Overexpression of parathyroid hormone-related protein in the skin of transgenic mice interferes with hair follicle development.

Parathyroid hormone-related peptide (PTHrP) was initially discovered as the cause of the syndrome of humoral hypercalcemia of malignancy. Subsequently, the PTHrP gene has been shown to be expressed in a wide variety of normal tissues, including skin. Because the biological function of PTHrP in skin remains unknown, we used the human keratin 14 promoter to target overexpression of PTHrP to the skin of transgenic mice. We achieved a 10-fold level of overexpression in skin, and human keratin 14 promoter-PTHrP transgenic mice displayed a disturbance in normal hair follicle development. These mice either failed to initiate follicle development or showed a delay in the initiation of follicles. These findings suggest that PTHrP normally plays a role in the early stages of hair follicle development and support previous speculation that the peptide may function in regulating cellular differentiation.     

Transplacental IgG Subclass Concentrations in Pregnancies at Risk of Haemolytic Disease of the Newborn

The relationship of haemolytic disease of the newborn (HDN) to the transplacental passage of the four IgG subclasses was assessed at varous gestational ages by comparing the maternal and fetal IgG subclass concentrations in 34 pregnancies at risk of HDN with those in 30 pregnancies not at risk. Higher maternal and fetal IgG1 levels were attained in pregnancies at risk of HDN than in pregnancies not at risk. In contrast, a slight decrease in maternal IgG2 and IgG4 levels occurred in pregnancies at risk of HDN, as compared with a slight rise in maternal IgG2 and IgG4 levels in pregnancies not at risk of HDN. Changes in fetal IgG2 and 4 concentrations in either type of pregnancy were very similar, showing only slight increases between the 19th and 34th week of gestation. A slight decrease in maternal IgG3 occurred in both types of pregnancy. In contrast, higher and fairly steady levels of fetal IgG3 were observed in fetuses not at risk of HDN throughout gestation, when compared with those in 'at risk' pregnancies. However, the statistical reliability of these results is not clear since only small numbers of samples were tested and because wide variations in IgG concentrations were observed. The IgG subclass concentrations in 50 paired maternal and cord blood samples were also measured and revealed that IgG1 levels were substantially higher in cord rather than maternal blood; cord and maternal IgG2, 3 and 4 levels, on the other hand, were fairly similar.     

Nasal masks for domiciliary positive pressure ventilation: patient usage and complications.

BACKGROUND--Nasal mask discomfort is a major factor in compliance with treatment by nasal intermittent positive pressure ventilation (NIPPV) and nasal continuous positive airway pressure (CPAP). METHODS--A study of skin complications resulting from mask usage, with particular reference to predisposing factors, was carried out in 66 patients by means of a postal questionnaire. An effective means of managing ulceration at the nasal bridge while continuing therapy is described. RESULTS--Some disruption of treatment due solely to mask discomfort was experienced by 35 patients (53%), consisting of broken skin or open sores in 11 cases (17%). CONCLUSIONS-Although complications resulting from nasal mask usage are common, early identification of patients at risk of developing such complications and appropriate intervention will result in improved patient compliance.     

Gram negative aerobic bacillus pneumonia in oral and maxillofacial surgery--a case for comment.

A case illustrating the potentially fatal complication of endogenous Gram Negative Aerobic Bacillus (GNAB) septicaemia secondary to nosocomial pneumonia is presented along with current theories as to its aetiology. The technique of selective decontamination of the digestive tract is designed and advocated to prevent such occurrences; oral and maxillofacial surgeons should be aware of this approach. It may be, however, that by using much simpler manoeuvres such as changes in policy regarding gastric stress ulcer prophylaxis, the already small risk of such an occurrence will be further reduced. Awareness of this condition will allow a higher index of suspicion when presented with catastrophic septic complications on the ITU and aid in more rational planning of antimicrobial therapy.     

