Pronounced cortisol response to acute psychosocial stress in type 2 diabetes patients with and without complications.

It is increasingly recognized that psychological stress is linked with type 2 diabetes mellitus and its late complications. Thus, the aim of the current study was to investigate the psychophysiological response to acute psychosocial stress in patients with type 2 diabetes. In total, 53 type 2 diabetes patients with complications, 16 type 2 diabetes patients without complications, and 47 age and gender matched non-diabetic participants underwent the Trier Social Stress Test. Subjective as well as biological parameters (i.e., blood levels of cortisol, adrenocorticotropic hormone (ACTH), norepinephrine, methylglyoxal) were assessed repeatedly before and after stress induction. Data were analyzed by means of multilevel regression. Patients with type 2 diabetes showed an exaggerated cortisol response to acute stress as compared to age matched control participants (diabetes*T2 est. = 1.23, p < .001), while stress-induced alterations of ACTH and subjective parameters did not differ. Norepinephrine levels were lower among patients (diabetes est. = -4.36, p = .044) and tended to decrease earlier than in controls. The subjective reaction of type 2 diabetes patients with complications was stronger than that of patients without complications (complication*T2 est. = -1.83, p = .032), while their endocrine response to stress was similar. Stress had no effect on methylglyoxal level, and there were no group differences regarding methylglyoxal response. These results show that the cortisol reactivity of patients with type 2 diabetes to acute psychosocial stress is increased compared to a control group. Thus, alterations of the hypothalamus-pituitary-adrenal axis - especially regarding its dynamic regulation - are a plausible link between psychological stress and type 2 diabetes and its complications.

Hearing outcome after tympanoplasty type III.

PURPOSE: We assessed overall hearing outcome after tympanoplasty type III in chronically infected ears with cholesteatoma (CH) and without cholesteatoma: otitis media chronica mesotympanalis, tympanosclerosis, and adhesive process (COM_T_AP). METHODS: 303 surgeries were evaluated: 229 CH-group and 74 COM_T_AP-group. Air-bone gaps (PTA-ABG) with pure-tone averages (PTA-4) at four frequencies (0.5, 1, 2 and 4 kHz) were compared preoperatively, early postoperatively (< 40 days) and late postoperatively (40-400 days). Hearing outcome was compared in various types of middle-ear reconstruction and in smokers and non-smokers. Correlations between hearing outcome and predictive staging indices were evaluated: Middle Ear Risk-Index (MER-I) and Ossiculoplasty Outcome Parameter Staging-Index (OOPS-I). RESULTS: Mean PTA-ABG in the CH-group increased from 20.9 ± 11.3 dB to 22.3 ± 10.4 dB early postoperatively and decreased significantly to 19.2 ± 10.1 dB late postoperatively. Mean PTA-ABG in the COM_T_AP-group decreased significantly from 27.3 ± 10.9 dB to 20.6 ± 10.9 dB early postoperatively and decreased to 20.0 ± 12.2 dB late postoperatively. No significant difference was seen between PTA-ABG-closures of partial or total ossicular replacement prosthesis (PORP/TORP) and cartilage ossiculoplasty in the CH-group. Patients receiving TORP showed a significantly higher preoperative PTA-ABG. All reconstruction types exhibited postoperative PTA-ABG around 20 dB. In the COM_T_AP-group, smokers had a significantly higher mean PTA-ABG early postoperatively; this equalized with that of non-smokers late postoperatively. PTA-ABG-closures and MER-I or OOPS-I were not significantly correlated. CONCLUSION: Tympanoplasty type III maintains hearing in patients with cholesteatoma and significantly improves hearing in chronically inflamed ears without cholesteatoma. All investigated ossicular replacement prostheses are equally beneficial. Healing postoperatively takes longer in smokers, but they eventually catch up with non-smokers.

Frequent, geographically structured heteroplasmy in the mitochondria of a flowering plant, ribwort plantain (Plantago lanceolata).

