Tendon healing induced by chemically modified mRNAs.

Tendon disorders are frequent both in human and veterinary medicine with high re-injury rates and unsatisfactory therapeutic treatments. Application of naked, chemically-modified mRNA (cmRNA), encoding for therapeutic proteins, is an innovative approach to address tendon healing. In the current study, we demonstrated that injection of naked cmRNA, diluted in a glucose-containing solution, into tendons resulted in high protein expression in healthy and experimentally-injured tendons. Injection of bone morphogenetic protein 7 (BMP-7)-encoding cmRNA resulted in a significantly higher expression of BMP-7 protein and reduced formation of collagen type III, compared to vehicle control. Moreover, in a large animal model, reporter protein expression was detectable not only in healthy, but also in experimentally-injured, severely inflamed tendons. Summarising, these results demonstrated the potential of cmRNAs encoding for therapeutic proteins as a new class of drugs for the treatment of tendon disorders.

Telemedicine: an important aid to perform high-quality endoscopic retrograde cholangiopancreatography in low-volume centers.

BACKGROUND AND STUDY AIMS: The aim of this study was to investigate whether telemedicine can help to ensure high-quality endoscopic retrograde cholangiopancreatography (ERCP) in patients living in rural areas. The study was conducted by investigators from two centers: the Karolinska University Hospital, a high-volume center which provided the teleguided support, and the Visby District Hospital, a low-volume center. PATIENTS AND METHODS: From September 2010 to August 2011, 26 ERCP procedures performed at a district hospital were teleguided by an experienced endoscopist at the Karolinska University Hospital. To ensure patient data protection, all communication went through a network (Sjunet) that was separate from the Internet and open only to accredited users. The indications for ERCP were common bile duct stones (n = 12), malignant strictures (n = 12), and benign biliary strictures (n = 2). In 15 cases, this was the patient's first ERCP procedure. RESULTS: The common bile duct was successfully cannulated in all 26 teleguided procedures. The local endoscopist scored the teleguided support as crucial for the successful outcome in 8 /26 cases, as an important factor in 8, and as being of less importance in the remaining 10. In the eight cases where the teleguided support was judged to be crucial, six subsequent percutaneous transhepatic cholangiography procedures and two repeat ERCPs were avoided. The overall cannulation rate at the district hospital improved from 85 % to 99 % after teleguided support was introduced. No procedure-related complications occurred. CONCLUSION: Distant guidance of advanced ERCP procedures in a low-volume center, through teleguided support from a high-volume center, has the potential to improve the quality of care, as reflected in high cannulation rates and the ability to complete the scheduled interventions.

Ovarian cortex transplantation in the baboon: comparison of four different intra-abdominal transplantation sites.

BACKGROUND: Several sites have been used for ovarian cortex transplantation (OCT) in humans. The present study was designed to evaluate different intra-abdominal transplantation sites in the baboon to gain further knowledge about alternative transplantation sites in a human setting. METHODS: Autologous fresh OCTs were performed in 12 baboons (Papio anubis). Four different sites were tested: the free portion of the omentum (OMF), the portion of the omentum adjacent to the spleen (OMS), the pouch of Douglas (D) and the pelvic wall on the psoas muscle (PW). Cortex survival, follicle density, cyclicity and hormonal levels were compared between the different sites, 3 and 6 months after transplantation. RESULTS: Macroscopically, antral follicles were only found in the OMS and OMF locations, which also showed a higher proportion of follicle-containing cortex at light microscopy (OMF 71.4%, OMS 83.3% versus PW 58.8% and D 40%, P< 0.05). Higher densities of primordial [OMF: 3.54 (0-13.18) follicles/grid, OMS: 3.85 (0-8.53), PW: 0 (0-13.25), D 0 (0-1.33), P< 0.05] and primary follicles [OMF: 3.54 (0-18.52), OMS: 3.85 (0-1), PW: 0 (0-4.58), D 0 (0-0.25), P< 0.05] was also found in the omental locations. CONCLUSIONS: Omental locations provide a better site, in terms of follicle survival, for intra-abdominal OCT in the baboon compared with the pelvic wall and the D.

Cyclosporine A exposure during pregnancy in mice: effects on reproductive performance in mothers and offspring.

