IVIg dose increase in multifocal motor neuropathy: a prospective six month follow-up

In this prospective, non-randomized 6-month observational study we evaluated the efficacy of intravenous immunoglobulin (IVIg) dose increase in patients with multifocal motor neuropathy (MMN). Diagnosis according to AAEM criteria, repetitive IVIg treatment for at least one year, persistent paresis and conduction block, stable symptoms and findings for at least six months were inclusion criteria. Nine patients (7 men) were identified and approved to standardized increase of IVIg dose. Patients were monitored using clinical scores and electrophysiological studies. Dose was increased from a baseline of 0.5 g/kg per month [mean, range: 0.1-1.1], given at variable intervals [4-12 weeks] to 1.2 g/kg per month given over 3 consecutive days planned for 6 cycles. If the patients' motor function did not improve after two cycles they entered step two: Dose was increased to 2 g/kg per month given over 5 consecutive days. The increased dose was maintained for 6 months. Assessments were performed by the same investigator, not involved in the patient's management, at baseline, after 2 and after 6 months. Following dose increase, motor function significantly improved in 6 patients (p = 0.014), 2 patients entered step two, 1 patient withdrew due to absent efficacy. Higher doses of IVIg caused more side effects, however, transient and rarely severe (p = 0.014). IVIg dose increase may improve motor functions in patients with stable MMN on long-term IVIg therapy independent of baseline dose. Improvement of motor function was associated with shorter disease duration (p = 0.008), but not with degree of muscle atrophy (p = 0.483). The treatment strategy to try to find the lowest effective dose and the longest tolerated interval might lead to underdosing in the long-term in many patients.

Computer-aided operation planning and 3-dimensional osteotomy guidance for alveolar distraction

Objectives: In alveolar distraction, in cases of severe atrophy in particular, it is often difficult to perform osteotomies in order to make a transport segment in optimal size and shape. Moreover care must be taken, not to damage the closely locating anato- mical structures such as the maxillary sinus, the inferior alveolar nerve, and the roots of the neighboring teeth. For setting ideal osteotomy lines exactly, we have developed a CT-based preoperative planning tool. Methods: 3-dimensional visual reconstruction of the jaw is created from the preoperative CT scans (1.0-mm slice thick- ness). Using the image-processing software Mimics (Materialise, Yokohama, Japan), various procedures of virtual cutting are simulated first to determine optimal osteotomy lines and to design an ideal transport segment. After the computer planning, data from the virtual solid model are transferred to a rapid prototype model, and a guiding splint is made to transfer the planned surgical simulation to the actual surgery. Results: The method was used in a case of severe atrophy of the anterior maxilla. The patient had a large maxillary sinus requir- ing a precise osteotomy in this critical area. Using the splint allowing a 3-dimensional guidance, alveolar osteotomies were easily done to achieve a transport segment in sufficient dimen- sion as planned, and any perforation of the maxillary sinus could be avoided. Finally the alveolar distraction of 10mm has suc- cessfully been performed. Conclusion: The preoperative planning method and the guiding splint described here are useful in problematic cases requiring an extremely precise osteotomy due to lack of bony space.

Transmembrane tumor necrosis factor alpha is required for enteropathy and is sufficient to promote parasite expulsion in gastrointestinal helminth infection

To study the specific role of transmembrane tumor necrosis factor (tmTNF) in protective and pathological responses against the gastrointestinal helminth Trichinella spiralis, we compared the immune responses of TNF-alpha/lymphotoxin alpha (LTalpha)(-/-) mice expressing noncleavable transgenic tmTNF to those of TNF-alpha/LTalpha(-/-) and wild-type mice. The susceptibility of TNF-alpha/LTalpha(-/-) mice to T. spiralis infection was associated with impaired induction of a protective Th2 response and the lack of mucosal mastocytosis. Although tmTNF-expressing transgenic (tmTNF-tg) mice also had a reduced Th2 response, the mast cell response was greater than that observed in TNF-alpha/LTalpha(-/-) mice and was sufficient to induce the expulsion of the parasite. T. spiralis infection of tmTNF-tg mice resulted in significant intestinal pathology characterized by villus atrophy and crypt hyperplasia comparable to that induced following the infection of wild-type mice, while pathology in TNF-alpha/LTalpha(-/-) mice was significantly reduced. Our data thus indicate a role for tmTNF in host defense against gastrointestinal helminths and in the accompanying enteropathy. Furthermore, they also demonstrate that TNF-alpha is required for the induction of Th2 immune responses related to infection with gastrointestinal helminth parasites.

