Dandruff: a condition characterized by decreased levels of intercellular lipids in scalp stratum corneum and impaired barrier function.

Dandruff is a major problem, yet little is known about the underlying mechanism and subsequent biochemical changes occurring in the scalp skin that lead to its manifestation. The characteristic flaking and scaling of the scalp experienced by dandruff sufferers suggests, similar to the changes classically seen in xerosis, that the desquamation process is impaired. We initiated studies to quantify the biochemical nature of the stratum corneum in the scalp of healthy individuals and dandruff sufferers. Total amounts and relative ratios of stratum corneum lipids species were analysed in scalp stratum corneum samples collected during studies conducted in the UK and Thailand in order to examine ethnic differences. In both populations, dandruff was associated with a dramatic decrease in free lipid levels, with significant decreases in ceramides, fatty acids, and cholesterol. Detailed sub-analysis of the major ceramide species within the total ceramide fraction revealed a decrease in ceramide 1 and increased proportions of ceramide 6i and 6ii. In a separate study, we demonstrated that dandruff sufferers show both an elevated blood flow and an increased reported incidence of itch in response to histamine topically applied to the scalp compared with no-dandruff controls. Taken together these two studies indicate that the quality and resilience of the epidermal water barrier is impaired in the scalp of dandruff sufferers. We propose that the perturbed barrier leaves dandruff sufferers more prone to the adverse effects of microbial and fungal toxins, and environmental pollutants, thus perpetuating their impaired barrier.

A phase II trial of 6-hydroxymethylacylfulvene (MGI-114, irofulven) in patients with advanced non-small cell cancer previously treated with chemotherapy.

PURPOSE: To test the efficacy and safety of the novel antitumor agent MGI-114 (NSC 683863) in patients with advanced non-small cell lung cancer (NSCLC) previously treated with chemotherapy. METHODS: A two-stage accrual design was used to ensure detection of a true response rate of at least 20% with a type I error of .04. Eligible patients received 11 mg/m2 daily for five consecutive days. Cycles were repeated every 28 days. RESULTS: Fifteen patients received a total of 34 cycles of MGI-114. All patients had a performance status of 0 or 1. Eleven patients had previously received carboplatin and paclitaxel +/- radiation. Two patients had received cisplatin and CPT-11, one patient had received weekly paclitaxel, and one patient had received carboplatin and docetaxel. None of the first 15 patients enrolled experienced objective tumor response, and the study was closed. Forty percent of patients developed > or = grade 2 thrombocytopenia. Grade 3 nausea and > or = grade 2 vomiting were observed in 40% and 47% of patients respectively. Thirty-three percent of patients experienced > or = grade 2 fatigue. CONCLUSIONS: MGI-114, at this dose and schedule, does not have significant activity as second line therapy for patients with advanced NSCLC.

Clinical utility of PET-FDG imaging in differentiation of benign from malignant adrenal masses in lung cancer.

This study was designed to evaluate the sensitivity, specificity, and predictive accuracy of PET-FDG imaging in detecting metastatic disease involvement of adrenal glands in patients with lung cancer. We wanted to compare efficacy of positron emission tomography (PET)-fluorodeoxyglucose (FDG) imaging to computed tomography (CT) scanning in differentiating benign from malignant involvement of adrenal glands in patients with lung cancer. Thirty patients with biopsy-proven lung cancer and abnormal findings on PET and/or CT scanning were studied for presence of adrenal abnormality suggestive of metastatic disease involvement (n = 26) or benign adrenal enlargement (n = 4). The results of PET and CT scanning were compared to histological findings and/or clinical follow-up for at least 1 year for presence or absence of adrenal metastases. PET-FDG imaging correctly detected the presence of metastatic involvement in 17 of 18 patients and excluded metastatic involvement in 11 of 12 patients for sensitivity, specificity, and accuracy of 94.4%, 91.6%, and 93.3%, respectively. CT scanning showed enlarged adrenals without metastases in 8 of 30 patients and normal-sized adrenals in the presence of metastases in 5 of 30 patients. There was a false-positive PET finding in 1 patient and a false-negative PET finding in another patient. PET-FDG imaging is a highly sensitive, specific, and accurate test to differentiate benign from malignant involvement of adrenal glands in patients with lung cancer and often ambiguous findings on CT scanning.

Maximum likelihood estimation of phylogenetic trees is consistent when substitution rates vary according to the invariable sites plus gamma distribution.

Maximum likelihood estimation of phylogenetic trees from nucleotide sequences is completely consistent when nucleotide substitution is governed by the general time reversible (GTR) model with rates that vary over sites according to the invariable sites plus gamma (I + gamma) distribution.

Treatment outcome of lung cancer patients as optimized by preoperative whole-body positron emission tomography fluorodeoxyglucose imaging.

