Hereditary disorders of the protein C system in central artery and branch arteriolar occlusions]

BACKGROUND: Resistance to activated protein C (APC) is the most common hereditary defect in patients with venous thrombosis. There are conflicting reports on the prevalence of APC resistance in patients with arterial thrombosis, e.g. coronary arteries, compared to the APC resistance prevalence among the normal population. The prevalence of APC resistance in branch retinal artery occlusion (BRAO) and central retinal artery occlusion (CRAO) is unknown. PATIENTS AND METHODS: 29 consecutive patients with arterial retinal occlusions (BRAO, n = 12; CRAO, n = 17) were included in this prospective study over a 23-months-period. We searched for APC resistance, protein C or S deficiencies, as well as for acquired vascular risk factors. Factor-V-deficient plasma and genetic analysis with a PCR method were employed for APC resistance determination. Protein C and protein S activity were determined with functional tests. RESULTS: APC resistance was found in 3 of 29 patients (10.3%). Two of these patients had BRAO and one patient CRAO. Comparing this prevalence to the APC resistance prevalence within the normal population (9%), the difference was not statistically significant. 27 patients (93.1%) had one or more vascular risk factors (arterial hypertension = 19 [65.5%], hyperlipidaemia = 14 [48.2%], smoking = 7 [24.1%], diabetes mellitus = 5 [17.2%], carotid artery stenosis = 5 [17.2%]). CONCLUSIONS: We could not find an increased prevalence of APC resistance in patients with CRAO or BRAO when compared to the normal population.     

Retinal vascular occlusion and deficiencies in the protein C pathway.

PURPOSE: To report abnormalities in the protein C pathway and other vascular occlusion risk factors in patients with retinal vascular occlusion. METHODS: In a study, we investigated 76 consecutive patients who had in-patient evaluation of venous or arterial retinal vascular occlusion. All patients underwent comprehensive tests for coagulation disorders including determinations of protein C, protein S, lupus anticoagulants, and resistance to activated protein C and were screened for vascular disease risk factors. Resistance to activated protein C was confirmed by a polymerase chain reaction method to detect the specific factor V R506Q mutation. For comparative purposes, we also screened 209 consecutive inpatients with deep vein thrombosis from the same geographic region for resistance to activated protein C as well as protein C and protein S deficiencies. RESULTS: Ten (29%) of 35 patients with central retinal vein occlusion (CRVO) had factor V R506Q mutation. The factor V R506Q mutation was detected in four (19%) of 21 patients with branch retinal vein occlusion. The higher frequency in factor V R506Q mutation compared with the expected 9% mutation prevalence in a white population was highly significant for the central retinal vein occlusion group but not for the branch retinal vein occlusion group. In all patients with resistance to activated protein C, the factor V R506Q mutation was detected; 16 were heterozygous, one homozygous. No cases of lupus anticoagulants, protein C, or protein S deficiencies were detected. Forty (19%) of 209 patients with deep vein thrombosis were carriers of the factor V R506Q mutation. CONCLUSIONS: The prevalence of the factor V R506Q mutation is similar in patients with central retinal vein occlusion and patients with deep vein thrombosis and represents a relevant risk factor. Screening for this mutation is therefore recommended in all patients with central retinal vein occlusion.     

Bilateral cystoid macular edema following successful treatment of AIDS-associated CMV retinitis

Background: Cystoid macular edema (CME) in AIDS patients with inactive cytomegalovirus (CMV) retinitis is an uncommon but potentially sight-threatening complication. The pathogenesis of CME in these patients is unclear. This study tries to identify possible risk factors by analyzing the charts of five patients. Methods: Ten eyes of 5 patients that finally developed CME were followed for an average of 18 months. The initial retinal lesions, their response to antiviral treatment, the development of CME, and the patients' immune status were prospectively monitored. Results: CMV retinitis was diagnosed at a median CD4+ count of 3 cells/mm³ (range 0–11). All eyes responded to the initial systemic anti-viral treatment. At the onset of CME, CMV retinitis was controlled by antiviral maintenance therapy in all patients [ganciclovir (n = 2), cidofovir (n = 2), foscarnet (n = 1)]. The median time between diagnosis of CMV retinitis and onset of CME was 11.5 months (range 5–24). Development of CME was associated with significant visual loss: acuity ranged from 0.05 to 0.7 when CME was first noticed, compared to 0.8–1.25 at diagnosis of CMV retinitis. Duration of inflammation, size or zone of retinal necrosis did not favor the development of CME, neither did the antiviral therapy. A weak correlation of CME development and immune status (expressed as increase of CD4+ cells) was found. Due to systemic corticosteroids CME resolved. Conclusions: CME is a new visual threat to AIDS-patients with CMV retinitis whose immune status improved under the latest combined antiretroviral therapy. Therapy with oral corticosteroids may positively influence this condition.      

