "en-bloc" excision of the rectum and total mesorectal excision (TME) preserving the autonomous nerve plexus. In very distal tumours, complex procedures such as very low anterior resections and intersphincteric resections are used where possible. These procedures can avoid incapacitating operations such as abdominoperineal amputation. The possibilities to perform these procedures even by laparoscopic means, with regard to it's advantages, are still under evaluation. The authors describe their own clinical experiences using such methods. PATIENTS AND METHODS: From 2005 to 2010, we performed by laparoscopic procedure 3 anterior resections and 3 inter-sphincteric resections for cancer of the low rectum . Medium age of patients was 70 years (range 52-80 years) and male to female ratio was 4/2. Mean operative time was 260 min ( range 220 - 360 min). No laparoscopic procedure was converted to the traditional open surgery. We noted 2 anastomotic leakages of which one required re-operation. Two patients were classified T2 (1 N0 and 1 N1); four patients T3 (3 N0 and 1 N2). In all the cases, resection margins were free. The mean distance from the anal verge was 3,8 cm (range 2,8 - 6 cm). In a mean followup of 48 months ( range 6-54 months), 1 patient developed hepatic metastasis and no local recurrence was noted. Two patients had urinary retention, resolved spontaneously. One patient presented erectile dysfunction. At 12 months from the operation, one patient had slight incontinence for gas and liquids. CONCLUSIONS: We believe that total mesorectal resection, even associated with sphincter preserving procedures, such as intersphincteric resection, in case of very low rectal tumours, can also be performed by laparoscopic approach with the same oncological and surgical principles of open surgery. However it is necessary to have broad based studies and randomised clinical trials in order to confirm the safety of such procedure and the results obtained.

[Laparoscopic surgery of adrenal tumours: indications and techniques]. / Chirurgia laparoscopica dei tumori del surrene: indicazioni e tecniche.

Laparoscopic adrenalectomy is a gold standard in the treatment of the majority of adrenal lesions. In fact, laparoscopic technique reduces post-operative morbidity, hospital stay, the necessity of blood transfusions, post-operative pain and complications. We examined the data of patients who were operated by laparoscopic technique from April 2000 to April 2010. The following data were evaluated: demographic data of the patients, type of operation, the operative time, the rate of conversion to laparotomic procedure, post-operative complications, histologic diagnosis and the dimensions of the lesions. A total of 41 patients underwent to laparoscopic procedure. Two patients developed complications which got resolved through medical treatment. No patient died after surgery. The time of laparoscopic procedure was 95 min in average. No patient was converted to laparotomy. The total average hospital stay was 4.18 days. Average diameter of the lesions was 4.43 cm (range 1.2-8.5 cm). The data we obtained from our studies confirm the safety and the feasibility of laparoscopic adrenalectomy and it's application can be considered even in case of malignant lesions. The only contraindication to laparoscopic procedure is the involvement of surrounding tissue and vascular invasion by tumour cells.

The unclampable ascending aorta in coronary artery bypass patients: A surgical challenge of increasing frequency.

BACKGROUND: The unclampable ascending aorta (UAA) is a condition increasingly encountered during CABG procedures. We report our experience with CABG patients with UAA and place particular emphasis on the preoperative diagnosis and surgical management. METHODS AND RESULTS: UAA was diagnosed in 211 of 4812 consecutive CABG patients (4.3%). On the basis of the chest radiograph, echocardiogram, and coronary angiograph, a preoperative diagnosis was achieved in only 58 patients (27.4%). An age of >70 years, diabetes, smoking, unstable angina, diffuse coronaropathy, and peripheral vasculopathy were all predictors of UAA. Patients were treated with hypothermic ventricular fibrillation (no-touch technique n=129) or beating heart revascularization (no-pump technique n=82) depending on the possibility of founding an arterial cannulation site. The overall in-hospital mortality rate was 2.8% (6 of 211) with no differences between the 2 surgical strategies. The no-touch technique was associated with a greater incidence of neurological complications (stroke and transient ischemic attack), renal insufficiency, and stay in the intensive care unit and hospital. However, at midterm follow-up, more patients of the no-pump group had ischemia recurrence. CONCLUSIONS: A preoperative diagnosis of UAA is achievable only in a minority of patients, which highlights the necessity revising the current diagnostic protocols. The use of the no-touch technique is associated with an high perioperative risk but a superior possibility of complete revascularization, whereas adoption of the no-pump strategy ensures a smoother postoperative course at the expense of an higher incidence of ischemia recurrence.

