[Pharmacological Management of Postoperative Delirium]. / Pharmakologisches Management des postoperativen Delir.

Postoperative delirium (POD) is a complex disorder with significant implications for health and well-being. Over the last few years, there has been a significant increase in awareness of the pathophysiological processes, the different clinical forms and the prevention of POD. It is known that POD develops when anaesthetic- and surgery-related precipitating factors coincide with the patient's predisposing vulnerability. Consequently, assessing the preoperative physical, cognitive, psychological, social and resilience capabilities of patients scheduled for surgery is critical to assessing overall risk and determining optimal preoperative, intraoperative and postoperative management, particularly as pharmacological treatment options remain limited. For treatment, non-pharmacological measures remain in the foreground, pharmacological therapy is only used for severe symptoms, and should be symptom-oriented and low-dosed. There is no drug that is suitable for delirium treatment alone.

Association of cholinesterase activities and POD in older adult abdominal surgical patients.

BACKGROUND: Postoperative delirium (POD) is a frequent complication after surgery. Older adult patients undergoing abdominal surgery are at higher risk for developing POD. Studies on the association of cholinesterase activities and POD are rare, but leading hypotheses implicate that the cholinergic pathway might play an important role in neuroinflammation and development of POD. The objective of this study was to figure out if there is an association between the development of POD and acetyl- and butyrylcholinesterase (AChE and BuChE) activities in older adult patients undergoing abdominal surgery. METHODS: The investigation was performed with a subpopulation of BioCog study patients. The BioCog project ( http://www.biocog.eu ) is a prospective multicenter observational study in older adult surgical patients. Patients ≥ 65 years undergoing elective surgery of at least 60 minutes who scored more than 23 points in the Mini-Mental-State-Examination were included. POD was assessed twice a day on seven consecutive days after the surgery, using the test instruments Nursing Delirium Screening Scale (Nu-Desc) and Confusion Assessment Method (CAM and CAM-ICU) and a patient chart review. Pre- and postoperative blood cholinesterase activities were measured with a photometric rapid-point-of-care-testing. The association between cholinesterase activities and POD was analyzed in a subpopulation of abdominal surgical patients using multivariable logistic regression analysis adjusting for confounders. RESULTS: One hundred twenty-seven patients were included for analysis (mean age 73 years, 59% female). Fifty-two patients (41%) fulfilled the criteria of POD. These patients were significantly older, had a longer time of surgery and anesthesia and achieved higher comorbidity scores compared to patients without POD. After adjusting for age, duration of surgery and charlson comorbity index, we found an association between pre- and postoperative AChE activity (U/gHb) and the development of POD (Odds ratio (OR), [95% confidence interval (CI)], preoperative 0.95 [0.89-1.00], postoperative 0.94 [0.89-1.00]). CONCLUSIONS: We found an association between POD and AChE activity and provided new information considering patients with abdominal surgery. Future analyses should examine course dynamics of postoperative cholinesterase activities in order to clarify interactions between the cholinergic system and pathophysiological mechanisms leading to POD. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02265263.

The Pivotal Role of CXCR7 in Stabilization of the Pulmonary Epithelial Barrier in Acute Pulmonary Inflammation.

Acute pulmonary inflammation is still a frightening complication in intensive care units and has a high mortality. Specific treatment is not available, and many details of the pathomechanism remain unclear. The recently discovered chemokine receptor CXCR7 and its ligand stromal cell-derived factor (SDF)-1 are known to be involved in inflammation. We chose to investigate the detailed role of CXCR7 in a murine model of LPS inhalation. Inflammation increased pulmonary expression of CXCR7, and the receptor was predominantly expressed on pulmonary epithelium and on polymorphonuclear neutrophil (PMNs) after transepithelial migration into the alveolar space. Specific inhibition of CXCR7 reduced transepithelial PMN migration by affecting the expression of adhesion molecules. CXCR7 antagonism reduced the most potent PMN chemoattractants CXCL1 and CXCL2/3. After inhibiting CXCR7, NF-κB phosphorylation was reduced in lungs of mice, tight junction formation increased, and protein concentration in the bronchoalveolar lavage diminished, showing the impact of CXCR7 on stabilizing microvascular permeability. In vitro studies with human cells confirmed the pivotal role of CXCR7 in pulmonary epithelium. Immunofluorescence of human lungs confirmed our in vivo data and showed an increase of the expression of CXCR7 in pulmonary epithelium. Highlighting the clinical potential of CXCR7 antagonism, nebulization of the agent before and after the inflammation showed impressive anti-inflammatory effects. Additional CXCR7 inhibition potentiated the effect of SDF-1 antagonism, most probably by downregulating SDF-1 and the second receptor of the chemokine (CXCR4) expression. In conclusion, our data identified the pivotal role of the receptor CXCR7 in pulmonary inflammation with a predominant effect on the pulmonary epithelium and PMNs.