Recent research has convincingly documented cases of mitochondrial heteroplasmy in a small set of wild and cultivated plant species. Heteroplasmy is suspected to be common in flowering plants and investigations of additional taxa may help understand the mechanisms generating heteroplasmy as well as its effects on plant phenotypes. The role of mitochondrial heteroplasmy is of particular interest in plants as cytoplasmic male sterility is controlled by mitochondrial genotypes, sometimes leading to co-occurring female and hermaphroditic individuals (gynodioecy). Paternal leakage may be important in the evolution of mating systems in such populations. We conducted a genetic survey of the gynodioecious plant Plantago lanceolata, in which heteroplasmy has not previously been reported, and estimated the frequencies of mitochondrial genotypes and heteroplasmy. Sanger sequence genotyping of 179 individuals from 15 European populations for two polymorphic mitochondrial loci, atp6 and rps12, identified 15 heteroplasmic individuals. These were distributed among 6 of the 10 populations that had polymorphisms in the target loci and represented 8% of all sampled individuals and 15% of the individuals in those 6 populations. The incidence was highest in Northern England and Scotland. Our results are consistent with geographic differences in the incidence of paternal leakage and/or the rates of nuclear restoration of male fertility.

Guideline-adherent therapy in patients with acute coronary syndromes. The EPICOR registry in Germany.

BACKGROUND: Representative data on the current management of patients with acute coronary syndromes (ACS) are of high interest. The EPICOR registry aimed to prospectively collect such real-life data with particular focus on antithrombotic drug utilization and outcomes. METHODS: As part of the international prospective EPICOR registry, 29 hospitals in Germany documented 296 patients with ST-elevation myocardial infarction (STEMI)-ACS and 333 with unstable angina or non-STEMI (NSTEMI)-ACS surviving the hospital phase. The statistical analysis was performed in a descriptive manner. The ClinicalTrials.gov identifier is NCT01171404. RESULTS: The mean age of patients was 62 ± 13 years, and 77.4 % were men. Treatment with antithrombotic agents was initiated in the prehospital phase in 50.7 % of STEMI and 33.3 % of NSTEMI patients. During the hospital stay (median 7.0 days), cardiac catheterization was performed in 97.6 %, percutaneous coronary intervention in 85.6 %, thrombolysis in 4.6 %, and coronary bypass surgery in 2.7 % patients. The use of acetylic salicylic acid (ASA) was reported in 95.6 % vs. 96.1 %, clopidogrel in 60.8 % vs. 73.0 %, prasugrel in 45.6 % vs. 22.5 %, any GP IIb/IIIa inhibitor in 52.4 % vs. 18.9 % [any dual combination of ASA+(clopidogrel/prasugrel)in 94.0 vs. 91.0 %], statins in 94.6 % vs. 92.2 %, beta blockers in 96.3 % vs. 94.6 %, and ACE-I/ARB in 91.6 % vs. 87.7 % of STEMI vs. NSTEMI patients, respectively. Combined use of the five drug classes recommended in the guidelines-ASA, P2Y12 antagonists, statin, beta blocker, and ACE-I/ARB-was reported in 81.1 % vs. 69.4 % of STEMI vs. NSTEMI patients, respectively. CONCLUSION: In Germany a high proportion of patients with ACS are treated according to current guidelines, receiving primary revascularization as well as antithrombotic drugs and other agents for prevention of secondary events; associated bleeding complications were less frequent as compared with published registries.

The functional and aesthetic reconstruction of midfacial and orbital defects by combining free flap transfer and craniofacial prosthesis.

OBJECTIVES: The reconstruction of complex facial defects should satisfy both aesthetic and functional requirements. In the midfacial area, the nasal passage should be sufficiently separated from the orbit and the oral cavity to avoid both dysphagia and articulation disorders and to allow unimpaired nasal breathing. In the case of large defects, the use of craniofacial prostheses alone is ineffective in the restoration of functional units in the majority of patients. Therefore, we evaluated the combination of microvascular tissue transfer and episthetic constructions in a series of patients. MATERIAL AND METHODS: Our case series included ten patients requiring one or more free flaps in combination with extraoral implants and episthetic work. RESULTS: Four women and six men with a mean age of 68 years were included. All patients were treated because of tumours in the midface area. Eight patients were free of recurrence, one patient died during the follow-up. For the reconstructions, we used anterolateral thigh flaps, radial forearm flaps, fibular flaps and iliac crest bone flaps. On average, we inserted four extraoral implants in the periorbital region. Seven implants of four patients did not osseointegrate and had to be removed. CONCLUSIONS: For complex reconstructions of extensive defects in the midfacial area, microvascular free tissue transfer in combination with extraoral implants and craniofacial prosthetic work yields reasonable functional and aesthetic outcomes and noticeably improves the quality of life. CLINICAL RELEVANCE: This work investigates patient cases with extensive defects in which free flap or episthetic work alone proved ineffective for reconstruction.

