A simple breathing circuit to maintain isocapnia during measurements of the hypoxic ventilatory response

We report the development and testing of a simple breathing circuit that maintains isocapnia in human subjects during hypoxic hyperpnea. In addition, the circuit permits rapid switching between two gas mixtures with different partial pressures of oxygen. Eleven volunteers breathed repeated cycles of exposure to air (2 min of 21% O(2), balance N(2)) and hypoxia (2 min of 8.3+/-0.1% O(2), balance N(2)). Hypoxia induced significant increases in minute ventilation, breathing frequency and tidal volume (P < 0.05) that were consistent over repeated cycles of hypoxia (P > 0.1, one-way ANOVA). The system successfully maintained isocapnia in all subjects, with an average change in end-tidal CO(2) of only -0.2 mmHg during hyperventilation in hypoxia (range 0.4 to -0.8 mmHg). This system may be suitable for repeated tests of the hypoxic ventilatory response (HVR) and may prove useful for exploring intra- and inter-individual variability of HVR in humans.     

Factors influencing levels of research activity in clinical psychologists: a new model

There are concerns in the USA and UK about low levels of research activity amongst clinical psychologists emerging from doctoral level training. The authors explore existing evidence and theory pertaining to this phenomenon. Three relevant theoretical strands are identified, along with related empirical studies and commentaries in practitioner journals. These different sources are integrated to suggest a more complete model of factors influencing clinical psychologists' research intentions, and in turn research activity itself: vocational preferences, research training experienced during qualifying training, practice context, value placed on expected outcomes of doing research, perceived norms for clinical psychologists in relation to doing research, research self‐efficacy, professional identity and, most tentatively, sex role identity. Our new model points to training interventions, either pre‐ or post‐qualification, that may increase the likelihood of clinical psychologists carrying out clinical research that will contribute to their profession's knowledge base, beyond their time in qualifying training. Copyright © 2006 John Wiley & Sons, Ltd.     

The effects of levetiracetam on objective and subjective sleep parameters in healthy volunteers and patients with partial epilepsy

Levetiracetam is a novel antiepileptic drug which has recently been released as an adjunctive treatment for partial epilepsy. In the two studies reported here we examined the objective and subjective effects of levetiracetam on sleep in 12 healthy volunteers and 17 patients [16 who could be evaluated for electroencephalogram (EEG) recordings] with a history of partial epilepsy on stable carbamazepine monotherapy. The studies were of a similar double-blind crossover placebo-controlled design with subjects' sleep being recorded in their own homes. The results from the two studies showed considerable similarities. In both, levetiracetam produced an increase in the time spent in stage 2 sleep, which in the patient study was accompanied by a decrease in the time spent in stage 4 sleep and in the volunteer study an increase in rapid eye movement (REM) latency. The subjective changes included reports that sleep was of a better quality with fewer awakenings and patients also reported that their sleep was more restful. Volunteers and patients did, however, feel less alert on waking in the morning. Therefore, both groups reported a decrease in awakenings after levetiracetam despite the finding from the EEG of no change in the actual number of awakenings. It may be concluded from both studies that levetiracetam does affect some indicators of subjective sleep perception, but does not influence objective sleep measures of sleep continuity. The results from the patient study during placebo add-on treatment also showed that patients on carbamazepine had a marked increase in SWS, an increase in stage 2 sleep and an increase in REM latency compared with healthy volunteers. Interestingly, levetiracetam also reduced bilateral epileptiform EEG activity, particularly in patients with more discharges.     

Inhibition of VEGFR2 prevents DMBA-induced mammary tumor formation

Preinvasive mammary pathologies in humans and rat chemical carcinogenesis model systems have an increased microvascular density relative to normal tissue. This suggests the possibility of preventing invasive breast cancer by inhibiting angiogenesis. Vascular endothelial cell growth factor (VEGF) is a potent angiogenic growth factor, commonly involved in tumor-induced angiogenesis. Here, we show that both VEGF and VEGFR2 expression increase with histological progression to invasive disease in the rat 7,12-dimethylbenz[a]anthracene (DMBA) model. Other VEGF receptors, VEGFR1, neuropilin 1 and neuropilin 2, are constitutively expressed throughout progression. To examine whether VEGF signaling is functionally relevant to tumor-induced endothelial tubule formation in vitro and for tumor formation in vivo, we utilized the VEGFR2 inhibitor, ZD6474. In vitro endothelial cell tubulogenesis induced by isolated mammary organoids or carcinoma in situ from DMBA-treated rats is inhibited by ZD6474, in a dose-dependent fashion. The administration of ZD6474 to DMBA-treated rats inhibits the formation of atypical ductal hyperplasia and carcinoma in situ by greater than 95% (P < 0.05), when administered 1 week or 6 weeks post-DMBA initiation. Invasive disease was absent in all ZD6474 cohorts. These data support the hypothesis that progression of DMBA-induced preinvasive mammary pathologies to palpable disease requires angiogenesis via a VEGF-dependent mechanism.     

An investigation into the relationship between salivary cortisol,stress, anxiety and depression

This study examined the relationship between indices of self-reported emotional distress and absolute versus change in cortisol levels. Fifty-four women attending a diagnostic breast clinic completed scales measuring stress, anxiety and depression and provided five saliva samples over the course of a single day for the measurement of cortisol. No significant relationships were evident between absolute cortisol levels and the distress measures. Analysis of the change in cortisol levels revealed a non-linear interaction effect between stress and anxiety and time of day. There was a non-linear relation between time of day and cortisol levels, but the extent of the non-linearity was dependent upon levels of stress and anxiety, not depression. A relationship was apparent between indices of distress and change in cortisol levels, but not absolute levels of the hormone.     

Genetic linkage analysis identifies new proximal and distal flanking markers for the X-linked agammaglobulinemia gene locus, refining its localization in Xq22

Genetic linkage analysis has been instrumental in mapping thegene for X-linked agammaglobulinemia (XLA) to the proximal longarm of the human X chromosome, to Xq22. Due to the relativerarity of this disease the localization of the gene within Xq22has remained imprecise. We have investigated twenty-nine familiesaffected by XLA and have found no recombinants with the DXS178locus in over 30 informative meioses. DXS178 is now the mostreliable and informative locus for use in pre-natal diagnosisand carrier detection of XLA. In addition, we have identifiednew closely linked proximal and distal flanking markers forXLA, DXS442 and DXS101, respectively. These loci are separatedby 2cM, considerably reducing the extent of DNA within whichthe XLA locus can be contained. This will open up the way formore directed positional cloning efforts for the isolation ofthe XLA gene.     

Laboratory compliance with federal government and professional society recommendations

Quality assurance issues have assumed growing importance in the cytology laboratory. The 1988 Clinical Laboratories Improvement Amendment (CLIA '88) (United States Department of Health and Human Services, Federal Register: U.S. Government Printing Office 1990;55:9495) regulates the patient identifiers and clinical data on the requisition form but does not mandate physician compliance to provide the information. We investigated the use of patient identifiers and clinical data by laboratories as specimen acceptance/rejection criteria. We surveyed 81 board certified cytopathologists and 235 randomly selected cytology laboratories for acceptance criteria of cytology specimens and received responses from 104. Approximately two thirds of all responding laboratories had specific criteria for rejecting specimens on the basis of inadequate identification or clinical data. While the vast majority required the specimens to be identified with patient name, collection date, and specimen source, a minority of laboratories required clinical information such as LMP, prior atypical cytologic/histologic specimens, and history of previous therapy. Little correlation was found between practice setting and the use of rejection criteria. Diagn Cytopathol 1994; 11:85–92. © 1994 Wiley-Liss, Inc.     

Estimation of size of clonal unit for keratinocytes in normal human skin

OBJECTIVE: It has been suggested that keratinocyte (KC) stem cells reside at the epicenter of a clonal population of cells. To estimate the territory or surface area covered by a single stem-cell-derived KC population in human skin, clonal skin maps were created from 3 healthy adult women and from normal skin of a psoriatic patient. DESIGN: Two hundred fifty-eight punch biopsy samples of various sizes (ranging from 2 to 8 mm in diameter) were analyzed for clonality employing X chromosome inactivation patterns at the human androgen receptor gene (HUMARA) locus. DNA was isolated and clonality established by significant decrease of either maternal or paternal X chromosome band patterns following restriction enzyme digestion, polymerase chain reaction amplification, and gel electrophoresis. RESULTS: Fifty-three (41%) of 128 two-mm biopsies were clonal, whereas only 6 (14%) of 43 three-mm, 5 (14%) of 36 four-mm, and 3 (8%) of 35 five-mm biopsies revealed a clonal population of KCs. By contrast, in 5 different biopsies from a psoriatic patient, including 4- or 5-mm sizes, all but 1 were clonal; even an 8-mm biopsy contained a clonal population of KCs. Mantel-Haenszel chi(2) analysis revealed a P value of.001, reflecting a strong trend in probability for presence of a single clone of KCs as related to size of the biopsy sample. By sequentially analyzing 30 contiguous 2-mm biopsy samples within a given strip of skin, 10 clonal domain changes, as reflected in maternal versus paternal switches, were observed. CONCLUSIONS: These results provide direct evidence of a clonal population of KCs in normal and psoriatic lesion-free skin, and indicate that a clonal epidermal unit of KCs frequently can be detected in small biopsies (2 mm), but that in normal skin sampling, overlapping clones are apparently present in larger (ie, 4-5-mm) biopsies, producing nonclonal patterns. The clonal domain of progeny in normal skin has a rather limited territorial boundary (2 mm in diameter). However, in lesion-free skin from a psoriatic patient, there may be clonal expansion of KCs due to perturbation in epidermopoiesis and/or stem cell distribution.     

The MD-MPH program at the University of North Carolina at Chapel Hill.

In 1997, the Schools of Medicine and Public Health at the University of North Carolina at Chapel Hill (UNC) developed a formal MD-MPH program, called the Health Care and Prevention (HC&P) Program, located in the Public Health Leadership Program in the UNC School of Public Health. Since then, and especially since 2003, the number of UNC medical students taking a year out of their medical studies to pursue an MPH has increased dramatically. At present, more than 20% of UNC medical students enter an MPH program at some point between entering medical school and leaving for residency.The HC&P Program is designed to introduce clinicians to the population sciences and to create physicians who can think in both individual and population terms. The curriculum is a rigorous, 12-month program that includes a practicum experience and a master's paper. Several of the traditional MPH introductory courses have been redesigned to be more relevant to physicians. The program allows a maximum number of electives and places a value on flexibility so that students, together with faculty, can design the educational experience that best meets their needs. Many members of the faculty of the program themselves have both MD and MPH degrees, and some have dual appointments in the schools of medicine and public health.The authors have begun a longitudinal cohort study of program graduates and other medical graduates to understand the effect of the program on students' perceptions of their competency and their ability to exert leadership in various areas of population health.