How does psychological processing relate to compliance behaviour after lung transplantation? A content analytical study.

Non-compliance is one of the crucial problems impairing outcome after transplantation. Fourteen lung transplant recipients were interviewed about their thoughts regarding transplant-related topics. Compliance was assessed by doctors. The psychological processing was investigated by content analysis. Highly compliant patients perceived more advantages by transplantation. In contrast, low-compliant patients reported either an emotional distance to the lung or a closer relationship to the donor. Furthermore, they showed a contradictory relationship to the medical staff. There are some indications that perception of advantages by transplantation is crucial to compliance. This experience takes place in the context of a good staff-patient relationship. Emotional distance to the lung or nearness to the donor are further contributing factors of non-compliance.

Disease activated drugs: a new concept for the treatment of asthma.

Disease activated drugs (DAD) are pro-drugs of one active principle or combinations of two drugs, which have a proven efficacy for the treatment of the target disease. In opposition to pro-drugs, DAD are activated in inflamed but not normal tissues. Due to the disease specific activation, the amount of locally released drug(s) should be related directly to the severity of the inflammation. To test this concept in asthma a PDE4 inhibitor, an isoquinoline derivative, was chemically derivatized into pro-drugs or combined with corticosteroids. These new compounds were more readily cleaved into active PDE4 inhibitor, in bronchoalveolar lavage fluid (BALF) from Brown-Norway rats with lung inflammation than in BALF from rats without airway inflammation. The DAD concept (local selective release and improved therapeutic window) was validated in vivo using the inhibition of methacholine induced bronchoconstriction in guinea pigs with or without ozone induced lung inflammation. An example of DAD hydrolysis (isoquinoline-dexamethasone) was also examined in BALF from asthmatics and healthy volunteers.

PMP22 carrying the trembler or trembler-J mutation is intracellularly retained in myelinating Schwann cells.

Missense mutations in the murine peripheral myelin protein-22 gene (Pmp22) underly the neuropathies in the trembler (Tr) and trembler-J (Tr-J) mice and in some humans with Charcot-Marie-Tooth disease. We have generated replication-defective adenoviruses containing epitope-tagged, wild-type-, Tr-, or Tr-J-PMP22 bicistronic with the Lac-Z reporter gene. These viruses were microinjected into the sciatic nerves of 10-day-old Sprague-Dawley rats and, later, analyzed by immunohistochemistry to determine the distribution of mutant protein in infected myelinating Schwann cells. We found that epitope-tagged, wild-type PMP22 is successfully transported to compact myelin, whereas the Tr and the Tr-J mutant proteins are retained in cytoplasmic compartment, colocalizing with the endoplasmic reticulum. These results provide in vivo evidence that the pathogenesis of the Tr and Tr-J mutations are most likely a function of abnormal retention within the endoplasmic reticulum of myelinating Schwann cells.

Membrane topology of peripheral myelin protein 22.

Peripheral myelin protein 22 (PMP22) is a structural component of compact peripheral nerve myelin and is likely to play a role in the modulation of cell proliferation and cell spreading. Molecular genetics revealed that mutations affecting the PMP22 gene are responsible for the most common forms of hereditary motor and sensory neuropathies in humans. Computer analysis predicts a tetraspan-membrane structure for the PMP22 protein. We have assessed the topology of PMP22 experimentally using chimeric proteins consisting of different PMP22 domains fused to reporter genes and internally tagged molecules. Based on in vitro transcription/translation assays and immunohistochemical analysis of transfected cells, we propose that PMP22 can adopt a non-tetraspan topology that has functional implications in normal and disease processes.

Isolation and synthesis of a novel immunosuppressive 17alpha-substituted dammarane from the flour of the Palmyrah palm (Borassus flabellifer).

The novel triterpene 1 with a dammarane skeleton and a hitherto unknown 17alpha-substitution pattern has been isolated from the Palmyrah palm in low yield and prepared by synthesis in larger quantities. 1 was shown to be an extremely potent immunosuppressant in vitro (MLR; IC50 = 10 ng/ml) and in vivo (DTH; ED50 = 0.01 mg/kg p.o.). A glucocorticoid like activity is excluded.

Transport of Trembler-J mutant peripheral myelin protein 22 is blocked in the intermediate compartment and affects the transport of the wild-type protein by direct interaction.

