Cerebral superb microvascular imaging in preterm neonates: in vivo evaluation of thalamic, striatal, and extrastriatal angioarchitecture.

PURPOSE: To explore the potential of superb microvascular imaging (SMI) in visualizing brain microvessels in preterm neonates of different gestational ages (GA). METHODS: In this retrospective, observational pilot study, 15 preterm newborns were equally divided into GA groups: extremely (GA < 28 weeks), very (28-31 weeks), and moderate to late (32-37 weeks) preterm. All patients underwent conventional transcranial ultrasounds during the first day of life following the American Institute of Ultrasound in Medicine practice guidelines. SMI was then performed; based on their SMI morphology and location, brain microvessels were classified as extrastriatal (cortical and medullary), striatal, or thalamic. Two examiners independently classified vessels as visible or invisible. To assess the association between vessel visibility and GA, binomial logistic regression analysis (separate for each microvessel group) was performed, taking visibility as a dependent variable and both examiners and GA as predictor variables. RESULTS: A statistically significant difference among GA groups was found in sex (P = 0.030), birth weight (P = 0.007), and Apgar score within 1 min after birth (P = 0.024). Microvascular visibility increased with GA for superficial vessels (P < 0.05 for both cortical and medullary), while striatal and thalamic vessels were visible in all neonates irrespective of their GA. CONCLUSIONS: SMI technology shows promise to assess brain microvasculature in preterm neonates, even potentially providing data on early brain development.

The Horton-Rogers-Lapwood problem for an inclined porous layer with permeable boundaries.

A formulation of the Horton-Rogers-Lapwood problem for a porous layer inclined with respect to the horizontal and characterized by permeable (isobaric) boundary conditions is presented. This formulation allows one to recover the results reported in the literature for the limiting cases of horizontal and vertical layer. It is shown that a threshold inclination angle exists which yields an upper bound to a parametric domain where the critical wavenumber is zero. Within this domain, the critical Darcy-Rayleigh number can be determined analytically. The stability analysis is performed for linear perturbations. The solution is found numerically, for the inclination angles above the threshold, by employing a Runge-Kutta method coupled with the shooting method.

From chronic overfeeding to hepatic injury: role of endoplasmic reticulum stress and inflammation.

We analyse how chronic overfeeding, by increasing circulating fatty acids, might lead to inflammation, insulin resistance (IR) and injury in the liver. Chronic overfeeding causes an increase in adipose tissue depots and is characterised by an increased presence of hypertrophic adipocytes when adipose tissue expandability is inadequate. Adipocyte hypertrophy is a possible stress condition for the endoplasmic reticulum (ER), which will activate inflammatory and apoptotic pathways and cause IR in adipose tissue. Insulin-resistant adipocytes, being more lipolytic and less liposynthetic, induce an increase in circulating free fatty acids. Moreover, the strongly compromised secretion/function of the adipocyte hormones, adiponectin and leptin, decreases lipid oxidation, particularly in the liver, causing lipid accumulation, ER stress and IR in hepatocytes. ER stress may lead to reduced very-low-density lipoprotein (VLDL) secretion and increased lipogenic gene expression despite the presence of IR. These events and reduced lipid oxidation may lead to further hepatic lipid accumulation. When the triglyceride storage capacity of hepatocytes is exceeded, hepatic injury may occur. ER-stressed steatotic hepatocytes activate apoptotic and inflammatory pathways, which trigger IR and the release of chemokines and cytokines, and these, in turn, elicit an increased influx of Kupffer cells (KCs) and hepatic stellate cells (HSCs) around dying hepatocytes. Soluble mediators, secreted mainly by ER-stressed steatotic hepatocytes and activated KCs, induce the transdifferentiation of HSCs to myofibroblasts, which secrete fibrogenic cytokines and matrix components that trigger fibrosis. In conclusion, chronic lipid overloading due to inadequate fat-storing capacity of adipose tissue can induce hepatic injury when triglyceride storage capacity of hepatocytes is exceeded.