Neer Award 2007: Reversion of structural muscle changes caused by chronic rotator cuff tears using continuous musculotendinous traction. An experimental study in sheep

HYPOTHESIS: Chronic rotator cuff tears are associated with irreversible architectural muscle changes and a high rate of repair failure. The changes observed in man and their irreversibility with a single stage repair can be reproduced in sheep. It was the purpose of this experiment to test the hypothesis that slow, continuous elongation of a retracted musculotendinous unit allows reversal of the currently irreversible structural muscle changes. MATERIALS AND METHODS: The infraspinatus tendon of 12 sheep was released using a greater tuberosity osteotomy and allowed to retract for 4 months. Then, a new device was mounted on the scapular spine and used to extend the infraspinatus muscuculotendinous unit transcutaneously by 1 mm per day. Thereafter, the tendon was repaired back to the greater tuberosity. We assessed the muscular architecture using magnetic resonance imaging, macroscopic dissection, histology, and electron microscopy. Fatty infiltration (in Hounsfield units 1/4 HU) and muscular cross-sectional area (in % of the control side) were monitored with computed tomography at tendon release, initiation of elongation, repair, and at sacrifice. RESULTS: Sixteen weeks after tendon release, the mean tendon retraction was 29 +/- 6 mm (14% of original length, P = .008). In 8 sheep, elongation was achieved as planned (group I), but in 4, the elongation failed technically (group II). The mean traction time was 24 +/- 6 days with a mean traction distance of 19 +/- 4 mm. At sacrifice, the mean pennation angle in the infraspinatus of group I was not different from the control side (29.8 degrees +/-7.5 degrees vs. 30 degrees +/-6 degrees , P = .575). In group II, the pennation angle had increased from 30 degrees +/-6 degrees to 55 degrees +/-14 degrees (P = .035). There was no fatty infiltration at the time of tendon release. After retraction, there was a significant increase in fatty infiltration of the infraspinatus muscle and a decrease of its cross-sectional area to 57% of the contralateral side (P = .0001). During traction, the degree of fatty infiltration remained unchanged (36 HU to 38 HU, P = .381), and atrophy improved to a muscle square area of 78% of the contralateral side (P = .0001) in group I. In group II, an increase of fatty infiltration was measured from 36 HU to 28 HU; however, this increase was not significant (P = .144). Atrophy did not change in group II (57-55%, P = .946). At sacrifice, the remaining muscle mass was 64% in group I and 46% in group II (P = .019). DISCUSSION: Our preliminary results document, that continuous elongation of a retracted, fatty infiltrated and atrophied musculotendinous unit is technically feasible. CONCLUSION: In the sheep, continuous elongation can lead to restoration of normal muscle architecture, to partial reversal of muscle atrophy, and to arrest of the progression of fatty infiltration. LEVEL OF EVIDENCE: Basic science level 2; Prospective comparative therapeutic study.