Randomized trial of fludarabine versus fludarabine and idarubicin as frontline treatment in patients with indolent or mantle-cell lymphoma.

PURPOSE: A first comparative trial of fludarabine (FLU) alone versus FLU plus idarubicin (FLU-ID) for indolent or mantle-cell lymphomas. PATIENTS AND METHODS: From September 1995 to July 1998, 199 patients aged 25 to 65 years (median, 54 years) with newly diagnosed stages II to IV indolent or mantle-cell lymphomas (standard risk according to the International Prognostic Index) were enrolled onto a multicenter, 1:1 randomized study. Of the 199 patients who were able to be assessed, 101 were assigned to the FLU group (six monthly cycles of FLU 25 mg/m(2)/d on days 1 through 5) and 98 to the FLU-ID group (six monthly cycles of FLU 25 mg/m(2)/d on days 1 through 3 and idarubicin 12 mg/m(2) on day 1). RESULTS: In the FLU group, complete response (CR) and partial response rates were 47% and 37%, respectively, whereas in the FLU-ID group, they were 39% and 42%, respectively. In-depth analysis of the CR rate with respect to histologic type showed that FLU seemed to be superior to FLU-ID in treating follicular lymphomas (60% v 40%, respectively), whereas FLU-ID seemed to be more effective than FLU in treating nonfollicular lymphomas (small lymphocytic, 43% v 29%, respectively; immunocytoma, 38% v 23%, respectively; P = not significant), excluding the mantle-cell subset (in which there was no difference between the two groups). No striking differences were observed between the two protocols in terms of overall response or toxicity, which was generally mild. However, with a median follow-up of 19 months, only 29 patients (62%) who received FLU alone have maintained their initial CR, compared with 32 (84%) of those who received FLU-ID therapy (P =.021). CONCLUSION: Although the FLU-ID regimen may not significantly improve the induction of CR in most indolent-lymphoma patients, our preliminary data do suggest that, with respect to FLU alone, it may be capable of conferring a longer-lasting CR and that it might be superior in terms of CR rate in small lymphocytic and immunocytoma subtypes.

Marked elevation of myocardial trace elements in idiopathic dilated cardiomyopathy compared with secondary cardiac dysfunction.

OBJECTIVES: We sought to investigate the possible pathogenetic role of myocardial trace elements (TE) in patients with various forms of cardiac failure. BACKGROUND: Both myocardial TE accumulation and deficiency have been associated with the development of heart failure indistinguishable from an idiopathic dilated cardiomyopathy. METHODS: Myocardial and muscular content of 32 TE has been assessed in biopsy samples of 13 patients (pts) with clinical, hemodynamic and histologic diagnosis of idiopathic dilated cardiomyopathy (IDCM), all without past or current exposure to TE. One muscular and one left ventricular (LV) endomyocardial specimen from each patient, drawn with metal contamination-free technique, were analyzed by neutron activation analysis and compared with 1) similar surgical samples from patients with valvular (12 pts) and ischemic (13 pts) heart disease comparable for age and degree of LV dysfunction; 2) papillary and skeletal muscle surgical biopsies from 10 pts with mitral stenosis and normal LV function, and 3) LV endomyocardial biopsies from four normal subjects. RESULTS: A large increase (>10,000 times for mercury and antimony) of TE concentration has been observed in myocardial but not in muscular samples in all pts with IDCM. Patients with secondary cardiac dysfunction had mild increase (< or = 5 times) of myocardial TE and normal muscular TE. In particular, in pts with IDCM mean mercury concentration was 22,000 times (178,400 ng/g vs. 8 ng/g), antimony 12,000 times (19,260 ng/g vs. 1.5 ng/g), gold 11 times (26 ng/g vs. 2.3 ng/g), chromium 13 times (2,300 ng/g vs. 177 ng/g) and cobalt 4 times (86,5 ng/g vs. 20 ng/g) higher than in control subjects. CONCLUSIONS: A large, significant increase of myocardial TE is present in IDCM but not in secondary cardiac dysfunction. The increased concentration of TE in pts with IDCM may adversely affect mitochondrial activity and myocardial metabolism and worsen cellular function.

Midterm clinical and angiographic results of radial artery grafts used for myocardial revascularization.

