Olfactory Heterogeneity in LRRK2 Related Parkinsonism

LRRK2 mutations can cause familial and sporadic Parkinson`s disease (PD) with Lewy-body pathology at post-mortem. Studies of olfaction in LRRK2 are sparse and incongruent. We applied a previously validated translation of the 16 item smell identification test from Sniffin` Sticks (SS-16) to 14 parkinsonian carriers of heterozygous G2019S LRRK2 mutation and compared with 106 PD patients and 118 healthy controls. The mean SS-16 score in LRRK2 was higher than in PD (p < 0.001, 95% CI for beta = -4.7 to -1.7) and lower than in controls (p = 0.007, 95% CI for beta = +0.6 to +3.6). In the LRRK2 group, subjects with low scores had significantly more dyskinesia. They also had younger age of onset, longer disease duration, and reported less frequently a family history of PD, but none of these other differences reached significance. Odor identification is diminished in LRRK2 parkinsonism but not to the same extent as in idiopathic PD. (C) 2010 Movement Disorder Society

Loss of heterozygosity of the APC gene in oral squamous cell carcinoma

The aim of this study was to investigate loss of heterozygosity (LOH) of the APC tumor suppressor gene loci, using restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) in 40 cases of oral squamous cell carcinoma (OSCC). Observed informativity was 72.5% for APC exon 11 and 82.5% for APC exon 15. LOH at APC exon 11 was observed in 2 (6.9%) of 29 informative cases, and no LOH was observed for APC exon 15. Our results suggest that inactivation of the APC gene plays a minor role in the carcinogenesis of OSCC. (C) 2008 Elsevier GmbH. All rights reserved.

Relationship between the appearance of tongue carcinoma on intraoral ultrasonography and neck metastasis

To evaluate the usefulness of intraoral ultrasonography (IOUS) as a tool for predicting neck metastasis. Squamous cell carcinoma (SCC) of the tongue is aggressive and has a great propensity to metastasize to cervical lymph nodes. SCC of the oral cavity has a worse prognosis when associated with metastatic cervical nodes. Therefore, the metastatic potential of tongue carcinoma should be graded preoperatively to help determine the requirement for neck dissection. Nineteen patients (11 men, 8 women) between 36 and 79 years of age (mean age 60) with T1 to T4a TNM-stage tongue carcinomas were evaluated preoperatively with IOUS. Clinical and pathological TNM classifications were performed. The average tumor thicknesses measured using histological sections were significantly (p < 0.01) lower than those with IOUS (1.3 vs. 1.6 cm, respectively). A significant correlation was observed between the tumor thickness measured using ultrasonography and that measured using histological sections (pathology). Based on this greater accuracy, the cutoff point of tumor thickness based on IOUS evaluation for predicting neck metastasis was determined to be 1.8 cm. Some factors may influence neck metastasis. A knowledge of these would help to avoid unnecessary surgical intervention for N0 patients. The results of this study indicates that there is a significant correlation between neck metastasis and tumor thickness. Intraoral ultrasonography is useful tool for identifying tongue tumors and measuring their thickness, with the thickness measured by IOUS showing a very good correlation with histological measurements. Moreover, IOUS provides prognostic information prior to surgical treatment since tumor thickness can predict the chance of recognizing metastatic cervical nodes.

In situ hybridization detection of homeobox genes reveals distinct expression patterns in oral squamous cell carcinomas

Aims: To analyse the expression of three homeobox genes (HOXA7, PITX1 and PRRX1) in oral squanous cell carcinomas (OSCC) and the relationship of such expression to certain distinct histopathological features of OSCC and in comparison to adjacent non-neoplastic epithelium (NT). Methods and results: Digoxigenin-labelled riboprobes that are specific for each homeobox gene were generated and in situ hybridization was carried out on frozen sections. In NT samples, HOXA7 and PITX1 transcripts were found more frequently in all epithelial layers, while PRRX1 was expressed in the basal layer. With OSCC samples, expression of the three genes was associated with all histological features. However, the HOXA7 and PITX1 signals were more intense in sheets and nests and PRRX1 in small nests and isolated cells. Conclusion: HOXA7, PIXT1 and PRRX1 homeobox genes have different patterns of expression in OSCC depending on its histological features.

