Peritransplant use of ultraviolet-B irradiation (UV-B) therapy is detrimental to allogeneic stem cell transplantation outcome.

Whole-body UV-B phototherapy has been used for the treatment of graft-versus-host disease (GVHD) of the skin and has systemic immunosuppressive and tolerogenic effects. We hypothesized that whole-body UV-B therapy would improve donor engraftment and decrease the incidence and severity of GVHD that is associated with decreased intensity allogeneic hematopoietic stem cell transplantation. This study tested the feasibility of using UV-B phototherapy that was initiated before grafting and continued until engraftment to determine its effect on transplantation outcome. Eight patients (median age, 55.5 years; range, 32-65 years) with hematologic malignancies were included. Allogeneic peripheral blood stem cells were obtained from matched related (n=5) or matched unrelated (n=3) donors. Conditioning regimen was fludarabine 30 mg/m2 intravenously for 5 days, cyclophosphamide 1 g/m2/d intravenously for 2 days, and equine antithymocyte globulin 30 mg/kg/d for 2 days. GVHD prophylaxis included cyclosporine, methylprednisolone, and escalating doses of narrowband UV-B (311 nm) according to skin tolerance, 3 days a week, from 10 days before to 28 days after transplantation. The conditioning regimen and the UV-B therapy were well tolerated. Two patients received all 14 prescribed UV-B treatments (cumulative doses of 2000 and 3260 mJ/cm2, respectively) and 6 patients received 8 to 13 treatments with a cumulative dose range of 528-3465 mJ/cm2. There was a rapid decrease in epidermal CD1a+ cells by day of transplantation. Myeloid engraftment was rapid. One patient had secondary engraftment failure at 3 months and another had mixed chimerism at day 100. Seven of 8 patients developed severe acute GVHD (grade III, n=5; grade IV, n=2). Six had skin involvement, 5 had gastrointestinal involvement, and 1 had liver involvement. Four patients died (2 from sepsis, 1 from acute GVHD, and 1 from chronic GVHD). Four patients are alive (130-287 days), 3 with extensive chronic GVHD. We conclude that extended peritransplant UV-B therapy at the standard minimally erythemogenic dose is detrimental to the outcome of allogeneic stem cell transplantation. It is unclear how UV-B at this immunsuppressive dose might have altered skin and systemic cytokine and immune cell compositions in the host and increased GVHD- and treatment-related mortalities. Different UV-B dose and schedules should be further explored. However, although other phototherapeutic modalities may be effective against GVHD, extended UV-B therapy should not be used during early phases of decreased conditioning allogeneic transplantation.     

Developing resources to teach and assess the core competencies: a collaborative approach.

Graduate medical education programs face new challenges as they seek to comply with the mandate from the Accreditation Council on Graduate Medical Education to demonstrate that they are teaching and assessing residents on the six core competencies. The authors describe a project designed as a collaborative venture between the American Academy of Allergy, Asthma, and Immunology (AAAAI) and the Center for Educational Outcomes at Dartmouth College (CEdO) to provide residency programs in allergy/immunology with resources for teaching and assessing the core competencies. The goal was to create a set of learning and assessment resources that maximized the content knowledge expertise provided by the AAAAI and the learning expertise provided by CEdO. A highly interactive, iterative process was used to create a set of Web-based modules. Bilateral communication, buy-in, and active involvement in the process were seen as crucial to the development of resources and their successful implementation. Approximately 18 months after the modules were made available to training program directors, 80% of the directors surveyed were aware of and had accessed the modules. The joint creation process used in this project, designed to be generally applicable across specialties, reveals how the burden of meeting new requirements can be decreased when experts in content knowledge and experts in learning collaborate.     

