The SPAIR mammaplasty

The SPAIR mammaplasty is a technically straight-forward and reliable technique for managing the excessively large or ptotic breast that gives consistent and stable results over time. Advantages related to improved shapes with limited postoperative shape change should encourage the serious student of breast surgery to be familiar with the technique and concepts involved. It is recommended as an excellent option for women seeking reduction or mastopexy.     

HLA associations with HBV carriage and proteinuria

Human leucocyte antigen (HLA) associations have been reported in children with hepatitis B virus (HBV) associated membranous nephropathy (MN). In a previous study, we found an association with HLA DQB1*0603 in black children with HBVMN. To determine whether HLA DQB1*0603 predisposes to HBV carriage and development of abnormal proteinuria, we studied 70 family members of 14 children with HBVMN positive for HLA DQB1*0603. HBV was determined using third generation ELISA, slot-blot hybridisation, and nested polymerase chain reaction. HLA class I antigens were determined using a two-staged lymphocytotoxic test whereas class II antigen typing was done using sequence-specific primers. Abnormal proteinuria was defined by a protein/creatinine ratio > or =0.2. Associations of HLA DQB1*0603 with HBV carriage and abnormal proteinuria were determined using the mean probability ratio (LOD scores). Forty-seven (67%) family members were positive for HBV infection. Nineteen (27%) had abnormal range proteinuria. LOD scores in the study subjects with DQB1*0603 who were HBV negative versus those with DQB1*0603 who were HBV positive was not significant (anti-log sum =2.0559 and average 0.23). When a similar calculation was made for abnormal proteinuria, there were no significant findings (anti-log sum =3.8587 and average 0.43). This lack of association of HLA DQB1*0603 with either HBV carriage or abnormal proteinuria in family members suggests that additional factors may play a role in predisposing children to chronic HBV carriage and the development of MN. We therefore conclude that the main effect of HLA DQB1*0603 that distinguishes family members from HBVMN is the degree of proteinuria, which is a reflection of the severity of glomerular basement membrane damage in the latter.     

Cytochrome P450 3A4-mediated bioactivation of raloxifene: irreversible enzyme inhibition and thiol adduct formation

Raloxifene is a selective estrogen receptor modulator which is effective in the treatment of osteoporosis in postmenopausal women. We report herein that cytochrome P450 (P450)3A4 is inhibited by raloxifene in human liver microsomal incubations. The nature of the inhibition was irreversible and was NADPH- and preincubation time-dependent, with K(I) and k(inact) values estimated at 9.9 microM and 0.16 min(-1), respectively. The observed loss of P450 3A4 activity was attenuated partially by glutathione (GSH), implying the involvement of a reactive metabolite(s) in the inactivation process. Subsequently, GSH adducts of raloxifene were identified in incubations with human liver microsomes; substitution with GSH occurred at the 5- or 7-position of the benzothiophene moiety or at the 3'-position of the phenol ring, with the 7-glutathionyl derivative being most abundant based on LC/MS and NMR analyses. These adducts are postulated to derive from addition of GSH to raloxifene arene oxides followed by dehydration and aromatization. Alternatively, raloxifene may be oxidized to an extended quinone intermediate, which then is trapped by GSH conjugation. The bioactivation of raloxifene most likely is catalyzed by P450 3A4, since the formation of GSH adducts was almost abolished when liver microsomes were pretreated with ketoconazole or with an inhibitory anti-P450 3A4 IgG. The GSH adducts also were detected in incubations of raloxifene with rat or human hepatocytes, while the corresponding N-acetylcysteine adducts were identified in the bile and urine from rats treated orally with the drug at 5 mg/kg. Taken together, these data indicate that P450 3A4-mediated bioactivation of raloxifene in vitro is accompanied by loss of enzyme activity. The significance of these findings with respect to the clinical use of raloxifene remains to be determined.     

