Emerging roles for the FCRL family members in lymphocyte biology and disease.

Members of the extended Fc receptor-like (FCRL) family in humans and mice are preferentially expressed by B cells and possess tyrosine-based immunoregulatory function. Although the majority of these proteins repress B cell receptor-mediated activation, there is an emerging evidence for their bifunctionality and capacity to counter-regulate adaptive and innate signaling pathways. In light of these findings, the recent discovery of ligands for several of these molecules has begun to reveal exciting potential for them in normal lymphocyte biology and is launching a new phase of FCRL investigation. Importantly, these fundamental developments are also setting the stage for defining their altered roles in the pathogenesis of a growing number of immune-mediated diseases. Here we review recent advances in the FCRL field and highlight the significance of these intriguing receptors in normal and perturbed immunobiology.

The role of the international prototype of the kilogram after redefinition of the International System of Units.

Since 1889, the international prototype of the kilogram has served to define the unit of mass in what is now known as the International System of Units (SI). This definition, which continues to serve mass metrology well, is an anachronism for twenty-first century physics. Indeed, the kilogram will no doubt be redefined in terms of a physical constant, such as the Planck constant. As a practical matter, linking the quantum world to the macroscopic world of mass metrology has, and remains, challenging although great progress has been made. The international prototype or, more likely, a modern ensemble of reference standards, may yet have a role to play for some time after redefinition, as described in this paper.

Possible new definitions of the kilogram.

The kilogram is the unit of mass in the International System. Its definition dates from 1889 and, therefore, predates most of modern physics. The definition simply states that the 'kilogram' is the mass of an object known as the international prototype. Thus, we have the extraordinary situation that certain fundamental physical constants (the Planck constant, the Newtonian constant of gravitation, the mass of an electron, the mass of an atom of carbon-12, etc.) are measured in terms of an artefact that was manufactured in the nineteenth century. We begin by describing what is presently known about the long-term stability of artefact standards and how this stability can be experimentally monitored with respect to fundamental constants of physics. Finally, we suggest that present experiments are close to achieving the target uncertainty of the order 10(-8), although the current incoherence between two classes of experiments is cause for concern.

A new determination of G using two methods.

We present the results of a measurement of G made with a torsion-strip balance used in two substantially independent ways. The two results agree to within their respective uncertainties; the correlation coefficient of the two methods is -0.18. The result is G = 6.675 59(27)x10(-11) m(3) kg(-1) s(-2) with a standard uncertainty of 4.1 parts in 10(5). Our result is 2 parts in 10(4) higher than the recent result of Gundlach and Merkowitz.

Identification of a family of Fc receptor homologs with preferential B cell expression.

Investigation of human genome sequences with a consensus sequence derived from receptors for the Fc region of Igs (FcR) led to the identification of a subfamily of five Ig superfamily members that we term the Fc receptor homologs (FcRHs). The closely linked FcRH genes are located in a chromosome 1q21 region in the midst of previously recognized FcR genes. This report focuses on the FcRH1, FcRH2, and FcRH3 members of this gene family. Their cDNAs encode type I transmembrane glycoproteins with 3-6 Ig-like extracellular domains and cytoplasmic domains containing consensus immunoreceptor tyrosine-based activating and/or inhibitory signaling motifs. The five FcRH genes are structurally related, and their protein products share 28-60% extracellular identity with each other. They also share 15-31% identity with their closest FcR relatives. The FcRH genes are expressed primarily, although not exclusively, by mature B lineage cells. Their conserved structural features, patterns of cellular expression, and the inhibitory and activating signaling potential of their transmembrane protein products suggest that the members of this FcRH multigene family may serve important regulatory roles in normal and neoplastic B cell development.

Solid-phase parallel synthesis of azarene pyrrolidinones as factor Xa inhibitors.

A focused library (4 x 14) prepared from 4-aminopyridine and 4-, 5-, and 6-azoindole templates was synthesized using 14 polymer supported 4-amido-2,3,5,6-tetrafluorophenyl (TFP) sulfonate esters inputs. Several compounds were identified as factor Xa inhibitors (IC50< or =0.1 microM) helping to establish the SAR among these four series of azarene pyrrolidinones.

Synthesis, SAR and in vivo activity of novel thienopyridine sulfonamide pyrrolidinones as factor Xa inhibitors.

Thienopyridine sulfonamide pyrrolidinones were found to be potent and selective inhibitors of the coagulation cascade enzyme factor Xa. SAR studies led to several compounds that were selected for further in vivo investigation. These novel aryl binding pocket moieties represent a structural modification to a series of fXa inhibitors. Several compounds proved to be efficacious i.v. antithrombotic agents.

Design and structure-activity relationships of potent and selective inhibitors of blood coagulation factor Xa.

The discovery of a series of non-peptide factor Xa (FXa) inhibitors incorporating 3-(S)-amino-2-pyrrolidinone as a central template is described. After identifying compound 4, improvements in in vitro potency involved modifications of the liphophilic group and optimizing the angle of presentation of the amidine group to the S1 pocket of FXa. These studies ultimately led to compound RPR120844, a potent inhibitor of FXa (K(i) = 7 nM) which shows selectivity for FXa over trypsin, thrombin, and several fibrinolytic serine proteinases. RPR120844 is an effective anticoagulant in both the rat model of FeCl(2)-induced carotid artery thrombosis and the rabbit model of jugular vein thrombus formation.