Adipogenic and myogenic gene expression in rotator cuff muscle of the sheep after tendon tear

Chronic rotator cuff tendon tears lead to fatty infiltration and muscle atrophy with impaired physiological functions of the affected muscles. However, the cellular and molecular mechanisms of corresponding pathophysiological processes remain unknown. The purpose of this study was to characterize the expression pattern of adipogenic (PPARgamma, C/EBPbeta) and myogenic (myostatin, myogenin, Myf-5) transcription factors in infraspinatus muscle of sheep after tenotomy, implantation of a tension device, refixation of the tendon, and rehabilitation, reflecting a model of chronic rotator cuff tears. In contrast to human patients, the presented sheep model allows a temporal evaluation of the expression of a given marker in the same individual over time. Semiquantitative RT/PCR analysis of PPARgammaã, myostatin, myogenin, Myf-5, and C/EBPbeta transcript levels was carried out with sheep muscle biopsy-derived total RNA. We found a significantly increased expression of Myf-5 and PPARgamma after tenotomy and a significant change for Myf-5 and C/EBPbeta after continuous traction and refixation. This experimental sheep model allows the molecular analysis of pathomechanisms of muscular changes after rotator cuff tear. The results point to a crucial role of the transcription factors PPARgamma, C/EBPbeta, and Myf-5 in impairment and regeneration of rotator cuff muscles after tendon tears in sheep.

Involvement of the ABC-transporter ABCC1 and the sphingosine 1-phosphate receptor subtype S1P(3) in the cytoprotection of human fibroblasts by the glucocorticoid dexamethasone

Glucocorticoids (GC) represent the most commonly used drugs for the treatment of acute and chronic inflammatory skin diseases. However, the topical long-term therapy of GC is limited by the occurrence of skin atrophy. Most interestingly, although GC inhibit proliferation of human fibroblasts, they exert a pronounced anti-apoptopic action. In the present study, we further elucidated the molecular mechanism of the GC dexamethasone (Dex) to protect human fibroblasts from programmed cell death. Dex not only significantly alters the expression of the cytosolic isoenzyme sphingosine kinase 1 but also initiated an enhanced intracellular formation of the sphingolipid sphingosine 1-phosphate (S1P). Investigations using S1P (3) ((-/-)) -fibroblasts revealed that this S1P-receptor subtype is essential for the Dex-induced cytoprotection. Moreover, we demonstrate that the ATP-binding cassette (ABC)-transporter ABCC1 is upregulated by Dex and may represent a crucial carrier to transport S1P from the cytosol to the S1P(3)-receptor subtype.

Prosthetically driven, computer-guided implant planning for the edentulous maxilla: a model study

OBJECTIVES: To analyze computer-assisted diagnostics and virtual implant planning and to evaluate the indication for template-guided flapless surgery and immediate loading in the rehabilitation of the edentulous maxilla. MATERIALS AND METHODS: Forty patients with an edentulous maxilla were selected for this study. The three-dimensional analysis and virtual implant planning was performed with the NobelGuide software program (Nobel Biocare, Göteborg, Sweden). Prior to the computer tomography aesthetics and functional aspects were checked clinically. Either a well-fitting denture or an optimized prosthetic setup was used and then converted to a radiographic template. This allowed for a computer-guided analysis of the jaw together with the prosthesis. Accordingly, the best implant position was determined in relation to the bone structure and prospective tooth position. For all jaws, the hypothetical indication for (1) four implants with a bar overdenture and (2) six implants with a simple fixed prosthesis were planned. The planning of the optimized implant position was then analyzed as follows: the number of implants was calculated that could be placed in sufficient quantity of bone. Additional surgical procedures (guided bone regeneration, sinus floor elevation) that would be necessary due the reduced bone quality and quantity were identified. The indication of template-guided, flapless surgery or an immediate loaded protocol was evaluated. RESULTS: Model (a) - bar overdentures: for 28 patients (70%), all four implants could be placed in sufficient bone (total 112 implants). Thus, a full, flapless procedure could be suggested. For six patients (15%), sufficient bone was not available for any of their planned implants. The remaining six patients had exhibited a combination of sufficient or insufficient bone. Model (b) - simple fixed prosthesis: for 12 patients (30%), all six implants could be placed in sufficient bone (total 72 implants). Thus, a full, flapless procedure could be suggested. For seven patients (17%), sufficient bone was not available for any of their planned implants. The remaining 21 patients had exhibited a combination of sufficient or insufficient bone. DISCUSSION: In the maxilla, advanced atrophy is often observed, and implant placement becomes difficult or impossible. Thus, flapless surgery or an immediate loading protocol can be performed just in a selected number of patients. Nevertheless, the use of a computer program for prosthetically driven implant planning is highly efficient and safe. The three-dimensional view of the maxilla allows the determination of the best implant position, the optimization of the implant axis, and the definition of the best surgical and prosthetic solution for the patient. Thus, a protocol that combines a computer-guided technique with conventional surgical procedures becomes a promising option, which needs to be further evaluated and improved.