Relevance of peripheral cholinesterase activity on postoperative delirium in adult surgical patients (CESARO): A prospective observational cohort study.

BACKGROUND: The cholinergic system is considered to play a key role in the development of postoperative delirium (POD), which is a common complication after surgery. OBJECTIVES: To determine whether peri-operative acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities are associated with the development of POD in in-hospital surgical patients, and raise hypotheses on cholinergic regulatory mechanisms in POD. DESIGN: A prospective multicentre observational study by the Peripheral Cholinesterase-activity on Neurocognitive Dysfunctions in Surgical Patients (CESARO) study group. SETTING: Nine German hospitals. PATIENTS: Patients of at least 18 years of age scheduled for inpatient elective surgery for a variety of surgical procedures. A total of 650 patients (mean age 61.5 years, 52.8% male) were included. METHODS: Clinical variables, and peripheral AChE and BuChE activities, were assessed throughout the peri-operative period using bedside point-of-care measurements (one pre-operative and two postoperative measurements). POD screening was conducted postoperatively for at least 24 h and up to the third postoperative day using a validated screening tool (nursing delirium screening scale). RESULTS: In all, 179 patients (27.5%) developed POD within the early postoperative phase. There was a lower BuChE activity in patients with delirium compared with patients without delirium pre-operatively (Cohen's r = 0.07, P = 0.091), on postoperative day 1 (Cohen's r = 0.12, P = 0.003) and on postoperative day 2 (Cohen's r = 0.12, P = 0.002). In contrast, there was a significantly higher AChE activity in patients with delirium compared with patients without delirium pre-operatively (Cohen's r = 0.10, P = 0.012), on postoperative day 1 (Cohen's r = 0.11, P = 0.004) and on postoperative day 2 (Cohen's r = 0.13, P = 0.002). After adjusting for covariates in multiple logistic regression, a significant association between both BuChE and AChE activities and POD was not found. However, in the multivariable analysis using the Generalized Estimating Equation, cholinesterase activities showed that a decrease of BuChE activity by 100 U L increased the risk of a delirium by approximately 2.1% (95% CI 1.6 to 2.8%) and for each 1 U g of haemoglobin increase in AChE activity, there was a 1.4% (95% CI 0.6 to 2.2%) increased risk of POD. CONCLUSION: Peri-operative peripheral cholinesterase activities may be related to the development of POD, but the clinical implications remain unclear. Further studies, in homogeneous patient groups with a strict protocol for measurement time points, are needed to investigate the relationship between cholinesterase activities and POD. TRIAL REGISTRATION: www.clinicaltrials.gov. Identifier NCT01964274.

Peri- and postoperative cognitive and consecutive functional problems of elderly patients.

PURPOSE OF REVIEW: From an elderly patient's perspective, acute and chronic cognitive disturbances are among the most harmful complications that can occur following surgery. For elderly patients, these complications often mean the end of an independent life. This article focuses on this serious aspect, which is increasingly prevalent in our aging society. Cognitive disturbances are associated with severe outcome impairments and increased mortality. This article aims to provide a current overview regarding the diagnosis, pathophysiology, prevention, and treatment of this severe social problem. RECENT FINDINGS: The current knowledge of risk factors, diagnosis, prevention, and treatment of postoperative delirium and postoperative cognitive dysfunction should help to raise awareness and improve the outcome of delirious patients, particularly in the elderly population. SUMMARY: Especially in elderly patients, postoperative delirium constitutes a common, severe complication. Early diagnosis and supportive treatment are essential to improve outcome. To date, no pharmacological treatment strategy was effective, so that further research about the underlying pathophysiology and the development of treatment strategies are urgently required.

["Symptomatic Treatment of Delirium, Anxiety and Stress, and Protocol Based Analgesia, Sedation and Management of Sleep in Intensive Care Patients"]. / Analgesie, Sedierung und Delirmanagement - Die neue S3-Leitlinie "Analgesie, Sedierung und Delirmanagement in der Intensivmedizin" (DAS-Leitlinie 2015).