Peripheral myelin protein 22 (PMP22) is an integral membrane protein that is essential for the normal formation and maintenance of peripheral myelin. Duplications, deletions, or mutations in the PMP22 gene account for a set of dominantly inherited peripheral neuropathies. The heterozygous Trembler-J (TrJ) genotype in mice is similar genetically to a Charcot-Marie-Tooth disease type 1A pedigree in humans, whereas the homozygous TrJ condition leads to the most severe form of PMP22-associated neuropathies. To characterize the consequences of the TrJ mutation, we labeled wild-type (wt-) and TrJ-PMP22 in the third loop of the protein with different epitope tags and expressed them separately or together in COS7 cells and primary Schwann cells. Here we show that the transport of the mutant TrJ-PMP22 is interrupted in the intermediate compartment, preventing its insertion into the plasma membrane and affecting the morphology of the endoplasmic reticulum. In addition, TrJ-PMP22 forms a heterodimer with the wt-PMP22. This interaction causes a fraction of the wt-PMP22 to be retained with TrJ-PMP22 in the intermediate compartment of COS7 and Schwann cells. The relative stability of a wt-mutant PMP22 heterodimer as compared with the wt-wt PMP22 homodimer may determine whether a particular mutation is semidominant or dominant. The neuropathy itself appears to result both from decreased trafficking of wt-PMP22 to the plasma membrane and from a toxic gain of function via the accumulation of wt- and TrJ-PMP22 in the intermediate compartment.

Impaired intracellular trafficking is a common disease mechanism of PMP22 point mutations in peripheral neuropathies.

The most common forms of hereditary motor and sensory neuropathies (HMSN) or Charcot-Marie-Tooth disease (CMT) are associated with mutations affecting myelin genes in the peripheral nervous system. A minor subgroup of CMT type 1A (CMT1A) is caused by point mutations in the gene encoding the peripheral myelin protein 22 (PMP22). To study the mechanisms by which these mutations cause the CMT pathology, we transiently transfected COS7 and Schwann cells with wild-type and PMP22 expression constructs carrying six representative dominant or de novo point mutations and one putative recessive point mutation. All but one of the first group of mutant PMP22 proteins failed to be incorporated into the plasma membrane and were retained in intracellular compartments of transfected cells. Surprisingly, the recessive PMP22 mutation produced a protein that was also mildly impaired in trafficking. Thus, our results suggest a common disease mechanism underlying the pathology of CMT1A due to PMP22 point mutations.

Sleep patterns in pregnancy: a longitudinal study of polysomnography recordings during pregnancy.

OBJECTIVE: To evaluate the differences in sleep of women throughout pregnancy compared with those of nonpregnant control subjects. STUDY DESIGN: Four pregnant women were studied longitudinally during their pregnancy using inpatient polysomnography. Measurements included electroencephalography, electrocardiography, and continuous-pulse oximetry. Four healthy nonpregnant women matched for age and weight were used as control subjects. The total sleep time was recorded, and percentages of each sleep stage were generated. RESULTS: Qualitative differences in sleep between pregnancy patients and control subjects were evident. Control subjects displayed a normal appearance of slow-wave sleep in stages 3 and 4 (delta sleep). When pregnant patients did display delta sleep, it appeared abnormal secondary to extensive alpha-wave intrusion. Even when including this abnormal delta sleep in a quantitative comparison, the pregnant patients had a significantly shorter percentage of total sleep time in delta sleep (4.9+/-1.9% vs 21.9+/-6.0%, p=0.03). CONCLUSION: Sleep in pregnancy is characterized by loss of normal slow-wave sleep. Thus, sleep stages 3 and 4 are shortened during pregnancy. This sleep alteration is persistent when followed longitudinally during pregnancy.

Home blood pressure monitoring for pregnant patients with hypertension.

