The 14-3-3 proteins positively regulate rapamycin-sensitive signaling.

BACKGROUND: The kinase Tor is the target of the immunosuppressive drug rapamycin and is a member of the phosphatidylinositol kinase (PIK)-related kinase family. It plays an essential role in progression through the G1 phase of the cell cycle. The molecular details of Tor signaling remain obscure, however. RESULTS: We isolated two Saccharomyces cerevisiae genes, BMH1 and BMH2, as multicopy suppressors of the growth-inhibitory phenotype caused by rapamycin in budding yeast. BMH1 and BMH2 encode homologs of the 14-3-3 signal transduction proteins. Deletion of one or both BMH genes caused hypersensitivity to rapamycin in a manner that was dependent on gene dosage. In addition, alterations in the phosphopeptide-binding pocket of the 14-3-3 proteins had dramatically different effects on their ability to relieve the growth-arresting rapamycin phenotype. Mutations that prevented 14-3-3 from binding to a phosphoserine motif abolished its ability to confer rapamycin resistance. In contrast, substitution of two residues in 14-3-3 that surround these phosphoserine-binding sites conferred a dominant rapamycin-resistant phenotype. CONCLUSIONS: Our studies reveal 14-3-3 as an important component in rapamycin-sensitive signaling and provide significant new insights into the structure and function of 14-3-3 proteins.

Laparoscopy and collagen metabolism.

The collagens represent a vital component within the wound healing process and physiological scar formation. Therefore, analysing the influence of new operative procedures on collagen metabolism is of great surgical interest. As the endoscopic technique has, nowadays, become routinely applied for diverse abdominal diseases worldwide, we present a review of literature facing its impact on collagen biology.

[Abdominal compartment syndrome]. / Abdominelles Kompartmentsyndrom.

Abdominal compartment syndrome (ACS) is characterized by a persistent pathologic increase in intra-abdominal pressure (IAP) exceeding 20 mmHg with consecutive dysfunction of multiple organ systems. The main causes of ACS are abdominal trauma, obstruction, infection, and sepsis, but it may also be initiated by extra-abdominal diseases. The gold standard for diagnosis is repeated assessment of the IAP measurements of bladder pressure. The incidence of ACS is up to 15% in operative ICUs and the therapy of choice for it is decompressive laparotomy. Nevertheless, mortality is high, up to 60%.

Bone marrow cells are targets for the anabolic actions of prostaglandin E2 on bone: induction of a transition from nonadherent to adherent osteoblast precursors.

Although prostaglandin E2 (PGE2) is known to stimulate bone formation in vivo, its mechanism of action is not well understood. Circumstantial evidence suggests that bone marrow cells (BMC) may well be involved in this, and in order to investigate this further we have studied the effect of PGE2 on proliferation and matrix synthesis in high-density BMC cultures and on colony-forming unit (CFU-f) formation efficiency by BMC in vitro. High-density cultures of BMC formed a collagenous, calcified matrix, synthesized osteocalcin and expressed alkaline phosphatase activity. The addition of PGE2 caused a concentration-dependent increase in total (but not specific) APase activity, cell number, and collagen accumulation. It was found that PGE2 need only be present during the first 48 hours of the culture period and that longer exposure had no additional effect. PGE2 also caused a concentration-dependent increase in CFU-f formation, and it was found that this was due to the recruitment of new mesenchymal precursor cells from the nonadherent fraction of the BMC. Once again, the presence of PGE2 for only the first 48 hours of the culture period was enough to precipitate a maximal response. We conclude that one mechanism for the anabolic actions of PGE2 may be the recruitment of OB precursors from a population of nonadherent mesenchymal precursor cells present in the bone marrow.

The cloning of GRK7, a candidate cone opsin kinase, from cone- and rod-dominant mammalian retinas.