Positron emission tomography (PET) fluorodeoxyglucose (FDG) imaging may be more accurate than computed tomography (CT) scanning for staging of lung cancer disease. In the present study, we evaluate whether whole-body PET-FDG imaging can accurately stratify lung cancer patients by stage and thus predict patient outcome. Forty-one consecutive patients underwent whole-body PET and CT scanning for preoperative staging, which was then confirmed by mediastinoscopy, thoracotomy, and/or other tests revealing distant metastases. The effect of PET on patient management was determined. PET was significantly more accurate than CT for staging of lung cancer (97.6% vs. 70.7%). One-year follow-up for survival rate and treatment response was also compared in different patient groups. PET accurately identified patients with resectable disease (Group A). Group B patients, with medically inoperable disease, and Group C patients, with unresectable advanced disease, had 100% and 53% incidence of adverse events (defined as recurrence, evidence of new disease, or death), respectively. Group A patients with resectable disease who underwent surgery showed the best patient outcome, with only 7% incidence of adverse events. In conclusion, whole-body PET can be useful in identifying a group of lung cancer patients with resectable disease most likely to benefit from surgical resection. Further studies are needed to explore whether PET can predict patient outcome of various lung cancer patients receiving different treatment regimens.

Multiple local maxima for likelihoods of phylogenetic trees: a simulation study.

Steel demonstrated that the maximum-likelihood function for a phylogenetic tree may have multiple local maxima. If this phenomenon were general, it would compromise the applicability of maximum likelihood as an optimality criterion for phylogenetic trees. In several simulation studies reported on in this paper, the true tree, and other trees of very high likelihood, rarely had multiple maxima. Our results thus provide reassurance that the value of maximum likelihood as a tree selection criterion is not compromised by the presence of multiple local maxima--the best estimates of the true tree are not likely to have them. This result holds true even when an incorrect nucleotide substitution model is used for tree selection.

Comparative efficacy of positron emission tomography with FDG and computed tomographic scanning in preoperative staging of non-small cell lung cancer.

OBJECTIVE: To determine the sensitivity, specificity, and accuracy of positron emission tomography with 2-fluorine-18-fluorodeoxyglucose (PET-FDG) in the preoperative staging (N and M staging) of patients with lung cancer. The authors wanted to compare the efficacy of PET scanning with currently used computed tomography (CT) scanning. MATERIALS AND METHODS: Results of whole-body PET-FDG imaging and CT scans were compared with histologic findings for the presence or absence of lymph node disease or metastatic sites. Sampling of mediastinal lymph nodes was performed using mediastinoscopy or thoracotomy. RESULTS: PET-FDG imaging was significantly more sensitive, specific, and accurate for detecting N disease than CT. PET changed N staging in 35% and M staging in 11% of patients. CT scans helped in accurate anatomic localization of 6/57 PET lymph node abnormalities. CONCLUSION: PET-FDG is a reliable method for preoperative staging of patients with lung cancer and would help to optimize management of these patients. Accurate lymph node staging of lung cancer may be ideally performed by simultaneous review of PET and CT scans.

Comparison of two systems for tibial external fixation in rabbits.

BACKGROUND AND PURPOSE: Use of rabbits in orthopedic investigations is common. In this study, focus is on factors that influence bone healing and on distraction osteogenesis. Biomechanical characteristics of two external fixator systems (Orthofix device and Hoffmann device) for long bones were tested. METHODS: Twelve freshly dissected tibiae were obtained from six skeletally mature New Zealand White rabbits, and four-point bending stiffness in two planes (90 and 180 degrees to the fixator pins) and torsional stiffness and strength of the bone-fixator complex were evaluated by use of a material testing machine. RESULTS: In four-point bending, Orthofix device had higher stiffness and strength, compared with Hoffmann device. When the load was applied 180 degrees to the pins, both devices had higher stiffness, compared with that at 90 degrees. In torsional testing, Orthofix device had significantly higher stiffness and strength. CONCLUSIONS: Significant differences in structural properties between the two systems were evident. Loading direction and gap conditions were important factors in determining properties of the systems. Therefore, type of external fixation system and fixation technique should be considered when designing experiments, using the rabbit long bone model.

Simultaneous palpation of the craniosacral rate at the head and feet: intrarater and interrater reliability and rate comparisons.

BACKGROUND AND PURPOSE: The main purpose of this study was to determine the interrater and intrarater reliability of measurements obtained during palpation of the craniosacral rate at the head and feet. Palpated craniosacral rates of head and feet measured simultaneously were also compared. Subjects. Twenty-eight adult subjects and 2 craniosacral examiners participated in the study. METHODS: A within-subjects repeated-measures design was used. A standard cubicle privacy curtain, hung over the subject's waist, was used to prevent the examiners from seeing each other. RESULTS: Interrater intraclass correlation coefficients (ICCs) were .08 at the head and .19 at the feet. Intrarater ICCs ranged from .18 to .30. Craniosacral rates simultaneously palpated at the head and feet were different. CONCLUSION AND DISCUSSION: The results did not support the theories that underlie craniosacral therapy or claims that craniosacral motion can be palpated reliably.

