[Treatment effects and cost-effectiveness of interdisciplinary multimodal pain treatment of patients with back pain : A controlled observational intervention study based on claims data and survey data of participants]. / Behandlungs- und Kosteneffekte der interdisziplinären multimodalen Schmerztherapie bei Patienten mit Rückenschmerz : Eine kontrollierte, nicht-randomisierte Interventionsstudie mit GKV-Daten und Teilnehmerbefragung.

BACKGROUND: Persons insured by AOK Nordost statutory health insurance (SHI) and on sick leave underwent a 20-day program of interdisciplinary multimodal pain therapy (IMST) following an initial assessment (IA). We evaluated its effectiveness regarding sick leave, utilization/costs of SHI services, and patient-reported characteristics of pain. MATERIALS AND METHODS: Participants with >14 days of IMST in 2013-2015 and with data necessary for comparison (intervention group, IG) were matched 1:1 in 2 steps. From AOK Nordost data, we identified a comparison group (CG) having characteristics matching exactly and by propensity score. Starting on the IA (IG) or a comparable reference day (CG), we analyzed utilization/costs of services related to back pain for 365 days. Participants' characteristics of pain were surveyed on the IA day and within 183-365 days. RESULTS: The 86 IG patients had on average 44.33 (median 12) days of sick leave less than the CG after their initial sick leave starting at the IA (significant, p <0.05). Fewer IG patients had ≥1 hospitalization (OR 0.33; 95%CI 0.12-0.88), ≥1 prescription of physiotherapy (OR 0.35; 95%CI 0.24-0.82), and ≥1 specialist visit (OR 0.39; 95%CI 0.10-0.52) related to back pain. More IG patients had "lasting absence of treatment" (OR 4.06; 95%CI 1.09-15.1). Follow-up interviews were available for 56 IG patients, showing less pain intensity, impairment by pain, and pain severity (significant). Regarding the SHI perspective, cost savings per patient nearly covered the IA and IMST costs. DISCUSSION: For a selected comparable population treated by protocol, IA and IMST was associated with reduction or "lasting absence" of treatment, pain relief, and major savings on sickness benefits. Other than in previous studies we found coverage of IA and IMST costs without consideration of productivity loss.

Interruption of electronically excited Xe dimer formation by the photoassociation of Xe(6s[3/2]2)-Xe(5p(6) (1)S0) thermal collision pairs.

The diatomic collisional intermediate responsible for the formation of an electronically excited molecule by teratomic recombination has been observed in both the spectral and temporal domains by laser spectroscopy. We report experiments demonstrating thermal Xe(6s[3/2]2)-Xe(5p(6) (1)S0) atomic collision pairs to be the immediate precursor to the formation of Xe2 (∗)(a(3)Σu (+),A(1)Σu (+)) by the three body process: Xe(∗)(6s) + 2Xe ⟶ Xe2 (∗) + Xe, where the asterisk denotes an excited electronic state. Photoassociating Xe(6s)-Xe atomic pairs by free ⟵ free transitions of the collision complex interrupts the production of the electronically excited Xe dimer, thereby suppressing Xe2 spontaneous emission in the vacuum ultraviolet (VUV, λ ∼ 172 nm, A(1)Σu (+)→X(1)Σg (+)). Intercepting Xe(6s)-Xe pairs before the complex is stabilized by the arrival of the third atom in the teratomic collision process selectively depletes the pair population in a specific Franck-Condon region determined by the probe laser wavelength (λ). Measurements of the variation of VUV emission suppression with λ provide a spectral signature of the [Xe(6s[3/2]2) - Xe((1)S0)](∗) complex and map the probe laser wavelength onto the thermal energy (ϵ″) of the incoming collision pairs.

Xe2 gerade Rydberg states observed in the afterglow of a microplasma by laser spectroscopy of a(3)Σ(+)(u)(1(u), O(-)(u)) absorption in the green (545-555 nm) and near-infrared (675-800 nm).