Numerical investigation of the mechanical loading of supporting soft tissue for partial dentures

The aim of this research was to study the impact of loading on partial dentures within the supporting soft tissue with respect to different attachment techniques. A finite element model was developed to calculate the stress and strain distribution in this tissue. The model consisted of the left half of a mandible with three remaining teeth that had suffered an atrophy in the anterior region, and a partial denture over the toothless area that was connected at the left mandibular canine using an attachment system. Resulting stress/strain distributions are presented for different load cases using a commercially available prefabricated attachment system.

Contractile function is preserved in unloaded hearts despite atrophic remodeling

OBJECTIVE: Recent studies have shown that mechanically unloading a failing heart may induce reverse remodeling and functional improvement. However, these benefits may be balanced by an unloading-related remodeling including myocardial atrophy that might lead to decrease in function. Using a model of heterotopic heart transplantation, we aimed to characterize the myocardial changes induced by long-term unloading. MATERIAL AND METHODS: Macroscopic as well as cellular and functional changes were followed in normal hearts unloaded for a 3-month period. Microscopic parameters were evaluated with stereologic methodology. Myocardial contractile function was quantified with a Langendorff isolated, perfused heart technique. RESULTS: Atrophy was macroscopically obvious and accompanied by a 67% reduction of the myocyte volume and a 43% reduction of the interstitial tissue volume, thus accounting for a shift of the myocyte/connective tissue ratio in favor of noncontractile tissue. The absolute number of cardiomyocyte nuclei decreased from 64.7 +/- 5.1 x 10(7) in controls to 22.6 +/- 3.7 x 10(7) (30 days) and 21.6 +/- 3.1 x 10(7) (90 days) after unloading (P < .05). The numeric nucleic density in the unloaded myocardium, as well as the mean cardiomyocyte volume per cardiomyocyte nucleus, remained constant throughout the 90 days of observation. Functional data indicated an increase in ventricular stiffness, although contractile function was preserved, as confirmed by unaltered maximal developed pressure and increased contractility (maximum rate of left ventricular pressure development) and relaxation (minimum rate of left ventricular pressure development). CONCLUSION: Atrophic remodeling involves both the myocyte and interstitial tissue compartment. These data suggest that although there is decreased myocardial volume and increased stiffness, contractile capacity is preserved in the long-term unloaded heart.

Benign prostatic obstruction and parkinson's disease--should transurethral resection of the prostate be avoided?

PURPOSE: According to the literature transurethral resection of the prostate in patients with Parkinson's disease has an increased risk of postoperative urinary incontinence. However, this conclusion might have been reached because some patients with multiple system atrophy incorrectly diagnosed as Parkinson's disease were included in these reports. Therefore, we investigated the outcome of transurethral prostate resection in patients with a secure neurological diagnosis of Parkinson's disease. MATERIALS AND METHODS: A total of 23 patients with Parkinson's disease who underwent transurethral prostate resection for benign prostatic obstruction were evaluated retrospectively. Subsequent neurological developments in patients were followed, ensuring that those with multiple system atrophy had not been included in analysis. RESULTS: At transurethral prostate resection median patient age was 73 years, median duration of Parkinson's disease before the resection was 3 years, and median Hoehn and Yahr scale was 2. Of the 14 patients with a preoperative indwelling urinary catheter transurethral prostate resection restored voiding in 9 (64%) and only 5 (36%) required catheterization postoperatively. Of the 10 patients with preoperative urge urinary incontinence, continence was restored in 5 and improved in 3 following transurethral prostate resection. There were no cases of de novo urinary incontinence after transurethral prostate resection. At a median postoperative followup of 3 years transurethral prostate resection was successful in 16 of the 23 patients (70%). CONCLUSIONS: Transurethral prostate resection for benign prostatic obstruction in patients with Parkinson's disease may be successful in up to 70% and the risk of de novo urinary incontinence seems minimal. Thus, Parkinson's disease should no longer be considered a contraindication for transurethral prostate resection provided that preoperative investigations including urodynamic assessment indicate prostatic bladder outlet obstruction.

