In vivo biological validation and biophysical modeling of the sensitivity and positive accuracy of endocrine peak detection. II. The follicle-stimulating hormone pulse signal

Despite interest in the in vivo control of gonadotropin release, valid assessment of the physiological regulation of the pulsatile secretion of the gonadotropin FSH has been hampered by the uncertain validity and reliability of available FSH peak detection algorithms. Difficulties in identifying FSH peaks accurately are believed to arise in part because of the slow metabolic clearance of this glycoprotein hormone. Here, we have used two complementary strategies to test the validity of FSH pulse detection. First, by means of a computer-assisted mathematical model for simulating episodic hormone secretion, we evaluated the effects of various putative FSH secretory pulse amplitudes and half-lives on the sensitivity and positive accuracy of peak detection. Secondly, we used an in vivo primate animal model, in which presumptively true FSH pulses were evaluated independently by continuous electrophysiological monitoring of mediobasal hypothalamic multiunit activity. These two approaches allowed us to define optimal pulse analysis parameters that yield maximal sensitivity and positive accuracy for detecting FSH peaks in synthetic and biological time series. We found (as predicted intuitively) that increasing half-times of hormone disappearance decrease both the sensitivity and positive accuracy of peak detection for any given peak detection thresholds and hormone secretory amplitudes. However, adequately sampled episodic FSH time series could be analyzed for FSH pulsatility by an appropriately constrained, objective computerized algorithm with reasonable (less than 10-15%) false negative and false positive errors, such that resultant sensitivity and positive accuracy exceed 85-90%. Of interest, computer simulations and the in vivo animal model exhibited similar discriminative capabilities. We conclude that increasing half-times of hormone (e.g. FSH) removal do impair hormone peak detection sensitivity and positive accuracy. Nevertheless, gonadotropin time series can be analyzed for FSH pulsatility in a valid manner with adequately constrained false negative and false positive error rates.     

Multimodale Behandlung einer Alopecia universalis

Alopecia universalis is characterized by total loss of body hair and can occur at any age, causing significant psychological morbidity in most cases. Though there is evidence to suggest that alopecia universalis is an autoimmune disease, the cause of the disease is still not known with certainty. Spontaneous recovery is unusual (<10%), and the long-term prognosis in cases not responding to therapy is poor, despite the variety of therapies available. Experience of immunosuppressive treatment in children with alopecia universalis is limited. We report on a 4-year-old boy, who was successfully treated for refractory alopecia universalis with prednisolone and cyclosporine A by mouth combined with topical application of tacrolimus. Our case report shows that systemic immunosuppression may be a promising treatment option for some children with alopecia universalis who are badly distressed by their condition. However, potential treatment-related risks have to be weighed against the psychosocial stress experienced by these patients and their families.     

Propofol and Sevoflurane in Subanesthetic Concentrations Act Preferentially on the Spinal Cord: Evidence from Multimodal Electrophysiological Assessment

Background: Animal experiments in recent years have shown that attenuation of motor responses by general anesthetics is mediated at least partly by spinal mechanisms. Less is known about the relative potency of anesthetic drugs in suppressing cortical and spinal electrophysiological responses in vivo in humans, particularly those, but not only those, connected with motor responses. Therefore, we studied the effects of sevoflurane and propofol in humans using multimodal electrophysiological assessment.

Methods: We studied nine healthy volunteers in two sessions during steady state sedation with 0.5, 1.0, and 1.5 [mu]g/l (targeted plasma concentration) propofol or 0.2 and 0.4 vol% (end-tidal) sevoflurane. Following a 15-min equilibration period, motor responses to transcranial magnetic stimulation and peripheral (H-reflex, F-wave) stimulation were recorded, while electroencephalography and auditory evoked responses were recorded in parallel.

Results: At concentrations corresponding to two thirds of C50 awake, motor responses to transcranial magnetic stimulation were reduced by approximately 50%, H-reflex amplitude was reduced by 22%, F-wave amplitude was reduced by 40%, and F-wave persistence was reduced by 25%. No significant differences between sevoflurane and propofol were found. At this concentration, the Bispectral Index was reduced by 7%, and the middle-latency auditory evoked responses were attenuated only mildly (Nb latency increased by 11%, amplitude PaNb did not change). In contrast, the postauricular reflex was suppressed by 77%.     

Effects of nerve growth factor on cortical and striatal acetylcholine and dopamine release in rats with cortical devascularizing lesions

The effects of intraventricular nerve growth factor (NGF) or saline treatments on extracellular acetylcholine (ACh), dopamine (DA) and adenosine (Ade) levels in the cortex and striatum of rats with unilateral devascularizing cortical lesions were studied in vivo with microdialysis. The devascularizing cortical lesion produced a decrease in extracellular ACh levels in both cortex and striatum as compared to those in normal rats, while the NGF treatment produced a significant increase in ACh levels in both regions. NGF could even increase cortical ACh levels in normal rats. The cortical lesion produced a decrease in extracellular DA in the cortex, while the NGF treatment appeared to reverse this effect. No significant changes in DA were observed in the striatum. The present study gives evidence that a unilateral cortical devascularizing lesion leads to changes in extracellular ACh and DA levels in cortex and striatum and that these changes could be reversed with intraventricular NGF treatment.     