Bound←bound transitions of the Xe dimer at small internuclear separation (R < 4.0 Å) have been observed in the 545-555 nm and 675-800 nm spectral regions by laser spectroscopy in the afterglow of a pulsed Xe microplasma with a volume of ∼160 nl. Transient suppression of Xe2 A(1)Σ(+)(u)(O(+)(u)) --> X(1)Σ(+)(g)(O(+)(g)) emission in the vacuum ultraviolet (∼172 nm), induced by laser excitation of Ω(g) ← a(3)Σ(+)(u)(1(u), O(-)(u)) [Rydberg←Rydberg] transitions of the molecule, has confirmed the existence of structure between 720 and 770 nm (reported by Killeen and Eden [J. Chem. Phys. 84, 6048 (1986)]) but also reveals red-degraded vibrational bands extending to wavelengths beyond 800 nm. Spectral simulations based on calculations of Franck-Condon factors for assumed Ω(g) ← a(3)Σ(+)(u) transitions involving Ω = 0(±),1 gerade Rydberg states suggest that the upper level primarily responsible for the observed spectrum is an Ω = 1 state correlated, in the separated atom limit, with Xe(5p(6) (1)S0) + Xe(5p(5) 6p) and built on a predominantly A(2)Π3/2g molecular ion core. Specifically, the spectroscopic constants for the upper state of the 1(g) ← 1(u), O(±)(u) absorptive transitions are determined to be Te = 13,000 ± 150 cm(-1), ω'(e) = 120 ± 10 cm(-1), ω'(e)x'(e) = 1.1 ± 0.4 cm(-1), De = 3300 ± 300 cm(-1), and ΔR(e) = R'(e) = R''(e) = 0.3 ± 0.1 Å which are in general agreement with the theoretical predictions of the pseudopotential hole-particle formalism, developed by Jonin and Spiegelmann [J. Chem. Phys. 117, 3059 (2002)], for both the (5)1g and (3)O(+)(g) states of Xe2. These spectra exhibit the most extensive vibrational development, and provide evidence for the first molecular core-switching transition, observed to date for any of the rare gas dimers at small R (<4 Ǻ). Experiments in the green (545-555 nm) also provide improved absorption spectra, relative to data reported in 1986 and 1999, associated with Xe2 Rydberg states derived from the Xe(7p) orbital.

Endothelin receptor blockade reduces ventricular dysfunction and injury after reoxygenation.

BACKGROUND: Reoxygenation of hypoxic myocardium during repair of congenital heart defects results in poor ventricular function and cellular injury. Endothelin-1 (ET-1), a potent vasoconstrictor that increases during hypoxia, may suppress myocardial function and activate leukocytes. The objective was to determine whether administration of an endothelin receptor antagonist could improve ventricular function and decrease cardiac injury after hypoxia and reoxygenation. METHODS: Fourteen piglets underwent 90 minutes of ventilator hypoxia, 1 hour of reoxygenation on cardiopulmonary bypass, and 2 hours of recovery (controls). Nine additional animals received an infusion of Bosentan, an ET(A/B) receptor antagonist, (5 mg/kg per hour) during hypoxia and reoxygenation. RESULTS: Right and left ventricular dP/dt in controls decreased to 78% and 52% of baseline, respectively, after recovery (p < 0.05). In contrast, Bosentan-treated animals had complete preservation of RV dP/dt and less depression of LV dP/dt. Bosentan reduced the hypoxia and reoxygenation-induced elevation of ET-1 and iNOS mRNA at the end of recovery (p < 0.05). Bosentan-treated animals had diminished myocardial myeloperoxidase activity and lipid peroxidation compared with controls (p < 0.05). Myocardial apoptotic index, elevated by hypoxia and reoxygenation, was lower in the Bosentan-treated animals (p < 0.05). CONCLUSIONS: Endothelin-1 receptor antagonism improved functional recovery and decreased leukocyte-mediated injury after reoxygenation. The reduction in cardiac cell death might also improve long-term outcome after reoxygenation injury.