OBJECTIVE: To evaluate the midterm angiographic results of the use of radial artery grafts for myocardial revascularization. METHODS: The first 68 consecutive surviving patients who received a radial artery graft proximally anastomosed to the aorta at our institution were studied again at 5 years (mean 59 +/- 6.5 months) of follow-up; 48 of these patients had previously undergone an early angiographic examination. The response of the radial artery to the endovascular infusion of serotonin was evaluated 1 and 5 years after the operation, and the midterm status of the radial artery graft was correlated with the degree of preoperative stenosis of the target vessel and with calcium-channel blocker therapy. RESULTS: The patency and perfect patency rates of the radial artery grafts 5 years after the operation were 91.9% and 87.0%, respectively. All radial artery grafts that were patent early after the operation remained patent at midterm follow-up, and early parietal irregularities in 7 patients were seen to have disappeared after 5 years. The early propensity toward graft spasm after serotonin challenge was markedly decreased at midterm follow-up. The continued use of calcium-channel antagonists after the first postoperative year did not influence the radial artery graft status, whereas the preoperative severity of the target-vessel stenosis markedly influenced the angiographic results. CONCLUSIONS: The midterm angiographic results of radial artery grafts used for myocardial revascularization are excellent. The correct surgical indication is essential. Continued therapy with calcium-channel antagonists after the first year does not influence the midterm angiographic results.

Individualized surgical strategy for the reduction of stroke risk in patients undergoing coronary artery bypass grafting.

BACKGROUND: This study was designed to evaluate the efficacy of a protocol of systematic screening of the ascending aorta and internal carotid arteries and individualization of the surgical strategy to the ascending aorta and internal carotid arteries status in reducing the stroke incidence among patients undergoing coronary artery bypass grafting. METHODS: On the basis of a pre- and intraoperative screening of the ascending aorta and internal carotid arteries, 2,326 consecutive patients undergoing coronary artery bypass grafting were divided in low, moderate, and high neurologic risk groups. In the high-risk group dedicated surgical techniques were always adopted and the reduction of the neurologic risk was considered more important than the achievement of total revascularization. RESULTS: The incidence of perioperative stroke in the high-risk group was similar to those of the other two groups (1.1 versus 1.3 and 1.1%, respectively; p = not significant); however, angina recurrence was significantly more frequent in the high-risk group. CONCLUSIONS: The described strategy allows a low rate of perioperative stroke in high-risk patients undergoing coronary artery bypass grafting. Whether the reduction of the neurologic risk outweighs the benefits of complete revascularization remains to be determined.

Should severe monolateral asymptomatic carotid artery stenosis be treated at the time of coronary artery bypass operation?

OBJECTIVE: The optimal treatment of severe monolateral asymptomatic carotid artery stenosis (SMACS) in patients undergoing coronary artery bypass grafting (CABG) is still controversial. MATERIALS AND METHODS: This study is based on the in-hospital and mid-term (>5 years) clinical results of a cohort of 139 consecutive CABG patients with SMACS operated at our Institution between January 1989 and December 1995. In the first 73 patients (no carotid surgery group), the SMACS was left untouched at the time of coronary surgery, whereas in the remaining 66 (carotid endoarterectomy group), the carotid stenosis was treated either immediately before or concomitantly with the CABG procedure (depending on the severity of the anginal symptoms). RESULTS: The overall preoperative characteristics of the patients were comparable. The in-hospital results were similar between the two groups with regard to mortality, stroke and major postoperative complications. However, at mid-term follow-up, significantly more patients of the no carotid surgery group suffered cerebral events (transient or permanent) ipsilateral to the SMACS or the lesion had to be operated on. CONCLUSIONS: The concomitant treatment (either staged or simultaneous) of SMACS at the time of CABG does not influence the in-hospital results, but confers significant neurological protection during the years after the operation.

Efficacy and tolerability of bendamustine, bortezomib and dexamethasone in patients with relapsed-refractory multiple myeloma: a phase II study.