BACKGROUND: Pregnancies after organ transplantation and under immunosuppressive treatment are associated with slightly elevated risks for obstetric and post-natal complications but can usually be managed well. However, little is known about the effects of intrauterine exposure (IUE) to immunosuppressants in the growing and adult offspring. One major issue is the potentially negative effects of immunosuppressive medication on reproduction. This study investigates the effect of exposure during pregnancy to the most commonly used immunosuppressant in organ transplantation, cyclosporine A (CsA), on the reproductive outcome in mothers and offspring. METHODS: Female C57CBA-F1 mice received 0, 10, 20 or 30 mg/kg bodyweight of CsA daily by subcutaneous mini-osmotic pumps during mating and pregnancy. Blood concentrations of CsA, implantation rates, resorption rates and fetal weights were analysed. In addition, female and male mice exposed to CsA in utero were mated to unexposed partners and pregnancy outcomes were analysed. RESULTS: Direct maternal exposure to CsA at high doses reduced implantation rates and fetal survival. IUE to CsA reduced adolescent growth but did not affect fertility, although a reduction in birthweight was seen in offspring of females exposed to CsA in utero. CONCLUSIONS: CsA exposure during pregnancy correlates with impaired reproductive outcome, but offspring fertility is not affected. The cause of reduction in adolescent weight gain and low birthweight in offspring of females exposed to CsA in utero need further investigation.

Rejection of allogenic uterus transplant in the mouse: time-dependent and site-specific infiltration of leukocyte subtypes.

BACKGROUND: Animal models of uterus transplantation are being developed ahead of a possible treatment for absolute uterus infertility in women. Our knowledge of inflammatory cell involvement in acute rejection of a uterus transplant is limited; therefore, we examined the pattern of invasion of leukocyte subtypes into an allogeneic uterus transplant. METHODS: The uterus and its vasculature were removed from BALB/c mice and transplanted into C57Bl/6 recipient mice at a heterotopic position, with the native uterus left in situ. Both uteri were removed on post-operative day 2 (D2, n = 5), D5 (n = 5) and D10 (n = 6). Immunohistochemistry for neutrophilic granulocytes, macrophages, cytotoxic CD8(+) T-cells, CD4(+) T-helper cells and B-cells was performed and cell density was evaluated in both myometrium and endometrium. RESULTS: Neutrophil density was increased in graft versus native uteri at D5 and D10 in myometrium and D10 in endometrium, and in endometrium was higher in the D5 than D2 graft (all P < 0.05). Infiltration of macrophages occurred from D2 in myometrium and from D5 in endometrium (P < 0.05, graft versus native). Density of CD8(+) cytotoxic T-cells increased in the graft versus native uteri at D5 in both uterine layers and for the graft versus D2 density (P < 0.01). In contrast, CD4(+) T-helper cells increased only transiently in graft endometrium at D5 (P < 0.05). Overall CD19(+) B-cell density was low, with no time-dependent changes in graft myometrium or endometrium. CONCLUSIONS: Acute rejection of an allogeneic uterus transplant in the mouse involves influx of predominately neutrophils, macrophages, CD8(+) T-cells and CD4(+) T-cells between D2 and D5 post-operatively.

Rejection of the transplanted uterus is suppressed by cyclosporine A in a semi-allogeneic mouse model.

BACKGROUND: A mouse uterus transplantation model has previously been developed for studies of various aspects of uterine transplantation, which in the future may be used as treatment for uterine infertility. The aim of the study was to evaluate the effect of the immunosuppressant cyclosporine A (CyA) on the rejection of the allotransplanted uterus in the mouse. METHODS: C57BL/6 mice were recipients of uteri from F1 hybrids (C57BL/6 x CBA/ca). Transplanted mice received vehicle (control, n=5), 10 or 20 mg/kg/day of CyA (CyA10, n=5 and CyA20, n=5). Untreated F1 hybrids with syngeneic transplants (n=3) were negative controls. On day 10 post-transplantation, the grafted uteri were examined, and biopsies were taken for histology and quantification of T cells. RESULTS: Histology analysis revealed necrosis of the uterine transplants in controls and to a lesser extent in the CyA groups. Apoptosis and inflammation was prominent in grafts from the CyA10 group but suppressed in the CyA20 group. A similar increase of CD4+ cells was seen in all groups, whereas the number of CD8+ cells was higher (P < 0.05) in the two allogeneic groups receiving CyA compared with the allogeneic vehicle group. CONCLUSIONS: CyA treatment clearly delays the progress of rejection of grafted uteri but is insufficient to suppress T cell infiltration. Interestingly, the number of CD8+ cells was higher in groups receiving CyA, possibly reflecting a CyA-dependent depression of activation-induced cell death (AICD) of cytotoxic T cells.

Rejection patterns in allogeneic uterus transplantation in the mouse.