Acute hypoxia and reoxygenation impairs exhaled nitric oxide release and pulmonary mechanics.

OBJECTIVE: Changes in exhaled nitric oxide levels often accompany conditions associated with elevated pulmonary vascular resistance and altered lung mechanics. However, it is unclear whether changes in exhaled nitric oxide reflect altered vascular or bronchial nitric oxide production. This study determined the effects of acute hypoxia and reoxygenation on pulmonary mechanics, plasma nitrite levels, and exhaled nitric oxide production. METHODS: Ten piglets underwent 90 minutes of hypoxia (fraction of inspired oxygen = 12%), 1 hour of reoxygenation on cardiopulmonary bypass, and 2 hours of recovery. Five additional animals underwent bypass without hypoxia. Exhaled nitric oxide, plasma nitrite levels, and pulmonary mechanics were measured. RESULTS: Exhaled nitric oxide decreased to 36% of baseline by end hypoxia (34 +/- 14 vs 12 +/- 9 ppb, P =.005) and declined further to 20% of baseline at end recovery (7 +/- 6 ppb). Aortic nitrite levels decreased from baseline during hypoxia (from 102 +/- 13 to 49 +/- 7 micromol/L, P =.05) but returned to baseline during recovery. Pulmonary arterial nitrite also decreased during hypoxia (from 31.4 +/- 7.8 to 22.9 +/- 9.5 micromol/L, P =.04) and returned to baseline at end recovery. Decreased production of exhaled nitric oxide was associated with impaired gas exchange (alveolar-arterial gradient = 32 mm Hg at baseline and 84 mm Hg at end recovery), decreased pulmonary compliance (6.6 +/- 0.9 mL/cm H(2)O at baseline, 5.0 +/- 0.7 mL/cm H(2)O at end hypoxia, and 5.4 +/- 0.7 mL/cm H(2)O at end recovery), and increased inspiratory airway resistance (41 +/- 4 cm H(2)O. L(-1). s(-1) at baseline, 56 +/- 4.9 cm H(2)O. L(-1). s(-1) at end hypoxia, and 50 +/- 5 cm H(2)O. L(-1). s(-1) at end recovery). CONCLUSIONS: A decrease in exhaled nitric oxide persisted after hypoxia, and plasma nitrite levels returned to baseline on reoxygenation, indicating that alterations in exhaled nitric oxide during hypoxia-reoxygenation might be unrelated to plasma nitrite levels. Furthermore, decreased exhaled nitric oxide corresponded with altered pulmonary mechanics and gas exchange. Reduced exhaled nitric oxide after hypoxia-reoxygenation might reflect bronchial epithelial dysfunction associated with acute lung injury.

Bosentan prevents hypoxia-reoxygenation-induced pulmonary hypertension and improves pulmonary function.

BACKGROUND: Acute hypoxia results in increased pulmonary vascular resistance. Despite reoxygenation, pulmonary vascular resistance remains elevated and pulmonary function is altered. Endothelin-1 might contribute to hypoxia-reoxygenation-induced pulmonary hypertension and to reoxygenation injury by stimulating leukocytes. This study was carried out using an established model of hypoxia and reoxygenation to determine whether endothelin-1 blockade with Bosentan could prevent hypoxia-reoxygenation-induced pulmonary hypertension and reoxygenation injury. METHODS: Twenty neonatal piglets underwent 90 minutes of hypoxia, 60 minutes of reoxygenation on cardiopulmonary bypass, and 2 hours of recovery. Control animals (n = 12) received no drug treatment, whereas the treatment group (n = 8) received the endothelin-1 receptor antagonist, Bosentan, throughout hypoxia. RESULTS: In controls, pulmonary vascular resistance increased during hypoxia to 491% of baseline and remained elevated after reoxygenation; however in the Bosentan group, it increased to only 160% of baseline by end-hypoxia, then decreased to 76% at end-recovery. Arterial endothelin-1 levels in controls increased to 591% of baseline after reoxygenation. Arterial nitrite levels decreased during hypoxia in controls but were maintained in the Bosentan group. Consequently, animals in the Bosentan group had better postreoxygenation pulmonary vascular resistance, A-a gradient, and airway resistance along with lower myeloperoxidase levels than controls. CONCLUSIONS: Acute hypoxia and postreoxygenation pulmonary hypertension was attenuated by Bosentan, which maintained nitric oxide levels during hypoxia, decreased leukocyte-mediated injury, and improved pulmonary function.

