Exogenous Lipocalin 2 Ameliorates Acute Rejection in a Mouse Model of Renal Transplantation.

Lipocalin 2 (Lcn2) is rapidly produced by damaged nephron epithelia and is one of the most promising new markers of renal injury, delayed graft function and acute allograft rejection (AR); however, the functional importance of Lcn2 in renal transplantation is largely unknown. To understand the role of Lcn2 in renal AR, kidneys from Balb/c mice were transplanted into C57Bl/6 mice and vice versa and analyzed for morphological and physiological outcomes of AR at posttransplantation days 3, 5, and 7. The allografts showed a steady increase in intensity of interstitial infiltration, tubulitis and periarterial aggregation of lymphocytes associated with a substantial elevation in serum levels of creatinine, urea and Lcn2. Perioperative administration of recombinant Lcn2:siderophore:Fe complex (rLcn2) to recipients resulted in functional and morphological amelioration of the allograft at day 7 almost as efficiently as daily immunosuppression with cyclosporine A (CsA). No significant differences were observed in various donor-recipient combinations (C57Bl/6 wild-type and Lcn2(-/-) , Balb/c donors and recipients). Histochemical analyses of the allografts showed reduced cell death in recipients treated with rLcn2 or CsA. These results demonstrate that Lcn2 plays an important role in reducing the extent of kidney AR and indicate the therapeutic potential of Lcn2 in transplantation.

Spiegelmer Inhibition of MCP-1/CCR2--Potential as an Adjunct Immunosuppressive Therapy in Transplantation.

The rejection process remains the key unsolved issue after transplantation of disparate tissue. The CC chemokine monocyte chemoattractant protein-1 (MCP-1/CCL2) has been reported to be involved in the process of alloimmune interaction. Spiegelmers are l-oligonucleotides that can be designed to bind to pharmacologically relevant target molecules. Here, we tested a high-affinity Spiegelmer-based MCP-1 inhibitor (mNOX-E36) in an allogeneic heart transplant model. Fully vascularized allogeneic heterotopic heart transplantations from BALB/c to C57BL/6 mice were performed. Mice were either treated with the anti-MCP-1-Spiegelmer (mNOX-E36) in monotherapy or in combination with subtherapeutic doses of cyclosporine A (CsA) (10 mg/kgBW/day) for 10 days. Controls received equivalent doses of a non-functional Spiegelmer (revmNOX-E36). Graft survival of allogeneic heart transplants was slightly but significantly prolonged under mNOX-E36 monotherapy (median graft survival 10 day ± 0.7) compared to revmNOX-E36 (median graft survival 7 day ± 0.3; P = 0.001). A synergistic beneficial effect could be seen when mNOX-E36 was administered in combination with subtherapeutic doses of CsA (18 day ± 2.8 versus 7 day ± 0.3; P < 0.0001). Levels of inflammatory cytokines and 'alarmins' were significantly reduced, and the number of F4/80(+) cells was lower under combination therapy (1.8% ± 1.3%; versus 14.6% ± 4.4%; P = 0.0002). This novel inhibitor of the MCP-1/CCR2 axis (mNOX-E36), which has already proven efficacy and tolerability in early clinical trials, alleviates acute rejection processes in allogeneic transplantation especially when combined with subtherapeutic doses of CsA. Thus, mNOX-E36 may have potential as an adjunct immunomodulatory agent.

[Transplantation and hepatic, pancreatic, and biliary (HPB) surgery fellowship--a pilot project for a structured training in Germany]. / Fellowship für Transplantation und hepato-pankreatiko-biliäre (HPB) Chirurgie - Pilotprojekt für eine strukturierte Weiterbildung in Deutschland.

Currently, there is no structured training plan to become a transplant surgeon in Germany. Similar to the Anglo-Saxonian educational system we have implemented a 3-year fellowship in transplant and hepatic-, pancreatic-, biliary (HPB) surgery. The educational curriculum is based on the guidelines of the European Board of Surgery (EBS) for transplant and HPB surgery. Here, we describe the underlying thoughts, the selection process, structure and curriculum for this fellowship. Furthermore, we critically compare our programme to the established international training standards. So far, our programme has proven valuable. We believe a fellowship for transplant and HPB surgery is a reasonable approach to ensure a high quality training of the following generations of surgeons in this field.

