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Biomedical subjects

A Fritsch

Publications and source records attributed to A Fritsch.

At least 19 recordsLinked to original sources
PubMed2001

Cell cycle and biochemical effects of PD 0183812. A potent inhibitor of the cyclin D-dependent kinases CDK4 and CDK6.

Progression through the G1 phase of the cell cycle requires phosphorylation of the retinoblastoma gene product (pRb) by the cyclin D-dependent kinases CDK4 and CDK6, whose activity can specifically be blocked by the CDK inhibitor p16(INK4A). Misregulation of the pRb/cyclin D/p16(INK4A) pathway is one of the most common events in human cancer and has lead to the suggestion that inhibition of cyclin D-dependent kinase activity may have therapeutic value as an anticancer treatment. Through screening of a chemical library, we initially identified the [2,3-d]pyridopyrimidines as inhibitors of CDK4. Chemical modification resulted in the identification of PD 0183812 as a potent and highly selective inhibitor of both CDK4 and CDK6 kinase activity, which is competitive with ATP. Flow cytometry experiments showed that of the cell lines tested, only those expressing pRb demonstrated a G1 arrest when treated with PD 0183812. This arrest correlated in terms of incubation time and potency with a loss of pRb phosphorylation and a block in proliferation, which was reversible. These results suggest a potential use of this chemical class of compounds as therapeutic agents in the treatment of tumors with functional pRb, possessing cell cycle aberrations in other members of the pRb/cyclin D/p16(INK4A) pathway.

Animals↗
PubMed2000

Pyrido[2,3-d]pyrimidin-7-one inhibitors of cyclin-dependent kinases.

The identification of 8-ethyl-2-phenylamino-8H-pyrido[2, 3-d]pyrimidin-7-one (1) as an inhibitor of Cdk4 led to the initiation of a program to evaluate related pyrido[2, 3-d]pyrimidin-7-ones for inhibition of cyclin-dependent kinases (Cdks). Analysis of more than 60 analogues has identified some clear SAR trends that may be exploited in the design of more potent Cdk inhibitors. The most potent Cdk4 inhibitors reported in this study inhibit Cdk4 with IC(50) = 0.004 microM ([ATP] = 25 microM). X-ray crystallographic analysis of representative compounds bound to the related kinase, Cdk2, reveals that they occupy the ATP binding site. Modest selectivity between Cdks is exhibited by some compounds, and Cdk4-selective inhibitors block pRb(+) cells in the G(1)-phase of the cell division cycle.

Adenosine Triphosphate↗
PubMed2000

Motor cortex disinhibition in acute stroke.

OBJECTIVES: To test whether a disinhibition occurs in the human motor cortex after stroke. METHODS: Patients with a mild to moderate hemiparesis after an acute unilateral ischemic stroke were compared with age-matched healthy controls. We used paired transcranial magnetic stimuli (TMS) to investigate intracortical inhibition and facilitation. Single TMS were applied to obtain a cortical silent period. RESULTS: Intracortical inhibition was significantly reduced in the affected hemisphere at interstimulus intervals of 2, 3 and 4 ms. The cortical silent period was significantly prolonged when compared to the unaffected hemisphere of the patients and to the control group. Motor cortex disinhibition observed in stroke patients was associated either with minimal impairment at the onset of symptoms or with rapidly improving motor functions. CONCLUSIONS: Motor cortex disinhibition occurs in humans after stroke. We suggest that this disinhibition is indicative of compensatory mechanisms, which are involved in recovery-related reorganization.

Acute Disease↗
PubMed1999

Oxidized low-density lipoprotein inhibits the binding of monoclonal antibody to platelet glycoprotein IIB-IIIA.