An HMG-I protein from human endothelial cells apparently is secreted and impairs activation of Hageman factor (factor XII).

A highly purified protein from lysates of human umbilical vein endothelial cells (HUVECs) inhibited the activation of factor XII [Hageman factor (HF)] and removed factor XIIa from an activating surface, thus impairing HF-dependent coagulation and kinin-releasing activities. Two tryptic peptides from this protein had 100% identity with amino acids 31-44 and 89-101 of a nonhistone DNA-binding protein known as high-mobility group protein (HMG-I). In specific antibody experiments, the clot-inhibiting property in purified lysate protein from HUVECs was associated with HMG-I. The molecular weight of the protein that inhibited clotting was consistent with that predicted for HMG-I. Protein that inhibited contact activation and had antigenic properties of HMG-I and HUVEC lysate protein also was found in conditioned media from unchallenged cultured HUVECs. After HUVECs were incubated with 14C lysine, conditioned media contained immunoprecipitable radiolabeled protein with the same molecular weight as that recovered from cell lysates, suggesting that this high-mobility group protein (HMG-I) may be secreted. Purified factor XII antigens were displaced from a glass surface by HMG-I from lysates in proportion to the amount of HMG-I protein that was added. This HMG-I probably inhibits factor XII functions because its high positive charge favors competitive binding to an activating substance.

An autoantibody to C1-inhibitor recognizes the reactive center of the inhibitor.

An autoantibody to C1-inhibitor produced a clinical disorder resembling that of patients with hereditary angioneurotic edema. The antibody could not interact with C1-inhibitor after exposure to synthetic peptides representing the primary structure of the reactive center region of the protein. Therefore the antibody recognized this domain of the inhibitor, and it probably impaired the function of C1-inhibitor by altering its conformational properties.

Angioneurotic edema with acquired C1- inhibitor deficiency and autoantibody to C1- inhibitor: response to plasmapheresis and cytotoxic therapy.

A patient with severe acquired angioneurotic edema had essentially no C1- inhibitor activity in his serum and nearly died of cardiopulmonary arrest during an acute episode of facial, oral, and pharyngeal edema. This patient had an antibody directed against C1- inhibitor and C1- inhibitor-anti-C1- inhibitor complexes in his serum. The antibody required a normal residue (Arg) in the reactive center of the inhibitor for its optimal interaction with the inhibitor. Plasmapheresis with 5% human serum albumin replacement relieved him of his antibody load and the edema; additional treatment with pulsed cyclophosphamide has provided a sustained remission. The 5% albumin solution that was used contained functional C1- inhibitor; other lots that were tested contained only traces or none. No underlying disease has yet been identified. During this acute episode of edema, the C1- inhibitor in the patient's plasma was a 92 kd component, and on recovery, a 105 kd component reappeared. C1- inhibitor isolated from the patient's plasma, which was obtained before pheresis, was mainly in lower molecular weight forms (56 kd and 45 kd). The antibody in the patient's serum appeared to render C1- inhibitor susceptible to proteolysis, for when purified antibody was added to normal serum, a cleaved form of C1- inhibitor was generated.