BACKGROUND: Transplantation of the uterus in the mouse has been developed as a model system for research towards human uterine transplantation. Previous studies in a mouse model have demonstrated that a syngeneic uterus transplant can give rise to normal offspring. The aim of this study was to characterize the time course of rejection in a fully allogeneic mouse uterus transplantation model. METHODS: Uteri of BALB/c mice were transplanted to a heterotopic position in C57BL/6 recipients, whose native uteri were left in situ. The blood flow of the uteri, their gross appearance and general histology and the density of T-lymphocytes were examined on postoperative days 2-28. RESULTS: Macroscopic signs of rejection were apparent from day 5. At the light microscopy level, minimal inflammatory changes were seen from day 5 and massive inflammation was seen from day 10 to day 15. At day 28, necrosis and fibrosis were seen. The density of T-lymphocytes (CD3(+)) was increased in the grafted uterus from day 2 in the myometrium and from day 5 in the endometrium. Blood flow in the grafted uteri was reduced from day 15. CONCLUSION: A murine model to study rejection of allogeneic uterus transplants was characterized. Signs of rejection were seen from day 2 to day 5 and severe rejection was seen from day 10 to day 15. The data will be useful in future studies on immunosuppressants in this model.

Visual attention and aging.

The present review of visual attentional processes and aging focuses on definitions of attention that emphasize some aspect of the control of information processing (selective attention) or the processing resources needed to drive these control processes (attentional capacity). Emphasis is placed on how increased adult age affects attentional mechanisms and how these age differences in attention affect overall information processing. Past research has emphasized that selective attention appears to be resistant to age-related decline. Age-related deficits in attentional capacity or processing resources, however, have been found. A review of more recent psychological research demonstrates the extension of the investigation of attention with emphasis on further defining what is selected in selective attention, and on reexamining the processing resources or capacity issue. Finally, developments in cognitive neuroscience are reviewed in terms of their relevance to attention and aging.

Influence of response selection and noise similarity on age differences in the redundancy gain.

We examined the impact of target redundancy for target-plus-noise (TPN) and target-only (TO) trials. Experiment 1 manipulated response selection load (two-choice vs go/no-go) and Experiment 2 (all two-choice) varied noise redundancy (single or cumulative noise letters) on a visual search, divided attention task in which target letters were presented in one, two, or three corners of a four-corner display. Half of the trials also included noise letters. For Experiment 1, there was a definite redundancy gain for TO trials. Furthermore, older adults, relative to young adults, evidenced an even larger redundancy gain for TO trials than for TPN trials, although response selection load did not interact with age. These results are consistent with the notion that older adults exhibit a processing resources decrement. For Experiment 2, older adults evidenced a relatively larger redundancy gain for TPN trials than for TO trials, and this was especially the case for TPN trials in which all nontarget locations were filled with noise letters. Experiment 2 results are consistent with the notion that older adults also exhibit a selective attention decrement.

Influence of age and processing stage on visual word recognition.

The authors used a lexical-decision task in 3 different experiments to examine whether age differences in word recognition were consistent across processing stage. In all experiments, word frequency and length were manipulated. In Experiments 1 and 2, encoding difficulty was varied, and in Experiment 3, response selection difficulty was varied. In all 3 experiments, there were no age differences for word frequency. However, in Experiments 1 and 2, older adults showed a larger decrement for encoding. In Experiment 3, age differences were larger when response selection load increased. These results suggest that age differences in word recognition occur because older adults exhibit primarily peripheral-rather than central-processing decrements. The implications of these data for generalized and localized slowing models are discussed.

Occurrence of plasmids in black-pigmented gram-negative anaerobes.

Black-pigmented Gram-negative anaerobes are causative agents of pyogenic infections and are closely linked to various forms of periodontal diseases. Whereas many studies have shown a high incidence of plasmids in intestinal Bacteroides spp., there have been only a few reports of plasmid analyses in pigmented Gram-negative anaerobes. According to previous reports and confirmed in this study, plasmids can be present in Porphyromonas asaccharolytica, Prevotella intermedia, Pr. melaninogenica, and B. levii but have not been detected in P. gingivalis or other black-pigmented species. There were no correlations between plasmids and phenotypes such as resistance to antibiotics or bacteriocinogenicity. The highest carriage rate was found in isolates from cases of chronic otitis media, but the relationship between this site of infection and a high incidence of plasmids could be incidental. The size of plasmids ranged from 1.5 to 29 MDa. Plasmids with molecular weight > 10 MDa were described for the first time in these organisms. Repeated plasmid analyses showed that the plasmid patterns were generally stable.

Impact of adult age and Alzheimer's disease on levels of neural noise for letter matching.