Two-stage laparoscopic liver resection for bilateral colorectal liver metastasis

Hepatectomy may prolong the survival of colorectal cancer patients with liver metastases. Two-stage liver surgery is a valid option for the treatment of bilobar colorectal liver metastasis. This video demonstrates technical aspects of a two-stage pure laparoscopic hepatectomy for bilateral liver metastasis. To the authors` knowledge, this is the first description of a two-stage laparoscopic liver resection in the English literature. A 54-year-old man with right colon cancer and synchronous bilobar colorectal liver metastasis underwent laparoscopic right colon resection followed by oxaliplatin-based chemotherapy. The patient then was referred for surgical treatment of liver metastasis. Liver volumetry showed a small left liver remnant. Surgical planning was for a totally laparoscopic two-stage liver resection. The first stage involved laparoscopic resection of segment 3 and ligature of the right portal vein. The postoperative pathology showed high-grade liver steatosis. After 4 weeks, the left liver had regenerated, and volumetry of left liver was 43%. The second stage involved laparoscopic right hepatectomy using the intrahepatic Glissonian approach. Intrahepatic access to the main right Glissonian pedicle was achieved with two small incisions, and an endoscopic vascular stapling device was inserted between these incisions and fired. The line of liver transection was marked following the ischemic area. Liver transection was accomplished with the Harmonic scalpel and an endoscopic stapling device. The specimen was extracted through a suprapubic incision. The falciform ligament was fixed to maintain the left liver in its original anatomic position, avoiding hepatic vein kinking and outflow syndrome. The operative time was 90 min for stage 1 and 240 min for stage 2 of the procedure. The recoveries after the first and second operations were uneventful, and the patient was discharged on postoperative days 2 and 7, respectively. Two-stage liver resections can be performed safely using laparoscopy. The intrahepatic Glissonian approach is a useful tool for pedicle control of the right liver, especially after previous dissection of the hilar plate.

Multifocal Renal Allograft Biopsy: Impact on Therapeutic Decisions

Objective. There are no data to support the suggestion that samples removed from one segment of the transplanted kidney are representative of the whole graft. The aim of this study was to compare the histological differences between biopsies obtained from different portions of the renal allograft and their impact on treatment recommendations. Patients and Methods. Two hundred percutaneous biopsies were performed on kidney allografts and samples were collected from the upper and lower poles (100 kidneys). All samples were randomized and blindly reviewed. We obtained the discordance rates between the poles for the grading of acute rejection and for the diagnosis of nephrotoxicity due to immunosuppression. We also checked if the differences found were sufficient to call for different clinical recommendations. These values were compared with the intrapathologist variation rates. Results. In 70 kidneys adequate sampling was obtained from both poles. The diagnosis of acute rejection were made in 1.7. The discordance rate between the upper and lower poles was 82.3% (kappa = 0.34), higher than the intrapathologist variation (P =.002). Nephrotoxicity was found in 14 kidneys. The discordance rate between the upper and lower poles was 28.6% (kappa = 0.88), with no difference compared with the intrapathologist variation. In 14 of the 70 kidneys (25.7%), discordances between poles had impact on clinical recommendations, most of these cases due to different gradings of acute rejection (78%). This number was higher than the intrapathologist variation (P =.04). Conclusions. The histopathological changes in the kidney allograft are not always homogeneous. This heterogeneity may affect the therapeutic recommendations.