Bendamustine demonstrated synergistic efficacy with bortezomib against multiple myeloma (MM) cells in vitro and seems an effective treatment for relapsed-refractory MM (rrMM). This phase II study evaluated bendamustine plus bortezomib and dexamethasone (BVD) administered over six 28-day cycles and then every 56 days for six further cycles in patients with rrMM treated with 4 prior therapies and not refractory to bortezomib. The primary study end point was the overall response rate after four cycles. In total, 75 patients were enrolled, of median age 68 years. All patients had received targeted agents, 83% had 1-2 prior therapies and 33% were refractory to the last treatment. The response ratepartial response (PR) was 71.5% (16% complete response, 18.5% very good PR, 37% partial remission). At 12 months of follow-up, median time-to-progression (TTP) was 16.5 months and 1-year overall survival was 78%. According to Cox regression analysis, only prior therapy with bortezomib plus lenalidomide significantly reduced TTP (9 vs 17 months; hazard ratio=4.5; P=0.005). The main severe side effects were thrombocytopenia (30.5%), neutropenia (18.5%), infections (12%), neuropathy (8%) and gastrointestinal and cardiovascular events (both 6.5%). The BVD regimen is feasible, effective and well-tolerated in difficult-to-treat patients with rrMM.

The hydrophobic TraM protein of pKM101 is required for conjugal transfer and sensitivity to donor-specific bacteriophage.

pKM101 is a self-transmissible plasmid of the IncN incompatibility group. Analysis of the DNA sequences of the genes required for conjugal transfer suggested the existence of a previously uncharacterized open reading frame, designated traM, that might be required for conjugation. Merodiploid strains containing transposon insertion mutations either in traM or in neighboring tra genes were used to demonstrate that traM constitutes a new complementation group essential for conjugation and donor phage sensitivity. The hydrophobicity profile of TraM suggests that it contains a signal sequence. The remainder of TraM is also composed predominantly of hydrophobic amino acids but contains one possible surface exposed loop. TraM-alkaline phosphatase and TraM-beta-galactosidase fusion proteins supported the hypothesis that TraM has a small cytoplasmic loop. We were unable to detect heterologous complementation between any tra mutation and its homolog from the virB operon of Agrobacterium tumefaciens.

Integrated approach for revascularization in multivessel coronary artery disease and porcelain aorta.

We report two cases in which combined beating heart revascularization of the left anterior descending artery (LAD) and percutaneous angioplasty of the non-LAD target arteries were adopted after the intraoperative detection of porcelain aorta and impossibility to complete surgical revascularization. This type of strategy preserves the benefits of surgical LAD grafting and complete revascularization and results in a simple and low-risk technical procedure in an otherwise challenging setting.

Breast cancer in patients with residual invasive carcinoma is more accurately staged with additive tumor size assessment.

BACKGROUND: Accurate assessment of tumor size for patients with breast cancer undergoing re-excision following breast-conserving therapy is important for appropriate staging and adjuvant treatment. We investigated the accuracy of additive vs. nonadditive size assessment in determining final tumor stage. METHODS: Patients with infiltrating carcinoma in the initial excision and in at least one additional re-excision (re-excision positive; n = 89) had tumor size assessed with additive and nonadditive techniques. This group was compared with patients undergoing re-excision but without identifiable residual carcinoma (re-excision negative; n = 105) regarding rates of lymph node (LN) metastasis. RESULTS: The re-excision positive patients had a different median final tumor size depending on the size assessment technique used (nonadditive: 1.8 cm; additive: 3.0 cm; P <.0001). Both groups of patients had a median tumor size consistent with T1c staging in nonadditive size assessment. However, re-excision positive patients had a significantly higher incidence of LN metastasis (P <.05) than did re-excision negative patients. Both groups were then separated into T1 and T2 stages and the LN metastasis rates were assessed. Compared with nonadditive size assessment, additive size assessment distributed re-excision positive patients into T stages whereby the LN metastasis rates more closely approximated those of re-excision negative patients (T1, 3% vs. 6% difference; T2, 4% vs. 13% difference). CONCLUSIONS: With regard to LN metastasis, staging for patients with residual invasive carcinoma in re-excision specimens is more accurate with additive tumor size assessment.

Factors associated with residual breast cancer after re-excision for close or positive margins.