From chronic overnutrition to insulin resistance: the role of fat-storing capacity and inflammation.

AIMS: We analyze how the inflammatory state in adipose tissue caused by a condition of chronically positive energy balance can lead to insulin resistance first in adipose tissue, then in all insulin-sensitive tissues. DATA SYNTHESIS: Chronic nutrient overload causes an increase in adipose depots that, if adipose tissue expandability is low, are characterized by an increased presence of hypertrophic adipocytes. This adipocyte hypertrophy is a possible stress condition for the endoplasmic reticulum (ER) that would lead to a proinflammatory state in adipose tissue. In this condition, ER stress would activate metabolic pathways that trigger insulin resistance, release of macrophage chemoattractant proteins, and in chronic inflammation, the death of the hypertrophic adipocyte. The infiltrated macrophages in turn release inflammatory proteins causing further recruitment of macrophages to adipose tissue and the release of inflammatory cytokines. Following these events, insulin resistance becomes extended to all adipose tissue. Insulin-resistant adipocytes, characterized by low liposynthetic capacity and high lipolytic capacity, cause increased release of free fatty acids (FFA). FFA released by lipolitic adipocytes may also activate Toll-like receptors 4 and then chemokines and cytokines release amplifying insulin resistance, lipolysis and inflammation in all adipose tissue. Moreover, increased circulating FFA levels, reduced circulating adiponectin levels and leptin resistance lead to decreased lipid oxidation in non-adipose tissues, thereby triggering ectopic accumulation of lipids, lipotoxicity and insulin resistance. CONCLUSION: All the conditions that increase circulating fatty acids and cause lipid overloading (obesity, lipoatrophy, lipodystrophy, catabolic states, etc.) induce a lipotoxic state in non-adipose tissues that gives rise to insulin resistance.

De novo autoimmune hepatitis following liver transplantation: a case report.

De novo autoimmune hepatitis (AIH), a rare disorder first described in 1998, appears in patients with liver transplants due to autoimmune and nonautoimmune etiologies. De novo AIH occurs in 2.5% to 3.4% of allografts; children seem to have a predilection for this syndrome. We have present herein a case of a liver allograft recipient who developed chronic hepatitis associated with autoimmune features outlining the clinical course, liver histology, and response to treatment.

Infectious complications in the renal transplant recipient.

The aim of this study was to estimate the incidence of infectious diseases in a group of patients who underwent kidney transplantation from January 1, 2004 to September 30, 2004, including 121 operations, with 119 from cadaveric and 2 from living donors. The protocol sought herpes viruses (CMV, VZV, and EBV), hepatitis viruses, human immunodeficiency virus, T. gondii, M. tubercolosis, and T. pallidum. Therapy for CMV was used both as prophylaxis in immunoglobulin (Ig)G-negative recipients from IgG-positive donors and preemptive therapy, that is, before the appearance of clinical symptoms, but after viremia reached borderline levels. For VZV infections, the treatment started after the appearance of papulo-vesicular cutaneous eruptions and antibody positivity. The treatment for pneumonia consisted of empirical therapy after radiography; for pyelonephritis, antibiotic therapy was based on the results of kidney echography, blood culture, and urine culture. Infectious complications appeared in 25 patients (20.7%), 3 of the which were polymicrobic: 12 CMV infections, 9 VZV infections, 3 pneumoniae, 4 pyelonephritis, and 1 salmonellosis. The most frequent infection was CMV, which occurred in the first 3 months after transplantation in 9 of 12 cases. This study showed that a knowledge of infection prevalence can help the physician to establish a more specific, efficacious antimicrobial therapy, despite the laboratory response not being available in a short time.

Urologic complications in kidney transplantation.