Previous studies have shown that oxidized low-density lipoprotein (LDL) induces platelet activation more effectively than native LDL. To achieve a better understanding of the mechanism underlying the activation of human platelets by oxidized LDL, the present study relates the effect of oxidized LDL to changes of binding characteristics for glycoprotein (GP) IIb-IIIa. Washed human platelets were treated by monoclonal antibody against GP IIb-IIIa, and the ligand-receptor complexes were revealed by immunocytochemical techniques on the ultrastructural level. The localization of the antiglycoprotein IIb-IIIa was time-dependent. After binding to the platelet surface membrane and open canalicular system, the surface-membrane labeling decreased during longer incubation periods. Preincubation with oxidized LDL inhibited the binding of antiglycoprotein IIb-IIIa. Our findings suggest that GP IIb-IIIa acts as a receptor for oxidized LDL. The binding of oxidized LDL to the GP IIb-IIIa might be the first step in platelet activation by plasma lipoproteins.

Antibodies, Monoclonal↗
PubMed1998

PAK4, a novel effector for Cdc42Hs, is implicated in the reorganization of the actin cytoskeleton and in the formation of filopodia.

The GTPases Rac and Cdc42Hs control diverse cellular functions. In addition to being mediators of intracellular signaling cascades, they have important roles in cell morphogenesis and mitogenesis. We have identified a novel PAK-related kinase, PAK4, as a new effector molecule for Cdc42Hs. PAK4 interacts only with the activated form of Cdc42Hs through its GTPase-binding domain (GBD). Co-expression of PAK4 and the constitutively active Cdc42HsV12 causes the redistribution of PAK4 to the brefeldin A-sensitive compartment of the Golgi membrane and the subsequent induction of filopodia and actin polymerization. Importantly, the reorganization of the actin cytoskeleton is dependent on PAK4 kinase activity and on its interaction with Cdc42Hs. Thus, unlike other members of the PAK family, PAK4 provides a novel link between Cdc42Hs and the actin cytoskeleton. The cellular locations of PAK4 and Cdc42Hs suggest a role for the Golgi in cell morphogenesis.

Actins↗
PubMed1998

Chp, a homologue of the GTPase Cdc42Hs, activates the JNK pathway and is implicated in reorganizing the actin cytoskeleton.

The p21-activated protein kinases (PAKs) are activated through direct interaction with the GTPases Rac and Cdc42Hs, which are implicated in the control of the mitogen-activated protein kinase (MAP kinase) c-Jun N-terminal kinase (JNK) and the reorganization of the actin cytoskeleton [1-3]. The exact role of the PAK proteins in these signaling pathways is not entirely clear. To elucidate the biological function of Pak2 and to identify its molecular targets, we used a novel two-hybrid system, the Ras recruitment system (RRS), that aims to detect protein-protein interactions at the inner surface of the plasma membrane (described in the accompanying paper by Broder et al. [4]). The Pak2 regulatory domain (PakR) was fused at the carboxyl terminus of a RasL61 mutant protein and screened against a myristoylated rat pituitary cDNA library. Four clones were identified that interact specifically with PakR and three were subsequently shown to encode a previously unknown homologue of the GTPase Cdc42Hs. This approximately 36 kDa protein, designated Chp, exhibits an overall sequence identity to Cdc42Hs of approximately 52%. Chp contains two additional sequences at the amino and carboxyl termini that are not found in any known GTPase. The amino terminus contains a polyproline sequence, typically found in Src homology 3 (SH3)-binding domains, and the carboxyl terminus appears to be important for Pak2 binding. Results from the microinjection of Chp into cells implicated Chp in the induction of lamellipodia and showed that Chp activates the JNK MAP kinase cascade.

Actins↗
PubMed1996

Laparoscopic unroofing of symptomatic congenital liver cysts.

BACKGROUND: Unroofing is the therapy of choice in patients with symptomatic, nonparasitic benign liver cysts-either solitary or diffuse. Techniques which require laparotomy, such as cystojejunostomy or pericystectomy, generally do not justify surgical morbidity in benign conditions. METHODS: We report the outcome of eight fenestration operations in seven patients with hepatic cysts in laparoscopic performance. Patients were reexamined after a mean follow-up period of 30 months. RESULTS: All operations were finished without conversion. There were no perioperative complications. Only one patient had a recurrence and was successfully reoperated via laparoscopy including cholecystectomy without refilling of the cyst until reexamination. CONCLUSIONS: Adoption of minimal access surgery in these patients occurred without loss of quality and offered the well-known benefits of laparoscopic surgery.