Renal allografts with IF/TA display distinct expression profiles of metzincins and related genes

Chronic renal allograft injury is often reflected by interstitial fibrosis (IF) and tubular atrophy (TA) without evidence of specific etiology. In most instances, IF/TA remains an irreversible disorder, representing a major cause of long-term allograft loss. As members of the protease family metzincins and functionally related genes are involved in fibrotic and sclerotic processes of the extracellular matrix (ECM), we hypothesized their deregulation in IF/TA. Gene expression and protein level analyses using allograft biopsies with and without Banff'05 classified IF/TA illustrated their deregulation. Expression profiles of these genes differentiated IF/TA from Banff'05 classified Normal biopsies in three independent microarray studies and demonstrated histological progression of IF/TA I to III. Significant upregulation of matrix metalloprotease-7 (MMP-7) and thrombospondin-2 (THBS-2) in IF/TA biopsies and sera was revealed in two independent patient sets. Furthermore, elevated THBS-2, osteopontin (SPP1) and beta-catenin may play regulatory roles on MMP. Our findings further suggest that deregulated ECM remodeling and possibly epithelial to mesenchymal transition (EMT) are implicated in IF/TA of kidney transplants, and that metzincins and related genes play an important role in these processes. Profiling of these genes may be used to complement IF/TA diagnosis and to disclose IF/TA progression in kidney transplant recipients.

Doxycycline-controlled splicing modulation by regulated antisense U7 snRNA expression cassettes

Many diseases affect pre-mRNA splicing, and alternative splicing is a major source of proteome diversity and an important mechanism for modulating gene expression. The ability to regulate a specific splicing event is therefore desirable; for example, to understand splicing-associated pathologies. We have developed methods based on modified U7 snRNAs, which allow us to induce efficient skipping or inclusion of selected exons. Here, we have adapted these U7 tools to a regulatable system that relies on a doxycycline-sensitive version of the Kruppel-associated box (KRAB)/KAP1 transcriptional silencing. Co-transduction of target cells with two lentiviral vectors, one carrying the KRAB protein and the other the regulatable U7 cassette, allows a tight regulation of the modified U7 snRNA. No leakage is observed in the repressed state, whereas full induction can be obtained with doxycycline in ng ml(-1) concentrations. Only a few days are necessary for a full switch, and the induction/repression can be repeated over several cycles without noticeable loss of control. Importantly, the U7 expression correlates with splicing correction, as shown for the skipping of an aberrant beta-globin exon created by a thalassaemic mutation and the promotion of exon 7 inclusion in the human SMN2 gene, an important therapeutic target for spinal muscular atrophy.

Cytotoxic T cells are preferentially activated in the duodenal epithelium from patients with florid coeliac disease

Villous atrophy and increased numbers of intraepithelial T cells in duodenal biopsies represent a hallmark of coeliac disease. In the present study, an attempt has been made to define whether cytotoxic cell subsets are activated in situ in the affected mucosa of susceptible individuals early after ingestion of a gluten-containing diet. Duodenal biopsies from 11 patients with coeliac disease who repeatedly underwent endoscopic biopsy after ingestion of individually dosed amounts of gluten were used for immunohistochemistry and in situ hybridization. To identify the cell subsets expressing perforin mRNA and protein, in situ hybridization and FACS analyses were performed on cells isolated from fresh biopsies. Compared with normal mucosa, the number of intraepithelial lymphocytes containing perforin mRNA and protein increased significantly in tissue samples showing moderate or florid coeliac disease and closely paralleled the severity of morphological alteration, whereas the frequency of perforin-expressing lamina propria lymphocytes increased only moderately. Cells isolated from florid biopsies that expressed perforin mRNA and protein were preferentially T-cell receptor (TCR) alphabeta T cells. The increase in both the absolute number and the percentage of lymphocytes expressing perforin mRNA indicates in situ activation of lymphocytes within the epithelial compartment in florid coeliac disease upon ingestion of a gluten-containing diet in patients predisposed to coeliac disease.

