Viral rescue of magnocellular vasopressin cells in adolescent Brattleboro rats ameliorates diabetes insipidus, but not the hypoaroused phenotype.

Dysregulated arousal often accompanies neurodevelopmental disorders such as attention deficit hyperactivity disorder and autism spectrum disorder. Recently, we have found that adolescent homozygous Brattleboro (Hom) rats, which contain a mutation in the arginine vasopressin (AVP) gene, exhibit lower behavioral arousal than their heterozygous (Het) littermates in the open field test. This hypoaroused phenotype could be due to loss of AVP in magnocellular cells that supply AVP to the peripheral circulation and project to limbic structures or parvocellular cells that regulate the stress axis and other central targets. Alternatively, hypoarousal could be a side effect of diabetes insipidus - polydipsia and polyuria seen in Hom rats due to loss of AVP facilitation of water reabsorption in the kidney. We developed a viral-rescue approach to "cure" magnocellular AVP cells of their Brattleboro mutation. Infusion of a recombinant adeno-associated virus (rAAV) containing a functional Avp gene and promoter (rAAV-AVP) rescued AVP within magnocellular cells and fiber projections of the paraventricular nucleus of the hypothalamus (PVN) of male and female adolescent Hom rats. Furthermore, water intake was markedly reduced, ameliorating the symptoms of diabetes insipidus. In contrast, open field activity was unaffected. These findings indicate that the hyporaoused phenotype of adolescent Hom rats is not due to the loss of AVP function in magnocellular cells or a side effect of diabetes insipidus, but favors the hypothesis that central, parvocellular AVP mechanisms underlie the regulation of arousal during adolescence.

Mutation in the vasopressin gene eliminates the sex difference in social reinforcement in adolescent rats.

The neuropeptide, arginine vasopressin (AVP), is thought to contribute to sex differences in normative and pathological social development by regulating social motivation. Recent studies using Brattleboro rats that have a mutation in the Avp gene, however, have suggested that AVP impacts adolescent social behaviors of males and females in a similar manner through actions on behavioral state (i.e., arousal). In the present study, we made use of a recently developed operant conditioning paradigm to test whether the chronic, lifelong AVP deficiency caused by the Brattleboro mutation impacts the reinforcement value of social stimuli during adolescence. Operant responding for access to a familiar conspecific was assessed in male and female adolescent wild type (WT; normal AVP), heterozygous Brattleboro (HET), and homozygous Brattleboro (HOM) rats. Following the social reinforcement test, rats were tested in the same operant paradigm except that the social reinforcer was replaced with a light reinforcer to determine whether effects of the Brattleboro mutation were specific to social stimuli or a general characteristic of operant conditioning. WT males directed a greater proportion of their responding toward the social and light stimuli than WT females; only males exhibited a preference for these reinforcers over unreinforced ports. The sex difference in social reinforcement was absent in HOM rats, whereas the sex difference in light reinforcement was present in all genotypes. These data indicate that adolescent males are more sensitive to the reinforcing properties of social and light stimuli, and that the sex difference in social, but not light, reinforcement depends upon normal levels of AVP. These findings support the hypothesis that AVP plays a critical role in sex differences in social development by acting on factors that influence social motivation.

Pharmacists' impact on opportunistic infection prophylaxis in patients with HIV/AIDS.

Pharmacists have demonstrated a positive impact on the care of patients with human immunodeficiency virus/acquired immunodeficiency syndrome through enhancing patient outcomes associated with antiretroviral therapy. This pre- and postintervention study assessed the impact of pharmacist intervention on improving the use of prophylactic medications for opportunistic infections (OI). Of the 139 patients screened, 42 patients were included in the prospective intervention group. A total of 27 interventions were made on 15 patients, and 24 recommendations (89%) were accepted by providers. Compared with the retrospective control group, prescribing of OI prophylaxis increased from 58% to 93% (P<0.001) with the addition of pharmacist intervention.