Modelling the effect of myosin X motors on filopodia growth.

We present a numerical simulation study of the dynamics of filopodial growth in the presence of active transport by myosin X motors. We employ both a microscopic agent-based model, which captures the stochasticity of the growth process, and a continuum mean-field theory which neglects fluctuations. We show that in the absence of motors, filopodia growth is overestimated by the continuum mean-field theory. Thus fluctuations slow down the growth, especially when the protrusions are driven by a small number (10 or less) of F-actin fibres, and when the force opposing growth (coming from membrane elasticity) is large enough. We also show that, with typical parameter values for eukaryotic cells, motors are unlikely to provide an actin transport mechanism which enhances filopodial size significantly, unless the G-actin concentration within the filopodium greatly exceeds that of the cytosol bulk. We explain these observations in terms of order-of-magnitude estimates of diffusion-induced and advection-induced growth of a bundle of Brownian ratchets.

A review of analytical parameters in 'rapid' liquid chromatographic methods for bioanalysis: Can we do better?

Rapid bioanalysis is beneficial to many applications. However, how 'rapid' a method is, or could be, is often an unanswered question. In this statistical review, the authors have assessed multiple pre-analytical (i.e. sample preparation), and analytical method parameters specifically for liquid chromatography to assist researchers in developing and validating 'rapid' bioanalytical methods. We restricted the search to urine and plasma matrices only. Data were extracted from over 2,000 recent studies and evaluated to assess how these parameters affected the 'on-instrument' analysis time. In addition to methods using ultra-violet (UV) detection, there were a large number of mass spectrometric (MS) methods, allowing additional review of the differences between high- and low-resolution MS on analysis time. We observed that most (N = 922, 70 %) methods used 5 or 10 cm columns, and that whilst uptake of ultra-high performance (U)HPLC columns was good, the use of sub-5 cm columns and/or flow rates in excess of 1 mL/min was incredibly rare (N = 25, 3 %). The detector of choice for quantitative (U)HPLC-MS remains the triple quadrupole, although a number of groups report the use of high-resolution MS for such methods.

"They just looked at me like I was human": The experiences of parenting women and providers with substance use disorder treatment.

BACKGROUND: The current US addiction treatment system does not effectively meet the needs of pregnant and parenting women with substance use disorder (SUD). The aim of this research was to identify barriers and facilitators to engagement and retention in SUD residential treatment for pregnant and parenting women. This research was part of a co-design process to collaboratively create a more patient-centered long-term residential program. DESIGN AND METHODS: The study conducted semi-structured individual interviews with both parenting women with lived experience (WWLE) in residential SUD treatment and SUD treatment providers. Interviews aimed to elicit participants' experiences either receiving or providing care. The study team analyzed data in NVivo-12 using a deductive codebook based on the six principles of trauma informed care (TIC). RESULTS: We conducted a total of 32 interviews (WWLE =13, SUD providers =19). The study identified four major themes: 1) peer relationships provide inspiration and diminish shame; 2) providing individuals safe space to stumble in recovery creates opportunities for growth and builds self-efficacy; 3) reasonable, clear boundaries create a structured, protective environment for early recovery; 4) nonjudgmental connections facilitate engagement and build trust. We identified small pivotal moments along the continuum of care that showed how the elements in the four themes enhanced engagement and retention in treatment. These interactions, along the care continuum, are either structural (workflow process) or relational (interpersonal). CONCLUSION: This research increases understanding of the interplay of the structural and relational barriers and facilitators to engagement and retention in treatment. These seemingly minor positive or negative interactions along the care continuum are pivotal to fully operationalizing TIC and optimizing women's engagement in treatment. Improvement strategies that integrate the voices of WWLE and collaboratively co-design a more patient-centered system are critical steps to improving engagement in SUD treatment and more equitable SUD treatment services.