Interactions of plasma kallikrein and C1-s with normal and dysfunctional C1(-)-inhibitor proteins from patients with hereditary angioneurotic edema: analytic gel studies.

Purified preparations of normal C1(-)-inhibitor (C1(-)-INH) formed high mol wt complexes with plasma kallikrein that were stable during sodium dodecyl sulfate (SDS)-gel electrophoresis, but most of the dysfunctional C1(-)-INH proteins isolated from plasma of patients with type II hereditary angioneurotic edema (HANE) did not. Two of eight dysfunctional C1(-)-INH proteins were cleaved to lower mol wt forms that were not seen following the reaction of normal C1(-)-INH with equimolar amounts, or less, of plasma kallikrein. Only the higher mol wt component of normal C1(-)-INH (106,000 mol wt) appeared to form a stable complex with the plasma kallikrein, whereas both the 106,000 and 96,000 mol wt forms made stable complexes with C1-s. When a preparation of normal C1(-)-INH containing a homogeneous single band of C1(-)-INH was exposed to C1-s or kallikrein, a "doublet" form evolved in which the heaviest band was in the original position of native C1(-)-INH; C1-s cleavage provided a second band of 96,000; and cleavage by kallikrein, a second band of 94,000 mol wt. We conclude that dysfunctional C1(-)-INH proteins from plasma of persons with type II hereditary angioneurotic edema have impaired interactions with plasma kallikrein and are heterogeneous with respect to these interactions. Moreover, the requirements for the formation of stable complexes between normal C1(-)-INH and plasma kallikrein differed from those for stable complex formation with C1-s. The doublet form of C1(-)-INH, which purified preparations frequently demonstrate, may be due to prior cleavage by C1-s or kallikrein.

Skin test suppression by antihistamines and the development of subsensitivity.

The suppression of skin test reactivity by single doses of six antihistamines was measured before and after a period of daily antihistamine ingestion in 18 subjects. Single doses of hydroxyzine, 50 mg; chlorpheniramine, 16 mg; and promethazine, 50 mg; induced significant suppression of skin test reactivity at 2 hr, whereas the suppression produced by tripelennamine, 100 mg; diphenhydramine, 50 mg; and cyproheptadine, 16 mg; did not differ significantly from that produced by placebo. After 3 wk of treatment with hydroxyzine, 75 mg per day, the suppressive effect of hydroxyzine as well as the five clinically unrelated antihistamines was significantly reduced. Although the response to chlorpheniramine was also reduced after chronic treatment with chlorpheniramine, 24 mg per day, the difference was not statistically significant. We conclude that antihistamines in the doses used differ greatly in their suppressive effect on skin test reactivity. The antihistamine producing the most skin test suppression, hydroxyzine, when it was taken daily for 3 wk, caused the development of partial tolerance not only to its own effect but to those of clinically unrelated antihistamines.

Variability in purified dysfunctional C1(-)-inhibitor proteins from patients with hereditary angioneurotic edema. Functional and analytical gel studies.