[Tumor and transplantation]. / Tumor und Transplantation.

Tumor treatment and transplantation-associated with unavoidable mandatory immunosuppression-appear to be unreconcilable opposites. The clinical reality shows, however, that transplantation in many early stage primary tumors is the most effective treatment. The essential immunosuppression after transplantation can however promote tumor recurrence. Immunosuppression also leads to a significant increased rate of de novo tumors-in all organ transplant recipients. However, not all immunosuppressant drugs have the same effect on tumors. In experimental and clinical settings, the class of mTOR inhibitors has a clear antitumoral effect and is recommended as the immunosuppression treatment of choice in patients with increased tumor risk. The purpose of this review is to provide the reader with the scientific background regarding the clinical problem of tumors and transplantation.

[Pancreatic cancer in the elderly: guidelines and individualized therapy]. / Pankreaskarzinom im hohen Alter: Leitlinien und individualisierte Therapie.

The considerable increase of the aged population in western civilisation within the next years will result in a rising incidence of pancreatic cancer. Until the year 2020 an increment of 20  % of patients beyond 65 years old can be anticipated. Therefore, the focus will be on management of old and geriatric surgical patients leading to strategical re-evaluation of surgical indications under critical consideration of feasibility and purpose. Even under modern interdisciplinary therapy concepts the prognosis of ductal adenocarcinoma of the pancreas remains poor with an overall 5-year survival rate of less than 5  %. The surgical resection is still considered as the only potential curative treatment option with extended life expectancy; however, it is technically demanding and furthermore associated with significant morbidity. In particular, the quality of surgery of the now interdisciplinary therapy of pancreatic cancer is markedly improved when performed at a high-volume centres. Until now only a few retrospective data analyses evaluating the perioperative and long-term outcome after pancreatic tumor resections in geriatric patients exist. The available results, however, support radical surgical procedures even beyond the age of 75 years.

Tolerance induction or sensitization in mice exposed to noninherited maternal antigens (NIMA).

Developmental exposure to noninherited maternal antigens (NIMA) exerts a tolerizing or sensitizing influence on clinical transplantation in humans and experimental animals. The aim of this study was to determine if strain and gender differences influence the NIMA effect. Six different mouse strain backcross matings of F(1) females with homozygous males ('NIMA backcross') and corresponding control breedings of F1 males with homozygous females were performed. H-2 homozygous offspring underwent heterotopic heart transplantation from fully allogeneic donors expressing noninherited H-2 antigens. A NIMA tolerizing effect on heart allograft outcome was found in three of six breeding models. In all three cases, the tolerizing antigens were from an H-2(d+) strain. The tolerogenic effect was greatest in male as compared with female recipients. Offspring from the three breeding models in which no tolerance was seen, appeared to be sensitized based on poorer graft survival, or enhanced T- or B-cell responses to the noninherited H-2(b or k) antigens. Significantly higher percentages of maternal antigen(+) cells were found in the peripheral blood of tolerant versus nontolerant strains of backcross mice prior to transplant. Our findings imply that transplants are predisposed to tolerance or rejection due to recipient developmental history and immunogenetic background.

[Traumatic thoracic aorta rupture: preclinical assessment, diagnosis and treatment options]. / Traumatische thorakale Aortenruptur: Präklinische Beurteilung, Diagnostik und Therapieoptionen.

Traumatic aortic rupture is a life-threatening injury which is frequently associated with blunt thoracic trauma or found coincidentally in heavily traumatized patients. Depending on the degree of disruption of the damaged aortic wall, vascular injury is associated with a high primary mortality rate and a significant risk of secondary aortic rupture. Early clinical signs which may indicate a ruptured thoracic aorta are left sided thoracic pain, reduced ventilation, tachycardia and dyspnoe as well as hypotension in the lower extremities. The primary aim for emergency treatment is to maintain vital organ function and to hemodynamically stabilize the patient. Surgical treatment was previously performed by either direct aortic suture or segmental alloplastic graft interposition using the clamp and sew technique with or without extra-anatomic shunts or extracorporeal circulation. However, endovascular stent graft implantation has now become another treatment option for traumatic aortic rupture. According to the reported data and our own experience there is increasing evidence that endovascular aortic repair might become the treatment of choice for patients with traumatic aortic rupture, with the option of an early, less invasive intervention thus avoiding thoracotomy. Regular follow-up is necessary to detect possible stent graft migration or leakage which could require additional endovascular or open surgical re-interventions.