Critically ill patients suffer from anxiety, stress, pain, sleep disturbance and delirium. The updated version of the German evidence and consensus based guideline "Analgesia, Sedation and Delirium management in Intensive Care - DAS 2015" contributes an improved therapeutic management and is aimed to improve clinical outcome based on the current state of evidence. The task force members were representatives from 17 national medical societies therefore have consented following guiding principle in common: "Patients in intensive care shall be awake, alert and free of pain, anxiety and delirium, to be able to participate in the healing process actively."

The effects of quarter-individual milking in conventional milking parlours on the somatic cell count and udder health of dairy cows.

The objective of this study was to examine the quarter health status of quarter-individually and conventionally milked cows. The MultiLactor®, a quarter-individual milking system (MULTI), has single guided tubes which provide milking on the quarter level with a low system vacuum level (37 kPa), sequential pulsation and periodic air inlet. The conventional milking system (CON) was equipped with a milking cluster where the system vacuum level was adjusted to 40 kPa. A total of 84 German Holstein cows, randomly divided into two groups, were included in the study. Over a period of 32 trial weeks, quarter foremilk samples were taken every week to determine somatic cell count (SCC). Bacteriological examinations and udder palpation were conducted at three different times. During the trial period, median SCC of quarter foremilk samples in both groups did not exceed the threshold value of 100,000 cells/ml. The results of the F test showed that the milking system (P = 0.0587) and days in milk (DIM) (P = 0.8066) had no significant effects on the quarter health status. On the other hand, lactation (P = 0.0396), quarter health status in the previous week (P < 0.0001) and trial week (P = 0.0061) affected quarter health status significantly. The estimated probabilities of the occurrence of a suspicious quarter (SCC > 100,000 cells/ml) were 19.97% (CON) and 31.72% (MULTI). However, the test of differences in the Least Square Means (LSM) showed no significant differences (P = 0.0585) between CON and MULTI. The estimated probability of quarters becoming suspicious during the first lactation was 12.51% for both groups. With an increasing number of lactation, the probability of a quarter becoming suspicious clearly increased (2nd lactation: 32.73% and 3rd lactation: 36.19%). The results also showed that the percentage of quarters with bacteriological findings revealed a stronger increase over time for MULTI than for CON.

In a secondary analysis from a randomised, double-blind placebo-controlled trial Dexmedetomidine blocks cholinergic dysregulation in delirium pathogenesis in patients with major surgery.

Dexmedetomidine is an alpha-2 adrenoreceptor agonist with anti-inflammatory and anti-delirogenic properties. Pathogenesis of postoperative delirium (POD) includes cholinergic dysfunction and deregulated inflammatory response to surgical trauma. Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are discussed as biomarkers for both POD and severity in acute inflammation. To show whether there is a link between blood cholinesterase activities and dexmedetomidine, we performed a secondary analysis of a randomised, double-blind, placebo-controlled trial that recently showed a lower incidence of POD in the dexmedetomidine group. Abdominal or cardiac surgical patients aged ≥ 60 years were randomised to receive dexmedetomidine or placebo intra- and postoperatively in addition to standard general anaesthesia. We analysed the course of perioperative cholinesterase activities of 56 patients, measured preoperatively and twice postoperatively. Dexmedetomidine resulted in no change in AChE activity and caused a rapid recovery of BChE activity after an initial decrease, while placebo showed a significant decrease in both cholinesterase activities. There were no significant between-group differences at any point in time. From these data it can be assumed that dexmedetomidine could alleviate POD via altering the cholinergic anti-inflammatory pathway (CAIP). We advocate for further investigations to show the direct connection between dexmedetomidine and cholinesterase activity.

Preoperative Comparison of Three Anticholinergic Drug Scales in Older Adult Patients and Development of Postoperative Delirium: A Prospective Observational Study.