Androgen dependent stimulation of aromatase activity in genital skin fibroblasts from normals and patients with androgen insensitivity

OBJECTIVE: To measure the effect of androgens or aromatase activity as an index of androgen responsiveness in patients with androgen insensitivity. DESIGN: Genital skin fibroblasts were established in culture using primary skin explants obtained from normal males at the time of circumcision and from androgen insensitive patients who had surgery either for gonadectomy (complete androgen insensitivity syndrome) or for reconstruction of the external genitalia (partial androgen insensitivity syndrome). PATIENTS: Foreskin samples were obtained at the time of circumcision in 27 normal males. Scrotal or labia majora skin was obtained at the time of surgery from 14 patients with the complete and 22 with the partial forms of the androgen insensitivity syndrome. MEASUREMENTS: Basal and stimulated levels of aromatase activity were measured in genital skin fibroblasts following preincubation with natural and synthetic, nonmetabolizable androgens. RESULTS: Following a 48-hour preincubation with testosterone or dihydrotestosterone, there was a five to six-fold stimulation of aromatase activity in normal fibroblasts. Mibolerone, a synthetic androgen, produced similar results. The stimulatory effect was blocked by anti-androgens. Seven patients with partial androgen insensitivity, of whom four were either receptor deficient or showed a qualitative defect in androgen binding, had reduced mibolerone induced stimulation of aromatase activity. All ten patients with receptor negative complete androgen insensitivity had an absent response. There was no aromatase induction in a further three patients with complete androgen insensitivity who were receptor positive. Two siblings in the latter group had an exon deletion encoding for part of the DNA binding domain of the androgen receptor. CONCLUSIONS: Androgens stimulate aromatase activity in genital skin fibroblasts from normals. The response is mediated via the androgen receptor and can be decreased or absent in patients with the androgen insensitivity syndrome. This may be a useful in-vitro marker of androgen responsiveness in such patients.     

Effects of hyperthermia on blood flow and cis-diamminedichloroplatinum(II) pharmacokinetics in murine mammary adenocarcinomas.

The effect of localized hyperthermia on blood flow and cis-diamminedichloroplatinum(II) (CDDP) pharmacokinetics in 7,12-dimethylbenz[a]anthracene-induced mammary adenocarcinomas was studied. Blood flow was determined in rat tumors and normal tissue immediately and 1, 2, and 3 h after local hyperthermia treatment (43 degrees C, 1 h) as well as in unheated tumors of rats. The rate of blood flow in the tumor was increased 1.9 times at the end of treatment relative to control values and returned to the control values by 3 h after hyperthermia. Similarly, the rate of blood flow in the peripheral skin around the tumor immediately after hyperthermia was 2.2 times greater than that of unheated skin and returned to near normal values by 3 h after heating. Tumor-bearing rats received CDDP 1 h before, at the beginning of, at the end of, and 1 h after hyperthermia administration. The CDDP plasma concentration versus time profiles for rats did not vary statistically between treatment groups. Two h after CDDP administration, the mean tumor CDDP concentration of the rats which received drug at the beginning of hyperthermia was statistically greater (P less than 0.05) than tumor CDDP concentrations in rats which received drug at the end of heat treatment. The latter group was given CDDP when tumor blood flow was the greatest; however, mean tumor drug concentration was lowest of all the groups. The mean drug concentration in tumor tissues of rats which received drug 1 h after hyperthermia was comparable to rats which received drug at the beginning of hyperthermia. This suggests that drug delivery or uptake in tumors may be altered when local hyperthermia is administered concurrently or sequentially.     

Altered establishment/clearance mechanisms during experimental micrometastasis with live and/or disabled bacterial lacZ-tagged tumor cells.