B cell early response gene expression coupled to B cell receptor,CD40 and interleukin-4 receptor co-stimulation: evidence for a role of the egr-2/krox20 transcription factor in B cell proliferation

B lymphocytes are activated following antigen stimulation of the B cell receptor but require co-stimulation with accessory molecules provided by interleukin (IL)-4/CD40 ligand for cell cycle progression and proliferation. By analyzing a panel of 11 early response genes induced by cross-linking of surface immunoglobulin, we show that CD40 signaling alone induces only 2 genes, c-myc together with an anonymous gene, 3L3, and that these are distinct from the set of genes induced in response to IL-4. Co-stimulation with the proliferative combination of anti-μ, IL-4 + CD40 signaling led to a fourfold enhancement of egr-2/krox20 expression over that seen with anti-μ alone. Egr-2 expression/activity was selectively inhibited by the immunosuppressive drug cyclosporin A, and antisense oligonucleotide blockade of Egr-2 activity elicited a dose-dependent inhibition of B cell proliferation. Taken together, these observations show that the early gene regulatory programs coupled to different surface receptors on B cells are largely distinct from each other, but that certain genes, exemplified by egr-2, may represent a point of convergence in the integration of different signaling pathways into the B cell proliferative response.     

Prevalence of mitochondrial DNA mutations in childhood/congenital onset non-syndromal sensorineural hearing impairment

Genetic factors are the major causes of childhood hearing impairment. Whereas autosomal recessive mutations account for the majority of prelingual non-syndromic sensorineural hearing impairment (NSSHI), the relative contribution of mitochondrial DNA (mtDNA) mutations to childhood onset NSSHI has not been established.
We screened 202 subjects with congenital/childhood onset NSSHI, consisting of 110 sporadic cases, 75 sib pairs, and 17 families with affected subjects in more than one generation, in order to determine the prevalence of mtDNA mutations associated with NSSHI.
mtDNA mutations were found in three of 10 families (30%) in whom the affected members were related through the maternal lineage. One sporadic case (0.9%) was also found to have a known mtDNA mutation but none was found in the sib pairs.
Although the prevalence of mtDNA mutations was low in the group as a whole (2%), we suggest that screening should be considered in cases of childhood hearing impairment when it is progressive and particularly in families where transmission is compatible with maternal inheritance.


Keywords: mitochondrial DNA; point mutation; hearing impairment     

Neuromuscular adaptation during prolonged strength training, detraining and re-strength-training in middle-aged and elderly people

Effects of a 24-week strength training performed twice weekly (24 ST) (combined with explosive exercises) followed by either a 3-week detraining (3 DT) and a 21-week re-strength-training (21 RST) (experiment A) or by a 24-week detraining (24 DT) (experiment B) on neural activation of the agonist and antagonist leg extensors, muscle cross-sectional area (CSA) of the quadriceps femoris, maximal isometric and one repetition maximum (1-RM) strength and jumping (J) and walking (W) performances were examined. A group of middle-aged (M, 37–44 years, n=12) and elderly (E, 62–77, n=10) and another group of M (35–45, n=7) and E (63–78, n=7) served as subjects. In experiment A, the 1-RM increased substantially during 24 ST in M (27%, P < 0.001) and E (29%, P < 0.001) and in experiment B in M (29%, P < 0.001) and E (23%, P < 0.01). During 21 RST the 1-RM was increased by 5% at week 48 (P < 0.01) in M and 3% at week 41 in E (n.s., but P < 0.05 at week 34). In experiment A the integrated electromyogram (IEMG) of the vastus muscles in the 1-RM increased during 24 ST in both M (P < 0.05) and E (P < 0.001) and during 21 RST in M for the right (P < 0.05) and in E for both legs (P < 0.05). The biceps femoris co-activation during the 1-RM leg extension decreased during the first 8-week training in M (from 29 ± 5% to 25 ± 3%, n.s.) and especially in E (from 41 ± 11% to 32 ± 9%, P < 0.05). The CSA increased by 7% in M (P < 0.05) and by 7% in E (P < 0.001), and by 7% (n.s.) in M and by 3% in E (n.s.) during 24 ST periods. Increases of 18% (P < 0.001) and 12% (P < 0.05) in M and 22% (P < 0.001) and 26% (P < 0.05) in E occurred in J. W speed increased (P < 0.05) in both age groups. The only decrease during 3 DT was in maximal isometric force in M by 6% (P < 0.05) and by 4% (n.s.) in E. During 24 DT the CSA decreased in both age groups (P < 0.01), the 1-RM decreased by 6% (P < 0.05) in M and by 4% (P < 0.05) in E and isometric force by 12% (P < 0.001) in M and by 9% (P < 0.05) in E, respectively, while J and W remained unaltered. The strength gains were accompanied by increased maximal voluntary neural activation of the agonists in both age groups with reduced antagonist co-activation in the elderly during the initial training phases. Neural adaptation seemed to play a greater role than muscle hypertrophy. Short-term detraining led to only minor changes, while prolonged detraining resulted in muscle atrophy and decreased voluntary strength, but explosive jumping and walking actions in both age groups appeared to remain elevated for quite a long time by compensatory types of physical activities when performed on a regular basis. Accepted: 2 May 2000     