BACKGROUND: Postoperative delirium (POD) is a frequent and serious complication after surgery. Evidence of a relationship between anticholinergic medication and the development of delirium is inconclusive, but studies on POD are rare. OBJECTIVES: The objective of this study was to evaluate the anticholinergic load of preoperative medication in older adult patients and its association with the development of POD. METHODS: This investigation was part of the European BioCog project ( http://www.biocog.eu ), a prospective multicenter observational study in older adult surgical patients (ClinicalTrials.gov identifier: NCT02265263, 15 October 2014). Patients with a Mini-Mental State Examination score ≤ 23 points were excluded. POD was assessed up to 7 days after surgery using the Nursing Delirium Screening Scale, Confusion Assessment Method and a patient chart review. The preoperative anticholinergic load was calculated using the Anticholinergic Drug Scale (ADS), the Anticholinergic Risk Scale (ARS) and the Anticholinergic Cognitive Burden Scale (ACBS), and associations with POD were analyzed using logistic regression analysis adjusting for age, comorbidities, duration of anesthesia and number of drugs used. RESULTS: In total, 837 participants were included for analysis, and 165 patients (19.7%) fulfilled the criteria of POD. After adjusting for confounders, we found no association between preoperative anticholinergic load and the development of POD (ADS [points] odds ratio [OR] 0.928; 95% confidence interval [CI] 0.749-1.150; ARS [points] OR 0.832; 95% CI 0.564-1.227; ACBS [points] OR 1.045; 95% CI 0.842-1.296). CONCLUSION: This study found no association between the anticholinergic load of drugs used preoperatively and the development of POD in older adult patients without severe preexisting cognitive impairment. Future analyses should examine the influence of intra- and postoperative administration of anticholinergic drugs as well as dosages of and interactions between medications.

Butyrylcholinesterase as a perioperative complication marker in patients after transcatheter aortic valve implantation: a prospective observational study.

OBJECTIVES: Transcatheter aortic valve implantation (TAVI) is performed in elderly patients with severe aortic valve stenosis and increased operative risks. We tested the hypothesis that acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) have a predictive value for prevalent complications after TAVI and could serve as indicators of systemic inflammation in the early postoperative period. DESIGN: Prospective observational study. SETTING: This study is a secondary analysis of multicentre CESARO- study. PARTICIPANTS: 48 patients with TAVI were included and 43 obtained the complete assessment. PRIMARY AND SECONDARY OUTCOME MEASURES: Patients' clinical parameters, demographic data, peripheral AChE and BChE activities and routine blood markers were assessed throughout the perioperative period using bedside point-of-care measurements for AChE and BChE. Postoperative complication screening was conducted up to the third postoperative day and included infections, delirium and heart-rhythm disturbances. After assessment, the patients were divided into complication and noncomplication group. RESULTS: Of 43 patients, 24 developed postsurgical complications (55.8%). Preoperative assessment showed no significant differences regarding demographic data and laboratory markers, but preoperative BChE levels were significantly lower in patients who developed postoperative complications (complication group 2589.2±556.4 vs noncomplication group 3295.7±628.0, Cohen's r=0.514, p<0.001). In complication group, we observed an early, sustained reduction in BChE activity from preoperative to postoperative period. In complication group, BChE levels were significantly lower at each time point compared with noncomplication group. AChE activity showed no significant difference between both groups. Complication group also had longer stay in hospital overall. CONCLUSION: BChE could be a useful perioperative biomarker to identify patients with a higher risk for postoperative complications after TAVI. By using point-of-care measurements, the levels of BChE are fast available and can lead to an early targeted therapy. Predicting the length of the hospital stay might play an important role in staff and resource management for these patients. TRIAL REGISTRATION NUMBER: NCT01964274; Post-results.

Radiological, Chemical, and Pharmacological Cholinergic System Parameters and Neurocognitive Disorders in Older Presurgical Adults.

BACKGROUND: A pre-existing neurocognitive disorder (NCD) is a relevant factor for the outcome of surgical patients. To improve understanding of these conditions, we investigated the association between parameters of the cholinergic system and NCD. METHOD: This investigation is part of the BioCog project (www.biocog.eu), which is a prospective multicenter observational study including patients aged 65 years and older scheduled for elective surgery. Patients with a Mini-Mental State Examination (MMSE) score ≤23 points were excluded. Neurocognitive disorder was assessed according to the fifth Diagnostic and Statistical Manual of Mental Disorders criteria. The basal forebrain cholinergic system volume (BFCSV) was assessed with magnetic resonance imaging, the peripheral cholinesterase (ChE) activities with point-of-care measurements, and anticholinergic load by analyzing the long-term medication with anticholinergic scales (Anticholinergic Drug Scale [ADS], Anticholinergic Risk Scale [ARS], Anticholinergic Cognitive Burden Scale [ACBS]). The associations of BFCSV, ChE activities, and anticholinergic scales with NCD were studied with logistic regression analysis, adjusting for confounding factors. RESULTS: A total of 797 participants (mean age 72 years, 42% females) were included. One hundred and eleven patients (13.9%) fulfilled criteria for mild NCD and 82 patients (10.3%) for major NCD criteria. We found that AcetylChE activity was associated with major NCD (odds ratio [95% confidence interval]: [U/gHB] 1.061 [1.010, 1.115]), as well as ADS score ([points] 1.353 [1.063, 1.723]) or ARS score, respectively ([points] 1.623 [1.100, 2.397]) with major NCD. However, we found no association between BFCSV or ButyrylChE activity with mild or major NCD. CONCLUSIONS: AcetylChE activity and anticholinergic load were associated with major NCD. Future research should focus on the association of the cholinergic system and the development of postoperative delirium and postoperative NCD.