Urologic complications in kidney transplantation have an incidence ranging from 3% to 20%, representing an important cause of organ loss. From January 2001 to September 2004, 123 renal transplantations were performed using an immunosuppressive protocol including basiliximab, mycophenolate mofetil, calcineurin inhibitors, and steroids. The surgical technique was vascular anastomoses to external iliac vessels, and ureteral anastomosis according to Lich Gregoire technique using a JJ ureteral stent. We report 5 renal complications (4.2%) and 4 extrarenal complications (3.5%), the majority of which required corrective surgery. The surgical strategy uses the clinical condition of the donor and the recipient; the anatomic anomalies of the graft, and a reduced cold ischemia time. Moreover, a reduction in acute rejection episodes and immediate renal function has been fundamental to reduce urologic complications. In fact, the main cause of urologic complications is ureteral ischemia, linked both to backtable surgery and to rejection episodes. Another important factor in the reduction of early urologic complications has been the routine use of a JJ stent, which allowed us a conservative approach in this setting.

Malignancies after kidney transplantation.

The most effective treatment of end-stage renal disease is renal transplantation; its superiority to prolong the longevity of patients is well established. Patient and graft survivals have improved with more potent immunosuppression but this advance has been associated with an increased incidence of cancer. The aim of this study was to assess the prevalence of cancer among 265 kidney transplant recipients engrafted between 1968 and October 2004. The overall prevalence of de novo malignancies was 3%. The mean age at diagnosis was 53.3 years (range, 28-63 years) and the duration of the transplant was 11.6 years (range, 0.3-33 years). One patient among 127 (0.8%) who had a history of less than 3 years under immunosuppression, developed a posttransplantation lymphoproliferative disorder (PTLD). Among the 138 patients who had more than 3 years immunosuppression, 7 (5%) developed neoplasms of vulva, colon, native kidneys, prostatic gland, and ovary. One patient was affected by de novo carcinoma in the transplanted kidney. Compared with other published studies, our early cancer prevalence is low, possibly due to a careful history before grafting, good HLA matching, and abstinence from anti-T-cell therapy for treatment of acute rejection episodes. The low level of immunosuppression may account for the low prevalence of neoplasia. The risk of developing a malignancy increases with long-term immunosuppression, comparable with most reports.

Modulation of hepatic mitochondrial energy efficiency with age.

This study was designed to examine the effect of youth-adulthood transition on hepatic mitochondrial energy efficiency. The changes in basal and palmitate-induced proton leak, which contribute to mitochondrial efficiency, were evaluated in mitochondria isolated from the liver of young and adult rats. Alterations in mitochondrial cytochrome oxidase and aconitase specific activities, and in adenine nucleotide translocator content were also assessed. There was no difference in basal proton leak or thermodynamic coupling and efficiency of oxidative phosphorylation in liver mitochondria between the two rat groups. On the other hand, palmitate-induced proton leak increased significantly in adult rats. The function of this uncoupling could be avoidance of elevated formation of reactive oxygen species, which are known to accelerate ageing.

Fat balance and serum leptin concentrations in normal, hypothyroid, and hyperthyroid rats.

OBJECTIVE: To study the influence of thyroid hormones on the relationship between serum leptin and fat mass, as well as on energy and macronutrient balance. DESIGN: Rats with different thyroid states were obtained by 7 and 15 days of treatment with the antithyroid drug propylthiouracil or with triiodothyronine (T3). MEASUREMENTS: Energy balance, macronutrient balance and serum leptin concentrations. RESULTS: In hypothyroid rats we found a decrease in metabolizable energy (ME) intake and energy expenditure together with an increase in lipid gain/lipid intake ratio and a decrease in protein gain/protein intake ratio. Consequently, body lipid percentage significantly increased compared to euthyroid rats. Hyperthyroid rats first increased energy expenditure and later ME intake, so that increased metabolism was balanced by increased intake, and energy gain was similar to that found in euthyroid rats. CONCLUSION: These results indicate that T3 plays a major role in the maintenance of energy and lipid balance. Our results also indicate that an inverse relationship exists between T3 and leptin serum concentrations, and that this relationship is not only the result of changes in body fat stores induced by changed T3 concentrations.