Apolipoprotein E-e4, processing speed, and white matter volume in a genetically enriched sample of midlife adults.

Healthy midlife children of a parent with Alzheimer's disease ([AD] N = 23; 9 male) participated in neuropsychological testing, and magnetic resonance imaging (MRI) of brain volumetrics were obtained. In all, 35% of the sample were apolipoprotein E (ApoE)-e4 positive (n = 8; 5 male). The ApoE-e4 group exhibited significantly slower performances on an executive function and processing speed measure and had less white matter volume than the non-ApoE-e4 group. Lesser white matter volume was significantly correlated with slower processing speed. Processing speed and changes in white matter volume might be indicators of preclinical decline in AD.

The infiltration of the AC joint performed by one specialist: ultrasound versus palpation a prospective randomized pilot study.

INTRODUCTION: The acromio-clavicular (AC) joint is very susceptible to degenerative processes that result in pain and functional impairment. One common modality of treatment has been local infiltration of the joint space. Although this procedure has produced notable positive results, needle misplacement occurs frequently. The aim of this investigation is to evaluate the effects of an intra articular infiltration by comparing precise needle placement into the joint space using high-resolution-ultrasound with the conventional palpation technique. METHODS: This prospective and randomized pilot study analysed 20 patients who were assigned either to the "ultrasound" or the "palpation" group. Clinical examinations were performed before treatment and at 1h, 1 week and 3 weeks after a single infiltration of local anaesthetic and corticoid carried out by one specialist. RESULTS: In both groups significant improvement in pain and function was obtained up to one-week post injection. Function remained significantly improved until the last follow-up and did not differ between the two groups. The agent was administered in all patients into the joint space in the ultrasound group. CONCLUSION: Ultrasound guided infiltration of the AC joint is an easily achieved procedure without any complications. However, clinical follow-up did not differ between free-hand and ultrasound-guided AC joint space infiltration.

Three-year clinical outcome after chondrocyte transplantation using a hyaluronan matrix for cartilage repair.

Repair of articular cartilage represents a significant clinical problem and although various new techniques - including the use of autologous chondrocytes - have been developed within the last century the clinical efficacy of these procedures is still discussed controversially. Although autologous chondrocyte transplantation (ACT) has been widely used with success, it has several inherent limitations, including its invasive nature and problems related to the use of the periosteal flap. To overcome these problems autologous chondrocytes transplantation combined with the use of biodegradable scaffolds has received wide attention. Among these, a hyaluronan-based scaffold has been found useful for inducing hyaline cartilage regeneration. In the present study, we have investigated the mid-term efficacy and safety of Hyalograft C grafts in a group of 36 patients undergoing surgery for chronic cartilage lesions of the knee. Clinical Outcome was assessed prospectively before and at 12, 24, and 36 months after surgery. No major adverse events have been reported during the 3-year follow-up. Significant improvements of the evaluated scores were observed (P < 0.02) at 1 year and a continued increase of clinical performance was evident at 2 and 3 years follow-up. Patients under 30 years of age with single lesions showed statistically significant improvements at all follow-up visits compared to those over 30 with multiple defects (P < 0.01). Hyalograft C compares favorably with classic ACT and is particularly indicated in younger patients with single lesions. The graft can be implanted through a miniarthrotomy and needs no additional fixation with sutures except optional fibrin gluing at the defect borders. These results suggest that Hyalograft C is a valid alternative to ACT.

[Arthroscopic menisectomy in older patients: assessing health-related quality of life]. / Die arthroskopische Teilmenisektomie bei älteren Patienten: Erfassung der gesundheitsbezogenen Lebensqualität.