Antimicrobial and immunoregulatory properties of human tryptophan 2,3-dioxygenase.

In mammals, the regulation of local tryptophan concentrations by the IFN-gamma-i inducible enzyme IDO is a prominent antimicrobial and immunoregulatory effector mechanism. Here, we show for the first time that another tryptophan-degrading enzyme, the liver-specific tryptophan 2,3-dioxygenase (TDO), is also capable of mediating antimicrobial and immunoregulatory effects. Using a tetracycline inducible eukaryotic system, we were able to express recombinant TDO protein, which exhibits functional properties of native TDO. We found that HeLa cells expressing recombinant TDO were capable of inhibiting the growth of bacteria (Staphylococcus aureus), parasites (Toxoplasma gondii) and viruses (herpes simplex virus). These TDO-mediated antimicrobial effects could be blocked by the addition of tryptophan. In addition, we observed that, similar to IDO-positive cells, TDO-positive cells were capable of inhibiting anti CD3-driven T-cell proliferation and IFN-gamma production. Furthermore, TDO-positive cells also restricted alloantigen-induced T-cell activation. Here, we describe for the first time that TDO mediates antimicrobial and immunoregulatory effects and suggest that TDO-dependent inhibition of T-cell growth might be involved in the immunotolerance observed in vivo during allogeneic liver transplantation.

ERj1p has a basic role in protein biogenesis at the endoplasmic reticulum.

ERj1p is a membrane protein of the endoplasmic reticulum (ER) that can recruit the ER lumenal chaperone BiP to translating ribosomes. ERj1p can also modulate protein synthesis at initiation and is predicted to be a membrane-tethered transcription factor. Here we attribute the various functions of ERj1p to distinct regions within its cytosolic domain. A highly positively charged nonapeptide within this domain is necessary and sufficient for binding to ribosomes. Binding of ERj1p to ribosomes involves the 28S ribosomal RNA and occurs at the tunnel exit. Additionally, ERj1p has a dual regulatory role in gene expression: ERj1p inhibits translation in the absence of BiP, and another charged oligopeptide within the cytosolic domain of ERj1p mediates binding of the nuclear import factor importin beta and import into the nucleus, thereby paving the way for subsequent action on genomic DNA.

The missing link between indoleamine 2,3-dioxygenase mediated antibacterial and immunoregulatory effects.

The interferon (IFN)-gamma-inducible tryptophan degrading enzyme indoleamine 2,3-dioxygenase (IDO) has not only been recognized as a potent antimicrobial effector molecule for the last 25 years but was recently found also to have potent immunoregulatory properties. In this study, we provide evidence that both tryptophan starvation and production of toxic tryptophan metabolites are involved in the immunoregulation mediated by IDO, whereas tryptophan starvation seems to be the only antibacterial effector mechanism. A long-studied controversy in the IDO research field is the seemingly contradictory effect of IDO in the defence against infectious diseases. On the one hand, IFN-gamma-induced IDO activity mediates an antimicrobial effect, while at the same time IDO inhibits T-cell proliferation and IFN-gamma production. Here, we suggest that both effects, dependent on the threshold for tryptophan, cooperate in a reasonable coherence. We found that the minimum concentration of tryptophan required for bacterial growth is 10-40-fold higher than the minimum concentration necessary for T-cell activation. Therefore, we suggest that during the first phase of infection the IDO-mediated tryptophan depletion has a predominantly antimicrobial effect whereas in the next stage, and with ongoing tryptophan degradation, the minimum threshold concentration of tryptophan for T-cell activation is undercut, resulting in an inhibition of T-cell growth and subsequent IDO activation.

The ER-membrane-resident Hsp40 ERj1 is a novel substrate for protein kinase CK2.