Salt intake by normotensive and spontaneously hypertensive rats: two-bottle and lick rate analyses

Spontaneously hypertensive rats (SHR) overconsume NaCl compared to the normotensive Wistar Kyoto rat (WKY) rat. In the present experiment, two-bottle preference for NaCl (0.01, 0.03, 0.1, 0.3, 0.5, 1.0, 3.0 M) and lick rate analyses were used to identify the possible mechanisms that underlie the intake of NaCl by male SHR. Two-bottle preference and absolute NaCl intake by SHR were greater than that of WKY rats. When NaCl intake was calculated on the basis of body weight, SHR consumed more NaCl per 100 g body weight than did WKY. Also, during the one-bottle test, SHR consumed more 0.1 and 0.3 M NaCl per 100 g body weight than did WKY. The increased intake of NaCl by SHR was most evident for 0.3 M NaCl. Intake is determined by the initial rate of licking and the decline in lick rate over time. Nonlinear regression analysis of lick rate showed that the initial lick rates (licks/min) were similar for male WKY and SHR. Lick rate declined more rapidly when WKY rats drank 0.3 M than when they drank 0.1 M NaCl, a result consistent with the role of negative feedback in controlling the decay in lick rate. This concentration-dependent change in lick rate was not seen in SHR. Also, SHR lick rate for 0.1 and 0.3 M NaCl decelerated more slowly than that of WKY rats. The increased intake of hypertonic NaCl by SHR was due to a decrease in the decline in lick rate, suggesting that SHR are less responsive to ingestion-contingent negative feedback.     

Filling the gaps in physician communication. The role of the Internet among primary care patients

BACKGROUND: Millions of people use the Internet as a source for health information yet little is understood about how the use of the Internet for health information is related to the doctor-patient relationship. OBJECTIVE: We conducted the present study to understand the association between one's interest in using the Internet for general and quality-oriented health information and attitudes about one's communications with health care provider(s). DESIGN: Cross-sectional survey. SETTING: Four community-based primary care practices in Rhode Island. MEASUREMENTS: A single self-administered survey included items to measure: interest in using the Internet to look for general and quality-oriented information and a patient's perceptions of the degree to which their doctors over the previous year have: (1) given them information and (2) engaged them in the decision-making process. RESULTS: A total of 300 patients completed the survey. Among patients without Internet access, interest in using the Internet for health related activities was less among patients who felt that their doctor gave less information: Odds ratio 0.83 (95% CI, 0.70-0.98) and greater among patients who felt that their doctor engaged them more in decision making: Odds ratio 1.3 (95% CI, 1.1-1.6). Among patients with Internet access, we found no relationship between interest in using the Internet for health related activities and measures of patient-physician communication or patient-physician decision making. CONCLUSIONS: Interest in using the Internet for health information is greater for those who (1) felt their doctors provided less information and (2) felt their doctors engaged them more in the decision-making process, but this is true only for those without access to the Internet.