Outpatient mental health care, self-help groups, and patients' one-year treatment outcomes.

OBJECTIVE: To examine the association between the duration and amount of outpatient mental health care, participation in self-help groups, and patients' casemix-adjusted one-year outcomes. METHODS: A total of 2,376 patients with substance use disorders, 35% of whom also had psychiatric disorders, were assessed at entry to treatment and at a one-year follow-up. Information about the duration and amount of outpatient mental health care was obtained from a centralized health services utilization database. RESULTS: Patients who obtained regular outpatient mental health care over a longer interval and patients who attended more self-help group meetings had better one-year substance use and social functioning outcomes than did patients who were less involved in formal and informal care. The amount of outpatient mental health care did not independently predict one-year outcomes. CONCLUSIONS: The duration of outpatient mental health care and the level of self-help involvement are independently associated with less substance use and more positive social functioning. The provision of low intensity treatment for a longer time interval may be a cost-effective way to enhance substance abuse and psychiatric patients' long-term outcomes.

Outcomes of four treatment approaches in community residential programs for patients with substance use disorders.

OBJECTIVE: Treatment approaches used in community residential facilities for patients with substance use disorders were identified, and patients' participation in treatment and case-mix-adjusted one-year outcomes for substance use, symptoms, and functioning in facilities with different treatment approaches were examined. METHODS: A total of 2,376 patients with substance use disorders treated in a representative sample of 88 community residential facilities were assessed at entry to and discharge from the facility and at one-year follow-up. The community residential facilities were classified into four types based on the major emphasis of the treatment program: therapeutic community, psychosocial rehabilitation, 12-step, and undifferentiated. RESULTS: Patients in programs that used the therapeutic community, psychosocial rehabilitation, and 12-step approaches had comparable one-year outcomes in symptoms and functioning that were better than those of patients in undifferentiated programs. A more directed treatment orientation, a longer episode of care, and completion of care were independently related to better one-year outcomes. These findings held for patients with only substance use disorders and for patients with both substance use and psychiatric disorders. CONCLUSIONS: Community residential programs that have a more directed treatment orientation and that motivate patients to complete treatment have better substance use outcomes. As an increasingly important locus of specialized care, community residential facilities need to develop and maintain more differentiated and distinctive treatment orientations.

The influence of list format and category headers on age differences in understanding medication instructions.

We examined whether instructions are better understood and remembered when they contain organizational cues. Our previous research found that older and younger adults organize medication information in similar ways, suggesting that they have a schema for taking medication. In the present study, list formats (vs. paragraphs) emphasized the order of information and category headers emphasized the grouping of information specified by this schema. Experiment 1 examined whether list and header cues improve comprehension (answer time and accuracy) and recall for adults varying in age and working memory capacity (measured by a sentence span task). List instructions were better understood and recalled than paragraphs, and reduced age differences in answer time and span differences in accuracy. Headers reduced paragraph comprehension for participants with lower levels of working memory capacity, presumably because they were not salient cues in the paragraphs. Experiment 2 investigated if headers were more effective when more saliently placed in paragraphs and lists, and if list and header cues helped readers draw inferences from the instructions. List formats again reduced age differences in comprehension, especially reducing the time needed to draw inferences about the medication. While headers did not impair comprehension, these cues did impair recall. The present study suggests that list-organized instructions provide an environmental support that improves both older and younger adult comprehension and recall of medication information.

The role of reader age and focus of attention in creating situation models from narratives.

We examined adult age differences in the mental representation of situations and how readers update this representation during narrative comprehension. Older and younger adults memorized a building layout and then read narratives about a protagonist's actions in this building. The narratives contained critical sentences that described the protagonist moving from one room (the "source room") into another (the "goal room"), through an unmentioned path room. Each critical sentence was followed by a target sentence referring to an object in one of these rooms. Half of the target sentences explicitly mentioned the room containing this object and half did not. Reading time increased when the target object was more distant from the protagonist and when the room containing the object was not mentioned, suggesting that readers tracked the protagonist's location in the layout and allocated resources in order to maintain coherence in the situation model. Older adults' reading times differentially slowed with distance, and older readers who more accurately understood the narrative differentially slowed when the location of the target object was not mentioned. Finally, the more accurate readers (older and younger) slowed primarily when updating was most difficult (i.e., both when the room containing the object was not mentioned and for more distant objects). While these findings reveal qualitative similarity in how older and younger readers update spatially organized situation models, they also suggest that older readers must sometimes allocate more resources to this updating process in order to maintain comprehension.