Effect of cold exposure on energy balance and liver respiratory capacity in post-weaning rats fed a high-fat diet.

Variations in energy balance, body composition, and nutrient partitioning induced by high-fat feeding, cold exposure or by concomitant high-fat feeding and cold exposure were studied in young Wistar rats. Changes in hepatic metabolism as well as in serum free triiodothyronine and leptin levels were also evaluated. Rats were exposed to either 24 or 4 degrees C and fed either a low- or high-fat diet (10 % or 50 % energy respectively) for 2 weeks. Relative to low-fat feeding at 24 degrees C, both energy intake and expenditure were increased by high-fat feeding or by cold exposure, and these changes were accompanied by increased serum triiodothyronine levels. In response to concomitant high-fat feeding and cold exposure, serum triiodothyronine tended to be further elevated, but no further increases in energy intake or energy expenditure were observed. Independently of diet, the increased energy expenditure in cold-exposed rats was not completely balanced by adaptive hyperphagia, with consequential reductions in protein and fat gain, accompanied by marked decreases in serum leptin. Furthermore, unlike high-fat feeding at 24 degrees C, cold exposure enhanced hepatic mitochondrial oxidative capacity both in the low-fat- and high-fat-fed groups. It is concluded that in this strain of young Wistar rats, despite similarly marked stimulation of energy expenditure by high-fat feeding at 24 degrees C, by cold exposure and by concomitant high-fat feeding and cold exposure, an increased hepatic oxidative capacity occurred only in the presence of the cold stimulus.

Effect of long-term high-fat feeding on energy balance and liver oxidative activity in rats.

The purpose of this work was to study the effect of early long-term high-fat feeding on energy balance and liver oxidative activity. To this end, rats aged about 30 d were fed a high-fat or a low-fat diet for 15, 30 or 60 d. Full energy balance and energy partitioning measurements were carried out. In addition, we measured hepatic mitochondrial and peroxisomal oxidative capacities. Serum levels of free triiodothyronine (T3) and leptin were also determined. Rats fed a high-fat diet showed an increase in metabolizable energy intake as well as in energy expenditure, while lipid gain over the whole period was lower than that expected due to a decrease in metabolic efficiency. An increase in serum free T3 levels was also found in rats fed a high-fat diet after 15 and 30 d. Statistically significant correlations between serum leptin levels and body fat mass were found after 15, 30 and 60 d of high-fat feeding. Finally, no variation in hepatic mitochondrial and peroxisomal fatty acid oxidation capacity was found in rats fed a high-fat diet for 15, 30 or 60 d. In conclusion, the results of the present study show that young Wistar rats fed a high-fat diet for up to 60 d are able to counteract, at least in part, obesity development.

Fat balance and hepatic mitochondrial function in response to fat feeding in mature rats.

OBJECTIVE: To study the effects of fat feeding on fat balance and hepatic mitochondrial function in postpubertal male rats. DESIGN: Rats were fed low fat, medium fat or high fat diet for 15 days. MEASUREMENTS: Energy balance, body composition, resting metabolic rate (RMR), mitochondrial state 3 and state 4 oxygen consumption rates, succinic dehydrogenase (EC 1.3.99.1) and mitochondrial alpha-glycerophosphate dehydrogenase (EC 1.1.1.8) activities. RESULTS: Rats fed medium fat or high fat diet, in comparison with rats fed low fat diet, showed a significantly greater metabolisable energy intake and energy expenditure. In addition, body energy and lipid gains were significantly higher in rats fed medium fat or high fat diet than in rats fed low fat diet. Mitochondrial respiration and enzymatic activities were not affected by fat feeding. CONCLUSION: These results indicate that in postpubertal rats fed high fat diets, the increase in energy expenditure counteracts only in part the excess fat deposition. This is probably due to the impairment in regulatory responses, and enhances thermogenesis.