PURPOSE: Desensitization in the rod cell of the mammalian retina is initiated when light-activated rhodopsin is phosphorylated by the G protein-coupled receptor kinase (GRK), GRK1, often referred to as rhodopsin kinase. A distinct kinase that specifically phosphorylates cone opsins in a similar manner has not been identified in mammals. To determine the existence of a cone opsin kinase, RNA from the retinas of cone- and rod-dominant mammals was analyzed by PCR. METHODS: RNA prepared from the retinas of two cone-dominant mammals, the thirteen-lined ground squirrel and the eastern chipmunk, and a rod-dominant mammal, the pig, was used to clone a new GRK family member by RT-PCR. The tissue distribution and localization of the kinase in retina were determined by Northern blot hybridization and in situ hybridization. The protein encoded by this cDNA was expressed in human embryonic kidney-293 (HEK-293) cells and compared with bovine GRK1 for its ability to phosphorylate bovine rhodopsin and to undergo autophosphorylation. RESULTS: The cDNA cloned from ground squirrel contains an open reading frame encoding a 548 amino-acid protein. Sequence analysis indicates that this protein is orthologous to GRK7 recently cloned from O. latipes, the medaka fish. Partial cDNA fragments of GRK7 were also cloned from RNA prepared from eastern chipmunk and pig retinas. In situ hybridization demonstrated widespread labeling in the photoreceptor layer of the ground squirrel retina, consistent with expression in cones. Recombinant ground squirrel GRK7 phosphorylates bovine rhodopsin in a light-dependent manner and can be autophosphorylated, similar to bovine GRK1. CONCLUSIONS: These results indicate that cone- and rod-dominant mammals both express GRK7. The presence of this kinase in cones in the ground squirrel and its ability to phosphorylate rhodopsin suggests that it could function in cone cells as a cone opsin kinase.

Diverticular disease of the jejunum and its complications.

Jejunal diverticulosis is an uncommon, acquired condition that has been encountered recently in four patients. These cases (two patients with diverticulitis, one patient with chronic abdominal pain, and one patient incidentally discovered at laparotomy for colonic diverticulitis) are reported. Acute complications of jejunal diverticulosis include diverticulitis, bleeding, and intestinal obstruction. Chronic complications include intractable abdominal pain, malabsorption, and intestinal pseudo-obstruction. Up to 15 per cent of patients with jejunal diverticulosis may require small-bowel resection for treatment of these acute or chronic complications. The clinical significance, proper diagnostic evaluation, and treatment of jejunal diverticular disease are reviewed.

Studies on the expression of mRNA for anion transport related proteins in corneal endothelial cells.

PURPOSE: Chloride and bicarbonate are necessary for maintenance of fluid transport by the corneal endothelium, however there is little information on the identity of anion transport proteins that could serve as anion efflux mechanisms in endothelial cells. Therefore, we ask whether mRNA for the anion transport related proteins, CFTR, CLC-2, ClC-3, ClC-5 and AE2, are expressed in human, bovine or rabbit corneal endothelium. METHODS: RT-PCR was performed for CFTR, CLC-2, ClC-3, ClC-5 and AE2 using total RNA from fresh human, bovine and rabbit corneal endothelium as well as cultured bovine corneal endothelial cells (CBCEC). Specificity of PCR products was confirmed by sequencing. RESULTS: RT-PCR analysis gave positive bands at the predicted size for CLC-3 and CLC-5 from fresh human, rabbit and bovine as well as CBCEC. However, for CLC-2, no band was apparent around the predicted size from fresh and cultured corneal endothelium. A band at the predicted size was obtained for CFTR from fresh human, rabbit and bovine endothelium, as well as from CBCEC. RT-PCR analysis for AE2 produced specific bands from fresh human, rabbit and bovine corneal endothelium, but no positive band was obtained from CBCEC. Sequencing analysis further confirmed the identities of CLC-3, CLC-5, CFTR and AE2 in corneal endothelium. CONCLUSIONS: CFTR, CLC-3 and ClC-5 are expressed in fresh and cultured corneal endothelial cells. However, consistent with previous immunoblots studies, AE2 is only expressed in fresh corneal endothelium. These results have implications for modeling possible apical anion efflux mechanisms in corneal endothelium.

Peritoneal release of TNFalpha and IL-6 after elective colorectal surgery and anastomotic leakage.

The evaluation of postoperative peritoneal drainage fluid tumor necrosis factor (TNF)alpha and interleukin (IL)-6 was studied prospectively over a 7-day period in 25 patients operated on for neoplastic colorectal diseases. In 22 cases, colon or rectum carcinoma was the reason for surgery, and in 3 patients resection was performed because of colonic adenoma. All patients received either an end-to-end colo-colonic or colorectal anastomosis. Of this group, 22 patients were free of complications defined as uneventful postoperative course without any signs of anastomotic leakage until the 14th postoperative day. All of these patients showed a significant rise in peritoneal TNFalpha with maximum on the 7th day during the study period (p <.05). In contrast, peritoneal IL-6 levels remained constant without significant change in time (p >.05). Three patients underwent relaparotomy because of anastomotic leakage. In these patients, peritoneal TNFalpha concentrations showed a rise until the day of operative confirmation of anastomotic leakage. This rise preceded the day of operative confirmation by at least 1 day but did not change significantly in time (p =.59). Peritoneal IL-6 concentrations in patients with anastomotic leakage remained constant and also did not change significantly in time (p =.21). After elective colorectal surgery, neither postoperative abdominal drainage fluid TNFalpha nor IL-6 monitoring is helpful to decide on the need for revision in patients with anastomotic leakage.