BACKGROUND: Successful breast conservation surgery (BCS) requires complete tumor excision. Margin status of the initial specimen determines the need for additional surgery. We explored factors associated with residual cancer (RC) upon follow-up surgery in patients with close, positive, or undetermined margins following BCS. METHODS: A retrospective analysis of 276 patients with initial close, positive, or undetermined margins who underwent re-excision (RE) or mastectomy was conducted. All initial excisions were intended as definitive procedures. Chi-square analysis was used to identify factors that may predict RC. RESULTS: Of 276 patients, 87 had close, 168 had positive, and 21 had undetermined margins on initial excision. Of this group, 63% (175/276) had RC upon RE or mastectomy. Of positive-margin patients, 68% had RC, compared with 53% of close-margin and 67% of undetermined-margin patients (P = .006). Tumors >/=2 cm were more often associated with RC than smaller tumors (70.8% vs. 56.5%; P = .07). This association was strongest in positive-margin patients (P = .04). High tumor grade was associated with RC in all groups. RC linearly increased with the number of involved margins (P = .02). Specimen inking with multiple colors was associated with decreased risk of RC (P = .004). CONCLUSIONS: Over half of patients with involved or undetermined margins had RC upon RE or mastectomy. Positive and undetermined margins were more often associated with RC than close margins. Larger tumor size was associated with RC in patients with positive. Increasing tumor grade suggests a greater chance of detecting RC in all groups. Multiple involved margins led to a greater risk of RC.

Efficacy of fludarabine and mitoxantrone (FN) combination regimen in untreated indolent non-Hodgkin's lymphomas.

PURPOSE: In the last years, fludarabine (FLU) alone or in combination with other drugs has been reported to be effective in the treatment of previously treated low-grade non-Hodgkin's lymphomas (LG-NHL). The aim of this study was to define the therapeutic efficacy and toxicity of a combination of FLU and mitoxantrone (FN regimen) in untreated LG-NHL. PATIENTS AND METHODS: We used a two-drug combination of FLU (25 mg/m2 i.v. on days 1 to 3) and mitoxantrone (10 mg/m2 i.v. on day 1) to treat 27 previously untreated patients with LG-NHL, Chemotherapy was repeated every four weeks for a total of six cycles. Among 27 patients, 17 (63%) were diagnosed with follicular, 6 (22%) with small lymphocytic, and 4 (15%) with immunocytoma subtypes. RESULTS: Of the 27 patients, 18 (67%) achieved complete response (CR) and 6 (22%) partial response, while the remaining 3 (11%) showed no benefit from the treatment. Regarding histology, in the follicular subtype we observed an overall response rate of 94%, with a 76.5% CR rate. The estimated two-year relapse-free survival was 83%, and overall survival was 92%. Hematologic grade 3-4 toxicity was seen in only five (3.3%) patients; no opportunistic infections or deaths were associated with the administration of the FN regimen. CONCLUSIONS: These preliminary data show that the FN regimen is a very active, well-tolerated combination chemotherapy for untreated patients with advanced LG-NHL.

Long-term follow-up of hairy cell leukemia patients treated with 2-chlorodeoxyadenosine.

BACKGROUND AND OBJECTIVES: The management of patients with hairy cell leukemia (HCL) has evolved significantly over the past two decades. In fact, both 2'-deoxycoformycin (DCF) and 2-chlorodeoxyadenosine (2-CdA) induce complete response (CR) in the majority of the patients with HCL. However, fewer data exist on the long-term follow-up of patients who have undergone the characteristically brief exposure to 2-CdA therapy. Thus, it is important to evaluate such long-term outcome data in order to increase understanding of the efficacy of this agent in the management of HCL. DESIGN AND METHODS: We reviewed the long-term follow-up data of 23 HCL patients pretreated with a-interferon and then treated with 2-CdA administered as a single continuous IV infusion for 7 days at the dose of 0.1 mg/kg/day in our institute between January 1991 and February 1992. RESULTS: Of 23 patients, 19 (83%) achieved a CR and 4 (17%) a partial response (PR), with an overall response rate of 100%. After a median follow-up of 102 months (range: 96-108), there have been 9 (39%) relapses. In the PR subset 100% of patients relapsed within the first 45 months of follow-up. In the group of patients who obtained a CR, 26% relapsed; all these relapses occurred between 54 and 86 months. Overall, the median time to relapse was 54 months (range: 16-86). All relapsed patients were re-treated with 2-CdA at the dose of 0.15 mg/kg/day for 5 days in a 2-hour infusion, and 67% and 22% then obtained CR or PR, respectively. The median duration of this second response was 48 months (range: 22-80). All but one of these patients are still maintaining the second response to 2-CdA. The 9-year overall and the relapse-free survivals are 91% and 70%, respectively. INTERPRETATION AND CONCLUSIONS: In HCL patients a single dose of 2-CdA induces a long-term CR with a 9-year survival > 90%. Over 50% of patients appear to be clinically cured by this procedure, but the lack of a long-term plateau in the relapse-free survival curve means caution on this point is still warranted.