The endoplasmic reticulum (ER) membrane protein ERj1, a member of the Hsp40 family, was proposed to be a regulator of protein biogenesis at the ER. With its lumenal J-domain, ERj1 recruits the lumenal Hsp70-type chaperone BiP to newly synthesized polypeptide chains. Its cytosolic domain interacts with ribosomes and inhibits protein synthesis in its BiP-free state. Additionally, the cytosolic domain may act as a transcription factor. Recent proteomic data suggest that ERj1 is a target of phosphorylation. Since protein kinase CK2 is present on the ER surface, we addressed the question whether ERj1 is a substrate for CK2. We show that native ERj1 is phosphorylated by CK2. Using deletion mutants, ERj1 peptides, and a mutational analysis, the major phosphorylation site for CK2 was mapped to the conserved sequence motif SSDEE at amino acid residues 477-481, which is located in the cytosolic domain of ERj1.

Ca2+-calmodulin inhibits tail-anchored protein insertion into the mammalian endoplasmic reticulum membrane.

Cytosolic components and pathways have been identified that are involved in inserting tail-anchored (TA) membrane proteins into the yeast or mammalian endoplasmic reticulum (ER) membrane. Searching for regulatory mechanisms of TA protein biogenesis, we found that Ca(2+)-calmodulin (CaM) inhibits the insertion of TA proteins into mammalian ER membranes and that this inhibition is prevented by trifluoperazine, a CaM antagonist that interferes with substrate binding of Ca(2+)-CaM. The effects of Ca(2+)-CaM on cytochrome b(5) and Synaptobrevin 2 suggest a direct interaction between Ca(2+)-CaM and TA proteins. Thus, CaM appears to regulate TA insertion into the ER membrane in a Ca(2+) dependent manner.

Evolutionary gain of function for the ER membrane protein Sec62 from yeast to humans.

Because of similarity to their yeast orthologues, the two membrane proteins of the human endoplasmic reticulum (ER) Sec62 and Sec63 are expected to play a role in protein biogenesis in the ER. We characterized interactions between these two proteins as well as the putative interaction of Sec62 with ribosomes. These data provide further evidence for evolutionary conservation of Sec62/Sec63 interaction. In addition, they indicate that in the course of evolution Sec62 of vertebrates has gained an additional function, the ability to interact with the ribosomal tunnel exit and, therefore, to support cotranslational mechanisms such as protein transport into the ER. This view is supported by the observation that Sec62 is associated with ribosomes in human cells. Thus, the human Sec62/Sec63 complex and the human ER membrane protein ERj1 are similar in providing binding sites for BiP in the ER-lumen and binding sites for ribosomes in the cytosol. We propose that these two systems provide similar chaperone functions with respect to different precursor proteins.

Protein transport into canine pancreatic microsomes: a quantitative approach.

Transport of presecretory proteins into the mammalian rough endoplasmic reticulum involves a protein translocase that comprises the integral membrane proteins Sec61alphap, Sec61betap, and Sec61gammap as core components. Electron microscopic analysis of protein translocase in rough microsomal membranes suggested that between three and four heterotrimeric Sec61p complexes form the central unit of protein translocase. Here we analyzed the stoichiometry of heterotrimeric Sec61p complexes present in cotranslationally active protein translocases of canine pancreatic microsomes and various other lumenal and membrane components believed to be subunits of protein translocase and to be involved in covalent modifications. Based on these numbers, the capacity for cotranslational transport was estimated for the endoplasmic reticulum of the human pancreas.

A novel type of co-chaperone mediates transmembrane recruitment of DnaK-like chaperones to ribosomes.

Recently, the homolog of yeast protein Sec63p was identified in dog pancreas microsomes. This pancreatic DnaJ-like protein was shown to be an abundant protein, interacting with both the Sec61p complex and lumenal DnaK-like proteins, such as BiP. The pancreatic endoplasmic reticulum contains a second DnaJ-like membrane protein, which had been termed Mtj1p in mouse. Mtj1p is present in pancreatic microsomes at a lower concentration than Sec63p but has a higher affinity for BiP. In addition to a lumenal J-domain, Mtj1p contains a single transmembrane domain and a cytosolic domain which is in close contact with translating ribosomes and appears to have the ability to modulate translation. The interaction with ribosomes involves a highly charged region within the cytosolic domain of Mtj1p. We propose that Mtj1p represents a novel type of co-chaperone, mediating transmembrane recruitment of DnaK-like chaperones to ribosomes and, possibly, transmembrane signaling between ribosomes and DnaK-like chaperones of the endoplasmic reticulum.