[Sigmoid diverticulitis. Emergency intervention in abscess, hemorrhage and stenosis]. / Sigmadivertikulitis. Notfallinterventionen bei Abszess, Blutung und Stenose.

Interventional techniques in treatment of complicated diverticulitis gain more and more importance. In particular abscesses and bleeding are treated successfully. In case of diverticular abscess (Hinchey classification stage I and II) percutaneous drainages are placed sonographically or CT guided. Interventional drainage offers the possibility of elective one-stage surgical treatment of diverticulitis with significant reduce of mortality and morbidity rates. Diverticular bleeding is usually diagnosed and treated endoscopically. Only if endoscopy is not able to manage bleeding, angiography or nuclear scan is demanded. In case of stenosis endoscopic treatment has not jet gained clinical relevance.

[Surgical therapy of myasthenia gravis and thymoma]. / Chirurgische Therapie bei Myasthenia gravis und Thymom.

Between 1986 and 1992 eighteen patients underwent transsternal radical thymectomy at the Department of Surgery of the RWTH Aachen. Operation was indicated for myasthenia gravis (n = 14) or suspect of thymoma (n = 4). Patients with myasthenia were preoperatively classified according to Osserman and postoperatively with respect to their clinical status and drug dosages. Patients with thymoma were classified according to Masaoka. After a mean follow-up period of 43.6 months 76.9% of the patients with myasthenia demonstrated a significant improvement. All patients with thymoma were free of recurrence.

[Para-esophageal omental incarceration--a rare complication of para-esophageal hernia]. / Paraoesophageale Netzincarceration--Eine seltene Komplikation einer paraoesophagealen Hernie.

Herniation of large omentum is a rare complication of parahiatal hernias. This paper presents by means of a case report clinical symptoms, radiologic procedure and operative management of parahiatal greater omentum incarceration.

[Material and structure of drainages]. / Material und Struktur von Drainagen.

The long history of surgical drainages stands in contradiction to available and reliable data. As of today, closed systems made of silicone are preferable. Taking possible complications into consideration and the good results of routine operations without drainages, indication for use should be critically evaluated. Interdisciplinary research,however, offers the chance of optimizing material and surface characteristics, biostability, biocompatibility, and flow rates. New drainages with improved performance and reduced side effects may counteract the current tendency to do without.

[Prevention and therapy of intra-abdominal adhesions. A survey of 1,200 clinics in Germany]. / Prophylaxe und Therapie intraabdomineller Adhäsionen. Eine Umfrage an 1200 Kliniken in Deutschland.

A survey of 1200 hospitals in Germany was undertaken to estimate the current standards of prevention and treatment of postoperative peritoneal adhesions. The 751 (62.2%) evaluated questionnaires showed a representative distribution according to postal zones and annual laparotomies. The rate of coeliotomies for adhesional bowel obstruction is 2.6%. Starch-powdered gloves are used in 54.2% and washed before operating in 69.3%. Dry swabs and towels are used in 60.7 and 22.5%, respectively. Most of the surgeons suture the peritoneum. Adhesions are divided in patients with respective symptoms but without intestinal obstruction by 32.6% and during laparotomies for non-adhesion-related diseases by 20.4%. Long intestinal tubes and plication procedures are applied by 43.9 and 33.7%, respectively. Medication is administered for routine prophylaxis of adhesion by 6%, for prevention of recurrencies by 17.2%. Although it has been revealed that adjuvant measures for prevention of adhesions are needed, as of today, no regimen has proofed its efficacy and gotten accepted for clinical usage.

[Birth control overseas]. / La régulation de la fécondité outre-mer.

After reminding the changes of ovarian cycle during sexual life, the authors propose some indications on the reversible means that can be used for birth control in the developing countries where they practice. As practicing is very peculiar to these countries and in order to enable married couples to decide freely upon different advisable possibilities, the authors underline the importance to develop all the educational ways and means on this topic.

[The role of surgery in acute epididymitis]. / Place de la chirurgie dans les épididymites aiguës.