OBJECTIVE: To determine whether automated measurement of blood pressure and pulse in a home setting can be easily accomplished by pregnant women with chronic hypertension. STUDY DESIGN: In this prospective investigation, seven women with chronic hypertension complicating pregnancy recorded their blood pressure at home twice a day. These data were offloaded once daily into a computer at a remote site, and a computerized printout of these data was received by the physician. RESULTS: The patients participated in the study for 12.2 +/- 5.8 weeks (range 4 to 18 weeks) and were between 23 and 42 weeks' gestation. Average mean arterial pressure in the home was 102 +/- 10 mm Hg, and average pulse was 81 +/- 11 beats per minute. In the clinic, the values were 112 +/- 13 mm Hg and 90 +/- 30 beats per minute (p < 0.05). Each patient was easily taught how to use the machine. CONCLUSIONS: The home blood pressure monitoring device was easy to use and correlated well with values recorded by health professionals for this limited number of subjects. It was particularly helpful to patients (n = 5) who lived long distances (more than 60 miles) from the clinic and to women who needed adjustments of antihypertensive medication.

Many facets of the peripheral myelin protein PMP22 in myelination and disease.

Peripheral myelin protein 22 (PMP22) is a small, hydrophobic glycoprotein, which is most prominently expressed by Schwann cells as a component of compact myelin of the peripheral nervous system (PNS). Recent progress in molecular genetics revealed that mutations affecting the PMP22 gene including duplications, deletions, and point mutations are responsible for the most common forms of hereditary peripheral neuropathies including Charcot-Marie-Tooth disease type 1A (CMT1A), hereditary neuropathy with liability to pressure palsies (HNPP), and a subtype of Dejerine-Sottas Syndrome (DSS). Functionally, PMP22 is involved in correct myelination during development of peripheral nerves, the stability of myelin, and the maintenance of axons. While most of these functions relate to a role of PMP22 as a structural component of myelin, PMP22 has also been proposed as a regulator of Schwann cell proliferation and differentiation. In this review, we will discuss our current knowledge of PMP22 and its related proteins in the normal organism as well as in disease. In particular, we will focus on how the function of PMP22 and its regulation may be relevant to particular disease mechanisms.

A matrix-less measles virus is infectious and elicits extensive cell fusion: consequences for propagation in the brain.

Measles viruses (MV) can be isolated from the brains of deceased subacute sclerosing panencephalitis patients only in a cell-associated form. These viruses are often defective in the matrix (M) protein and always seem to have an altered fusion protein cytoplasmic tail. We reconstituted a cell-free, infectious M-less MV (MV-DeltaM) from cDNA. In comparison with standard MV, MV-DeltaM was considerably more efficient at inducing cell-to-cell fusion but virus titres were reduced approximately 250-fold. In MV-DeltaM-induced syncytia the ribonucleocapsids and glycoproteins largely lost co-localization, confirming the role of M protein as the virus assembly organizer. Genetically modified mice were inoculated with MV-DeltaM or with another highly fusogenic virus bearing glycoproteins with shortened cytoplasmic tails (MV-Delta(tails)). MV-DeltaM and MV-Delta(tails) lost acute pathogenicity but penetrated more deeply into the brain parenchyma than standard MV. We suggest that enhanced cell fusion may also favour the propagation of mutated, assembly-defective MV in human brains.

Premature rupture of membranes at 34 to 37 weeks' gestation: aggressive versus conservative management.

OBJECTIVE: Our purpose was to compare induction of labor with preterm rupture of membranes between 34 and 37 weeks' gestation with expectant management. STUDY DESIGN: In this prospective investigation 120 gravid women at > or = 34 weeks 0 days and < 36 weeks 6 days of gestation were randomized to receive oxytocin induction (n = 57) or observation (n = 63). RESULTS: Estimated gestational age at rupture of membranes (34.3 +/- 1.4 weeks vs 34.5 +/- 1.4 weeks) and ultrasonographically estimated fetal weight (2230 +/- 321 gm vs 2297 +/- 365 gm) were equivalent between groups (not significant). Chorioamnionitis occurred more often (16% vs 2%, p = 0.007), and maternal hospital stay (5.2 +/- 6.8 days vs 2.6 +/- 1.6 days, p = 0.006) was significantly longer in the control group. Neonatal sepsis was also more common in the observation group (n = 3) than among induction patients (n = 0), but the difference was not statistically significant. CONCLUSION: Aggressive management of preterm premature rupture of the membranes at > or = 34 weeks 0 days of gestation by induction of labor is safe for the infant in our population and avoids maternal-neonatal infectious complications.

A new all-ceramic post and core system: clinical, technical, and in vitro results.