C1(-)-inhibitor (C1(-)-INH) proteins from normal persons and members of eight different kindred with dysfunctional C1(-)-INH proteins associated with hereditary angioneurotic edema (HANE) were compared with respect to their inhibitory activity against purified preparations of C1s-, plasma kallikrein, activated forms of Hageman factor, and plasmin. Each dysfunctional C1(-)-INH protein showed a unique spectrum of inhibitory activity against these enzymes. Although none of the dysfunctional C1(-)-INH proteins significantly impaired amidolysis by plasmin, all but one inhibited activated Hageman factor. One purified dysfunctional C1(-)-INH (Ta) inhibited purified C1s- to a normal degree. Another C1(-)-INH (Za) had almost seven times as much inhibitory activity as normal C1(-)-INH against activated Hageman factor, but had decreased activity against C1s- and no activity against plasmin. Analyses of mixtures of plasmin and C1(-)-INH proteins in SDS gel electrophoresis revealed variability in the patterns of complex formation and cleavage of dysfunctional proteins after exposure to C1s- and plasmin. Some bound to plasmin and were cleaved, even though none significantly impaired the amidolytic activity of plasmin. Two were cleaved by C1s-, whereas neither normal or other dysfunctional C1(-)-INH were cleaved. Dysfunctional C1(-)-INH proteins from patients with HANE are thus heterogeneous in their inhibitory properties and there must be different structural requirements for the inhibition of the various plasma enzymes that can be regulated by normal C1(-)-INH. The data suggest that in addition to common sites of interactions between these proteases and C1(-)-INH, there are also points of contact that are specific for each protease. Genetic mutations leading to structural changes at some of these sites may have differing effects on the interaction between individual proteases and abnormal C1(-)-INH proteins. These alterations may allow these proteins to serve as probes for structural requirements for inhibitory actions of normal C1(-)-INH.

Relation between positive small air ions, weather fronts and pulmonary function in patients with bronchial asthma.

Some patients with bronchial asthma report increased symptoms in association with weather fronts. It has been reported that a rise in positive small air ions occurs several hours before other evidence of a storm front, and it has been suggested that the increase in these ions might be responsible for the changes in clinical status reported by such patients. Twelve patients were selected on the basis of a history of weather-induced worsening of asthma. They measured pulmonary functions four times daily at the same time that measurements of small air ions and other meteorologic parameters were obtained. Two episodes of inclement weather were monitored during the study period. The mean peak flow rates in this group of patients did not vary significantly with the changes in ion levels or other meteorologic factors which resulted from the passage of these weather fronts.

Lability of blocking antibody during ragweed immunotherapy.

The long-term immunologic changes with allergy injection therapy have been widely studied. There are few data, however, on the immunologic response to a single injection during the course of this therapy. Ten patients who had attained maintenance (1:100 w/v) within six months and 13 patients who had been on maintenance longer than three years were compared. Following baseline studies patients received their standard ragweed injections and were followed without further injections for 30 days. Titrated prick tests to short ragweed, specific IgE to short ragweed and IgG antibody to ragweed AgE were determined at intervals during the 30 days. Baseline values of skin tests, specific IgE and specific IgG did not differ significantly for the two groups. Values for all three parameters did not fluctuate significantly during the study. This study suggests that blocking antibody levels are stable soon after reaching maintenance and that allergy injections can be safely administered at monthly intervals beginning at that time.

Some molecular and functional changes in high molecular weight kininogen induced by plasmin and trypsin.

When purified human HMW-kininogen was digested by plasmin, its specific antigenic properties were initially enhanced and then gradually destroyed, but its clot-promoting activity (Fitzgerald factor activity) was only slightly decreased. When endogenous serum plasminogen was activated by streptokinase, similar alterations in specific HMW-kininogen antigens and Fitzgerald factor activity occurred. In contrast, trypsin induced increased antigenic properties initially, but readily destroyed the Fitzgerald factor activity and less readily destroyed the specific HMW-kininogen antigenic properties in purified HMW-kininogen and in normal human serum. When normal serum was treated with streptokinase, the antigenic properties shared by HMW and LMW-kininogens were in Sephadex G-200 fractions of lower molecular weight than in the case of untreated serum, but the elution volumes of specific HMW-kininogen antigens and Fitzgerald factor activity were not significantly altered. When prekallikrein-deficient serum was subjected to the same G-200 gel filtration process, there was a broad overlap in the elution volumes of antigens shared by both HMW and LMW-kininogens with specific HMW-kininogen antigenic and coagulant properties, which remained after streptokinase treatment of the serum. Depsite the disparate rates of destruction of the antigenic and clot-promoting portion of HMW-kininogen by proteases these properties did not separate from one another during ion exchange chromatography.