Hyrax appliance opening and pattern of skeletal maxillary expansion after surgically assisted rapid palatal expansion: a computed tomography evaluation

Objective. The objective of this study was to evaluate, using computed tomography, correlations between Hyrax appliance opening and post-SARPE skeletal changes. Study design. Fifteen patients underwent SARPE according to a specific protocol and were followed. Linear and angular measurements of the anterior, intermediate, and posterior portions of the maxilla were evaluated. The correlation between maxillary expansion and appliance opening was investigated. Results. Significant overall expansion was observed. In the anterior and intermediate portions of the maxilla, the increase in maxillary width was greater than that observed in the posterior portion. The degree of appliance opening was significantly greater than that of the skeletal expansion. Also, no linear correlation between appliance opening and regional maxillary expansion was established. Conclusion. The transverse expansion of the maxilla was less than uniform. The lack of linear correlation between appliance opening and skeletal expansion is attributable to multiple factors, including those related to the device, the surgical technique, and the craniofacial deformity itself. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008; 106: 812-819)

Effects of Chronic Exposure to Air Pollution from Sao Paulo City on Coronary of Swiss Mice, from Birth to Adulthood

To explore the hypothesis that air pollution promotes cardiovascular changes, Swiss mice were continuously exposed, since birth, in two open-top chambers (filtered and nonfiltered for airborne particles <= 0.3 mu m) placed 20 m from a street with heavy traffic in downtown Sao Paulo, twenty-four hours per day for four months. Fine particle (PM(2.5)) concentration was determined gravimetrically; hearts were analyzed by morphometry. There was a reduction of the PM(2.5) inside the filtered chamber (filtered = 8.61 +/- 0.79 mu g/m(3), nonfiltered = 18.05 +/- 1.25 mu g/m(3), p < .001). Coronary arteries showed no evidence of luminal narrowing in the exposed group but presented higher collagen content in the adventitia of LV large-sized and RV midsized vessels (p = .001) and elastic fibers in both tunicae adventitia and intima-media of almost all sized arterioles from both ventricles (p = .03 and p = .001, respectively). We concluded that chronic exposure to urban air since birth induces mild but significant vascular structural alterations in normal individuals, presented as coronary arteriolar fibrosis and elastosis. These results might contribute to altered vascular response and ischemic events in the adulthood.

p63 Protein expression in high risk diffuse large B-cell lymphoma

Background: p63 gene is a p53 homologue that encodes proteins with transactivation, DNA-binding and tetramerisation domains. The isoforms TAp63 and TAp73 transactivate p53 target genes and induce apoptosis, whereas the isoforms Delta Np63 and Delta Np73 lack transactivation and might have dominant-negative effects in p53 family members. p63 is expressed in germinal centre lymphocytes and can be related to the development of the lymphoma, but the prognostic significance of its expression in the survival of patients with diffuse large B-cell lymphoma (DLBCL) remains unclear. Aims: To determine whether quantitative immunohistochemical (IHC) analysis of p63 protein expression correlates with CD10 antigen, Bcl-6 antigen and IRF4 antigen expression and to determine whether p63 is a surrogate predictor of overall survival in high-intermediate and high risk DLBCL populations. Methods: CD10, Bcl-6 and IRF4 expression were retrospectively evaluated by IHC in 73 samples of high intermediate and high risk DLBCL and were used to divide the lymphomas into subgroups of germinal centre B-celllike (GCB) and activate B-cell-like (ABC) DLBCL. Similarly, p63 expression was evaluated by IHC and the results were compared with subgroups of DLBCL origin and with the survival rates for these patients. Results: p63 was expressed in more than 50% of malignant cells in 11 patients and did not show correlation with subgroups of GCB-like DLBCL or ABC-like DLBCL, but p63(+) patients had better disease-free survival (DFS) than those who were negative (p = 0.01). Conclusions: p63(+) high-intermediate and high risk DLBCL patients have a better DFS than negative cases.

Biliary and pancreatic dysgenesis in mice harboring a mutation in Pkhd1

Autosomal recessive polycystic kidney disease is a hereditary fibrocystic disease that involves the kidneys and the biliary tract. Mutations in the PKHD1 gene are responsible for typical forms of autosomal recessive polycystic kidney disease. We have generated a mouse model with targeted mutation of Pkbd1 by disrupting exon 4, resulting in a mutant transcript with deletion of 66 codons and expression at similar to 30% of wild-type levels. Pkhd1(del4/d3l4) mice develop intrahepatic bile duct proliferation with progressive cyst formation and associated periportal fibrosis. In addition, these mice exhibit extrahepatic manifestations, including pancreatic cysts, splenomegaly, and common bile duct dilation. The kidneys are unaffected both histologically and functionally. Fibrocystin is expressed in the apical membranes and cilia of bile ducts and distal nephron segments but is absent from the proximal tubule. This pattern is unchanged in orthologous models of autosomal dominant polycystic kidney disease due to mutation in Pkd1 or Pkd2. Mutant fibrocystin in Pkhd1(del4/d3l4) mice also retains this expression pattern. The hypomorphic Pkhd1(del4/d3l4) mouse model provides evidence that reduced functional levels of fibrocystin are sufficient for cystogenesis and fibrosis in the liver and pancreas, but not the kidney, and supports the hypothesis of species-dependent differences in susceptibility of tissues to Pkbdl mutations.