Effect of the new imidazoline derivative S-22068 (PMS 847) on insulin secretion in vitro and glucose turnover in vivo in rats.

We have investigated the possible mechanisms underlying the antihyperglycaemic effect of the imidazoline derivative S-22068. In vitro, in the presence of 5 mmol/l glucose, S-22068 (100 micromol/l) induced a significant and sustained increase in insulin secretion from isolated, perifused, rat islets and a marked sensitization to a subsequent glucose challenge (10 mmol/l). S-22068 (100 micromol/l was able to antagonize the stimulatory effect of diazoxide on 86Rb efflux from preloaded islets incubated in the presence of 20 mmol/l glucose. Experiments were also performed to investigate whether S-22068 can alter glucose turnover and peripheral insulin sensitivity in vivo in mildly diabetic rats and obese, insulin resistant, Zucker rats. Neither glucose production nor individual tissue glucose utilization was modified by S-22068 in either group of rats. Similar results were obtained whether the studies were performed under basal conditions or during euglycaemic/hyperinsulinemic clamps. The results suggest that S-22068 exerts part of its antihyperglycaemic effect by promoting insulin secretion without alteration of peripheral insulin sensitivity.     

Design and synthesis of imidazoline derivatives active on glucose homeostasis in a rat model of type II diabetes. 2. Syntheses and biological activities of 1,4-dialkyl-, 1,4-dibenzyl, and 1-benzyl-4-alkyl-2-(4',5'-dihydro-1'H-imidazol-2'-yl)piperazines and isosteric analogues of imidazoline

Piperazine derivatives have been identified as new antidiabetic compounds. Structure-activity relationship studies in a series of 1-benzyl-4-alkyl-2-(4',5'-dihydro-1'H-imidazol-2'-yl)piperazines resulted in the identification of 1-methyl-4-(2', 4'-dichlorobenzyl)-2-(4',5'-dihydro-1'H-imidazol-2'-yl)piperazine, PMS 812 (S-21663), as a highly potent antidiabetic agent on a rat model of diabetes, mediated by an important increase of insulin secretion independently of alpha2 adrenoceptor blockage. These studies were extended to find additional compounds in these series with improved properties. In such a way, substitution of both piperazine N atoms was first optimized by using various alkyl, branched or not, and benzyl groups. Second, some modifications of the imidazoline ring and its replacement by isosteric heterocycles were carried out, proceeding from PMS 812, to evaluate their influence on the antidiabetic activity. The importance of the distance between the imidazoline ring and the piperazine skeleton was studied third. Finally, the influence of the N-benzyl moiety was also analyzed compared to a direct N-phenyl substitution. The pharmacological evaluation was performed in vivo using glucose tolerance tests on a rat model of type II diabetes. The most active compounds were 1,4-diisopropyl-2-(4', 5'-dihydro-1'H-imidazol-2'-yl)piperazine (41a), PMS 847 (S-22068), and 1,4-diisobutyl-2-(4',5'-dihydro-1'H-imidazol-2'-yl)piperazine (41b), PMS 889 (S-22575), which strongly improved glucose tolerance without any side event or hypoglycemic effect. More particularly, PMS 847 proved to be as potent after po (100 micromol/kg) as after ip administration and appears as a good candidate for clinical investigations.     