AIM: Little information is available on partial arthroscopic menisectomy in patients 60 years of age or older. Due to the co-morbidity of meniscal tears and osteoarthritis in this age group, the effectiveness of this procedure is controversial. The purpose of this study was to evaluate the outcome of this procedure in terms of function and mobility in patients 60 years of age or older. METHOD: Between 1990 and 1999, 1920 arthroscopies of the knee were performed in a single primary care institution, and 51 patients, 60 years of age or older, had a partial arthroscopic menisectomy done. Outcomes were rated using the SF-36 Health Survey and a specially designed questionnaire including items of published scores. RESULTS: The mean age at surgery was 67 years (range: 60.3 - 78.9) and the mean follow-up was 5 years (range: 2 - 12). Due to persistent pain, 4 patients underwent a second operation including knee replacement in 3 cases and a high tibial osteotomy in 1 case. 41 patients (87.1 %) stated the arthroscopy had improved their quality of life. In terms of pain and daily life activities, the majority of the subjects showed an improvement after surgery. The SF-36 showed no clinically relevant difference compared to the control in all but one subscale. CONCLUSION: Despite of the presence of osteoarthritis in this age group, arthroscopic partial menisectomy can improve pain, function and mobility in the mid-term course.

Effects of extracorporeal shock waves on human articular chondrocytes and ovine bone marrow stromal cells in vitro.

INTRODUCTION: We investigated the effects of extracorporeal shock waves on cytotoxicity and on the proliferation of human chondrocytes and ovine bone marrow stromal cells. MATERIALS AND METHODS: Isolated cells were cultured to confluence, and 500 shock waves were applied at energy flux densities of 0, 0.02, 0.06, and 0.17 mJ/mm(2 )for the cytotoxicity assay. The same energies at 100, 500, and 1000 impulses were used for the proliferation assay. RESULTS: Although bone marrow stromal cells revealed a dose- and impulse-dependent increase in the proliferation rate, no significant differences were found. Chondrocytes had less proliferative potential than untreated control groups. In the experimental set-up using 1000 impulses, proliferation was even higher in the control group. Both types of cells revealed a dose-dependent increase in cytotoxicity in the lactate dehydrogenase (LDH) assay. CONCLUSION: As femoral head necrosis, osteochondritis dissecans, and similar disorders are increasingly treated with shock waves, their effect on human cartilage and chondrocytes deserves attention. We recommend further in vitro experiments with bone marrow stromal cells, as the latter might play an important role in the presumed multifactorial osteogenetic mechanism of shock waves due to their pluripotent character.

[Physical activity after total knee replacement]. / Körperliche Aktivität nach Knietotalprothesenimplantation.

AIM: The aim of the study is to find out to what extent patients can do sports after total knee replacement and how patients change their activities compared to the preoperative situation. METHOD: 167 patients, not older than 65 years at time of surgery, who had total knee replacement during the years 1988 to 1998 were asked about their physical activity habits before and after surgery and 112 of them were seen for follow-up examination. RESULTS: 138 (83%) patients correctly answered the questionnaire about their activities. The average age at time of surgery was 55.3 years (21 - 65 yrs), at time of follow-up examination or questioning it was 63.8 years (24 - 78 yrs). The preoperative activity rate was 80.4%. Postoperatively it sank to 75.4%. 99 of the 111 (89.2%) patients returned to some kind of activity after surgery. Walking proved to be the most popular activity (92.8%), followed by swimming (34.2%) and cycling (18.0%). Follow-up examination was done after an average of 74 months (24 - 156) postoperatively and revealed an average Knee Society Knee Score for all patients of 84/70. With a score of 83.4/55.7 the less active group lay under the more active group with a score of 85.2/72.3. CONCLUSION: A tendency towards low impact physical activities could be seen after total knee replacement. Even so, the percentage of patients participating in physical activities was not reduced in a strong way by surgery.

[3D-navigated high energy shockwave therapy and axis correction after failed distraction treatment of congenital tibial pseudarthrosis]. / 3D-navigierte hochenergetische Stosswellentherapie und Achskorrektur nach fehlgeschlagener Distraktionsbehandlung bei kongenitaler Tibiapseudarthrose.