Influence of estrogen deficiency and its treatment with alendronate and estrogen on bone density around osseointegrated implants: radiographic study in female rats

Objective. This study evaluated the influence of estrogen deficiency and its treatment on bone density around integrated implants. Study design. Implants were placed in female rat tibiae. The animals were assigned to 5 groups: control, sham, ovariectomy, estrogen, and alendronate. The control group was humanely killed to confirm integration of the implant. The others were submitted to ovariectomy or sham surgery. Bone density was measured by digital radiographs at 6 points on sides of the implant. Results. The analysis of radiographic bone density revealed estrogen privation had a negative impact only in the cancellous bone. The estrogen group differed significantly ( P <.05) from the ovariectomy and alendronate groups. The alendronate group presented the highest density for all evaluated regions. Conclusion. Ovariectomy caused a decrease in the radiographic bone density in the cancellous region. Estrogen replacement therapy and alendronate were effective treatments in preventing bone mass loss around integrated implants.

The effect of hearing impairment on the vocal characteristics of older people

Measures of vocal intensity, frequency and harshness were compared for 19 hearing-impaired and 21 normal-hearing people over 60 years of age. Significantly greater comfortable intensity levels were found in the hearing-impaired group, but the other measures of frequency and harshness were not significantly different. A large proportion of the subjects in both groups reported a history of gastro-oesophageal reflux (GER), a condition associated with vocal fold pathology and hoarseness. Comparison of the GER and non-GER subjects on the measures of vocal function showed that the female GER speaker exhibited lower frequency on the vowel /u/ than the non-GER subjects. Clinicians need to be aware of the effect of highly prevalent disorders such as hearing impairment and GER on the voices of elderly speakers.

Collagen is reduced and disrupted in human aneurysms and dissections of ascending aorta

In ascending aorta aneurysms, there is an enlargement of the whole vessel, whereas aortic dissections (ADs) are characterized by the cleavage of the wall into 2 sheets at the external half. We searched if alterations in collagen could be related to these diseases. Sections of aortas from 14 case patients with acute dissections, 10 case patients with aneurysms, and 9 control subjects were stained with picrosirius. Slides were analyzed under polarized microscopy to evaluate the structure of collagen fibers. The proportion of collagen was calculated in each half of the medial layer by color detection in a computerized image analysis system. Collagen appearance under polarized light was consistent with collagenolysis. The mean collagen proportions at the inner and outer halves, respectively, were 0.50 +/- 0.13 and 0.40 +/- 0.08 in the control group, 0.20 +/- 0.10 and 0.18 +/- 0.12 in the AD group, and 0.33 +/- 0.12 and 0.19 +/- 0.12 in the aneurysm group. The AD (P < .01) and control (P = .04) groups had less collagen at the external half, no difference was found in the aneurysm group (P = .71). In both halves, there was less collagen in the case patients than in the control subjects (all P < .01), but at the internal half, the decrease was significantly greater in the case patients with aneurysms than in those with dissections (P = .03; at the external half, P = .99). Aortic dissections and aneurysms show a decrease in collagen content that could be related to a weakness of the wall underlying the diseases, but the locations of the decrease differ: in dissections, it is situated mostly at the external portion of the media (site of cleavage), whereas in aneurysms, it is more diffuse, consistent with the global enlargement. (c) 2008 Elsevier Inc. All rights reserved.