Secondary flexor tendon reconstruction]

Secondary flexor tendon repair has lost its dominant position since Claude Verdan and other pioneers demonstrated, that primary tendon suture within the former "no man's land" is even more successful than secondary tendon grafting. Secondary reconstruction may concern delayed direct tenorrhaphy, one or two staged, short or long tendon grafts, pedicled tendon transplants, pulley reconstruction, tenodesis and tendon transfer. Secondary repair may be indicated for overlooked tendon injuries, for infected wounds, traumatic or septic tendon defects, for rheumatic ruptures and finally for failed primary repair of tenolysis. The indications and techniques of the different procedures are demonstrated and discussed.     

Double-stem silicone implant arthroplasty of all metatarsophalangeal joints in patients with rheumatoid arthritis

Double-stem silicone implants have been used to reconstruct destroyed hallux metatarsophalangeal joints (MTPJ) for many years. When smaller implants became available, they were used to reconstruct the lateral four MTPJ. An arthroplasty of all MTPJ was performed using these implants in 44 patients (72 feet) with rheumatoid arthritis (RA). The mean age of patients was 46 years (range, 21 to 66) and 84% were female. Previous surgery had been performed on 28% of the feet. All patients were followed prospectively for an average of 67 months (range, 36 to 111). The patients were evaluated clinically and radiographically; results were recorded on a standardized foot form that allowed computer analysis of the data. The results showed improvement in the hallux valgus angle from 41.6 degrees to 16.1 degrees postoperatively, with no loss of correction over time. Similarly, other forefoot deformities, such as plantar callus and lateral toe abnormalities, all improved both clinically and radiographically. The pain, walking, and function scores all improved, with the greatest improvement being pain relief. Radiographic analysis showed some evidence of fracture in seven hallux (9.7%) and nine lateral toe (3%) implants. Only three toes with implant fracture had some pain at follow-up examination. Three other lateral toe implants were removed for pain. There was no evidence of deep infection or silicone synovitis. Other complications included superficial infection, delayed wound healing, and second surgery for heterotopic bone excision.(ABSTRACT TRUNCATED AT 250 WORDS)     

Human acoustic neurinomas: Nervous system specific biochemical parameters

Summary A series of 24 human acoustic neurinomas from 24 patients has been assayed for several biochemical parameters characteristic of the nervous system. S 100 protein, 2, 3-cyclic nucleotide 3-phosphohydrolase activity, and the myelin lipids galactosylceramide and sulfogalactosylceramide (sulfatide). Myelin basic protein was not detected. These findings further support the neuroectodermal origin of the human acoustic neurinoma, and provide additional biochemical markers for further study.     

The conduct of in vitro and in vivo drug-drug interaction studies: a Pharmaceutical Research and Manufacturers of America (PhRMA) perspective.

Current regulatory guidances do not address specific study designs for in vitro and in vivo drug-drug interaction studies. There is a common desire by regulatory authorities and by industry sponsors to harmonize approaches, to allow for a better assessment of the significance of findings across different studies and drugs. There is also a growing consensus for the standardization of cytochrome P450 (P450) probe substrates, inhibitors and inducers and for the development of classification systems to improve the communication of risk to health care providers and to patients. While existing guidances cover mainly P450-mediated drug interactions, the importance of other mechanisms, such as transporters, has been recognized more recently, and should also be addressed. This article was prepared by the Pharmaceutical Research and Manufacturers of America (PhRMA) Drug Metabolism and Clinical Pharmacology Technical Working Groups and represents the current industry position. The intent is to define a minimal best practice for in vitro and in vivo pharmacokinetic drug-drug interaction studies targeted to development (not discovery support) and to define a data package that can be expected by regulatory agencies in compound registration dossiers.     

Methylated DNA collected by tampons--a new tool to detect endometrial cancer.

This proof of principle study aimed to define a new and simple strategy for detection of endometrial cancer using epigenetic markers. We investigated DNA isolated from vaginal secretion collected from tampon for aberrant methylation of five genes (CDH13, HSPA2, MLH1, RASSF1A, and SOCS2) using MethyLight in 15 patients with endometrial cancer and 109 patients without endometrial cancer. All endometrial cancer patients revealed three or more methylated genes, whereas 91% (99 of 109) of the patients without endometrial cancer had no or fewer than three genes methylated in their vaginal secretion. The methods developed in this study provide the basis for a prospective clinical trial to screen asymptomatic women who are at high risk for endometrial cancer.