Aged↗
PubMed1995

Complications of endoscopic thoracic sympathectomy.

BACKGROUND: Endoscopic resection of the thoracic sympathetic trunk has been performed in various diseases of the upper limb. The success rates in endoscopic techniques and open surgical procedures are reportedly between 95% and 100%. However, the incidence of complications varied significantly depending on the technique used. We report our experience with complications after endoscopic resection of the thoracic sympathetic trunk. METHODS: To evaluate the complications of endoscopic thoracic sympathectomy, we retrospectively investigated 412 patients operated on since 1965. In 412 patients 698 procedures had been performed: a bilateral trunk resection in 81.9%, right thoracic sympathectomy in 12.9%, and left sympathetic trunk resection in 5.2%. RESULTS: Complications demanding intervention were found in 2.7% of the procedures, and in 9.7% complications not indicating active therapy were seen. In all cases requiring intervention a pneumothorax that needed to be drained was found on postoperative x-ray film. An asymptomatic small apical pneumothorax was found in 4.4%, cutaneous emphysema in 2%, pleural effusion in 1.1%, and segmental atelectasis in 0.4% of the procedures. One case of bleeding from an intercostal vessel occurred (0.1%). A permanent Horner's ptosis was seen in 1.7% of the patients. CONCLUSIONS: The endoscopic resection of the thoracic sympathetic trunk is a safe and minimally invasive procedure with a low complication rate. We believe that endoscopic sympathectomy should be preferred to open surgical procedures.

Adolescent↗
PubMed1995

Necrosectomy and laparostomy--a combined therapeutic concept in acute necrotising pancreatitis.

OBJECTIVE: To present our experience with laparostomy and necrosectomy in the treatment of acute necrotising pancreatitis, and to show how refinements in our treatment regimen improved mortality over the years despite no reduction in the severity of the disease. DESIGN: Retrospective study. SETTING: University hospital, Austria. SUBJECTS: 125 patients treated by laparostomy/necrosectomy with repeated revisions during the period January 1983 to December 1991. INTERVENTIONS: Laparostomy, blunt necrosectomy, operative lavage, and open drainage. MAIN OUTCOME MEASURES: Mortality and morbidity. RESULTS: The severity of disease was assessed by the APACHE II score (median 15, range 4-30). In 106 of the 125 patients (85%) the necrotic pancreatic tissue was infected. Patients were operated on if they deteriorated clinically or if organ failure was suspected. A change in the protocol from revisions on demand (1983/4) to planned re-exploration at 48 hour intervals (1985/8) was associated with a reduction in mortality from 53% (16/30) to 28% (20/72). This was further reduced in 1989/91 to 17% (4/23) when a protocol of revisions planned for individual patients was introduced (p = 0.02). The incidence of gastrointestinal fistulas during the three periods was 6/30 (20%); 24/72 (33%); and 1/23 (4%); (p = 0.022), whereas that of intraabdominal bleeding remained much the same (7/23, 23%; 13/72, 18%; and 4/23, 17%; p = 0.56). The median (range) APACHE II scores for the three periods were 12 (4-27), 15 (5-30), and 14 (4-25). CONCLUSION: By continual revision of our protocol, together with accompanying improvements in intensive care, our mortality decreased significantly during the nine year period.

Acute Disease↗
PubMed1994

On interleukins 4, 6 and 10 and their interrelationship with immunoglobulins G and M in common variable immunodeficiency.