Community residential program policies, services, and treatment orientations influence patients' participation in treatment.

The study sought to identify community residential program characteristics that predict patients' participation in treatment and to examine the association between these characteristics, participation, and outcomes at discharge from treatment. A sample of 2,790 patients with substance abuse disorders was assessed at entry into and discharge from 87 community residential facilities (CRFs). The CRFs were assessed using a survey that obtained information about program size and staffing, policies and services, and treatment orientation. High expectations for patients' functioning, clear policies, structured programming, a high proportion of staff in recovery from substance abuse problems, and more emphasis on psychosocial treatment were associated with patients' participation in program services and activities. Higher expectations for functioning and a strong treatment orientation enhanced participation more among better functioning patients; program support and structure enhanced participation more among impaired patients. Participation in treatment independently predicted outcomes at discharge even after both patient and program characteristics were controlled. These findings show that community residential program policies, services, and treatment orientations play a key role in influencing patients' engagement in treatment, which, in turn, improves patients' outcomes at discharge.

Medication instruction design: younger and older adult schemas for taking medication.

We examined whether older and younger adults share a schema for taking medication and whether instructions are better recalled when they are organized to match this schema. Experiment 1 examined age difference in schema organization. Participants sorted medication items (e.g., purpose, dose, possible side effects) according to similarity and then ordered the items to create a preferred instruction set. Cluster analysis of the sort and order data showed that younger and older adults share a schema for taking medication. Secondary regression analyses found that verbal ability (i.e., vocabulary scores) predicted individual differences in schema organization. In Experiment 2 participants recalled instructions that were either compatible with this schema in terms of grouping and order of items or were presented in nonpreferred orders. Younger participants remembered more information than did older participants, but both age groups better remembered and preferred the more schema-compatible instructions. Secondary analyses showed that recall was also positively related to verbal ability. Along with our earlier research, this study suggests that older and younger adults possess a schema for taking medication and that instructions that are compatible with this schema provide an environmental support that improves memory for medication information.

Using icons to convey medication schedule information.

We examined older adult comprehension and memory for medication schedules conveyed by different types of visual icons as well as text. Three icons were compared: a timeline, a pair of 12 h clocks (one for AM and one for PM hours) and a 24 h clock. In Experiment 1, older and younger participants paraphrased and then recalled schedules that were conveyed by the three icons or by text. Text and timeline schedules were paraphrased more accurately than either clock icon. Paraphrase errors suggested that subjects had trouble integrating schedule information across the two 12 h clocks. Analysis of paraphrase times showed that the text schedule was paraphrased most quickly, followed by the timeline, the 24 h clock and the 12 h clock. No differences were found for the accuracy of recalling the icon and text schedules. Experiment 2 examined free and cued recall after limited study time by older adults. Because text superiority in Experiment 1 may have reflected greater familiarity with text than with icons, recall was examined across four trials in Experiment 2. Text was recalled most accurately, followed by the timeline, the 24 h clock and the 12 h clock. Study-test trials did not influence recall. Text schedules may have been generally more effective than the icons because of their greater familiarity. The timeline may have been the most effective icon because it was more compact and familiar than the clock icons used in the study. The findings suggest that including such icons in medication instructions requires training.

Computerization of the urologic office. Billing, record keeping, and education.

Careful initial evaluation of the options is vital to successful medical office automation. The many available software programs should be scrutinized to be certain the one chosen satisfies all one's listed needs. In addition to the usual functions expected of computers, the data gathered can be used to market the urologic practice. Word processing, spreadsheet, and database programs can enhance relations among the urologist's office, referring physicians, and patients.

Staphylococcus epidermidis in diabetic urological patient.

We present 6 patients in whom prosthetic failure occurred because of sepsis owing to Staphylococcus epidermidis. Such failure occurs in grafts in other areas and is caused by the high resistance of the organism to conventional antibacterial measures. Therapy with appropriate antibiotics, that is aminoglycosides, vancomycin and rifampin, and the need for an early operation are stressed.