The treatment of congenital tibial pseudarthrosis using a distraction procedure as described by Ilizarov is a standard surgical intervention. Nevertheless, there are problems in achieving bony stability in about 10% of cases even after repeated surgery as reported by Lammens et al. (2000). Traub et al. (1999) found a rate of 50% amputations in 33 cases treated since 1927. To prevent an Ilizarov procedure from resulting in a delayed union or nonunion, Paley et al. (1992) recommended autografting immediately after distraction. Based on the good results in the stimulation of osteogenesis in adults, we started to treat delayed bone union following distraction treatment with high-energy shock wave therapy also in children. In patients suffering from congenital tibial pseudarthrosis with a deviation of the bony axis, we combine this surgery-substituting therapy with fixation of a Taylor spatial frame in order to correct the axis. Using this new method of treatment, we were able to achieve stability in four children who previously had had nonunion even after multiple surgical interventions.

Subcutaneous low-dose epoetin beta for the avoidance of transfusion in patients scheduled for elective surgery not eligible for autologous blood donation.

This randomized, multicentre, parallel-group study assessed the efficacy of epoetin beta in reducing the transfusion frequency in patients ineligible for autologous blood donation prior to surgery. The patients (n = 194) received either epoetin beta (125 or 250 IU/kg, once weekly) or no therapy for 3-4 weeks before surgery. The pre-operation haemoglobin levels were markedly increased in the epoetin beta groups (125 IU/kg: +1.1 g/dl; 250 IU/kg: +1.6 g/dl), but not in the control group. The transfusion frequency was significantly reduced in both epoetin groups as compared with the control group (p = 0.046). Epoetin beta was well tolerated, and no serious adverse events were observed. Low-dose administration of epoetin beta before elective surgery reduces the transfusion frequencies in patients not eligible for autologous blood donation.

Calcium induces a conformational change in the ligand binding domain of the low density lipoprotein receptor.

We previously have shown that LDL-R354, a truncated low density lipoprotein (LDL) receptor, is a calcium binding protein. LDL-R354 is composed of the ligand binding domain and repeat A of the EGF precursor homology domain of the full-length human LDL receptor. We also found that Ca2+ was required for the interaction between LDL-R354 and its ligand, LDL (Dirlam et al. 1996. Protein Expt. Purif. 8: 489-500). In the current study, calcium-induced changes in the structure and function of LDL-R354 were examined. When calcium bound to LDL-R354, its apparent size increased, as determined by native and SDS-gel electrophoresis. The calcium-saturated form of LDL-R354 was more resistant to trypsin proteolysis than the calcium-depleted form. In the presence of calcium, the disulfide bonds in the truncated receptor were stabilized, rendering them more resistant to reduction by dithiothreitol. Calcium binding affinities were measured by monitoring increased tryptophan fluorescence intensities. LDL-R354 bound Ca2+ with high affinity (EC50 = 60 nM at pH 7.4) and specificity, as 400 microM Mg2+ did not compete for calcium binding. The affinity of LDL-R354 for calcium decreased when the pH was lowered. These results suggest that calcium induces a conformational change in the ligand binding domain of the LDL receptor and that a receptor conformer capable of binding ligand should be stabilized at physiological extracellular Ca2+ concentration and pH. Drops in pH may regulate LDL receptor function by altering the amount of calcium bound to the receptor.

Osteoarthrosis after the Max Lange procedure for unstable shoulders.

Thirty-four patients were followed for a mean of 14.4 years after the Max Lange operation for instability of the shoulder. This procedure consists of an anterior capsulorraphy with lateralisation of the subscapularis tendon and the insertion of a bone block at the inferior and anterior part of the glenoid. The Rowe score showed 87% good and excellent results. External rotation and abduction were significantly limited as compared to the normal side. Radiographs revealed osteoarthrosis in 47%. Double contrast computed tomography in 18 cases showed a bony defect in the anterior and inferior part of the humeral head in 12 who had significantly limited external rotation as compared to those without the defect. Lateralisation of the subscapularis tendon with limitation of external rotation may lead to increased contact stress and shear forces at the anterior rim of the glenoid which contributes to the development of osteoarthrosis.