Following culture of human peripheral blood mononuclear cells (PBMNC) from 25 normal donors and 15 patients with common variable immunodeficiency (CVID), we were unable to identify any IL10-defective patients. Clear-cut effects of IL4 could be demonstrated in controls, while in CVID all effects are less pronounced. While in both controls and CVID baseline levels of IL6, IgG and IgM were found to be correlated, this was altered by the addition of either IL4 or Poke Weed Mitogen (PWM). We therefore conclude that the inability of PBMNC to produce IL10 is not the cause of CVID in our patients. In CVID, the regulating circuitry triggered by IL4 remains principally intact, however, some subgroups of CVID behave significantly differently.

Adult↗
PubMed1994

Endoscopic thoracic sympathectomy for primary hyperhidrosis of the upper limbs. A critical analysis and long-term results of 480 operations.

OBJECTIVE: This evaluated the long-term outcome after endoscopic thoracic sympathectomy (ETS) from below D1 to D4, using a single-site access technique for primary hyperhidrosis of the upper limbs. SUMMARY BACKGROUND DATA: Primary hyperhidrosis of the upper limbs is a distressing and often socially disabling condition. Endoscopic thoracic sympathectomy is considered the treatment of choice, causing minimal morbidity and high initial success rates. However, data regarding long-term results are scarce. METHODS: Two hundred seventy of 323 patients (83.7%), in whom 480 sympathectomies were performed, answered a questionnaire after a mean of 14.6 years postoperatively regarding the early postoperative result, side effects, and complications caused by the operation and long-term results with particular emphasis on patient satisfaction. RESULTS: There was no postoperative mortality and no major complications requiring surgical reintervention. A majority of the patients (98.1%) were relieved, and 95.5% were satisfied initially. Permanent side effects included compensatory sweating in 67.4%, gustatory sweating in 50.7% and Horner's trias in 2.5%. However, patient satisfaction declined over time, although only 1.5% recurred. This left only 66.7% satisfied, and a 26.7% partially satisfied. Compensatory and gustatory sweating were the most frequently stated reasons for dissatisfaction. Individuals operated for axillary hyperhidrosis without palmar involvement were significantly less satisfied (33.3% and 46.2%, respectively).

Adolescent↗
PubMed1993

CCK-8 and gastrin plasma levels in cholecystectomized and colorectal cancer patients.

The elevated incidence of large bowel carcinoma after cholecystectomy has long been controversial. The pathomechanism of this entity, however, is still unclear. Many authors have demonstrated a correlation between cholecystokinin (CCK) and gastrin levels and the occurrence of colorectal cancer. As yet, no clear data are available on the potential impact of cholecystectomy on CCK level alterations. Moreover, no reports have yet been published on CCK receptors. We have investigated the role of CCK-8 and gastrin plasma levels in patients with prior cholecystectomy and CCK receptor levels in patients with colorectal cancer. 125 patients entered a prospective study. Of these, 45 served as controls. 40 patients had prior cholecystectomy, 5 patients underwent cholecystectomy during the ongoing trial. 35 patients had a colorectal cancer, 5 of these had prior cholecystectomy. No patient had elevated CCK-8 plasma levels. Gastrin levels were slightly elevated in 2 patients. There was no correlation between large bowel carcinoma and CCK-8 and gastrin levels. Elevated CCK-8 levels following cholecystectomy occur neither immediately after surgery nor on a long-term basis. Immunohistochemical studies in patients with colorectal cancer showed no CCK receptors in the normal colonic or tumor tissue. These findings are contrary to gastrin receptor data.

Cholecystectomy↗
PubMed1993

[Laparoscopic colon surgery--from experiment to initial clinical experience].

The technique of Laparoscopic resection of the colon sigmoideum was practised in an experimental model before starting a clinical program of laparoscopic colonic surgery. Until now, two resections of the colon sigmoideum, one ileocecal resection, one right colectomy, one Hartmann's procedure and one transversostomy have been performed laparoscopically. Three patients had colonic carcinoma. One sigmoid resection had to be converted to open surgery and this patient underwent relaparotomy because of postoperative ileus. The postoperative course of the other patients was uncomplicated. The promising initial experience demonstrates that laparoscopic colonic surgery is feasible, although further studies have to prove advantages and indications, especially with respect to oncology.

Adolescent↗