One third of the acute épididymitis (A.E.) admitted in the Military Hospital in Marseilles have been operated, i.e. 33 cases; out of them the last 12 cases have been systematically monitored by ultrasonography. Twice out of three times, clinical picture suggested a possible twisting that led to an emergency surgical exploration. Interest of ultrasonography of the scrotum is underlined as far as diagnosis is concerned but also in monitoring A.E. Indeed, despite medical treatment (antibiotics + anti-inflammatory drugs), it is possible that some A.E. are evolving either to abscess or to their "vascular" form; The ultimate form of the acute epididymo-orchitis is necrosis of the testis. This is due to, or amplified by, vascular compression linked up with edema. Surgical intervention has therefore to investigate by inguinal path the entire spermatic cord and the épididymis-testis system, and to apply the "decompression technique" requested.

[Cancer of the penis in Cambodia]. / Cancer de la verge au Cambodge.

The prevalence of penis cancer in Cambodia is comparable with some Far-East and Latino-American countries. Circumcision performed as a religious observance among Jews or undergone as a regular practice among older Moslems children (the Islam Kmers in Cambodia) might provide an indirect protection against this kind of cancer. It indeed helps in ensuring proper personnal hygiene and in improving the detection, the treatment and the aftercare of all the mild lesions which possibly can pave the way to cancer. Out of of 253 observed cases recorded during a 10 years period (from 1960 to 1970), 164 were treated and followed up by the same surgical team from 1964 to 1970. They stress on those etiopathogenic factors and make possible a description of the reported "anatomoclinical" forms. The use of radiumtherapy either by contact or by means of needles is quite effective; however, when corpora cavernosa are involved, it will be often necessary to perform either a partial amputation or to an emasculation in case of entirely overspreading lesions. As metastases are of rare occurence, it is regarded as a "mild cancer"; however the sequelae due to the treatment are far from small importance. Through better personnal hygiene, detection, treatment, and surveillance of inflammations and benign tumors, with the renforcement of circumcision as a regular practice for every case of phimosis or chronic lesions, an effective prevention of this kind of cancer will expectedly be carried out in Cambodia and its prevalence will be reduced to a rate similar to that in European countries.

The tragedy of schizophrenia without psychotherapy.

No one who read Frieda Fromm-Reichmann's "Transference Problems in Schizophrenia" could reasonably think about persons with schizophrenia in the same way as before. Her writings made clear that schizophrenia is a human experience with meaning, meaning that is hard to uncover, but it only takes patience, kindness, a tolerance for not understanding as well as for the patient's desperate defenses, and a willingness to understand the human condition at its most painful and to take psychoanalytic ideas seriously when patients talk about them. Understanding persons with schizophrenia means facing facts about ourselves, our families, and our society that we do not want to know, or to know again (in the case of repressed feelings and experiences). Families and professionals are settling for treatments that aim at making the patient a lifelong cripple who is not too disturbing. Psychoeducational programs, which potentially could be helpful, usually give false information which makes worse the burdens of both patients and their families. The ultimate genetic experiment, the Nazi sterilization and annihilation of patients, led to no decrease in schizophrenia in the next generation. Long-term follow-up studies show one third of schizophrenics fully recover within 25 years and another third have social recoveries with or without treatment--and psychological treatments before the neuroleptic era, from "moral treatment" to psychoanalytic therapies, produced superior results, but we are not using them. The central role of terror in producing symptoms and the genesis and psychotherapeutic handling of symptoms, including delusions and hallucinations, will be described.

Physicians' experiences with Medicaid managed care: the Tennessee American College of physicians survey on TennCare.

Despite widespread introduction of Medicaid managed care (MMC), physicians have not been surveyed regarding its impact on patient care. This study documented physician experiences with MMC in Tennessee, where a statewide experimental managed care program (TennCare) delivers services through 12 capitated managed care organizations (MCOs). Practicing Tennessee American College of Physician (ACP) members (n = 1,181) were questioned regarding recent experience with the TennCare program, assessment of the program, and suggestions for improvement. The results, derived from 306 physician respondents (response rate 26%), were as expected, based on findings of a prior administrative focus group and independent surveys. Physicians' experiences were similar regardless of practice type. Most physicians rated the TennCare program as either fair (43%) or poor (42%) overall. The majority cited administrative complexity as a major problem that frequently adversely affected patient care. Physician experience suggests that administrative procedures and medication formularies should be streamlined and standardized to improve patient care.