Abnormal expression of telomerase/apoptosis limits type II alveolar epithelial cell replication in the early remodeling of usual interstitial pneumonia/idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis is a distinctive, usually fatal, type of chronic fibrosing interstitial pneumonia of unknown cause that increases in prevalence with advanced age, characterized by failure of alveolar re-epithelization and progressive scar formation. Recently, limitation of the replicative capacity of tissues determined by telomerase/apoptosis balance has been implicated in pathogenesis of age-related diseases. In this study, we validated the importance of the expression of type 2 alveolar epithelial cells telomerase protein and studied the relationships between telomerase and apoptosis in early remodeling of usual interstitial pneumonia. We determined type 2 alveolar epithelial cells density, telomerase expression, and apoptosis in surgical lung biopsies from 24 patients with usual interstitial pneumonia, and in normal lung tissues from 18 subjects. We used immunohistochemistry, deoxynucleotidyl transferase method of end labeling, electron microscopy, and histomorphometry to evaluate the amount of type 2 alveolar epithelial cells staining for surfactant-A, telomerase, and in situ detection of apoptotic cells. Unaffected areas of usual interstitial pneumonia and normal lung tissue had similar densities of type 2 alveolar epithelial cells, but a significant minor subpopulation of type 2 alveolar epithelial cells was telomerase positive and a large population was telomerase negative. A significant inverse association was found between low type 2, alveolar. epithelial cell telomerase expression and high apoptosis in unaffected areas of usual interstitial pneumonia. Although type 2 alveolar epithelial cell telomerase expression was higher than apoptosis in NLT group, no significant association was found between them. Electron microscopy confirmed epithelial apoptosis, alveolar collapse, and initial fibroplasia. We conclude that abnormal type 2 alveolar epithelial cells telomerase/apoptosis balance may reduce alveolar epithelial regenerative capacity, thus contributing to the early remodeling response in usual interstitial pneumonia. (C) 2010 Elsevier Inc. All rights reserved.

Ethanol feeding enhances inflammatory cytokine expression in lipopolysaccharide-induced hepatitis

Elevated concentrations of plasma tumour necrosis factor (TNF)-alpha, interleukin (IL)-1 and IL-6 have been detected in patients with alcoholic hepatitis and have been implicated in the pathogenesis of hepatocyte necrosis. The present study used a rat model to conduct a detailed histological and biochemical examination of the expression of various pro-inflammatory cytokines and associated liver pathology in ethanol-potentiated lipopolysaccharide (LPS)-induced liver injury. Male Wistar rats were pair-fed either the control or ethanol-containing (36% of caloric intake as ethanol) form of the Lieber-DeCarli liquid diet for 6 weeks. Liver injury was induced by the i.v. injection of LPS (1 mu g/g bodyweight), with animals being killed at O, 1, 3, 6, 12 and 24 h after injection. At the later time points, plasma transaminase and transpeptidase activities were significantly elevated in ethanol-fed LPS-treated rats compared with control-fed LPS-treated animals. At these times after LPS treatment, hepatocytes in ethanol-fed animals displayed fatty change and necrosis with an associated neutrophil polymorph infiltrate. Time course analysis revealed that plasma TNF-alpha (1-3 h post-LPS) and IL-6 (3 h post-LPS) bioactivity was significantly elevated in ethanol-fed compared with control-fed animals. No difference was seen in plasma IL-1 alpha concentration (maximal in both groups 6 h post-LPS). The expression of TNF-alpha, IL-1 alpha, IL-1 beta and IL-6 mRNA were elevated between 1 and 6 h post-LPS in the livers of both control and ethanol-fed rats. However, ethanol-fed LPS-treated animals exhibited significantly higher maximal expression of IL-1 and IL-6 mRNA. Comparison of the appearance of cytokine mRNA and plasma bioactivity indicated an effect of ethanol feeding on post-transcriptional processing and/or the kinetics of the circulating cytokines. Elevated levels of both hepatic cytokine mRNA expression and the preceding plasma cytokines are presumably a necessary prerequisite for hepatic injury seen in this model and, therefore, possibly for the damage seen in human alcoholics. Further studies using this model may lead to significant advances in our understanding of the pathogenic mechanisms of alcoholic liver disease in humans.