Substance use and mental health factors associated with self-reported higher risk cannabis use among people with HIV screened in primary care.

Background: While cannabis use is prevalent among people with HIV (PWH), factors associated with higher-risk use require further study. We examined factors associated with indicators risk for cannabis use disorder (CUD) among PWH who used cannabis. Methods: Participants included adult (≥18 years old) PWH from 3 HIV primary care clinics in Kaiser Permanente Northern California who reported past three-month cannabis use through the computerized Tobacco, Alcohol, Prescription medication, and other Substance use (TAPS) screening. Primary outcome was TAPS cannabis score (range 1-3), categorized as any use (1) and higher risk for CUD (≥2). Measures included sociodemographics (age, sex, race, neighborhood deprivation index [NDI]), Charlson Comorbidity Index (CCI), HIV RNA, CD4 cell counts, higher risk tobacco use (TAPS tobacco score≥2), depression, and anxiety symptoms. Unadjusted and multivariable logistic regression examined factors associated with higher risk for CUD. Results: Of the complete sample (N=978; 94.1% Male; 58.3% White; Age Mode=51-60), 35.8% reported higher risk for CUD. Unadjusted models indicated younger age, Black race, higher CCI, depression, anxiety, and higher risk tobacco use were associated with higher risk, while only Black race (OR=1.84, 95% CI[1.29, 2.63]), anxiety (OR=1.91, 95% CI[1.22, 2.98]), and higher risk tobacco use (OR=2.27, 95% CI[1.47, 3.51]) remained significant in the multivariable model. Conclusions: Black race, anxiety and tobacco use, but not HIV clinical markers, were associated with higher risk for CUD among PWH. Clinical efforts to screen and provide interventions for preventing CUD alongside anxiety and tobacco use among PWH should be evaluated.

Flow analyses of microvascular bifurcation using laser Doppler anemometry.

INTRODUCTION: Vascular surgery affects, among other factors, vessel geometry and might result in significant flow changes. For this reason a basic understanding of flow behavior at bifurcations plays an important role for microsurgeons. The aim of the present work was to establish an experimental model that enables rheological analyses of microvascular techniques. METHODS: Laser Doppler anemometer (LDA) measurements in a total of four cross-sections of a true-to-scale silicone model were performed. The model was installed in a circulatory experimental setup that simulates the physiologic human blood flow. The flow velocity data measured with the LDA system was processed and analyzed with an image-processing system. RESULTS: The flow curve at each cross-section was recorded for sevem cycles. A physiologic flow separation at bifurcational level was seen. Maximal and minimal horizontal velocities of all measurement points were between 0.32 and -0.15 m/s. No signs of turbulentlike flow were seen in the cross-sections distal to the bifurcation. A total, centrally located backflow in the diastolic phases in all four cross-sections was registered, resembling an oscillatorylike flow. CONCLUSIONS: The LDA analysis represents a valid experimental method for rheological evaluation of microvessels. Due to its unique high spatial and temporal resolution, it represents a worthwhile alternative to other flow investigations.

[Certification of head and neck tumor centers by the German Cancer Society : an overview]. / Zertifizierung von Kopf-Hals-Tumor-Zentren durch die Deutsche Krebsgesellschaft : Ein Überblick.

The German Cancer Society has certified centers of oncological care since 2003. This is realized by clearly specified criteria that are implemented in the centers' clinical practice and thus enable holistic care of oncology patients. The most important instrument here is the interdisciplinary and multiprofessional teamwork of all relevant disciplines. This transsectoral cooperation leads to continuous cooperation between out- and inpatient partners and contributes significantly to the high-quality care of oncology patients in all stages of disease. Validation of the fulfillment and implementation of the required criteria proceeds in the form of audits, the feedback from which enables the centers to continually improve their quality of care. The integration of these sustainable approaches into clinical practice not only increases patient satisfaction, but also improves the motivation of the center staff.

Substance misuse among health care workers: national survey of occupational physicians.