Sulfonamidopyrrolidinone factor Xa inhibitors: potency and selectivity enhancements via P-1 and P-4 optimization.

Sulfonamidopyrrolidinones were previously disclosed as a selective class of factor Xa (fXa) inhibitors, culminating in the identification of RPR120844 as a potent member with efficacy in vivo. Recognizing the usefulness of the central pyrrolidinone template for the presentation of ligands to the S-1 and S-4 subsites of fXa, studies to optimize the P-1 and P-4 groups were initiated. Sulfonamidopyrrolidinones containing 4-hydroxy- and 4-aminobenzamidines were discovered to be effective inhibitors of fXa. X-ray crystallographic experiments in trypsin and molecular modeling studies suggest that our inhibitors bind by insertion of the 4-hydroxybenzamidine moiety into the S-1 subsite of the fXa active site. Of the P-4 groups examined, the pyridylthienyl sulfonamides were found to confer excellent potency and selectivity especially in combination with 4-hydroxybenzamidine. Compound 20b (RPR130737) was shown to be a potent fXa inhibitor (K(i) = 2 nM) with selectivity against structurally related serine proteinases (>1000 times). Preliminary biological evaluation demonstrates the effectiveness of this inhibitor in common assays of thrombosis in vitro (e.g. activated partial thromboplastin time) and in vivo (e.g. rat FeCl(2)-induced carotid artery thrombosis model).

Intratesticular spermatocele.

High resolution ultrasound has increased our awareness of benign testicular cysts that appear to arise from the intratesticular sperm conduit system of the intratesticular ducts of the mediastinum and rete testis. The location of these benign cysts in the area of the mediastinum and rete testis and the absence of signs of a germ cell tumor may permit testicle preservation. These benign cysts may contain sperm. We present a case of a benign sperm-containing cyst with visible communication to the rete testis, designated an intratesticular spermatocele and managed with testicle preservation.

Aromatic analogs of arcaine inhibit MK-801 binding to the NMDA receptor.

Aromatic analogs of arcaine were shown to have inhibitory effects on the binding of the channel blocking drug [3H]MK-801 to the NMDA receptor complex. The most potent compound of the series was an N,N'-bis(propyl)guanidinium which inhibited [3H]MK-801 binding with an IC50 of 0.58 microM and an IC50 of 12.17 microM upon addition of 100 microM spermidine. The increase in IC50 upon addition of spermidine suggests competitive antagonism between the inhibitor and spermidine at the arcaine-sensitive polyamine site of the NMDA receptor complex.

Workload management in an outpatient ophthalmology clinic.

1. An RVU system can forecast staffing needs for a busy ambulatory ophthalmology clinic. 2. The average amount of time needed for basic ophthalmic screening is 15 minutes. 3. Further studies should be conducted of infrequent tasks and for indirect care before an RVU system can be accurately used.

Bacillus Calmette-Guerin and interleukin-2 for treatment of superficial bladder cancer.

A total of 22 patients with bladder cancer received bacillus Calmette-Guerin (BCG) and interleukin-2. Significant bladder tumor remissions were noted in 15 of 17 patients (88%). Of 5 patients with carcinoma in situ 1 was noncompliant and he died of carcinoma in situ. The other 4 patients are in remission. BCG alone was instilled in 22 additional patients with superficial bladder cancer. The remission rates were encouraging. Of the 22 patients 13 (59%) had remission of the bladder tumor. A half dose of BCG (60 mg.) is adequate when given weekly for 6 weeks. Maintenance therapy is important as noted in both of our clinical arms. BCG and interleukin-2 therapy results in a higher remission rate.

Extracorporeal shock-wave lithotripsy in patients with spinal cord dysfunction.

Patients with spinal cord dysfunction are at an increased risk for urolithiasis. A retrospective study was undertaken to determine the effectiveness of extracorporeal shock-wave lithotripsy (ESWL) in this population. Thirteen kidneys received 19 treatments averaging 2,350 shocks per renal unit. All but one of the stones showed good fragmentation; however, none of the patients was stone-free at three months. Four of 9 patients with long-term follow-up were stone-free at five to fifteen months. Our poor stone-free rate is similar to that found in other studies of patients with spinal cord dysfunction. ESWL was well tolerated in this population, however, the clearance of stones is poor and delayed.

Metaplastic cystitis complicated with Von Brunn nests, cystitis cystica, and intestinal type of glandular metaplasia.

It is well documented that under certain stimuli the bladder epithelium can undergo metaplasia. The origin of glandular epithelium, which may be found in the bladder, is somewhat controversial. Endoscopic and histopathologic features of an eighty-one-year-old white man with proliferative metaplastic cystitis are presented. This case demonstrates that glandular differentiation was due to progressive cystitis rather than congenital intestinal rest.

Voiding dysfunction in tertiary syphilis.

After years of decline to near disappearance, there recently has been an increasing incidence of syphilis in America. New cases of tertiary neurosyphilis are being reported which often have associated significant urologic sequelae. For the first time in the English literature, the uro-dynamic findings of a patient with tabes dorsalis are presented. Our findings indicate that treatment of urinary retention associated with tabes dorsalis is better managed by intermittent catheterization than by prostate surgery because of the impaired detrusor activity. A review of neurosyphilis and its urologic implications and urodynamic findings are presented. Prompt recognition of this entity should encourage a full urodynamic evaluation prior to a commitment to prostatic surgery.