Magnum system for routine coronary angioplasty: A randomized study

The Magnum system, initially designed for coronary angioplasty (PTCA) of chronic total occlusion, consists of a balloon catheter and a solid steel 0.021 inch (0.53 mm) steerable and removable wire with a soft and moldable distal portion, tipped with a 1 mm olive. To evaluate its performance in routine PTCA, 200 unselected consecutive patients were randomized to two equal groups, i.e., group Magnum (100 patients, 115 vessels) and group Standard (100 patients, 118 vessels) including 18 and 21 patients with chronic total occlusions, respectively. Randomization was performed by the sealed envelope system in the catheterization laboratory and crossover of system was imposed if it was not possible to place a balloon correctly within 20 min of fluoroscopy time. There were no significant differences between groups concerning clinical and angiographic baseline characteristics, size of initial balloons (3.0±0.3 mm in both groups), fluoroscopy time to cross the lesion with the wire (Magnum: 4±5, Standard: 5±6 min), total fluoroscopy time (Magnum: 11 ± 9, Standard: 12±12 min), and need for crossover (Magnum: 10%, Standard: 16%). Success rates per lesion were comparable with 90% in group Magnum and 84% in group Standard, as were the complications with one inhospital death in group Standard, occurring three weeks after PTCA and stent implantation. There was no emergency operation. Six patients per group had myocardial infarction of whom two in group Magnum and one in group Standard developed a Q-wave. The following variables were significantly in favor of the Magnum system compared with the Standard system: success rate in nontotal lesions (97% versus 90%) crossover success in total occlusions (0 vs. 33%), fluoroscopy time to cross the lesion with the balloon once the wire was in place (1 ± 2 vs. 2 ± 4 min), and use of a single versus 1.2±0.5 wires per lesion. The only advantage of the Standard systems was the more common use of 7 French guiding catheters (Magnum: 40%, Standard: 53%, p = 0.09). The Magnum system compares favorably with standard systems for routine PTCA. The robust design of the Magnum wire does not impair ease of placement and safety but saves material and facilitates balloon advancement across the lesion.     

Efficacy of autograft and freeze-dried allograft to enhance fixation of porous coated implants in the presence of interface gaps.

Autogenous cancellous bone and freeze-dried allogeneic cancellous bone were tested in a total of 41 adult male mongrel dogs. In each humerus, an implant with a commercially pure titanium fiber metal porous coating was placed in an overreamed cavity so that a uniform 3-mm gap was present between the implant and host cancellous bone. Graft material was placed in the gap of one humerus while the gap of the other humerus was left empty and served as a paired negative control. Histologically, both autograft and allograft appeared to aid repair of the defect, but quantitatively only autograft enhanced new bone formation within the defect. Treatment with autograft significantly increased the amount of bone ingrowth within the implants by nearly three-fold at 4 weeks and eight-fold at 8 weeks. The enhancing effect was recognizable as early as 2 weeks. The strength of fixation was increased by nearly seven-fold at 4 weeks and two-fold at 8 weeks in the autograft group, but this was only statistically significant at 4 weeks. Treatment with allograft did not enhance bone ingrowth at any time period, but had a small positive effect on strength of fixation at 4 weeks.     

Differences in CMV-Specific T-Cell Levels and Long-Term Susceptibility to CMV Infection after Kidney, Heart and Lung Transplantation

Patients after kidney, heart and lung transplantation differ in their immunosuppressive drug regimens and in susceptibility to infectious complications with cytomegalovirus (CMV). In this study, CMV-specific T-cell responses were characterized in long-term transplant recipients and associated with the frequency of infectious complications. CMV-reactive CD4 T cells from 50 healthy controls, 68 renal, 14 heart and 24 lung transplant recipients were flow cytometrically quantified by the induction of cytokines after specific stimulation. Moreover, the immunosuppressive effect of calcineurin inhibitors on specific T-cell reactivity was quantified in vitro and compared with responses in vivo. Median CMV-specific T-cell frequencies in long-term renal (1.48%; range 0.06-17.26%) and heart transplant recipients (0.90%; 0.13-12.49%) did not differ from controls (1.82%; 0.26-21.00%). In contrast, CMV-specific T-cell levels were significantly lower in lung transplant recipients (0.50%; <0.05-4.98%) and showed a significant correlation with the frequency of infectious episodes (r =-0.57, p = 0.005). The differences within the groups were associated with increasing dosages of immunosuppressive drugs, as exemplified for calcineurin inhibitors that dose dependently reduced specific T-cell reactivity in vitro. In conclusion, monitoring CMV-specific CD4 T cells may serve as a measure for long-term disease susceptibility and may contribute to an improved management of CMV complications after lung transplantation.     

Acute megakaryocytic leukemia in children. Clinical, immunologic, and cytogenetic findings in two patients.

An unusual presentation of acute megakaryocytic leukemia (AMKL) is reported in two young children. The first child had a 10-day history of ptosis of the right eyelid as the initial manifestation of AMKL, a clinical picture not previously described in this variant of leukemia. Computed tomographic scanning showed multiple intracranial mass lesions, and the diagnosis of AMKL was confirmed by immunophenotyping of bone marrow blasts. The second child had Down syndrome and received alkylating agents and radiation therapy for treatment of metastatic rhabdomyosarcoma of the orbit. She had AMKL as second malignancy. Both patients had acquired chromosome 21 anomalies in their leukemic blasts. The first patient, constitutionally normal, had an i(21q) in his leukemic blasts; the patient with constitutional trisomy 21 had tetrasomy 21 and additional chromosomal changes. The clinical symptoms and the results of morphologic, immunologic, and cytogenetic studies are discussed.