We tested healthy young and older adults as well as higher-scoring (Mini-Mental State Exam, MMSE, scores between 14-20) and lower-scoring patients diagnosed with probable Alzheimer's disease (AD) on a letter-matching task. Subjects were instructed to respond "same" if two simultaneously presented letters were identical, or "different" if the letters did not match. Healthy older adults showed a larger "fast-same" effect than healthy young adults. Also, higher-scoring AD patients showed a large "false-different" effect for errors, but lower-scoring AD patients showed a large "false-same" effect. These data indicate that older adults exhibit higher neural noise levels than younger adults. The cross-over error pattern for AD suggests that moderately demented AD patients show evidence of forming degraded visual percepts whereas more severely demented AD patients show evidence of forming incomplete percepts.

Impact of age, redundancy, and perceptual noise on visual search.

We examined adult age differences in the impact of redundancy and perceptual noise during visual search. Using a two-choice, visual search task, subjects responded to letters presented in one to four corners of an imaginary display square. On each trial, one, two, or three instances of a given target letter were presented. In the target-plus-noise condition, all nontarget corners of the imaginary square were filled with distractor (i.e., noise) letters. In the target-only condition, all nontarget corners were left blank. The results indicated that older adults showed relatively greater redundancy benefits than the young adults for the target-plus-noise trials than for the target-only trials. These results are interpreted within an internal noise framework.

Immediate and sustained reduction in serum cholesterol achieved in 4-week Heart Tune program.

Currently, there is limited information about educational models effective in assisting individuals to lower their serum cholesterol. Dietitians and nutritionists involved in cholesterol-reduction programs need to inform other health professionals about programs utilized and the success of those programs. The National Cholesterol Education Program has published guidelines for the detection, evaluation, and treatment of high blood cholesterol in adults. Educational programs should be systematically evaluated to confirm their success in cholesterol reduction. The Heart Tune program is a 4-week class developed by a dietitian to assist clients in cholesterol reduction. An evaluation of the lipoprotein levels of 49 program participants demonstrated that serum total cholesterol levels significantly decreased at the completion of the 4-week class (0.65 mmol/L) and after 1 year (0.80 mmol/L).

Code teams and the review of cardiac arrests.

A new system for responding to Codes, or resuscitations of patients with cardiopulmonary arrest, was implemented at St Luke's Medical Center, Milwaukee. A teaching program was begun to establish the Advanced Cardiac Life Support (ACLS) guidelines as the standard of care. A task force defined the composition of the Code team and was then designated the Code Review Committee, meeting monthly to review all Codes. Indicators for review were established. Code review is followed by a letter to the physician Code team leader and/or registered nurse. Data for 18 months, still preliminary, show improved compliance with indicators for documentation and for adherence to ACLS guidelines.

Evaluation of cervical stimulation for chronic treatment of spasticity.

Electrical stimulation of the spinal cord (SCS) to reduce spasticity was evaluated in seven patients who, along with their physicians, perceived significant and prompt benefit from stimulation. In two 24-hour test periods, on or off stimulation, we used two independent methods of evaluation: quantitative measures of joint compliance and stretch reflexes, and a standardized neurologic examination. Neither method did better than chance in determining whether SCS was actually being received. Problems with the experimental protocol are discussed, but the results cannot be interpreted as supporting the efficacy of SCS as a treatment for spasticity.

[Objectification of the efficacy of an ointment for joint injuries using a volumetric method]. / Zur Objektivierung der Wirksamkeit eines Externums bei Sprunggelenksverletzungen mit Hilfe einer volumetrischen Methode.

Distorsions of the upper ankle joint in 27 sport students were treated with an ointment dressing once daily in a double-blind test over 8 days. 14 cases were treated with Hepathrombin-50,000-Salbe Adenylchemie (100 g contain 50,000 I.E. heparin, 300 mg allantoin and 400 mg dexpanthenol) and 13 cases with the ointment base. The therapeutic effect was objectified based on measurements taken after 1, 2, 4, and 8 days of the foot volume (weight of displaced water by overflow at 23 cm height) and mobility of the joint. Moreover, resting, movement and pressure pain were individually assessed and compiled as a pain score (0-12). In the Hepathrombin group, swelling subsided continuously from 100 to 42% and the pain score decreased from 12 to 3. With application of the ointment base, swelling increased at first to 114% after 2 days, then decreased until Day 8 to 86% of the initial value. The pain score decreased from 12 to 7. The superiority of Hepathrombin-Salbe over the ointment base could be statistically demonstrated; the difference between the two groups was significant with respect to swelling after just one day, and with respect to joint mobility after just 2 days of treatment.