To study micrometastasis at its earliest stages, the bacterial lacZ marker gene was introduced into human EJ Ha-ras-transformed BALB/c 3T3 cells (LZEJ), followed by their intravenous injection into nude mice. Lung micrometastases were easily identified by blue staining of lacZ-tagged cells minutes/hours after injection, permitting effective evaluation of establishment/clearance mechanisms of LZEJ cells. Different treatments were used to disable LZEJ cells (fixation, irradiation, or mitomycin C) to determine modulation of these processes--although unable to divide, these cells stain for lacZ expression for days after treatment. Fixation-killed cells generated large microfoci (> 13-15 cells/focus) with well-rounded morphologies while live, irradiated, or mitomycin-treated cells generated smaller, irregularly shaped foci (3-7 cells/focus). Fixed-cell foci were cleared more slowly from lungs than the other three classes, even when prefiltered to remove large aggregates. All foci of disabled cells were eventually cleared while a basal level of live-cell foci persisted. Co-injection of fixed and live cells (or preinjection of fixed cells, followed by live cells) resulted in complete clearance of live-cell microfoci; in contrast, preinjection of live cells (then injection of fixed cells) led to survival of live-cell micrometastases. Therefore, altered deformability and/or cell surface interactions of tumor cells modulate the effectiveness of host-clearing mechanisms in the lung and in some situations these altered cells facilitate clearance of live tumor cells that are normally tumor-progressing.     

Assessment of post-vaccination tuberculin sensitivity in Lagos-Nigeria.

An increase in the number of cases of tuberculosis, especially in children, has been observed recently. Post-vaccination conversion rate in babies immunised with BCG was assessed. Sensitization was detected as early as 4 weeks after BCG inoculation. Although 84.2% had physical evidence of BCG inoculation only 69.8% had developed detectable sensitization to the tubercle bacilli as shown by the Mantoux test.     

The relation of the accumulation of cadmium in human placenta to the intake of high-fibre grains and maternal iron status.

Exposure to cadmium via the diet is known to depend to a large extent on the intake of cereal grains, particularly the high-fibre fractions of wheat. Subjects with low iron status absorb more cadmium than those with better iron status. The purpose of the present study was to determine to what extent cadmium accumulation in human placenta is affected by the intake of grain fibre and maternal iron status during pregnancy. Thirty-nine pregnant women participated in the study. In each trimester the women were requested to complete a dietary history and to allow blood samples to be taken for haemoglobin, serum ferritin and serum thiocyanate determinations, the latter as a marker for smoking. At delivery the whole placenta was taken for the determination of the cadmium concentration. The 32 women who had serum thiocyanate levels less than 70 mumol/l, who had completed at least one dietary history and from whom a blood sample was obtained in the third trimester, were included in the final statistical analyses. In the group of women who consumed less than the median intake of grain fibre and had more than 15 micrograms ferritin/l serum in the third trimester, the placenta cadmium concentration was nearly half that in the placentae of women who had consumed more grain fibre or had lower iron status in late pregnancy.     

Formation of mitochondrial phospholipid adducts by nephrotoxic cysteine conjugate metabolites.

Nephrotoxic cysteine conjugates derived from a variety of halogenated alkenes are enzymatically activated via the beta-lyase pathway to yield reactive sulfur-containing metabolites which bind covalently to cellular macromolecules. Mitochondria contain beta-lyase enzymes and are primary targets for binding and toxicity. Previously, mitochondrial protein and/or DNA have been considered as molecular targets for cysteine conjugate metabolite binding. We now report that metabolites of nephrotoxic cysteine conjugates form covalent adducts with rat kidney mitochondrial phospholipids. Rat kidney mitochondria were incubated with the 35S-labeled conjugates S-(1,1,2,2-tetrafluoroethyl)-L-cysteine (TFEC), S-(2-chloro-1,1,2-trifluoroethyl)-L-cysteine (CTFC), S-(1,2-dichlorovinyl)-L-cysteine, and S-(1,2,3,4,4-pentachlorobutadienyl)-L-cysteine. Quantitation of metabolite binding to whole mitochondria and to mitochondrial protein and lipid fractions revealed that as much as 42% of the 35S-label associated with the mitochondria was found in the lipid fraction. Total lipids were also extracted from 35S-treated mitochondria and separated by thin-layer chromatography. 35S-Containing metabolites were found in the lipid fractions from mitochondria treated with each of the conjugates. Lipids from both [35S]CTFC- and [35S]-TFEC-treated mitochondria contained major 35S-labeled lipid adducts which had similar mobility by thin-layer chromatography. Fatty acid analysis, 19F and 31P NMR spectroscopy, and mass spectrometric analyses confirmed that the major TFEC and CTFC adducts are thioamides of phosphatidylethanolamine.