BACKGROUND: National Health Service (NHS) occupational health departments assist in the identification and assessment of substance-use disorders among health care workers (HCWs) and are involved in the management of an individual's return to work after treatment. AIMS: To determine the experience and training of NHS occupational health physicians (OHPs) in identifying substance misuse among HCWs. METHODS: A national, cross-sectional, postal-based questionnaire was administered to the Association of National Health Occupational Physicians membership. RESULTS: A total of 145/224 (65%) OHPs (55% male), with a mean age of 49 years (SD ± 9.1; range 28-76), who had worked in the NHS on average for 9.6 years took part. The majority of respondents were consultant grade (59%). Since taking up their NHS post, 26% had received no training in substance misuse. Of those who had undergone formal training, the mean duration received was 2.8 days for drugs and 3.5 days for alcohol. OHPs reported that they did not feel sufficiently trained in this area. Most (65%) did not routinely include standardized screening tools or deliver 'brief interventions' (78%), although many reported that they would routinely ask about substance use when there was no clear indication of use (42%). The majority did not feel they were adequately supported (54%) in this work, nor did they have adequate resources for these patients within their organization (68%). CONCLUSIONS: OHPs see HCWs with substance-use problems as part of their work, but the support provided is likely limited by insufficient training and inadequate support.

Evaluation of a new optical measuring system for experiments on fractured human mandibles: a biomechanical feasibility study in maxillofacial surgery.

OBJECTIVES: Biomechanical loading on human mandibles was performed and a new optical measurement device was introduced for the quantification of interfragmentary movement in fractured mandibles stabilized with different osteosynthesis systems. MATERIALS AND METHODS: Comparison tests were performed with monocortical non-locking double plates and bicortical single locking plate. For the experiments on a specialized test bench, 18 ex vivo fractured human cadaveric mandibles were tested. Interfragmentary motion was detected in all three spatial dimensions using the optical measurement device PONTOS®. The movement was investigated over increasing incisal force and one summarized parameter was investigated. RESULTS: For the maximal tested load of 300 N m, the resultant interfragmentary movements in the two investigated groups were 2.96 ± 1.85° for the fixation with two conventional miniplates (six hole, profile 1.0 mm) and 4.53 ± 2.49° for single bicortically fixed locking plates (four hole, profile 1.5 mm). For both plate systems, we used the 2.0 mm screw system. CONCLUSIONS: The test bench in combination with the new optical device PONTOS(®) can test the primary stability of osteosynthesis. We offer a solution to the problem of rate of twist of the mandible as well as typical rotational problem in recent measurements. Further, the method can be used for development of new osteosynthesis products. CLINICAL RELEVANCE: Pseudoarthrosis formation is a common problem based on unsatisfying fixation of the fracture gap. The here presented combination of mechanical tests and numerical simulations can provide support for an improved treatment of fractured mandibles.

[Screening for glaucoma by blue light-pattern ERG and OCT--are the methods comparable?]. / Glaukomscreening mit dem blaulicht-muster-ERG und dem OCT--sind beide verfahren gleichwertig?

BACKGROUND: Up to now, several examinations are necessary to identify early glaucoma. It is also possible to analyse the peripapillary retinal nerve fibre layer thickness by means of OCT. The loss of retinal ganglion cells can be measured by pattern ERG, therefore this method could be used for the detection of early glaucoma. This study compares the results of the blue light-pattern ERG with the Stratus OCT for glaucoma early recognition. PATIENTS AND METHODS: We studied 30 healthy test persons, 20 patients with glaucoma and 20 patients with suspected glaucoma. Each group was examined using eye pressure measurements, funduscopy, perimetry, pachymetry und analysing the retinal nerve fibre layer by the Stratus OCT. The diagnostic work-up was completed by the pattern ERG and an upgrade with a blue light filtering glass. The results of the blue light-pattern ERG and the OCT ("healthy" or "pathological") were compared in a cross table and the agreement between these two raters was measured by the Cohen's kappa coefficient. RESULTS: Pattern ERG and blue light-pattern ERG decrease with advancing age. After developing an age-matched calibration graph we defined standard values up to the age of 56 years. All included subjects were classified by Stratus OCT and blue light-pattern ERG as healthy. We recognised a significant reduction of the retinal nerve fibre layer thickness and the amplitude in the pattern ERG in the cluster of glaucoma patients. For most of them, a blue light-pattern ERG could not be recorded. Nine out of 40 glaucoma suspect eyes were judged as "pathological". Regarding the amplitudes of the blue light-pattern ERG 25 of 28 eyes under suspicion of glaucoma were assigned as "healthy". With the aid of the cross table we estimated a Cohen's kappa of 0.4. The sensitivity of the blue light-pattern ERG was computed to be 70 % and the specificity to be 97.7 %. For the OCT we calculated the sensitivity to be 50 % and the specificity to be 100 %. CONCLUSION: The blue light-pattern ERG correlates in 87 % of our cases with the OCT. Healthy test persons are certainly identified just as well as definitely glaucomatous patients. To distinguish people suspected of early glaucoma the blue light-pattern ERG can be used as an additional, fast and economic diagnostic procedure.