Root-filled teeth with fractured or discolored coronal aspects invariably need to be restored by crowns. The prepared abutment tooth is usually reinforced by a metallic post and core system. The grayish discoloration of the root, and consequently of the gingiva, caused by the metal color may be an enormous esthetic disadvantage in the anterior teeth. In 1993 ceramic posts made of zirconia were introduced by the authors, allowing a new all-ceramic concept for nonvital abutment teeth. A new ceramic post and core system has now been developed with the idea of further improving esthetic appearance. In this system the core material is heat pressed directly onto the zirconia post. This article describes the material and the fabrication procedures (chairside and in the laboratory) of the system. Clinical results are presented. The retention of the core material is evaluated by in vitro tests.

Quinazolines: combined type 3 and 4 phosphodiesterase inhibitors.

A series of quinazolines has been prepared and evaluated for its ability to inhibit cyclic AMP phosphodiesterase type 3, type 4A, 4B and 4D. The most potent inhibitors showed IC50 values in the nanomolar range for type 3 and type 4 isoforms and bind with high affinity to the [3H]rolipram binding site. These quinazolines represent a new family of potent mixed PDE 3/4 inhibitors and are expected to have a therapeutic potential.

Analysis of compound heterozygous mice reveals that the Trembler mutation can behave as a gain-of-function allele.

The most common form of Charcot-Marie-Tooth disease, CMT1A, is correlated with a 1.5 megabase duplication on chromosome 17p.11.2 containing the peripheral myelin protein 22 (PMP22) gene. Deletion of the same region is associated with a second inherited neural disorder, the hereditary neuropathy with liability to pressure palsies (HNPP). Moreover, several distinct point mutations within the PMP22 coding region are associated with CMT1A and Dejerine-Sottas Syndrome in humans and the Trembler (Tr) and Trembler-J phenotypes in mice. Heterozygous Tr mutants (Tr/+) display severe hypomyelination of peripheral nerve fibers while heterozygous pmp22 knockout mice (pmp22+/0) are characterized by focal hypermyelination. These findings suggest that the Tr mutation does not generate a pmp22 null allele but rather produces its deleterious effects by either a dominant-negative or gain-of-function mechanism. To address this question in detail, we have compared various combinations of pmp22 alleles including Tr/+, Tr/Tr, Tr/0, pmp22+/0, and pmp22(0/0) mice with respect to the resulting myelin abnormalities. The combined analysis of these mutants demonstrates that the Tr allele can act as a true gain-of-function mutation in both, the heterozygous state on a null background (Tr/0) as well as in homozygous Tr animals (Tr/Tr). Furthermore, increasing the relative Tr gene dosage correlates with more pronounced myelin deficiencies and decreased levels of MBP and P0 in 18-day-old mice.

Neurons promote the translocation of peripheral myelin protein 22 into myelin.

Schwann cells express low levels of myelin proteins in the absence of neurons. When Schwann cells and neurons are cultured together the production of myelin proteins is elevated, and myelin is formed. For peripheral myelin protein 22 (PMP22), the exact amount of protein produced is critical, because peripheral neuropathies result from its underexpression or overexpression. In this study we examined the effect of neurons on Schwann cell PMP22 production in culture and in peripheral nerve using metabolic labeling and pulse-chase studies as well as immunocytochemistry. Most of the newly synthesized PMP22 in Schwann cells is rapidly degraded in the endoplasmic reticulum. Only a small proportion of the total PMP22 acquires complex glycosylation and accumulates in the Golgi compartment. This material is translocated to the Schwann cell membrane in detectable amounts only when axonal contact and myelination occur. Myelination does not, however, alter the rapid turnover of PMP22 in Schwann cells. PMP22 may therefore be a unique myelin protein in that axonal contact promotes its insertion into the Schwann cell membrane and myelin without altering its rapid turnover rate within the cell.

Cesarean section for suspected fetal distress. Does the decision-incision time make a difference?