Dynamic patterns of ventricular remodeling and apoptosis in hearts unloaded by heterotopic transplantation

BACKGROUND Mechanical unloading of failing hearts can trigger functional recovery but results in progressive atrophy and possibly detrimental adaptation. In an unbiased approach, we examined the dynamic effects of unloading duration on molecular markers indicative of myocardial damage, hypothesizing that potential recovery may be improved by optimized unloading time. METHODS Heterotopically transplanted normal rat hearts were harvested at 3, 8, 15, 30, and 60 days. Forty-seven genes were analyzed using TaqMan-based microarray, Western blot, and immunohistochemistry. RESULTS In parallel with marked atrophy (22% to 64% volume loss at 3 respectively 60 days), expression of myosin heavy-chain isoforms (MHC-α/-β) was characteristically switched in a time-dependent manner. Genes involved in tissue remodeling (FGF-2, CTGF, TGFb, IGF-1) were increasingly upregulated with duration of unloading. A distinct pattern was observed for genes involved in generation of contractile force; an indiscriminate early downregulation was followed by a new steady-state below normal. For pro-apoptotic transcripts bax, bnip-3, and cCasp-6 and -9 mRNA levels demonstrated a slight increase up to 30 days unloading with pronunciation at 60 days. Findings regarding cell death were confirmed on the protein level. Proteasome activity indicated early increase of protein degradation but decreased below baseline in unloaded hearts at 60 days. CONCLUSIONS We identified incrementally increased apoptosis after myocardial unloading of the normal rat heart, which is exacerbated at late time points (60 days) and inversely related to loss of myocardial mass. Our findings suggest an irreversible detrimental effect of long-term unloading on myocardium that may be precluded by partial reloading and amenable to molecular therapeutic intervention.

Nonanimal stabilized hyaluronic acid for tissue augmentation of the dorsal hands: a prospective study on 38 patients

BACKGROUND Often ignored, hands are one of the most telltale signs of aging. This prospective study was initiated to evaluate the effect of subcutaneous hyaluronic acid (HA) injections in aging hands, with special attention to complications and long-term outcomes. METHODS Between January 2010 and December 2010, a total of 38 patients with skin phototypes II-IV and between 58 and 76 years old were treated with HA injection for aging hands. The quantity of injection never exceeded 1.0-1.5 ml HA per hand. A clinical follow-up was performed at 2 weeks, 4 weeks, 3 months, and 6 months after injection. Complications were reviewed for the whole series. At the first follow-up, 2 weeks after the procedure, ultrasound was carried out to determine if additional filling material was required. At each follow-up, patients were asked to fill out a satisfaction questionnaire. RESULTS Nine patients developed slight ecchymosis that disappeared after 1 week. No other complications were seen in the series. Pain during the injection and discomfort after the procedure were minimal. At the 2-week follow-up, after ultrasound control, nine patients received a complementary injection. At each follow-up, overall patient satisfaction was high and was validated by clearance of rhytids, veins, bony prominences, and dermal and subcutaneous atrophy. CONCLUSION Skin revitalization with injectable HA can improve the clinical appearance of the back of the hands. However, this therapy requires knowledge of the possible complications and their remediation as well as knowledge and respect of injected doses. Moreover, despite excellent results at each follow-up, the results of our series are not as good after 6 months, and a longer follow-up would be needed to determine if this procedure provides long-lasting benefit. LEVEL OF EVIDENCE III This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .