Comparison of the effects of short, high-voltage and long, medium-voltage pulses on skin electrical and transport properties.

High-voltage pulses have been shown to increase rates of transport across skin by several orders of magnitude on a time scale of minutes to seconds. Two main pulse protocols have been employed to promote transport: the intermittent application of short ( approximately 1 ms) high-voltage (approximately 100 V across skin) pulses and a few applications of long (=100 ms) medium-voltage (>30 V across skin) pulses. In order to better evaluate the benefits of each protocol for transdermal drug delivery, we compared these two protocols in vitro in terms of changes in skin electrical properties and transport of sulforhodamine, a fluorescent polar molecule of 607 g/mol and a charge of -1. Whereas both protocols induced similar alterations and recovery processes of skin electrical resistance, long pulses of medium-voltage appeared to be more efficient in transporting molecules across skin. Skin resistance decreased by three (short pulses) and two (long pulses) orders of magnitude, followed by incomplete recovery in both cases. For the same total transported charge, long pulses induced faster and greater molecular transport across skin than short pulses. In addition, a greater fraction of the aqueous pathways created by the electric field was involved in molecular transport when using long pulse protocols. Transport was concentrated in localized transport regions (LTRs) for both protocols but LTRs created by long pulses were an order of magnitude larger than those formed by short pulses and the short pulses created an order of magnitude more LTRs. Overall, this study is consistent with the creation of fewer, but larger aqueous pathways by long, medium-voltage pulses in comparison to short, high-voltage pulses.     

Memory/effector T cells in TCR transgenic mice develop via recognition of enteric antigens by a second, endogenous TCR.

The majority of clonotypic CD4(+) T cells in the intestinal lamina propria of DO11.10 TCR transgenic mice have an activated/memory phenotype and produce effector cytokines despite the absence of prior exposure to ovalbumin (OVA), the transgene-specific antigen. A small number of splenic T cells have a similar phenotype. Clonotypic T cells from Peyer's patch are intermediate in both phenotype and effector cytokine production. Flow cytometric analysis of cells isolated from thymectomized, OVA-naive DO11.10 mice treated with continuous administration of BrdU indicated that a significant fraction of clonotype-positive T cells in the lamina propria and Peyer's patch were in the cell cycle, with significantly fewer cycling cells in the spleen. Most of the cycling cells from each anatomic site expressed low levels of CD45RB. Effector cytokine expression was enriched in the CD45RB(low) populations. These memory/effector cell populations were eliminated in DO11.10/SCID and DO11.10/RAG-2(-/-) mice, suggesting that recognition of non-OVA antigens through a second, non-clonotypic TCR was driving differentiation of memory/effector cells in naive BALB/c DO11.10 mice. Clonotypic CD4(+) T cells isolated from DO11.10, but not from DO11.10/SCID or DO11.10/RAG-2(-/-) mice, were stimulated to enter the cell cycle by antigen-presenting cells pulsed with an intestinal bacterial antigen extract. These data provide direct evidence that enteric bacterial antigens can activate transgenic T cells through a second, non-clonotypic TCR, and support the notion that the development and turnover of memory/effector cells in vivo is driven by the intestinal flora.     

Prenatal diagnosis of tuberous sclerosis with intracerebral signs at 14 weeks' gestation.

We report the ultrasound detection of cranial abnormalities at 14 weeks' gestation in a fetus subsequently confirmed as having tuberous sclerosis using DNA linkage analysis within the affected family. The presence of asymmetrical ventricular enlargement persisted antenatally. Magnetic resonance imaging at 26 weeks indicated the possibility of poor gyral formation consistent with a neuronal migration disorder. Cardiac rhabdomyomata were not visualized on ultrasound scan until 30 weeks' gestation. Postnatal cranial ultrasound confirmed the significant neuropathology which was manifested by severe developmental delay and intractable fits in the child. The potential benefits of earlier diagnosis of tuberous sclerosis by cranial imaging are discussed, although in this patient the routine booking scan resulted in a path of prenatal diagnosis being undertaken which had originally been declined. A mechanism is proposed to explain the variable expression of tuberous sclerosis within this family based on altered TSC2 activity affecting neuronal migration.     

Symptoms of 100 patients with electromyographically verified carpal tunnel syndrome.

To determine the symptoms of carpal tunnel syndrome (CTS), screening evaluations were performed in 244 consecutive patients with sensory symptoms in the hand and unequivocal slowing of median nerve conduction at the wrist. This yielded 100 patients thought to have no explanation other than CTS for their upper limb complaints. These patients completed a hand symptom diagram (HSD) and questionnaire (HSQ) about their symptoms. CTS symptoms were most commonly reported in median and ulnar digits, followed by median digits only and a glove distribution. Unusual sensory patterns were reported by some patients. Based on the HSQ, paresthesias or pain proximal to the wrist occurred in 36.5% of hands. The usefulness of the HSD and HSQ for diagnosis was determined by asking three physicians, blinded to the diagnosis, to rate the likelihood of CTS in the patients with CTS and in 50 patients with other causes of upper extremity paresthesia. The sensitivities of the instruments ranged from 54.1% to 85.5%. Combining the HSD and HSQ ratings increased the range of sensitivities to 79.3% to 93.7%.     

Prediction of interindividual variation in drug plasma levels in vivo from individual enzyme kinetic data and physiologically based pharmacokinetic modeling.

A strategy is presented to predict interindividual variation in drug plasma levels in vivo by the use of physiologically based pharmacokinetic modeling and human in vitro metabolic parameters, obtained through the combined use of microsomes containing single cytochrome P450 enzymes and a human liver microsome bank. The strategy, applied to the pharmaceutical compound (N-[2-(7-methoxy-1-naphtyl)-ethyl]acetamide), consists of the following steps: (1) estimation of enzyme kinetic parameters K(m) and V(max) for the key cytochrome P450 enzymes using microsomes containing individual P450 enzymes; (2) scaling-up of the V(max) values for each individual cytochrome P450 involved using the ratio between marker substrate activities obtained from the same microsomes containing single P450 enzymes and a human liver microsome bank; (3) incorporation into a physiologically based pharmacokinetic model. For validation, predicted blood plasma levels and pharmacokinetic parameters were compared to those found in human volunteers: both the absolute plasma levels as well as the range in plasma levels were well predicted. Therefore, the presented strategy appears to be promising with respect to the integration of interindividual differences in metabolism and prediction of the possible impact on plasma and tissue concentrations of drugs in humans.     

COVID-19 Vaccine-Related Axillary and Cervical Lymphadenopathy in Patients with Current or Prior Breast Cancer and Other Malignancies: Cross-Sectional Imaging Findings on MRI,CT, and PET-CT

Breast radiologists are increasingly seeing patients with axillary adenopathy related to COVID-19 vaccination. Vaccination can cause levels I–III axillary as well as cervical lymphadenopathy. Appropriate management of vaccine-related adenopathy may vary depending on clinical context. In patients with current or past history of malignancy, vaccine-related adenopathy can be indistinguishable from nodal metastasis. This article presents imaging findings of oncology patients with adenopathy seen in the axilla or neck on cross-sectional imaging (breast MRI, CT, or PET-CT) after COVID-19 vaccination. Management approach and rationale is discussed, along with consideration on strategies to minimize false positives in vaccinated cancer patients. Time interval between vaccination and adenopathy seen on breast MRI, CT, or PET-CT is also reported.     

Environmental factors can confound identification of a major gene effect: Results from a segregation analysis of a simulated population of lung cancer families

Proper control of environmental factors can be crucial to the identification of genes that influence susceptibility to a complex trait, especially for a trait such as lung cancer, for which the environmental factor (smoking) accounts for a significant etiologic fraction of the disease. An earlier segregation analysis of 337 Louisiana families, which incorporated direct measure of tobacco consumption, provided evidence for autosomal codominant inheritance of a major gene that influenced age at onset of lung cancer. Subsequent analyses were performed in which the families were stratified into two subsets based on birth cohort of the proband; results suggested the presence of heterogeneity that were postulated to reflect the influence of cohort trends in tobacco consumption. To evaluate this hypothesis further, we simulated a population of three-generation pedigrees in which an autosomal dominant mode of susceptibility to lung cancer was transmitted, but tobacco use varied across generations corresponding to published trends in smoking. A total of 200,000 individuals in families of various sizes, ages, and cigarette smoking habits were simulated from 1900 to 1980. From this population, 324 families (2,405 individuals) with 380 cases of lung cancer were ascertained through 328 lung cancer probands. Complex segregation analysis was performed using the REGTL program of S.A.G.E. in which pack-years of tobacco exposure were incorporated directly into the likelihood calculations. Although the no major gene, environmental, and Mendelian recessive hypotheses were rejected, both dominant and codominant transmission provided a good fit to the data. Thus in a population of simulated families with autosomal dominant susceptibility to lung cancer, intergenerational differences in tobacco consumption led to the detection of autosomal codominant transmission as an acceptable hypothesis. These results underscore the potential danger of segregation analysis of complex traits in which exposure to known environmental influences may differ across generations. Genet. Epidemiol. 15:251–262, 1998. © 1998 Wiley-Liss, Inc.     

Anxiety as a predictor of response to interpersonal psychotherapy for recurrent major depression: An exploratory investigation

Major depression and anxiety frequently co-occur, but the implications for psychological treatments have rarely been studied. We examined predictors of acute response to interpersonal psychotherapy in 134 consecutively treated female outpatients with recurrent unipolar depression. Women who failed to remit with interpersonal psychotherapy alone experienced higher levels of somatic anxiety, were more likely to meet criteria for lifetime panic disorder, were more likely to meet criteria for nonendogenous or nonmelancholic depression, and reported greater vocational impairment, higher levels of global severity, a longer duration of the index episode, and, somewhat surprisingly, lower levels of social impairment at pretreatment evaluation. A series of backwards stepping logistic regression analyses showed higher levels of baseline somatic anxiety and social functioning to be the most consistent predictors of nonresponse. Our findings strengthen existing evidence that concomitant anxiety can adversely affect the outcome of interpersonal therapy for depression. Depression and Anxiety 8:135–141, 1998. © 1998 Wiley-Liss, Inc.     

Bone mineral density and laboratory evaluation of a type II autosomal dominant osteopetrosis carrier

Type II autosomal dominant osteopetrosis (ADO2) is an inherited disorder characterized by increased skeletal mass and characteristic abnormalities evident on radiography. Although previous investigators have described nonpenetrant individuals (carriers), it is not known whether carriers manifest subtle abnormalities. We hypothesized that ADO2 carriers would have an abnormality of osteoclast function that would lead to changes in bone mineral density (BMD), in serum tartrate-resistant acid phosphatase (TRAP), or in creatine kinase isoenzyme BB (CK-BB) levels that would permit carrier recognition. We identified a female carrier in a well-established ADO2 family and measured BMD, serum TRAP, and CK-BB concentrations. She had normal BMD, serum TRAP, and CK-BB concentrations. Thus, these measurements cannot be used to exclude carrier status in individuals who are seen for genetic counseling. However, measurements in other asymptotic carriers are necessary before concluding that these measurements are normal in all or most nonpenetrant individuals. Am. J. Med. Genet. 85:9–12, 1999. © 1999 Wiley-Liss, Inc.