Accounting for the association between childhood maltreatment and alcohol-use disorders in males: a twin study.

BACKGROUND: An association between childhood maltreatment and subsequent alcohol abuse and/or dependence (AAD) has been found in multiple studies of females. Less is known about the association between childhood maltreatment and AAD among males, and the mechanisms that underlie this association in either gender. One explanation is that childhood maltreatment increases risk for AAD. An alternative explanation is that the same genetic or environmental factors that increase a child's risk for being maltreated also contribute to risk for AAD in adulthood. METHOD: Lifetime diagnosis of AAD was assessed using structured clinical interviews in a sample of 3527 male participants aged 19-56 years from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders. The sources of childhood maltreatment-AAD association were estimated using both a matched case-control analysis of twin pairs discordant for childhood maltreatment and bivariate twin modeling. RESULTS: Approximately 9% of participants reported childhood maltreatment, defined as serious neglect, molestation, or physical abuse occurring before the age of 15 years. Those who experienced childhood maltreatment were 1.74 times as likely to meet AAD criteria compared with males who did not experience childhood maltreatment. The childhood maltreatment-AAD association largely reflected environmental factors in common to members of twin pairs. Additional exploratory analyses provided evidence that AAD risk associated with childhood maltreatment was significantly attenuated after adjusting for measured family-level risk factors. CONCLUSIONS: Males who experienced childhood maltreatment had an increased risk for AAD. Our results suggest that the childhood maltreatment-AAD association is attributable to broader environmental adversity shared between twins.

bcl-2 antisense therapy chemosensitizes human melanoma in SCID mice.

Malignant melanoma is a prime example of cancers that respond poorly to various treatment modalities including chemotherapy. A number of chemotherapeutic agents have been shown recently to act by inducing apoptosis, a type of cell death antagonized by the bcl-2 gene. Human melanoma expresses Bcl-2 in up to 90% of all cases. In the present study we demonstrate that bcl-2 antisense oligonucleotide treatment improves the chemosensitivity of human melanoma grown in severe combined immunodeficient (SCID) mice. Our findings suggest that reduction of Bcl-2 in melanoma, and possibly also in a variety of other tumors, may be a novel and rational approach to improve chemosensitivity and treatment outcome.

[Mandibular osteoma in a case of Gardner's syndrome]. / Mandibuläres Osteom bei Gardner-Syndrom.

Gardner's syndrome is characterized by the triad of intestinal polyposis accompanied by multiple hard- and soft-tissue tumors. Untreated, all patients will develop gastrointestinal cancer by the age of 40. Although incurable, progression can be prevented by close monitoring and prophylactic colectomy to prevent malignancy. Multiple osteomas of the head and jaw bones are common extraintestinal manifestations of Gardner's syndrome and can be helpful in the diagnostic work-up. The disease pattern should be known to the treating physician, since extraintestinal manifestations usually occur long before intestinal polyposis and early diagnosis is critical for the prognosis.

Preventing glycaemic relapse in recently controlled type 2 diabetes patients: a randomised controlled trial.