In vitro antitumour activity and cellular pharmacological properties of the platinum-iminoether complex trans-[PtCl2[E-HN=C(OMe)Me]2].

The platinum complex trans-[PtCl2¿E-HN=C(OMe)Me¿2] was compared to cisplatin for cytotoxicity towards tumour cells, and for cellular pharmacological properties in A2780 and cisplatin-resistant A2780/Cp8 ovarian cancer cells. Trans-[PtCl2¿E-HN=C(OMe)Me¿2] was comparably cytotoxic to cisplatin (mean IC50 after 72 h exposure = 6. 1 microM and 7 microM, respectively) and did not show cross-resistance in A2780/Cp8 cells (resistance factor = 0.9). Cellular accumulation measurements after treatment with equimolar drug concentrations showed that trans-[PtCl2¿E-HN=C(OMe)Me¿2] entered both A2780 and A2780/Cp8 cells much more efficiently than cisplatin, whose accumulation was reduced in A2780/Cp8 cells. Unlike cisplatin, trans-[PtCl2¿E-HN=C(OMe)Me¿2] induced rapidly cell death and cell cycle modifications of treated cells, thus indicating substantially different mechanistic properties.

Radiation therapy alone in stage III-B cancer of the uterine cervix--a 17-year old experience in southern Brazil.

PURPOSE: External irradiation followed by intracavitary therapy (EBIC) has been considered the standard treatment for stage III-B cancer of the uterine cervix. For different reasons, some patients are not suited for intracavitary therapy (ICT), and the treatment may be given entirely by external beam irradiation alone (EBRTA). The purpose of our study is to discuss treatment results and complications for patients undergoing EBIC or EBRTA. METHODS AND MATERIALS: A retrospective study was carried out on 202 eligible patients with stage III-B cancer of the uterine cervix admitted for radiotherapy from 1980-1997. Ninety-three patients were able to receive EBIC (50 Gy, 8 MV RX whole pelvis followed by one session of 38-45 Gy ICT to point A). The remaining received EBRTA (50-70 Gy for 5-9 or more weeks). Median follow-up procedure was 18.5 months (range: 4-182) for all patients and 26 months (range 4-147) for the patients at risk. RESULTS: The most frequent reason for precluding ICT was large residual tumor volume (32.1%). Ten-year overall survival rates, relapse free survival, and pelvic failure rate for the EBIC and EBRTA patients were, respectively, 22.5% x 15.6% (p = 0.0087), 23.5% x 14.8% (p = 0.005), and 51.6% x 68.8% (p = 0.005). However, when the same comparisons were performed with EBIC patients x EBRTA patients receiving a high dose schedule (60 Gy/6-8 wk to 70 Gy/7-9 wk), the results of the EBIC group remained higher, but the differences became insignificant: respectively, 22.5% x 18.9% (p = 0.17), 23.5% x 15.3% (p = 0.052), and 51.6% x 60.0% (p = 0.10). The distribution of complications was similar in both groups. CONCLUSIONS: We found that EBIC was the best treatment modality in our patients with stage III-B cancer of the uterine cervix, whereas for patients who were not candidates for ICT, EBRTA with a high dose schedule appears to be an efficient and safe alternative.

Energy intake and utilization vary during development in rats.

Energy intake, utilization, and partitioning were determined in male Wistar rats from 25 to 180 d of age. Serum free triiodothyronine, leptin, and free fatty acid concentrations were also measured. Energy balance measurements allowed us to identify a period from 25 to 90 d, characterized by a rapid body growth rate and another from 90 to 180 d, during which body growth rate slowed. From 25 to 180 d, we found decreases in daily energy intake and expenditure, which were faster before 90 d. The first period was characterized by storage of lipid and protein. In the second period, protein deposition approached zero and the excess of ingested energy was entirely stored as fat, so that age-associated obesity began to develop. The inability of rats to maintain a stable body weight after the cessation of growth of lean body mass is not due to decreased resting metabolism but rather to a partial leptin resistance.