Expression patterns of retinoblastoma protein in Parkinson disease

Cellular mechanisms implicated in Parkinson disease (PD) include oxidative stress, inflammatory response, excess dopamine, DNA damage, and loss of trophic support. These stimuli have been observed to induce changes in cell cycle proteins in several cell types. One of the key regulators of cell cycle progression is the retinoblastoma protein (pRb); therefore, we assessed the staining for pRb and its inactive hyperphosphorylated isoform, ppRb, in autopsy tissue from patients with PD. In PD we found abundant pRb staining in neuronal cytoplasm of the substantia nigra, mid-frontal cortex, and hippocampus by immunohistochemistry. In controls, pRb weakly stained nucleoli of neurons in the substantia nigra and exhibited no detectable staining in mid-frontal cortex and hippocampus. Staining for ppRb resulted in a shift from weak cytoplasmic staining in neurons from control cases to strong nuclear staining in PD cases, especially within the substantia nigra, mid-frontal cortex, and hippocampus. In the substantia nigra, ppRb also co-localized to Lewy bodies, which are a pathologic feature of PD. Lewy bodies are also found in diffuse Lewy body disease (DLBD) that do not consistently exhibit changes in pRb or ppRb. These results indicate that there are changes in pRb and its inactive phospho-isoform in neurons responding to neurodegenerative stimuli associated with PD.     

Effect of acute iNOS inhibition on glomerular function in tubulointerstitial nephritis

BACKGROUND: Tubulointerstitial nephritis (TIN) is characterized by progressive inflammatory infiltrate of the renal interstitium, induction of cortical tubular inducible nitric oxide synthase (iNOS) and reductions in glomerular filtration rate (GFR). These studies were designed to examine the changes in glomerular hemodynamics 7 and 21 days after induction of TIN and to evaluate the effect of acute iNOS blockade on glomerular function in the early stages of this model. METHODS: TIN was induced by immunizing Brown Norway rats with renal tubular antigen in complete Freund's adjuvant (RTA/CFA). Control rats were immunized with CFA alone. Micropuncture and morphologic studies were performed 7 and 21 days after immunization. RESULTS: Histology revealed minimal peritubular and interstitial inflammation in the RTA/CFA group one week after immunization while extensive interstitial inflammation with few preserved superficial nephron was observed three weeks after RTA/CFA immunization. Micropuncture studies on day 7 in the RTA/CFA group revealed a significant reduction in single nephron GFR due to a profound reduction in nephron plasma flow and in the ultrafiltration coefficient. Studies performed on day 21 revealed that single nephron GFR (SNGFR), nephron plasma flow (SNPF) and the ultrafiltration coefficient had returned to the normal baseline value despite the severe reduction in GFR. To assess the role of increased nitric oxide production secondary to iNOS induction on the glomerular hemodynamic changes observed in the early stages of the disease, the iNOS blocker (l-N(6)-iminoethyl lysine, L-NIL) was administered IV (1 mg/h) in RTA/CFA rats and CFA rats. L-NIL had no effect in CFA rats but produced significant increases in GFR, SNGFR and SNPF in RTA/CFA rats.CONCLUSIONS: These results demonstrate that TIN is associated with a progressive reduction in GFR, which is likely the result of functional vasoconstriction and decreases in the ultrafiltration coefficient in the early stages of the disease and on a significant reduction in the number of functioning nephron in the later stages. Induction of iNOS with increased NO production actively participates in the functional changes observed in the early stages of the disease most likely by inhibiting normal endothelial NOS activity.     

Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma

A correlative study was performed to address the impact of epidermal growth factor receptor (EGFR) overexpression on survival and pattern of failure in patients with advanced head and neck squamous cell carcinomas (HNSCCs) enrolled in a Phase III trial and randomized to receive conventional radiotherapy. The study population comprised 155 of 268 (58%) randomized patients with sufficient pretreatment biopsy specimens for immunohistochemical assay. The specimens were dewaxed and incubated after standard preparation with mouse monoclonal antibodies recognizing the extracellular domain of the EGFR molecule. The catalyzed product was visualized with 3,3'-diaminobenzidine Chromogen Kit and lightly counterstained with Mayer's hematoxylin. Quantitative EGFR immunohistochemistry (IHC) was done with SAMBA 4000 Cell Image Analysis System, without knowledge of the clinical outcome, to yield mean absorbance (MOD), staining index (SI), and quick score (QS). These EGFR IHC parameters were correlated with the T stage, N stage, combined stage grouping, and recursive partitioning analysis classes. Subsequently, the EGFR parameters were correlated with the outcome end points, i.e., overall survival (OS), disease-free survival (DFS), local-regional (LR) relapse, and distant metastasis rates. We found that HNSCCs exhibited a wide variation in EGFR expression (MOD, 0.2-66.0; SI, 0.3-97.0; QS, 0.01-69.9) with a relatively strong but nonlinear correlation between MOD and SI (r = 0.79). There was no correlation between EGFR expression and T stage, N stage, stage grouping, and recursive partitioning analysis classes (r = -0.07 to 0.17). The OS and DFS rates of patients with high EGFR-expressing HNSCCs (>median MOD) were highly significantly lower (P = 0.0006 and P = 0.0016, respectively) and the LR relapse rate was highly significantly higher (P = 0.0031) compared with those of patients with low EGFR-expressing HNSCCs. However, there was no difference in the distant metastasis rate between the two groups (P = 0.96). Significant correlations, although somewhat less robust than MOD, were also observed between SI and QS and the OS, DFS, and LR relapse rates. Multivariate analysis showed that EGFR expression was an independent determinant of survival and a robust independent predictor of LR relapse. In summary, this correlative study in a large series of patients revealed that EGFR expression, which varied considerably among HNSCCs, was a strong independent prognostic indicator for OS and DFS and a robust predictor for LR relapse but not for distant metastasis. The data suggest that EGFR IHC should be considered for selecting patients for more aggressive combined therapies or enrollment into trials targeting EGFR signaling pathways.     