A fast method for approximating maximum likelihoods of phylogenetic trees from nucleotide sequences.

We have developed a rapid parsimony method for reconstructing ancestral nucleotide states that allows calculation of initial branch lengths that are good approximations to optimal maximum-likelihood estimates under several commonly used substitution models. Use of these approximate branch lengths (rather than fixed arbitrary values) as starting points significantly reduces the time required for iteration to a solution that maximizes the likelihood of a tree. These branch lengths are close enough to the optimal values that they can be used without further iteration to calculate approximate maximum-likelihood scores that are very close to the "exact" scores found by iteration. Several strategies are described for using these approximate scores to substantially reduce times needed for maximum-likelihood tree searches.

Antiphospholipid antibodies: standardization and testing.

A phenomenon originally scorned as a laboratory nuisance has turned out to be an important cause of thromboembolism, fetal death, and other forms of human disease. Investigations of this inaptly named "lupus anticoagulant" has led to the discovery of at least two distinct types of autoimmune antibodies. In spite of recent discoveries regarding the pathophysiology of these antibodies, their clinical significance is still controversial.

The controversy of cranial bone motion.

Cranial bone motion continues to stimulate controversy. This controversy affects the general acceptance of some intervention methods used by physical therapists, namely, cranial osteopathic and craniosacral therapy techniques. Core to these intervention techniques is the belief that cranial bone mobility provides a compliant system where somatic dysfunction can occur and therapeutic techniques can be applied. Diversity of opinion over the truth of this concept characterizes differing viewpoints on the anatomy and physiology of the cranial complex. Literature on cranial bone motion was reviewed for the purpose of better understanding this topic. Published research overall was scant and inconclusive. Animal and human studies demonstrate a potential for small magnitude motion. Physical therapists should carefully scrutinize the literature presented as evidence for cranial bone motion. Further research is needed to resolve this controversy. Outcomes research, however, is needed to validate cranial bone mobilization as an effective treatment.

A cytoplasmic inhibitor of the JNK signal transduction pathway.

The c-Jun amino-terminal kinase (JNK) is a member of the stress-activated group of mitogen-activated protein (MAP) kinases that are implicated in the control of cell growth. A murine cytoplasmic protein that binds specifically to JNK [the JNK interacting protein-1 (JIP-1)] was characterized and cloned. JIP-1 caused cytoplasmic retention of JNK and inhibition of JNK-regulated gene expression. In addition, JIP-1 suppressed the effects of the JNK signaling pathway on cellular proliferation, including transformation by the Bcr-Abl oncogene. This analysis identifies JIP-1 as a specific inhibitor of the JNK signal transduction pathway and establishes protein targeting as a mechanism that regulates signaling by stress-activated MAP kinases.

Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine.

Protein kinases activated by dual phosphorylation on Tyr and Thr (MAP kinases) can be grouped into two major classes: ERK and JNK. The ERK group regulates multiple targets in response to growth factors via a Ras-dependent mechanism. In contrast, JNK activates the transcription factor c-Jun in response to pro-inflammatory cytokines and exposure of cells to several forms of environmental stress. Recently, a novel mammalian protein kinase (p38) that shares sequence similarity with mitogen-activated protein (MAP) kinases was identified. Here, we demonstrate that p38, like JNK, is activated by treatment of cells with pro-inflammatory cytokines and environmental stress. The mechanism of p38 activation is mediated by dual phosphorylation on Thr-180 and Tyr-182. Immunofluorescence microscopy demonstrated that p38 MAP kinase is present in both the nucleus and cytoplasm of activated cells. Together, these data establish that p38 is a member of the mammalian MAP kinase group.

Hypercoagulable states.

A hypercoagulable state is an enhanced tendency to form venous or arterial thrombi. In 1845, Virchow postulated three factors responsible for thrombosis that remain relevant today: alterations of the blood (hypercoagulability); changes in vessel wall (vascular injury); and impairment of blood flow (stasis). An increased understanding of the molecular basis of thrombosis has been aided by the identification of individuals with specific inherited defects in the natural anticoagulation system. These primary hypercoagulable states include antithrombin III, protein C and protein S deficiencies, dysfibrinogenemias, plasminogen deficiency, and decreased plasminogen activator activity. Individuals with thrombosis at an early age, a family history of thromboembolic disease, unusual sites of thrombosis, or recurrent thrombosis without apparent cause should be evaluated for a primary hypercoagulable defect. The majority of patients do not have a recognizable specific defect. However, there are a variety of underlying conditions or diseases that are associated with an increased risk for thrombosis. The etiologies of secondary hypercoagulable states are often unclear and may be multifactorial. Treatment of these inciting conditions or diseases may decrease the thrombotic tendency.