Metastatic site and p53 primary tumor expression in previously untreated stage IV breast cancer patients.

p53 mutations have been reported to correlate with prognosis and response to therapy in patients with different tumor types. However, although p53 status is related to the primary tumor aggressiveness, an association between its expression and specific metastatic pattern has not yet been investigated. We immunohistochemically analyzed p53 (Pab1801) and ki67 (mib1) primary tumor expression in a series of advanced breast cancer patients presenting a selected pattern of distant metastases at the time of first diagnosis. Forty-eight percent of the overall series was classified as p53 positive while 22% as mib1 positive tumors. The overall agreement between p53 and mib1 expression was statistically significant (p = 0.03). While mib1 primary tumor expression did not show any association with the type of metastasis, p53 positivity was significantly higher in patients with soft tissue metastasis than in patients with bone or viscera metastasis (p = 0.002). No association with the probability of clinical response or different overall survival was found for patients with different p53 or mib1 status either in the overall series of patients or in subgroups of cases with different sites of distant metastasis.

Oxidative activity in mitochondria isolated from rat liver at different stages of development.

The purpose of this study was to evaluate the oxidative capacities in hepatic mitochondria isolated from prepubertal, young adult and adult rats (40, 90 and 180 days of age, respectively). In these rats, mitochondrial respiratory rates using FAD- and NAD-linked substrates as well as mitochondrial protein mass were measured. The results show that only the oxidative capacity of FAD-linked pathways significantly declined in mitochondria from 180-day-old rats compared with those from younger animals. When we consider FAD-linked respiration expressed per g liver, no significant difference was found among rats of different ages because of an increased mitochondrial protein mass found in 180-day-old rats. However, when FAD-linked and lipid-dependent respiratory rates were expressed per 100 g body weight, significant decreases occurred in 180-day-old rats. Therefore, the decrease in liver weight expressed per 100 g body weight rather than an impaired hepatic cellular activity may be the cause of body energy deficit in 180-day-old rats.

Successful ablation of atrioventricular nodal reentry tachycardia in a patient with persistent left superior vena cava.

We report the case of a patient with atrioventricular nodal reentry tachycardia associated with persistent left superior vena cava draining to a large coronary sinus. Successful ablation was performed at the level of the superior lip of the coronary sinus ostium.

DNA flow cytometry, p53 levels and proliferative cell nuclear antigen in human colon dysplastic, precancerous and cancerous tissues.

BACKGROUND: The cancerogenic process of colorectal cancer depends on a series of events involving oncogenes and inactivation of suppressor genes. This study concerns changes in DNA content, p53 and PCNA expression in human colon in dysplastic, precancerous and cancerous tissues. MATERIALS AND METHODS: These characteristics were analyzed in a series of hyperplastic polyps (HP), adenomas (AD), adenocarcinomas evolved within adenomas (AC-AD) and adenocarcinomas (AC) of the large bowel. DNA ploidy was analyzed by flow cytometry and PCNA and p53 expression was evaluated by immunohistochemistry using monoclonal antibodies PC10 and PAb 1801. RESULTS: Aneuploidy was found in 43/67 (64%) of AC and only occasionally in other subgroups (AC vs all other groups: 64% vs 99%; p = 0.00002). PCNA positivity gradually increased in the sequence from HP to AC and were significantly higher in AC compared to HP (90% vs 44%; p = 0.00007). p53 positive cells were found in 67% of AC while only occasionally in other groups (HP vs AC: p = 0.0002, AD (low dysplasia) vs AC: p = 0.001; AD (moderate dysplasia) vs AC: p = 0.001). CONCLUSIONS: These results demonstrated a progressive immunoreactivity for PCNA in the HP to AC sequence, while p53 positivity and aneuploidy seemed specific for colon carcinoma.