AIMS/HYPOTHESIS: After achieving glycaemic control, many type 2 diabetic patients relapse to clinically significant levels of hyperglycaemia. We sought to determine the optimal frequency of telephone contact by nurse practitioners that was necessary to prevent glycaemic relapse. METHODS: This parallel, randomised controlled trial ran from June 2002 to February 2006 at an academic medical centre, studying 164 type 2 diabetic patients who had recently achieved glycaemic control. Participants were randomly assigned by sequential, concealed, computer-generated allocation to a 2 year maintenance strategy consisting of: (1) routine follow-up (n = 54); (2) routine follow-up and quarterly telephone contact (n = 55); or (3) routine follow-up and monthly telephone contact (n = 55). Blinding was not possible. The primary outcome was cumulative incidence of glycaemic relapse, defined as an increase in HbA(1c) of > or =1%; all participants were analysed. Cumulative incidence and prevalent proportions were compared. Weight change and hypoglycaemia were also assessed. RESULTS: All participants randomised were included in the analyses. The study was completed by 90% of participants and intervention fidelity was high. At 24 months, the cumulative incidence of relapse was 41%. At 12 months, prevalent proportions of relapse were 20%, 14% and 15% for control, quarterly contact and monthly contact, respectively. At 24 months, they were 25%, 21% and 29%, respectively. There was no statistically significant difference in cumulative incidence or prevalent proportions of relapse among the study arms. Adverse events did not differ between study arms. CONCLUSIONS/INTERPRETATION: This first randomised controlled trial to test an intervention to prevent glycaemic relapse found that regularly scheduled telephone contact by a nurse practitioner was no more effective than routine follow-up care in preventing glycaemic relapse.

Rearrangement of exogenous immunoglobulin VH and DJH gene segments after retroviral transduction into immature lymphoid cell lines.

A model substrate for the joining of Ig VH and DJH elements has been constructed in a retroviral vector carrying a selectable marker whose expression is independent of the arrangement of the resident Ig gene segments. The substrate was introduced into lymphoid and nonlymphoid cells, and site-specific recombination between the VH and DJH elements was monitored by a direct hybridization assay. Joining of the exogenous gene segments was observed in cell lines representative of three distinct stages in early B cell differentiation. Rearrangement was not observed in three cell lines derived from mature B cells, or in a fibroblastoid cell line. The VH and DJH elements were initially arranged so that the VH-DJH junction and the recombined flanking sequences could be recovered after rearrangement. By molecular cloning and nucleotide sequence determination, VH-DJH junctions formed upon rearrangement of the substrate were found to resemble closely similar junctions in functional H chain genes. The joining of VH and DJH elements was observed to be asymmetric; loss of nucleotides occurred at the coding joints, but not at the junctions between flanking sequences. Our results suggest that Ig H and L chain gene segments are joined by a common mechanism that is more active in B cell precursors than in mature B cells. These observations provide further evidence that the rearrangement of Ig gene segments occurs by a nonreciprocal recombinational mechanism. The model substrate described here is likely to be of use in defining the nucleotide sequences that mediate rearrangement and in examining the developmental specificity of this process.

Autoantibodies to desmoplakin I and II in patients with erythema multiforme.

Erythema multiforme (EM) represents a syndrome of chronic recurrent inflammatory skin disease. Depending on the severity and extent of skin and mucosal involvement, it is defined either as EM minor or EM major. In this study we demonstrate the presence of autoantibodies (aAbs) against desmoplakin I and II, two major proteins of the desmosomal plaque, in six of six patients with the severe variant of EM, EM major. Light microscopic studies of lesional skin and mucous membranes localized in vivo bound immunoglobulin G (IgG) in a dotted desmosomal pattern along the cytoplasmic membranes of keratinocytes. By immunoelectronmicroscopy, in vivo bound IgG was confined to the desmosomal plaques. These findings were confirmed by indirect immunolocalization studies that demonstrated the presence of IgG aAbs in the serum of patients during active disease. These aAbs did not only bind to desmosomal plaques of epithelial cells where they colocalized with defined murine monoclonal antibodies directed against desmoplakin I and II, but also labeled the intercalated discs of myocardial cells. Biochemical characterization of circulating IgG aAbs revealed desmoplakin I and II as actual target autoantigens. By passive transfer of serum into newborn mice, in vivo binding of serum aAbs to keratinocytes was shown. The findings presented in this study imply a humoral immune response in certain patients with EM major and indicate a potential pathogenetic role of aAbs against desmoplakin I and II in this disease.