OBJECTIVE: To compare perinatal outcomes in patients at term (37 weeks) in whom the decision-incision time for cesarean delivery was due to suspected fetal distress. STUDY DESIGN: All parturients who underwent cesarean delivery primarily for possible fetal distress during a three-year period were identified retrospectively. Student's t test and the chi 2 test were utilized, and P < .05 was considered significant. A regression analysis of decision-incision time and umbilical arterial pH was performed. RESULTS: From 1991 to 1993, 1.3% (117/9,137) of term laboring patients underwent emergency cesarean delivery for the primary indication of possible fetal distress. In 61 patients (52%) the decision-incision time was 30 minutes, while it exceeded 30 minutes in the remaining 56 women. The two patient groups were similar in maternal demographics, antepartum complications, oxytocin usage, thick meconium, type of abnormal fetal heart rate tracing prompting surgery, use of amnioinfusion (41% vs. 36%), general anesthesia (97% vs. 93%), mean birth weight and Apgar score < 7 at five minutes. Three adverse outcomes were observed more frequently in association with decision-incision time > 30 minutes: (1) lower mean (+/-SD) umbilical arterial pH (7.16 +/- 0.15 vs. 7.26 +/- 0.06, P = .001), (2) pH < 7.00 (8/61 vs. 0/56, P = .005), and (3) admission to the neonatal intensive care unit (P = .008). When the incision was made longer than 30 minutes after the decision, there was no apparent adverse neonatal or infant outcome. CONCLUSION: Although a cesarean decision-incision time < or = 30 minutes is a desirable goal for the fetus possibly in distress, failure to achieve this goal is not associated with a measurable negative impact on newborn outcome.

Aberrant protein trafficking in Trembler suggests a disease mechanism for hereditary human peripheral neuropathies.

The naturally occurring mouse mutant Trembler (Tr) represents an animal model for inherited human neuropathies caused by point mutations affecting peripheral myelin protein 22 (PMP22). We describe the likely pathogenic cellular mechanism underlying the observed myelin deficiency. In Tr/+ animals, PMP22 immunoreactivity was found not only in compact myelin but also abundantly in the cytoplasm of Schwann cells. Based on these observations, the biosynthesis of wildtype and Tr protein was examined in transfected cells. While wildtype PMP22 was readily transported to the plasma membrane, Tr protein was localized mainly in the endoplasmic reticulum. Coexpression revealed a dominant effect of Tr on protein trafficking of wildtype PMP22. In agreement with the findings in vitro, Tr protein was not detectable in myelin of Tr/0 mice.

Adjustment of localized alveolar ridge defects by soft tissue transplantation to improve mucogingival esthetics: a proposal for clinical classification and an evaluation of procedures.

Esthetically correct treatment of a localized alveolar ridge defect is a frequent prosthetic challenge. Such defects can be overcome not only by a variety of prosthetic means, but also by several periodontal surgical techniques, notably soft tissue augmentations. Preoperative classification of the localized alveolar ridge defect can be greatly useful in evaluating the prognosis and technical difficulties involved. A semiquantitative classification, dependent on the severity of vertical and horizontal dimensional loss, is proposed to supplement the recognized qualitative classification of a ridge defect. Various methods of soft tissue augmentation are evaluated, based on initial volumetric measurements. The roll flap technique is proposed when the problem is related to ridge quality (single-tooth defect with little horizontal and vertical loss). Larger defects in which a volumetric problem must be solved are corrected through the subepithelial connective tissue technique. Additional mucogingival problems (eg, insufficient gingival width, high frenum, gingival scarring, or tattoo) should not be corrected simultaneously with augmentation procedures. In these cases, the onlay transplant technique is favored.

Resorbable versus nonresorbable membranes in combination with Bio-Oss for guided bone regeneration.

The purpose of this clinical investigation was to compare the new resorbable collagen membrane, Bio-Gide, to the conventional expanded polytetrafluoroethylene material (Gore-Tex) for guided bone regeneration in situations involving exposed implant surfaces. Over a 2-year period, 25 split-mouth patients were treated randomly: one defect site was treated with Bio-Gide and the other defect site with Gore-Tex; all 84 defects were filled with Bio-Oss and covered with the respective membrane. The defect types, their dimensions, and their morphology were measured in detail initially and at re-entry to allow for calculation of the exposed implant surface. Changes in defect surface for both types of membranes were statistically significant (P < .0001); however, no statistical significance (P > .94) could be detected between the two membranes. The mean average percentage of bone fill was 92% for Bio-Gide and 78% for Gore-Tex sites. In the latter group, 44% wound dehiscences and/or premature membrane removal occurred. The resorbable membrane, Bio-Gide, in combination with a bone graft, can be a useful alternative to the well-established expanded polytetrafluoroethylene membranes.