Early speech changes in children with multichannel cochlear implants.

A number of studies have demonstrated that cochlear implants provide an improved auditory signal and enhance the development of speech-perception and production skills for profoundly deaf children. However, exactly when these early speech skills begin to develop remains unclear. To explore this issue, we observed, for a 1-year period, four prelingually deaf children who underwent implantation consecutively within 1 month of each other, and we paid particular attention to the first few months of rehabilitation. We found immediate speech scores as early as the first day of implant tune-up. Speech production continued to improve rapidly throughout the first 4 months but exhibited a generally slower rate of progress in some of the speech-production skills at 1 year. We also found vowel-production skills to be the easiest to achieve, with word-pattern recognition and consonant voicing of intermediate difficulty. Consonant placing and manner of consonant production were the hardest skills to achieve. Results of speech-perception tests 1 year after implantation were markedly improved over preimplantation levels in three of the four children. These early speech changes stress the need for maximization of the capability of the cochlear implant by institution of immediate and intensive speech rehabilitation efforts for prelingually deaf children.

Vascular reconstruction for limb salvage in sarcoma of the lower extremity.

OBJECTIVES: To examine the patency and limb-salvage characteristics of vascular reconstruction in patients with sarcomas of the lower extremity who had been treated with limb-preserving resection and to examine patient survival during a long follow-up period. DESIGN: Retrospective cohort study. SETTING: University hospital, tertiary referral center. PATIENTS: From 1984 to 1992, 14 patients underwent limb-preserving resection of sarcomas in the proximal lower extremity, with 20 vascular reconstructions performed. OUTCOME MEASURES: Color Doppler scans documented patency of the vascular reconstructions. Clinical evaluation included functional results in terms of limb movement and quality of life. Local tumor control and systemic recurrence were examined by repeated radiologic examination. Overall survival as well as time and cause of death were assessed. RESULTS: A total of 13 patients had patent vascular grafts, while the venous graft became occluded in 1 patient. Limb function was rated as excellent or good in 9 patients, as fair in 3, as poor in 1, and could not be clinically estimated in 1. Postoperative thrombosis of the venous graft was detected in 3 patients and was effectively managed by thrombectomy in 2. Three patients underwent reoperation because of hematoma or complications caused by local infection. The tumor endoprosthesis had to be replaced in 3 patients. During follow-up periods that ranged from 15 to 132 months (mean, 55 months), 4 patients died. In all of these patients the cause of death was systemic recurrence in the lung. Two additional patients developed pulmonary metastases, but at the time of this report, they were still alive as long as 132 months after operative resection or chemotherapy. No local recurrence was found. CONCLUSION: Limb-preserving resection of sarcoma of the lower extremity can be performed with satisfactory function of the limb maintained, even if it becomes necessary to resect the femoral vessels. Autologous venous graft for vascular reconstruction is the treatment of choice. In spite of the high incidence of metastases, considerable long-term survival is possible.

Endoscopic and videofluoroscopic evaluations of swallowing and aspiration.

A new procedure for evaluating oropharyngeal dysphagia utilizing fiberoptic laryngoscopy was compared to the videofluoroscopy procedure. Twenty-one subjects were given both examinations within a 48-hour period. Results of the fiberoptic endoscopic evaluation of swallowing (FEES) and videofluoroscopy examinations were compared for presence or absence of abnormal events. Good agreement was found, especially for the finding of aspiration (90% agreement). The FEES was then measured against the videofluoroscopy study for sensitivity, specificity, positive predictive value, and negative predictive value. Sensitivity was 0.88 or greater for three of the four parameters measured. Specificity was lower overall, but was still 0.92 for detection of aspiration. It was concluded that the FEES is a valid and valuable tool for evaluating oropharyngeal dysphagia. Some specific patients and conditions that lend themselves to this procedure are discussed.