Issues and barriers to development of clinically useful tumor markers: a development pathway proposal

There are few tumor markers that are clinically useful in predicting therapeutic responses or patient outcomes despite nearly 20 years of advances in molecular biology. We discuss a variety of issues and barriers that have affected movement of clinical tests from research into clinical practice. Studies of new markers frequently lack clear hypotheses and are generally underpowered to reach statistically valid conclusions. Relevant clinical endpoints may not be possible to evaluate, often leading to suboptimal study designs. Major stumbling blocks exist because studies are rarely comparable. This makes it difficult to determine why results vary from study to study. It also prevents pooling of small datasets for analysis. We propose a tumor marker development pathway that we think will be more efficient and effective. The pathway depends on developing statistically valid study designs, focusing on assay refinement and standardization early in the process, including assay details in publications, and providing data in a format that allows comparison with other studies. The process described should be applicable to development of new technologies that include analysis and interpretation of large, complex datasets. The proposed marker development pathway will require thoughtful refinement and expansion, but it should begin a productive dialog.     

Correlates of human handedness in primary motor cortex: a review and hypothesis

A review of the research on anatomical and functional asymmetries in human primary motor cortex suggests that the area of hand representation is greater in the dominant than in the non-dominant hemisphere and that there is a greater dispersion of elementary movement representations with more profuse horizontal connections between them. The more profuse interconnections in motor cortex (M1) of the dominant hemisphere might form a neural substrate which favors the formation of experience-dependent excitatory and inhibitory interactions between elementary movement representations. Motor practice might lead to more precise spatiotemporal coordination of the activity of the elementary movement representations in M1 of the dominant than that of the non-dominant hemisphere, thus leading to more dexterous behavior of the dominant than that of the non-dominant hand.     

Population growth and collapse in a multiagent model of the Kayenta Anasazi in Long House Valley

Long House Valley in the Black Mesa area of northeastern Arizona (U.S.) was inhabited by the Kayenta Anasazi from about 1800 before Christ to about anno Domini 1300. These people were prehistoric ancestors of the modern Pueblo cultures of the Colorado Plateau. Paleoenvironmental research based on alluvial geomorphology, palynology, and dendroclimatology permits accurate quantitative reconstruction of annual fluctuations in potential agricultural production (kg of maize per hectare). The archaeological record of Anasazi farming groups from anno Domini 200-1300 provides information on a millennium of sociocultural stasis, variability, change, and adaptation. We report on a multiagent computational model of this society that closely reproduces the main features of its actual history, including population ebb and flow, changing spatial settlement patterns, and eventual rapid decline. The agents in the model are monoagriculturalists, who decide both where to situate their fields as well as the location of their settlements. Nutritional needs constrain fertility. Agent heterogeneity, difficult to model mathematically, is demonstrated to be crucial to the high fidelity of the model.     

Evaluation of a self-management programme for congestive heart failure patients: design of a randomised controlled trial

Background  

Congestive heart failure (CHF) has a substantial impact on care utilisation and quality of life. It is crucial for patients to cope with CHF adequately, if they are to live an acceptable life. Self-management may play an important role in this regard. Previous studies have shown the effectiveness of the 'Chronic Disease Self-Management Program' (CDSMP), a group-based cognitive behavioural programme for patients with various chronic conditions. However, the programme's effectiveness has not yet been studied specifically among CHF patients. This paper presents the design of a randomised controlled trial to evaluate the effects of the CDSMP on psychosocial attributes, health behaviour, quality of life, and health care utilisation of CHF patients.